variation in mutation rates among human...

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Variation in mutation rates among human populations 1

Iain Mathieson1, David Reich1,2,3 2 3

1 Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. 4 2 Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA. 5 3 Howard Hughes Medical Institute, Harvard Medical School, Boston, Massachusetts 02115, USA. 6

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Abstract 9

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Mutations occur at vastly different rates across the genome, and between populations. Here, we measure 11

variation in the mutational spectrum in a sample of human genomes representing all major world populations. We 12

find at least two distinct signatures of variation. One, private to certain Native American populations, is novel and 13

is concentrated at CpG sites. The other is consistent with a previously reported signature characterized by 14

TCC>TTC mutations in Europeans and other West Eurasians. We describe the geographic extent of this signature 15

and show that it is detectable in the genomes of ancient, but not archaic humans. We hypothesize that these two 16

signatures are driven by independent processes and both result from differences in either the rate, or repair 17

efficiency, of damage due to deamination of methylated bases – respectively guanine and cytosine for the two 18

processes. Variation in these processes could be due to environmental, genetic, or life-history variation between 19

populations, and dramatically affects the spectrum of rare variation in different populations. 20

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Introduction 22

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For a process that provides such a fundamental contribution to genetic diversity, the human germline 24

mutation rate is surprisingly poorly understood. Different estimates of the mutation rate–the mean number of 25

mutations per-generation, or per-year–are largely inconsistent with each other [1,2], and similar uncertainty 26

surrounds parameters such as the paternal age effect [3-5], the effect of life-history traits [6,7], and the sequence-27

context determinants of mutations [5,8]. Here, we investigate a related question. Rather than trying to determine 28

the absolute values of parameters of the mutation rate, we ask how much the relative mutation rate–specifically, 29

the relative rate of different classes of mutations–varies between different human populations. 30

. CC-BY 4.0 International licensepeer-reviewed) is the author/funder. It is made available under aThe copyright holder for this preprint (which was not. http://dx.doi.org/10.1101/063578doi: bioRxiv preprint first posted online Jul. 13, 2016;

http://dx.doi.org/10.1101/063578

http://creativecommons.org/licenses/by/4.0/

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Motivation for this comes from two sources. First, analysis of tumor genomes has demonstrated a number 32

of different mutational signatures operating at different rates in somatic cells and cancers, many of which can be 33

linked to specific biological processes or environmental exposures [9-11]. It seems plausible that population-34

specific genetic factors of environmental exposures might similarly lead to variation in germline mutation rates. 35

Second, it is known that some mutations, most notably TCC>TTC, are enriched in Europeans relative to East 36

Asians and Africans [8] though the geographical extent, history, and biological basis for this signal are unclear. 37

By analyzing whole-genome sequence data from diverse world populations, together with high coverage ancient 38

genomes, we aimed to further characterize variation in human mutation rates, to place this variation in a historical 39

context, and to determine the underlying biological or environmental explanations. 40

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Results 42

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We first analyzed data from 300 individuals sequenced to high coverage (mean coverage depth 43X) as 44

part of the Simons Genome Diversity project [12] (SGDP). We classified single nucleotide polymorphisms 45

(SNPs) into one of 96 mutational classes according to the SNP, and the two flanking bases. We represent these by 46

the ancestral sequence and the derived base so for example “ACG>T” represents the ancestral sequence 3’–ACG–47

5’ mutating to 3’–ATG–5’. In order to increase power to detect population-specific variation, we first focused on 48

variants where there were exactly two copies of the derived allele in the sample (f2 variants). For each individual, 49

we counted the number of f2 mutations in each mutational class that they carried, and normalized by the number 50

of ATA>C mutations (the most common class and one that did not seem to vary across populations in a 51

preliminary analysis). The residual mutation intensities form a 96×300 matrix, and we used non-negative matrix 52

factorization [10,13] (NMF, implemented in the NMF package [14] in R) to identify specific mutational features. 53

NMF decomposes a matrix into a set of sparse factors, here putatively representing different mutational processes, 54

and individual-specific loadings for each factor, measuring the intensity of each process in each individual. 55

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NMF requires us to specify the number of signatures (the factorization rank) in advance. For f2 variants 57

we chose a factorization rank of 4, based on standard diagnostic criteria (Supplementary Fig. 1). This identified 58

four mutational signatures; of which two were uncorrelated with each other, were robust across frequencies, 59

replicated in non-cell-line samples, were consistent across samples from the same populations, and had clear 60

geographic distributions (Figure 1, Supplementary Fig. 2). Signature 1 corresponds to the previously described 61

European signal [8] characterized by TCC>T, ACC>T, CCC>T and TCT>T (possibly also including CCG>T, 62

which overlaps with signature 2). Loadings of this component almost perfectly separate West Eurasians from 63


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other populations, with South-West Asians intermediate. This component is seen most strongly in Western and 64

Mediterranean Europe, with decreasing intensity in Northern and Eastern Europe, the Middle East and South-west 65

Asia. This signal is similar to signature 11 from the COSMIC catalog of somatic mutation in cancer [15] (Pearson 66

correlation ρ=0.85) which is most commonly found in melanoma and glioblastoma and is associated with use of 67

chemotherapy drugs which act as alkylating agents, damaging DNA through guanine methylation. 68

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Signature 2 is restricted to some South and Central American populations and, possibly, Aboriginal 70

Australians. It is characterized by NCG>T mutations similar to the signature caused by deamination of methylated 71

cytosine at CpG sites, corresponding to COSMIC signature 1 (ρ=0.96). Interestingly, this signal is found in South 72

America in Andean populations like Quechua and Piapoco, and in Central American populations such as Mayan 73

and Nahua, but not in the Amazonian Surui and Karitiana, nor in North American populations. 74

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The remaining two signatures are more difficult to identify (Supplementary Fig. 2). Signature 3 is 76

characterized by GT>GG mutations, particularly GTG>GGG. It is found in some East Asian and some South 77

American populations but is not consistent within populations and does not have a consistent geographic pattern. 78

All affected samples are derived from cell lines. It does not match any mutational signature seen in COSMIC 79

(maximum ρ=0.05). Plausibly this represents some as-yet uncharacterized sample-specific process or cell-line 80

artifact. Signature 4 is diffuse, possibly representing a background mutation rate and is most correlated with 81

COSMIC signature 5 (ρ=0.52) which is found in all cancers and has unknown aetiology. It is significantly 82

reduced in only a single cell-line derived sample (Quechua-2), so probably represents some unknown cell-line or 83

data processing artifact. 84

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We checked that these signatures were robust when we looked at different frequencies and factorization 86

ranks. For f3 variants with rank 4 we recovered the same signatures as with f2 variants (Supplementary Fig. 3), and 87

retained signatures 1 and 2 when we used rank 3 (Supplementary Fig. 4). At f1 the variation is apparently 88

dominated by cell line artifacts because principal component analysis (PCA) separates cell line from non cell line 89

derived samples (Supplementary Fig. 5A). However, NMF on f1 variants excluding cell line derived samples 90

recovers signatures consistent with signatures 1 and 2 (Supplementary Fig. 5B-C). PCA on f2 variants does not 91

distinguish cell line samples, but does separate samples by geographic region, and recovers factor loadings 92

consistent with NMF-derived signatures 1-3 (Supplementary Fig. 6). To check that our results were not an artifact 93

of the normalization we used, we repeated the analysis normalizing by the total number of mutations in each 94

sample, rather than the number of ATA>C mutations, and obtained equivalent results (Supplementary Figure 7). 95

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Demographic effects such as population size changes confound direct estimates of mutation rate 97

differences. However, the proportion of mutations likely attributable to signature 1 (i.e TCT>T, TCC>T, CCC>T 98

and ACC>T) increases from a mean of 7.8% in Africans to 10.0% (range 8.8-11.1%) in West Eurasians which, 99

with the strong assumption that the only differences in mutation are the ones we detected, would provide a lower-100

bound for the increase in genome-wide mutation rate of 2.3% (range 1.1-3.6%). A similar calculation for 101

American samples with apparent excess of signature 2 gives a range of increase of 4.9-10.8%. 102

103

We replicated these results using data from phase 3 of the 1000 Genomes project [16], confirming that 104

mutations consistent with signature 1 are enriched in populations of European and South Asian ancestry (Figure 105

2A) and that mutations consistent with signature 2 are enriched in Peruvians (PEL) and Mexicans (MXL) – the 106

two 1000 Genomes populations with the most Native American ancestry (Figure 2B). 107

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To study the time depth of these signals, we investigated whether signature 1 could be detected in ancient 109

samples by constructing a corrected statistic, that measures the intensity of the mutations enriched in signature 1, 110

normalized to reduce spurious signals that arise from ancient DNA damage (methods). This statistic is enriched to 111

European levels in both an eight thousand year old European hunter-gatherer and a seven thousand year old Early 112

European Farmer [17] but not in a 45,000 year old Siberian [18], nor in the Neanderthal [19] or Denisovan[20] 113

genomes (Figure 3). This statistic is predicted by neither estimated hunter-gatherer ancestry, nor early farmer 114

ancestry, in 31 samples from 13 populations for which ancestry estimates were available [17] (linear regression p-115

values 0.22 and 0.15, respectively). Thus the effect is not strongly driven by this division of ancestry. If it has an 116

environmental basis, it is not predicted by latitude (linear regression of signature 1 loadings against latitude; 117

p=0.68), but is predicted by longitude (p=6×10-8; increasing east to west). We cannot apply the same approach to 118

Signature 2, because post-mortem deamination of methylated CpG sites is common in all ancient DNA, even 119

when treated with uracil-DNA glycosylase [21]. 120

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Finally, we investigated the dependence of the two signatures on four genomic features. First we 122

investigated dependence on transcriptional strand. Signature 1 shows a skew whereby the C>T mutation is more 123

likely to occur on the transcribed (i.e. noncoding) strand in West Eurasians, relative to populations from other 124

regions (Figure 4 A&B). Because transcription coupled repair is more likely to repair mutations on the transcribed 125

strand [22] this result, consistent with Harris (2015) [8], suggests that the excess signature 1 mutations in West 126

Eurasians are driven more by G>A than by C>T mutations. Signature 2 shows a global skew where the C>T 127

mutation is more likely to occur on the untranscribed strand, consistent with these mutations resulting from 128

deamination of methylated cytosine, and we do not see a significant difference between individuals with high 129

versus low levels of signature 2 mutations (Figure 4 C,D). Second, we obtained methylation data for a testis cell 130


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line, produced by the Encyclopedia of DNA Elements (ENCODE) project [23]. Signature 2 mutations are ~8.5 131

times as likely to occur in regions of high (>=50%) versus low (<50%) methylation. We do not detect any 132

difference in this ratio between regions, or between individuals with high versus low signature 2 mutation rates, 133

although the number of mutations involved is probably too low to provide much power (Methods; Fisher’s exact 134

test P=0.14). Third, we tested dependence on B statistic [24], a measure of conservation. We found that the 135

relative magnitudes of both signatures 1 and 2 depend on B statistic, but that both these dependencies were 136

independent of the per-population intensities of the signatures (Figure 5 A,B). This, along with a similar result for 137

recombination rate, (Figure 5 C,D) confirm that the differences we detect are truly due to differences in mutation 138

rate, and not some other force like natural selection, recombination or biased gene conversion. 139

140

Discussion 141

142

We characterized two independent signals of variation in mutation rates between human populations, 143

however this may not be comprehensive. Our power to detect differences in mutation rates depends on a number 144

of factors, including sample size, and the level of background variation. For example, we would expect to have 145

more power to detect recent variations in Native Americans because they have relatively low background 146

variation. Nonetheless, it is clear that the patterns we did identify are robust, and represent real differences in 147

mutation rates. 148

149

We cannot be definitive about the causes of these patterns, but our analyses provide a number of clues. In 150

terms of the immediate mutagenic cause, signature 1 is most similar to COSMIC [15] signature 11 (Pearson 151

correlation ρ=0.85), which is associated with alkylating agents used as chemotherapy drugs, damaging DNA 152

through guanine methylation. The reversal of transcriptional strand bias for this signature in West Eurasians 153

supports the idea that the increased rate of these mutations in West Eurasians is driven by damage to guanine 154

bases, consistent with deamination of methyl-guanine to adenine, leading to the G>A (equivalently C>T) 155

mutations that we observe. Signature 1 is also highly correlated with COSMIC signature 7 (ρ=0.76), caused by 156

ultraviolet (UV) radiation exposure but it is difficult to imagine how this could affect the germline, would not 157

explain our observed increase in ACC>T mutations, would not be expected to reverse the strand bias, and should 158

produce an enrichment of CC>TT dinucleotide mutations in West Eurasians that we do not observe (p=0.41). 159

Harris (2015) [8] suggested that UV might cause germline mutations indirectly through folate deficiency in 160

populations with light skin pigmentation (since folate can be degraded in skin by UV radiation). It is unknown 161

what mutational signature would be caused by this effect, but the fact that we do not observe enrichment of 162

signature 1 in other lightly pigmented populations like Siberians suggests that it is not driving the signal. 163


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164

Signature 2 seems most likely to be driven by deamination of methylated cytosine at CpG sites, which is 165

the major source of C>T muations at these sites. We find no evidence of any qualitative difference between the 166

CpG mutations in populations with high rates of signature 2 compared to other populations. Therefore we 167

hypothesize that variation in both signatures is driven by differences either in methylation (of guanine and 168

cytosine, respectively) level, rate of deamination of methylated bases, or in the efficiency of repair of damage 169

caused by deamination of methylated bases. 170

171

Why these factors would vary between populations is another question and, for this study, a matter for 172

speculation. Possibilities include variation in life-history traits, variation in environment, or systematic variation 173

in mutational or DNA repair processes due to either natural selection or neutral evolution. Over longer timescales, 174

variation in life history traits, for example the timing of reproduction and the onset of fertility, can lead to 175

variation in both total mutation rate and in the mutational spectrum, particularly in the relative rates of CpG and 176

non-CpG mutations [1,6,7,25,26]. While these effects are dramatic and important on the timescale of hominid 177

evolution, we do not think that variation in life-history traits drives the variation that we observed within humans. 178

First, we see little variation within African populations, despite great social and cultural diversity across the 179

populations represented in our study. Second, variation in signature 1 across Eurasia seems very smooth (Figure 180

1B) and we know of no life-history traits that vary so smoothly across populations. Signature 2 varies less 181

smoothly, and the relative rate of CpG mutations is known to be affected by life-history traits, although the 182

magnitude of the signal seems too large. For example, in the 1000 Genomes project, the proportion of rare C>T 183

mutations at CpG sites (a lower bound for the difference in mutation rate) varies by up to ~5% across populations 184

(Figure 2 B), on the same order as the difference in the proportion of CpG substitutions between human and 185

baboon lineages [26]. Studies of de novo mutations in humans have found no significant effect of paternal age on 186

CpG:non-CpG mutation ratio [4,5], but we cannot exclude the possibility that variation in signature 2 is driven by 187

dramatic variation in some other life history trait. 188

189

Other than life-history traits, damage or repair rates might vary either because of inherited variation in 190

DNA repair efficiency or other biochemical processes, or because of external environmental factors. In the first 191

case, a promising approach to detecting a causal locus would be to map mutation rate variation, either in large 192

pedigrees or in an admixed population like African Americans. In the second, we might identify the factor by 193

looking for correlations with environmental features, through mutation accumulation experiments in other 194

species, or comparison with mutational signatures identified in cancer with known causes. So far, however, the 195

ultimate cause of this variation remains unknown. 196

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It is important to understand changes in the mutation rate on the timescale of hominid evolution in order 198

to calibrate demographic models of human evolution [27] and the observation of variation in mutation rates 199

between populations [8] made this calibration even more complicated. One further consequence of our results is 200

that the rate of CpG mutations, often assumed to be almost “clock-like” [7,25,26] may also vary over short 201

timescales, meaning that they may not be as useful for model calibration as previously though. Further work in 202

this area will involve more detailed measurement of mutation rates in diverse populations – to date, most work on 203

somatic, cancer, or de novo germline mutations has been conducted in popualtions of West Eurasian origin – and 204

the extension of these approaches to other populations will be required to fully understand variation in mutation 205

rates and its consequences for demographic modeling. 206

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Methods 208

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Identifying mutational signatures 210

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We used SNPs called in 300 individuals from the Simons Genome Diversity Project [12] (SGDP). 212

Variant sites were called at filter level 1, and then any site that was variable in any sample was genotyped in every 213

sample. We polarized SNPs with the ancestral allele inferred in the human-chimp ancestor, and classified by the 214

two flanking bases in the human reference (hg19). We restricted to sites of given frequencies and merged reverse 215

complement classes to give counts of SNPs occurring in 96 possible mutational classes. We then normalized these 216

counts by the frequency of ATA>ACA mutations. The remaining matrix represents the normalized intensity of 217

each mutation class in each sample, relative to the sample with the lowest intensity. Formally, let Cij be the 218

counts of mutations in class i for sample j. Then, the intensities that we analyze, Xij are given by, 219

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Xij =Cij

C{ATA>C} j 221

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We decomposed this matrix X using non-negative matrix factorization [13] implemented in the NMF R 223

package [14] with the multiplicative algorithm introduced by Lee & Seung (1999) [13], initialized using the non-224

negative components from the output of a fastICA analysis[28] implemented in the fastICA package in R 225

(https://cran.r-project.org/web/packages/fastICA/index.html). For the diagnostic plots in Supplementary Fig. 2, 226

we used 200 random starting points to compare the results of different runs. When we initialized the matrix 227

randomly, rather than using fastICA, we obtained a slightly closer fit to the data (root-mean-squared error in X of 228

0.024 vs 0.025) and similar factor distributions (Supplementary Fig. 8A), except that all signatures were 229


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dominated by CpG mutations (Supplementary Fig. 8B). Removing a constant amount of each CpG mutation from 230

each signature recovered signatures close to the fastICA-initialized signatures (Supplementary Fig. 8C), so we 231

concluded that this was a model-fitting artifact, and did not reflect true signatures. Finally we performed the 232

analysis on a matrix normalized be the total number of mutations in each sample 𝐶!"! rather than the number of 233

ATA>C mutations. (Supplementary Figure 7). 234

235

The ordering of the factors is arbitrary so, where necessary, we reordered for interpretability. To plot 236

mutational signatures and compare with the COSMIC signatures, we rescaled the intensities of each class 237

according to the trinucleotide frequencies in the human reference genome. The scale of the weightings is therefore 238

not easily interpretable. To perform principal component analysis on X, we normalized so that the variance of 239

each row was equal to 1. 240

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Analysis of 1000 Genomes data 242

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We classified 1000 Genomes mutations according to the ancestral allele inferred by the 1000 Genomes 244

project, and counted the number of f2 and f3 variants carried by each individual in each mutation class. We ignored 245

SNPs that were multi-allelic or where the ancestral state was not confidently assigned (confident assignment 246

shown by a capital letter in the “AA” tag in the “INFO” field of the vcf file). We excluded the four outlying 247

samples: HG01149(CLM), NA20582 & NA20540 (TSI), NA12275(CEU), NA19728(MXL). 248

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Analysis of ancient genomes 250

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We identified heterozygous sites in five ancient genomes from published vcf files, and restricted to sites 252

where there was a single heterozygote in the SGDP. The corrected signature 1 log-ratio is defined by 253

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M = log2X{TCC>A} jX{ACC>A} jX{TCT>A} jX{CCC>A} jX{TCA>A} jX{ACA>A} jX{TCA>A} jX{CCA>A} j

⎧⎨⎪

⎩⎪

⎫⎬⎪

⎭⎪ 255

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and then normalized so that the distribution in African populations has mean 0 and standard deviation 1. We 257

estimated bootstrap quantiles by resampling the counts Cij for the ancient samples and recomputing M. 258

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Transcriptional strand 262

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We downloaded the knownGenes table of the UCSC genes track from the UCSC genome browser 264

(http://genome.ucsc.edu/). Taking the union of all transcripts in this table, we classified each base of the genome 265

according to whether it was transcribed on the + or – strand, both, or neither (including uncalled bases). These 266

regions totaled 607Mb, 637Mb, 36Mb and 1,599Mb of sequence respectively. We then counted mutations in our 267

dataset that occurred in regions that were transcribed on the + or – strand, ignoring regions where both or neither 268

strand was transcribed. 269

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Methylation status 271

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We downloaded the Testis_BC 1 and 2 (two technical replicates from the same sample) tables from the 273

HAIB Methyl RRBS track from the UCSC genome browser (http://genome.ucsc.edu/). We constructed a list of 274

33,305 sites where both replicates had >=50% methylation and another list of 166,873 sites where both replicates 275

had <50% methylation. We then classified the CpG mutations in our dataset according to which, if either, of these 276

lists they fell into. Ultimately, there were only 1186 classified mutations in the whole dataset, including 43 in 277

Native American samples and 12 in Native American samples with high rates of signature 2. Therefore, although 278

we found no significant interactions between methylation status and population, it may be simply that we lack 279

power to detect it. 280

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B statistic and recombination rate 282

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We classified each base of the genome according to which decile of B statistic [24] or HapMap 2 284

combined recombination rate [29] (in 1kb blocks) it fell into and counted mutations in each class. 285

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Code availability 287

Scripts used to run the analysis are available from https://github.com/mathii/spectrum. 288

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Acknowledgments 290

We thank Mark Lipson and Priya Moorjani for helpful comments. I.M. was supported by a long-term 291

fellowship from the Human Frontier Science Program LT001095/2014-L. D.R. is a Howard Hughes Medical 292

Institute investigator. 293


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Figure 1: Distribution and characterization of mutational signatures 1 and 2. A: Factor coefficients for these two 295

signatures, for 300 individual samples colored by region. B: Geographic representation of the factor loadings from 296

panel A. Darker colors represent higher loadings. C: Characterization of the signatures in terms of mutation 297

intensity for each of 96 possible classes. Bars are scaled by the frequency of each trinucleotide in the human 298

reference genome. Below, the most highly correlated signatures from the COSMIC database are shown for 299

comparison. 300

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T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

PCA4

PC

A1

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PC

A3

Signature 1

Signature 1 Signature 2

Signature 2

A B

CC>A C>G C>T T>A T>C T>G C>A C>G C>T T>A T>C T>G

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

5

Component 2

Loadin

g

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ●●

● ● ●●

● ● ●● ●

● ●●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

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●● ●

● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00

.05

0.1

00

.15

Component 1

Lo

ad

ing

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

COSMIC Signature 11 COSMIC Signature 1

Chane-1

Piapoco-2

Quechua-3

Mayan-1

Mayan-2 Quechua-1

Nahua-2

Nahua-1

Quechua-2

Mixtex-1Australian-3

Zapotec-1

Sign

atur

e 2

Signature 1


http://dx.doi.org/10.1101/063578


11

302 Figure 2: Signatures 1 and 2 in the 1000 Genomes. A: Proportions of f2 and f3 variants in signature 1 (here 303

defined as TCT>T, TCC>T, CCC>T and ACC>T) in each 1000 Genomes individual, by population. B: 304

Proportions of f2 and f3 variants in signature 2 (here defined as NCG>T, for any N) in each 1000 Genomes 305

individual, by population (five outlying samples excluded). 306

1000 Genomes population labels

ASW African Ancestry in Southwest USA

ACB African Caribbean in Barbados

BEB Bengali in Bangladesh

GBR British From England and Scotland, UK

CDX Chinese Dai - Xishuangbanna, China

CHD Chinese in Metropolitan Denver, USA

CLM Colombian in Medellin, Colombia

ESN Esan in Nigeria

FIN Finnish in Finland

GIH Gujarati Indians in Houston, USA

CHB Han Chinese in Beijing, China

CHS Han Chinese South, China

IBS Iberian populations in Spain

ITU Indian Telugu in the UK

JPT Japanese in Tokyo, Japan

KHV Kinh in Ho Chi Minh City, Vietnam

LWK Luhya in Webuye, Kenya

MKK Maasai in Kinyawa, Kenya

MSL Mende in Sierra Leone

MXL Mexican Ancestry in Los Angeles, USA

PEL Peruvian in Lima, Peru

PUR Puerto Rican in Puerto Rico

PJL Punjabi in Lahore, Pakistan

STU Sri Lankan Tamil in the UK

TSI Toscani in Italia

YRI Yoruba in Ibadan, Nigeria

Population

Sig

na

ture

1

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0.0

70

.08

0.0

90

.10

KHV CHS CHB JPT PEL CDX MXL GWD MSL ASW ACB ESN YRI LWK CLM FIN PUR BEB STU GIH ITU GBR IBS CEU PJL TSI

A

B

Population

Sig

na

ture

2

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LWK MSL PUR FIN ESN GWD ASW CDX ACB GIH YRI STU JPT CLM KHV CHS ITU PJL GBR BEB CHB CEU IBS TSI MXL PEL


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12

307

Figure 3: Signature 1, corrected to be more robust to ancient DNA damage (Methods), for f2 variants in the SGDP 308

individuals, by region, and in five high coverage ancient genomes. Solid lines show 5-95% bootstrap quantiles. 309

M2

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5

10

15A

fric

a

Oceania

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sia

Centr

alA

sia

Sib

eri

a

Am

eri

ca

South

Asia

WestE

ura

sia

Loschbour

Stu

ttgart

Ust' I

shim

Neandert

al

Denis

ova

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8,00

0 ye

ar-o

ld E

urop

ean

hunt

er-g

athe

rer

7,00

0 ye

ar-o

ld E

urop

ean

farm

er

45,0

00 y

ear-

old

Sibe

rian

Alta

i Nea

nder

thal

Alta

i Den

isova

n


http://dx.doi.org/10.1101/063578


13

310 Figure 4: Transcriptional strand bias in mutational signatures. We plot the log of the ratio of mutations occurring 311

on the untranscribed versus transcribed strand. Therefore a positive value indicates that the C>T mutation is more 312

common than the G>A mutation on the untranscribed (i.e. coding) strand. P values in brackets are, respectively, 313

ANOVA P-values for a difference between regions and t-test P-values for a difference between i) West Eurasia 314

and other regions (excluding South Asia) in A&B ii) 11American samples with high rates of signature 2 315

mutations and other regions in C&D. A: Boxplot of per-individual strand bias for mutations in signature 1 316

(TCT>T, TCC>T, CCC>T and ACC>T). One sample (S_Mayan-2) with an extreme value (0.48) is not shown. B: 317

Population-level means for each of the mutations comprising signature 1. C,D: as A&B but for signature 2. We 318

separated out the 11 American samples with high rates of signature 2 mutations. 319

●

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−0.4

−0.2

0.0

0.2

0.4

Signature 1 (P=6e−06 , 7.4e−07)

Log−

ratio

stra

nd b

ias

Afric

a

Amer

ica

Cen

tralA

siaS

iber

ia

East

Asia

Oce

ania

Sout

hAsi

a

Wes

tEur

asia

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● ●

−0.4

−0.2

0.0

0.2

0.4

TCT>T (P=0.3 , 0.094)

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0.4

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CCC>T (P=0.13 , 0.71)

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0.0

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0.4

ACC>T (P=0.049 , 0.087)

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0.0

0.2

0.4

Signature 2 (P=0.23 , 0.029)

Log−

ratio

stra

nd b

ias

Afric

a

Amer

ica

(hig

h)

Amer

ica

(low

)

Cen

tralA

siaS

iber

ia

East

Asia

Oce

ania

Sout

hAsi

a

Wes

tEur

asia

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GCG>T (P=0.014 , 0.49)

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●●

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−0.2

0.0

0.2

0.4

TCG>T (P=0.25 , 0.84)

A B

C D


http://dx.doi.org/10.1101/063578


14

320 Figure 5: Dependence of mutational signatures on genomic features. A,B: dependence on conservation, measured 321

by B statistic (0=lowest B statistic; highest conservation). A: Comparison of proportions of signature 1 mutations 322

between West Eurasia and other populations (excluding South Asia). Blue dashed lines show a fitted linear model 323

of dependence with no interaction term. B: Comparison of proportions of signature 2 mutations between the 11 324

American samples with the highest proportions, and all other samples. Blue dashed lines show a fitted quadratic 325

model of dependence with no interaction term. C,D: As A&B, but showing dependence on recombination rate 326

decile computed in 1kb bins. 327

0.15

0.20

0.25

0.30

Recombination rate decile

Prop

ortio

n of

sig

natu

re 2

mut

atio

ns

0−10% 10−20% 20−30% 30−40% 40−50% 50−60% 60−70% 70−80% 80−90% 90−100%

0.04

0.06

0.08

0.10

0.12

Recombination rate decile

Prop

ortio

n of

sig

natu

re 1

mut

atio

ns

0−10% 10−20% 20−30% 30−40% 40−50% 50−60% 60−70% 70−80% 80−90% 90−100%

0.04

0.06

0.08

0.10

0.12

B statistic decile

Prop

ortio

n of

sig

natu

re 1

mut

atio

ns

0−10% 10−20% 20−30% 30−40% 40−50% 50−60% 60−70% 70−80% 80−90% 90−100%

0.15

0.20

0.25

0.30

B statistic decile

Prop

ortio

n of

sig

natu

re 2

mut

atio

ns0−10% 10−20% 20−30% 30−40% 40−50% 50−60% 60−70% 70−80% 80−90% 90−100%

A B

C D

West EurasiaExcluding West Eurasia and South Asia

11 American samples with strongest sig. 2Other samples


http://dx.doi.org/10.1101/063578


15

References 328

329

1. Segurel L, Wyman MJ, Przeworski M (2014) Determinants of mutation rate variation in the human germline. 330 Annu Rev Genomics Hum Genet 15: 47-70. 331

2. Scally A (2016) Mutation rates and the evolution of germline structure. Philos Trans R Soc Lond B Biol Sci 332 371. 333

3. Genome of the Netherlands C (2014) Whole-genome sequence variation, population structure and demographic 334 history of the Dutch population. Nat Genet 46: 818-825. 335

4. Kong A, Frigge ML, Masson G, Besenbacher S, Sulem P, et al. (2012) Rate of de novo mutations and the 336 importance of father's age to disease risk. Nature 488: 471-475. 337

5. Rahbari R, Wuster A, Lindsay SJ, Hardwick RJ, Alexandrov LB, et al. (2016) Timing, rates and spectra of 338 human germline mutation. Nat Genet 48: 126-133. 339

6. Amster G, Sella G (2016) Life history effects on the molecular clock of autosomes and sex chromosomes. Proc 340 Natl Acad Sci U S A 113: 1588-1593. 341

7. Gao Z, Wyman MJ, Sella G, Przeworski M (2016) Interpreting the Dependence of Mutation Rates on Age and 342 Time. PLoS Biol 14: e1002355. 343

8. Harris K (2015) Evidence for recent, population-specific evolution of the human mutation rate. Proc Natl Acad 344 Sci U S A 112: 3439-3444. 345

9. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, et al. (2013) Signatures of mutational 346 processes in human cancer. Nature 500: 415-421. 347

10. Alexandrov LB, Nik-Zainal S, Wedge DC, Campbell PJ, Stratton MR (2013) Deciphering signatures of 348 mutational processes operative in human cancer. Cell Rep 3: 246-259. 349

11. Behjati S, Huch M, van Boxtel R, Karthaus W, Wedge DC, et al. (2014) Genome sequencing of normal cells 350 reveals developmental lineages and mutational processes. Nature 513: 422-425. 351

12. Mallick S, Li H, Lipson M, Mathieson I, Gymrek M, et al. (2016) The landscape of human genome diversity. 352 In press. 353

13. Lee DD, Seung HS (1999) Learning the parts of objects by non-negative matrix factorization. Nature 401: 354 788-791. 355

14. Gaujoux R, Seoighe C (2010) A flexible R package for nonnegative matrix factorization. BMC 356 Bioinformatics 11: 367. 357

15. Forbes SA, Beare D, Gunasekaran P, Leung K, Bindal N, et al. (2015) COSMIC: exploring the world's 358 knowledge of somatic mutations in human cancer. Nucleic Acids Res 43: D805-811. 359

16. Genomes Project C, Auton A, Brooks LD, Durbin RM, Garrison EP, et al. (2015) A global reference for 360 human genetic variation. Nature 526: 68-74. 361

17. Lazaridis I, Patterson N, Mittnik A, Renaud G, Mallick S, et al. (2014) Ancient human genomes suggest three 362 ancestral populations for present-day Europeans. Nature 513: 409-413. 363

18. Fu Q, Li H, Moorjani P, Jay F, Slepchenko SM, et al. (2014) Genome sequence of a 45,000-year-old modern 364 human from western Siberia. Nature 514: 445-449. 365

19. Prufer K, Racimo F, Patterson N, Jay F, Sankararaman S, et al. (2014) The complete genome sequence of a 366 Neanderthal from the Altai Mountains. Nature 505: 43-49. 367

20. Meyer M, Kircher M, Gansauge MT, Li H, Racimo F, et al. (2012) A high-coverage genome sequence from 368 an archaic Denisovan individual. Science 338: 222-226. 369

21. Briggs AW, Stenzel U, Meyer M, Krause J, Kircher M, et al. (2010) Removal of deaminated cytosines and 370 detection of in vivo methylation in ancient DNA. Nucleic Acids Res 38: e87. 371

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23. Consortium EP (2012) An integrated encyclopedia of DNA elements in the human genome. Nature 489: 57-374 74. 375


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24. McVicker G, Gordon D, Davis C, Green P (2009) Widespread genomic signatures of natural selection in 376 hominid evolution. PLoS Genet 5: e1000471. 377

25. Kim SH, Elango N, Warden C, Vigoda E, Yi SV (2006) Heterogeneous genomic molecular clocks in 378 primates. PLoS Genet 2: e163. 379

26. Hwang DG, Green P (2004) Bayesian Markov chain Monte Carlo sequence analysis reveals varying neutral 380 substitution patterns in mammalian evolution. Proc Natl Acad Sci U S A 101: 13994-14001. 381

27. Scally A, Durbin R (2012) Revising the human mutation rate: implications for understanding human 382 evolution. Nat Rev Genet 13: 745-753. 383

28. Hyvärinen A (1999) Fast and Robust Fixed-Point Algorithms for Independent Component Analysis. IEEE 384 Transactions on Neural Networks 10. 385

29. International HapMap Consortium (2005) A haplotype map of the human genome. Nature 437: 1299-1320. 386 387


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17

388 Supplementary Figure 1: Diagnostic plots for NMF using variants of different frequencies. Rows from top- 389

variants at frequency 2, 3 and 4. Columns- each plot shows the value of a measure, computed over 50 random 390

start points, for factorization ranks from 2 to 8. From left to right: Dispersion, a measure of reproducibility of 391

clusters across runs (1=perfectly reproducible); Residual sum of squares (lower=better fit); Silhouette, a measure 392

of how reliably elements can be assigned to clusters (1=perfectly reliably). In supplementary plots, we denote the 393

signatures obtained from fr variants with rank k by signaturer,k, so the signatures in the main text are equivalent to 394

signature2,4. 395

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dispersion rss silhouette

0.6

0.7

0.8

0.9

1.0

20

30

40

0.00

0.25

0.50

0.75

1.00

2 3 4 5 6 7 8 2 3 4 5 6 7 8 2 3 4 5 6 7 8Factorization rank

Measure type●

●

●

●

Basis

Best fit

Coefficients

Consensus

NMF rank survey

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25

30

35

40

45

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1.00


Measure type●

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Basis

Best fit

Coefficients

Consensus

NMF rank survey

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25

30

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40

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1.00


Measure type●

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Basis

Best fit

Coefficients

Consensus

NMF rank survey

f2

f3

f4


http://dx.doi.org/10.1101/063578


18

396 Supplementary Figure 2: Distribution and characterization of mutational signatures2,4 3 and 4. A: Per-sample 397

coefficients for signatures 3 and 4. B: Geographic distribution of signatures 3 and 4. C: Mutational spectrum of 398

signature 3. D: Mutational spectrum of signature 4. E-F: Comparison of loadings of 1 and 2 with signatures 3 and 399

4. 400

●

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● ●

● ●

0.0

00.0

10.0

20.0

30.0

40.0

50.0

6

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

●

●

● ● ●

●

●

●

●

●

●●

● ● ●

●● ● ● ● ● ● ●

●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ●● ● ● ● ●

● ● ● ●● ●

● ●●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ●

● ●

●

●

● ● ● ●

0.0

00

.05

0.1

00

.15

0.2

00

.25

Component 3

Pro

po

rtio

n o

f m

uta

tio

ns

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

Han-3

Pima-2

MIxe-3

Mongola-1

Russian-1

Dai-4

Miao-1

Miao-2

Quechua-2

Signature 3

Sign

atur

e 4

Signature 3

Signature 4


C>A C>G C>T T>A T>C T>G C>A C>G C>T T>A T>C T>G

Signature 4

Sign

atur

e 1

Signature 2

Sign

atur

e 3

A B

C D

E FCell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia


http://dx.doi.org/10.1101/063578


19

401 Supplementary Figure 3: Mutational signatures inferred from f3 variants with rank 4. A: Factor coefficients for 402

signature3,4 1 and 2 – compare with Figure 1A. B: Factor coefficients for signature3,4 3 and 4 – compare with 403

Supplementary Figure 2A. C: Mutational signatures3,4 1-4 – compare with Figure 1 C and D, and Supplementary 404

Figure 2 C and D. 405

●

●

●

● ● ●

●

●

●●

●

● ● ●

●●

● ●

●●

●●

●

●● ●

●● ● ●

●●

●

●

●

● ● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●● ● ● ● ●

● ● ●

●● ● ●

●

●

●

●

●

●

●

●

●

●

●●

●

●●

●

● ●●

● ● ● ● ●

● ● ● ●

● ●● ●

0.0

00.0

20.0

40.0

60.0

8

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●●

●

●

●

●

●

● ● ●

●

●● ● ●

●

●

● ● ● ● ● ●●

●

● ● ●●

● ● ●

●

● ● ● ●

●

● ●

●

● ●

●

●

●

● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●

●

●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

00.3

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ●●

● ● ●

●

● ● ● ● ● ● ●●

● ● ●●

● ● ●● ● ● ●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

PCA2

PC

A4

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA3

PC

A1

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA4

PC

A3

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA2

PC

A1

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA2

PC

A4

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA3

PC

A1

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA4

PC

A3

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA2

PC

A1

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

Signature3,4 1 Signature3,4 3

Sign

atur

e 3,4 2

Sign

atur

e 3,4 4

C>A C>G C>T T>A T>C T>G C>A C>G C>T T>A T>C T>G

Signature3,4 1

Signature3,4 2

Signature3,4 3

Signature3,4 4

A B

C

Nahua-2

Chipewyan-2

Quechua-2

Mayan-2

Pima-2

Piapoco-2

Zapotec-1

Mixe-1

Pima-2

Han-3

Dai-4

Russian-1

Miao-2

Mongola-1

Karitiana-3

Quechua-2

Chippewayan-2

Nahua-2

Piapoco-1Australian-3

Australian-4

●

●

●

● ● ●

●

●

●●

●

● ● ●

●●

● ●

●●

●●

●

●● ●

●● ● ●

●●

●

●

●

● ● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●● ● ● ● ●

● ● ●

●● ● ●

●

●

●

●

●

●

●

●

●

●

●●

●

●●

●

● ●●

● ● ● ● ●

● ● ● ●

● ●● ●

0.0

00.0

20.0

40.0

60.0

8

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●●

●

●

●

●

●

● ● ●

●

●● ● ●

●

●

● ● ● ● ● ●●

●

● ● ●●

● ● ●

●

● ● ● ●

●

● ●

●

● ●

●

●

●

● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●

●

●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

00.3

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ●●

● ● ●

●

● ● ● ● ● ● ●●

● ● ●●

● ● ●● ● ● ●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●

● ● ●

●

●

●●

●

● ● ●

●●

● ●

●●

●●

●

●● ●

●● ● ●

●●

●

●

●

● ● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●● ● ● ● ●

● ● ●

●● ● ●

●

●

●

●

●

●

●

●

●

●

●●

●

●●

●

● ●●

● ● ● ● ●

● ● ● ●

● ●● ●

0.0

00.0

20.0

40.0

60.0

8

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●●

●

●

●

●

●

● ● ●

●

●● ● ●

●

●

● ● ● ● ● ●●

●

● ● ●●

● ● ●

●

● ● ● ●

●

● ●

●

● ●

●

●

●

● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●

●

●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

00.3

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ●●

● ● ●

●

● ● ● ● ● ● ●●

● ● ●●

● ● ●● ● ● ●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●

● ● ●

●

●

●●

●

● ● ●

●●

● ●

●●

●●

●

●● ●

●● ● ●

●●

●

●

●

● ● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●● ● ● ● ●

● ● ●

●● ● ●

●

●

●

●

●

●

●

●

●

●

●●

●

●●

●

● ●●

● ● ● ● ●

● ● ● ●

● ●● ●

0.0

00.0

20.0

40.0

60.0

8

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●●

●

●

●

●

●

● ● ●

●

●● ● ●

●

●

● ● ● ● ● ●●

●

● ● ●●

● ● ●

●

● ● ● ●

●

● ●

●

● ●

●

●

●

● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ●

●

●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

00.3

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ●●

● ● ●

●

● ● ● ● ● ● ●●

● ● ●●

● ● ●● ● ● ●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G


http://dx.doi.org/10.1101/063578


20

406 Supplementary Figure 4: Mutational signatures inferred from f3 variants with rank 3. A: Factor coefficients for 407

signature3,3 1 and 2. B: Factor coefficients for signature3,3 3 and. C: Mutational signatures3,3 1-3. 408

PCA2

PC

A3

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA2

PC

A1

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

C>A C>G C>T T>A T>C T>GC>A C>G C>T T>A T>C T>G

Signature3,3 1

Signature3,3 1

Signature3,3 2

Signature3,3 3

Signature3,3 2

Sign

atur

e 3,3 2

Sign

atur

e 3,3 3

A B

C●

●●

● ●●

●

●● ●

●

● ● ●

●● ● ●

● ●●

● ●●

● ● ● ● ● ●● ●

●

●

●

● ● ●

●

● ●●

●

●

●

●

●

●●

● ●● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

●

●

●

●●

●

●● ●

●● ●

●● ● ● ● ● ● ● ●

● ● ● ●● ● ● ●

0.0

00.0

50.1

00.1

5

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ● ● ●●

● ● ●● ● ● ●

●●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

00.3

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

0.1

0.2

0.3

0.4

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

● ●●

●

●● ●

●

● ● ●

●● ● ●

● ●●

● ●●

● ● ● ● ● ●● ●

●

●

●

● ● ●

●

● ●●

●

●

●

●

●

●●

● ●● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

●

●

●

●●

●

●● ●

●● ●

●● ● ● ● ● ● ● ●

● ● ● ●● ● ● ●

0.0

00.0

50.1

00.1

5

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ● ● ●●

● ● ●● ● ● ●

●●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

00.3

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

0.1

0.2

0.3

0.4

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

● ●●

●

●● ●

●

● ● ●

●● ● ●

● ●●

● ●●

● ● ● ● ● ●● ●

●

●

●

● ● ●

●

● ●●

●

●

●

●

●

●●

● ●● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

●

●

●

●●

●

●● ●

●● ●

●● ● ● ● ● ● ● ●

● ● ● ●● ● ● ●

0.0

00.0

50.1

00.1

5

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ● ● ●●

● ● ●● ● ● ●

●●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

00.3

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

0.1

0.2

0.3

0.4

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

Pima-2

Mixe-1

Nahua-2

Han-3

Quechua-3

Dai-4Piapoco-2

Mayan-2

Chipewyan-2

Zapotec-2Quechua-3

Chane-1 Kurumba-1


http://dx.doi.org/10.1101/063578


21

409 410

Supplementary Figure 5: Analysis of f1 variants A: The first two principal components of the mutational 411

spectrum of f1 variants, showing the difference between cell line and primary tissue derived samples. B&C: 412

Mutational signatures inferred from f1 variants with rank 2, but excluding cell line samples. B: Factor loadings for 413

signature1*,2 1 and 2 (asterisk denotes no cell lines). C: Mutational signatures1*,2 1 and 2. Signature1*,2 1 is 414

confounded with CpG mutations in this case, but clearly shows an elevated level of TCC>T and ACC>T 415

mutations. 416

PCA1

PC

A2

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

●●●●●●●●●●●

●●●

●

●●●●●●●●

●●●●●●●

●●

●

●

●

●

●

●

●

●●

●

●

●

●●

●

●

●●●●●●●●●●●●●●●●

●

●

●

●

●

●●

●●●

●●

●●

●●●●●●●●●●●●●●●●●●

0.0

00

.04

0.0

80

.12

Component 1

Pro

po

rtio

n o

f m

uta

tio

ns

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.AAT

C.A

AT

G.A

AT

T.A

CTA

.AC

TC

.AC

TG

.AC

TT.A

GTA

.AG

TC

.AG

TG

.AG

TT.A

TTA

.AT

TC

.AT

TG

.AT

TT.A

ATA

.CAT

C.C

AT

G.C

AT

T.C

CTA

.CC

TC

.CC

TG

.CC

TT.C

GTA

.CG

TC

.CG

TG

.CG

TT.C

TTA

.CT

TC

.CT

TG

.CT

TT.C

ATA

.GAT

C.G

AT

G.G

AT

T.G

CTA

.GC

TC

.GC

TG

.GC

TT.G

GTA

.GG

TC

.GG

TG

.GG

TT.G

TTA

.GT

TC

.GT

TG

.GT

TT.G

●●●

●●●●●●●

●●●●●●●●●●●●●

●●●●●●●●●●

●

●

●●

●

●

●●●

●

●

●●

●

●●●●●●●●●●●●●●●●●

●●●●

●●●●●

●●●

●●●●●●●●●●●●●●●●●●●●

0.0

00

.05

0.1

00

.15

Component 2

Pro

po

rtio

n o

f m

uta

tio

ns

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.AAT

C.A

AT

G.A

AT

T.A

CTA

.AC

TC

.AC

TG

.AC

TT.A

GTA

.AG

TC

.AG

TG

.AG

TT.A

TTA

.AT

TC

.AT

TG

.AT

TT.A

ATA

.CAT

C.C

AT

G.C

AT

T.C

CTA

.CC

TC

.CC

TG

.CC

TT.C

GTA

.CG

TC

.CG

TG

.CG

TT.C

TTA

.CT

TC

.CT

TG

.CT

TT.C

ATA

.GAT

C.G

AT

G.G

AT

T.G

CTA

.GC

TC

.GC

TG

.GC

TT.G

GTA

.GG

TC

.GG

TG

.GG

TT.G

TTA

.GT

TC

.GT

TG

.GT

TT.G

Signature1*,2 1

Sign

atur

e 1*,2 2

Signature1*,2 1

Signature1*,2 2

B C

−10 0 10 20 30 40 50

−50

51

0

PCA1

PC

A2

Cell line sample

Primary tissue sample

A

Hawaiian-1Surui-1


http://dx.doi.org/10.1101/063578


22

417 Supplementary Figure 6: Principal component analysis of the mutational spectrum of f2 variants. A&B: 418

Principal component positions. Labeled by sample source (A) and geographic region (B). C: Component loadings. 419

Note that principal components 2,3 and 4 correspond roughly to mutational signatures2,4 3, 2 and 1 respectively. 420

PCA1

PC

A2

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA2

PC

A3

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA3

PC

A4

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA4

PC

A5

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

●●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●●

●●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

● ●

●

●

●

●

●

●

●

●

●

● ●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●●

●

●

●

●● ●

●

●

0.0

50.1

00.1

5

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●●

●

●

●

●

●

●●

●

●

●

●

●

●●

●

● ●●

●

●●

●

●

●●

●●

●

●

●

●

●

●

●

●

●

●●

●

●

●●

●

●

●

● ●●

●

● ●

●

●

●

●

●

●

●

● ●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●●

●●

● ●

●

●

● ●

●

●

● ●

●

−0.3

−0.2

−0.1

0.0

0.1

0.2

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●

●

●

●

●●

●

●

●

●

●

●

●●

●●

●●

●

●

●

●●

●

●

●●

●●

●

● ●

●

● ●●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

● ●

● ●

●

●

●

● ●

●●

●

●●

● ●●

●●

● ●

●●

●

●

●

●

●

●

● ●

●

●●

●

●

●

●●

●

−0.2

−0.1

0.0

0.1

0.2

0.3

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ● ●

●

●

●●

●

●● ●

●

●

●

●

●

●

●●

●

●

●

●

● ●

●

●

● ●●

●

●

●

●

●

●

●

●

●

● ●●

●

●

●

●

●

●

●

●

●

●

●

●●

● ●

●

●

●

● ●● ●

●

●

●

●

● ●

●

●

●●

●

●

● ●

●

●

●

● ● ●

●

●

●● ● ●

● ●

●

●

−0.1

0.0

0.1

0.2

0.3

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●●

●●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

● ●

●

●

●

●

●

●

●

●

●

● ●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●●

●

●

●

●● ●

●

●

0.0

50.1

00.1

5

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●●

●

●

●

●

●

●●

●

●

●

●

●

●●

●

● ●●

●

●●

●

●

●●

●●

●

●

●

●

●

●

●

●

●

●●

●

●

●●

●

●

●

● ●●

●

● ●

●

●

●

●

●

●

●

● ●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●●

●●

● ●

●

●

● ●

●

●

● ●

●

−0.3

−0.2

−0.1

0.0

0.1

0.2

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●

●

●

●

●●

●

●

●

●

●

●

●●

●●

●●

●

●

●

●●

●

●

●●

●●

●

● ●

●

● ●●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●

● ●

● ●

●

●

●

● ●

●●

●

●●

● ●●

●●

● ●

●●

●

●

●

●

●

●

● ●

●

●●

●

●

●

●●

●

−0.2

−0.1

0.0

0.1

0.2

0.3

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ● ●

●

●

●●

●

●● ●

●

●

●

●

●

●

●●

●

●

●

●

● ●

●

●

● ●●

●

●

●

●

●

●

●

●

●

● ●●

●

●

●

●

●

●

●

●

●

●

●

●●

● ●

●

●

●

● ●● ●

●

●

●

●

● ●

●

●

●●

●

●

● ●

●

●

●

● ● ●

●

●

●● ● ●

● ●

●

●

−0.1

0.0

0.1

0.2

0.3

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

B

C

−10 −5 0 5 10 15

−15

−10

−50

PCA1

PC

A2

Cell line sample

Primary tissue sample

A

Piapoco-2

Pima-2

Han-3Mixe-1

Piapoco-2

Pima-2

Han-3

Mixe-1

Han-3Mixe-1

Pima-2

Dai-4

Chane-1

Quechua-2

Piapoco-2

Chane-1

Nahua-1

Chane-1

Piapoco-2

Han-3

Mixe-1

Dai-4

Pima-2


http://dx.doi.org/10.1101/063578


23

421 Supplementary Figure 7: NMF analysis of f2 variants at rank 4 - as the main analysis, but normalizing the 422

mutational spectra by the total number of mutations in each sample, rather than the number of ATA>C mutations. 423

Component 2

Com

ponent 4

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

Component 3

Com

ponent 1

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

Component 3

Com

ponent 4

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

Component 3

Com

ponent 2

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia


Sign

atur

e 2

Sign

atur

e 4

A B

C>A C>G C>T T>A T>C T>GC>A C>G C>T T>A T>C T>GC

C>A C>G C>T T>A T>C T>GC>A C>G C>T T>A T>C T>G

●

●●

● ● ●

●

●

● ●

●

● ●● ●

●

● ●

●

●

●● ● ●

●● ● ● ●

●

●●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

● ●

●

●

● ● ● ● ●

●●

●●

● ● ●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●●

●● ● ● ● ●

● ● ● ●

● ●

●●

0.0

00.0

10.0

20.0

30.0

40.0

50.0

60.0

7

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ●● ● ● ●

●● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

● ● ●● ●

● ● ● ●

●

●

●

●

●

● ●

●●

●

●

●●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

●

●

● ● ●

●

●

●

●

●

●●

● ● ●

●● ● ● ● ● ● ●

●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ●● ● ● ● ●

● ● ● ● ●●

● ●●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ●

●●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

● ● ●

●

●

● ●

●

● ●● ●

●

● ●

●

●

●● ● ●

●● ● ● ●

●

●●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

● ●

●

●

● ● ● ● ●

●●

●●

● ● ●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●●

●● ● ● ● ●

● ● ● ●

● ●

●●

0.0

00.0

10.0

20.0

30.0

40.0

50.0

60.0

7

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ●● ● ● ●

●● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

● ● ●● ●

● ● ● ●

●

●

●

●

●

● ●

●●

●

●

●●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

●

●

● ● ●

●

●

●

●

●

●●

● ● ●

●● ● ● ● ● ● ●

●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ●● ● ● ● ●

● ● ● ● ●●

● ●●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ●

●●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

● ● ●

●

●

● ●

●

● ●● ●

●

● ●

●

●

●● ● ●

●● ● ● ●

●

●●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

● ●

●

●

● ● ● ● ●

●●

●●

● ● ●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●●

●● ● ● ● ●

● ● ● ●

● ●

●●

0.0

00.0

10.0

20.0

30.0

40.0

50.0

60.0

7

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ●● ● ● ●

●● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

● ● ●● ●

● ● ● ●

●

●

●

●

●

● ●

●●

●

●

●●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

●

●

● ● ●

●

●

●

●

●

●●

● ● ●

●● ● ● ● ● ● ●

●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ●● ● ● ● ●

● ● ● ● ●●

● ●●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ●

●●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

● ● ●

●

●

● ●

●

● ●● ●

●

● ●

●

●

●● ● ●

●● ● ● ●

●

●●

●

●

●

●●

●

●

●

●

●

●

●

●

●

●

●

● ●

●

●

● ● ● ● ●

●●

●●

● ● ●

●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●●

●● ● ● ● ●

● ● ● ●

● ●

●●

0.0

00.0

10.0

20.0

30.0

40.0

50.0

60.0

7

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ●● ● ● ●

●● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

● ● ●● ●

● ● ● ●

●

●

●

●

●

● ●

●●

●

●

●●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

●

●

● ● ●

●

●

●

●

●

●●

● ● ●

●● ● ● ● ● ● ●

●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ●● ● ● ● ●

● ● ● ● ●●

● ●●

● ● ●●

● ● ●

●

● ● ● ● ● ● ● ● ● ●

●●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

● ● ●

●

● ● ●

●

● ● ●

●

● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

50.3

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G




http://dx.doi.org/10.1101/063578


24

424 Supplementary Figure 8: NMF analysis of f2 variants at rank 4 with random initialization of the NMF algorithm. 425

A: Distribution of signatures across samples. B: Mutational signatures 1-4 (starting top left, anticlockwise). C: 426

Mutational signatures 1-4 where, for each CpG mutation class, we subtracted the minimum over all four 427

signatures from the signature. 428

●

●●

● ● ●

●

●● ●

●

● ● ●●

● ● ●●

●● ●

●●

● ● ● ● ● ●

●●

●

●

●

● ● ●

●

●●

●

●

●

●

●

●

●●

● ●● ● ● ● ● ●

● ● ● ● ● ● ●

●

●

●

●

●

●

●●

●

●● ●

●●

●●

● ●● ● ● ● ● ●

● ● ●● ● ●

● ●

0.0

00.0

20.0

40.0

60.0

80.1

0

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ●

●

● ● ●

●

● ● ●

●

● ●●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ●

● ● ● ●● ● ● ●

● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ●

●

●

●

●

●

●

●

● ●●

●

● ●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

● ●●

● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ●

● ● ● ● ●● ●

●

●● ●

●● ● ●

● ● ● ● ● ● ● ●●

● ● ●● ●

●●

●

● ● ●

●

● ● ●

●

●●

●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●●

● ● ● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

5

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

● ● ●

●

●● ●

●

● ● ●●

● ● ●●

●● ●

●●

● ● ● ● ● ●

●●

●

●

●

● ● ●

●

●●

●

●

●

●

●

●

●●

● ●● ● ● ● ● ●

● ● ● ● ● ● ●

●

●

●

●

●

●

●●

●

●● ●

●●

●●

● ●● ● ● ● ● ●

● ● ●● ● ●

● ●

0.0

00.0

20.0

40.0

60.0

80.1

0

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ●

●

● ● ●

●

● ● ●

●

● ●●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ●

● ● ● ●● ● ● ●

● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ●

●

●

●

●

●

●

●

● ●●

●

● ●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

● ●●

● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ●

● ● ● ● ●● ●

●

●● ●

●● ● ●

● ● ● ● ● ● ● ●●

● ● ●● ●

●●

●

● ● ●

●

● ● ●

●

●●

●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●●

● ● ● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

5

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

● ● ●

●

●● ●

●

● ● ●●

● ● ●●

●● ●

●●

● ● ● ● ● ●

●●

●

●

●

● ● ●

●

●●

●

●

●

●

●

●

●●

● ●● ● ● ● ● ●

● ● ● ● ● ● ●

●

●

●

●

●

●

●●

●

●● ●

●●

●●

● ●● ● ● ● ● ●

● ● ●● ● ●

● ●

0.0

00.0

20.0

40.0

60.0

80.1

0

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ●

●

● ● ●

●

● ● ●

●

● ●●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ●

● ● ● ●● ● ● ●

● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ●

●

●

●

●

●

●

●

● ●●

●

● ●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

● ●●

● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ●

● ● ● ● ●● ●

●

●● ●

●● ● ●

● ● ● ● ● ● ● ●●

● ● ●● ●

●●

●

● ● ●

●

● ● ●

●

●●

●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●●

● ● ● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

5

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●●

● ● ●

●

●● ●

●

● ● ●●

● ● ●●

●● ●

●●

● ● ● ● ● ●

●●

●

●

●

● ● ●

●

●●

●

●

●

●

●

●

●●

● ●● ● ● ● ● ●

● ● ● ● ● ● ●

●

●

●

●

●

●

●●

●

●● ●

●●

●●

● ●● ● ● ● ● ●

● ● ●● ● ●

● ●

0.0

00.0

20.0

40.0

60.0

80.1

0

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

● ●

●

● ● ●

●

● ● ●

●

● ●●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

00.2

5

Component 2P

roport

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ●

● ● ● ●● ● ● ●

● ● ● ● ● ● ● ● ● ● ●●

● ● ● ● ● ● ● ● ●

●

●

●

●

●

●

●

● ●●

●

● ●

●

●

●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

● ●●

● ● ● ● ● ● ●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

5

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●● ●

● ● ● ● ●● ●

●

●● ●

●● ● ●

● ● ● ● ● ● ● ●●

● ● ●● ●

●●

●

● ● ●

●

● ● ●

●

●●

●

●

●● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

●●

● ● ● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●●

●

●

● ● ● ●

0.0

00.0

50.1

00.1

5

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

C>A C>G C>T T>A T>C T>G C>A C>G C>T T>A T>C T>GB

CC>A C>G C>T T>A T>C T>G C>A C>G C>T T>A T>C T>G

●

●

●

● ●●

●

●

● ●

●

● ●

●

●

●

●●

●

●

●

●

●

●

●

●●

●●

●

●

●

●

●

●

●● ●

●

●

●

●

●

●

●

●

●

●

●

●●

● ● ● ● ●●

●

●●

●● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

● ● ●●

●

● ●

●

●● ●

●●

0.0

00.0

10.0

20.0

30.0

4

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●●

● ● ● ● ● ● ● ● ●● ● ●

●● ● ● ● ● ● ●

●● ● ● ● ● ● ● ● ●

● ●

●

●● ●

●

● ●●

●

● ●●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

● ●● ●

● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●

● ●●

●

●●

●●

● ● ●●

● ● ●● ●

●●

●

●● ●

● ● ● ●● ●

●

●

●

●

●

●

●

● ●

●

●

●●

●

●

●

● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

●●

●

●●

● ● ● ●●

●●

●● ● ● ● ● ● ● ●

● ● ● ●● ● ● ●

0.0

00.0

20.0

40.0

60.0

80.1

00.1

2

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●

●

●● ●

●

●

●

●

●

●●

●

● ● ●

●

●●

●●

●●

●

●

● ● ●

●●

●

●

●

●● ●

●

●●

●

●

●

●

●

●

●

●●

●● ● ● ● ●

●●

● ● ● ● ● ●

●

●

●

●

●●

●●

●

● ●●

● ● ●●

● ●● ● ● ● ● ●

●

●

●

●

● ●●

●

0.0

00.0

20.0

40.0

60.0

80.1

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●

● ●●

●

●

● ●

●

● ●

●

●

●

●●

●

●

●

●

●

●

●

●●

●●

●

●

●

●

●

●

●● ●

●

●

●

●

●

●

●

●

●

●

●

●●

● ● ● ● ●●

●

●●

●● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

● ● ●●

●

● ●

●

●● ●

●●

0.0

00.0

10.0

20.0

30.0

4

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●●

● ● ● ● ● ● ● ● ●● ● ●

●● ● ● ● ● ● ●

●● ● ● ● ● ● ● ● ●

● ●

●

●● ●

●

● ●●

●

● ●●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

● ●● ●

● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●

● ●●

●

●●

●●

● ● ●●

● ● ●● ●

●●

●

●● ●

● ● ● ●● ●

●

●

●

●

●

●

●

● ●

●

●

●●

●

●

●

● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

●●

●

●●

● ● ● ●●

●●

●● ● ● ● ● ● ● ●

● ● ● ●● ● ● ●

0.0

00.0

20.0

40.0

60.0

80.1

00.1

2

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●

●

●● ●

●

●

●

●

●

●●

●

● ● ●

●

●●

●●

●●

●

●

● ● ●

●●

●

●

●

●● ●

●

●●

●

●

●

●

●

●

●

●●

●● ● ● ● ●

●●

● ● ● ● ● ●

●

●

●

●

●●

●●

●

● ●●

● ● ●●

● ●● ● ● ● ● ●

●

●

●

●

● ●●

●

0.0

00.0

20.0

40.0

60.0

80.1

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●

● ●●

●

●

● ●

●

● ●

●

●

●

●●

●

●

●

●

●

●

●

●●

●●

●

●

●

●

●

●

●● ●

●

●

●

●

●

●

●

●

●

●

●

●●

● ● ● ● ●●

●

●●

●● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

● ● ●●

●

● ●

●

●● ●

●●

0.0

00.0

10.0

20.0

30.0

4

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●●

● ● ● ● ● ● ● ● ●● ● ●

●● ● ● ● ● ● ●

●● ● ● ● ● ● ● ● ●

● ●

●

●● ●

●

● ●●

●

● ●●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

● ●● ●

● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●

● ●●

●

●●

●●

● ● ●●

● ● ●● ●

●●

●

●● ●

● ● ● ●● ●

●

●

●

●

●

●

●

● ●

●

●

●●

●

●

●

● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

●●

●

●●

● ● ● ●●

●●

●● ● ● ● ● ● ● ●

● ● ● ●● ● ● ●

0.0

00.0

20.0

40.0

60.0

80.1

00.1

2

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●

●

●● ●

●

●

●

●

●

●●

●

● ● ●

●

●●

●●

●●

●

●

● ● ●

●●

●

●

●

●● ●

●

●●

●

●

●

●

●

●

●

●●

●● ● ● ● ●

●●

● ● ● ● ● ●

●

●

●

●

●●

●●

●

● ●●

● ● ●●

● ●● ● ● ● ● ●

●

●

●

●

● ●●

●

0.0

00.0

20.0

40.0

60.0

80.1

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

●

●

● ●●

●

●

● ●

●

● ●

●

●

●

●●

●

●

●

●

●

●

●

●●

●●

●

●

●

●

●

●

●● ●

●

●

●

●

●

●

●

●

●

●

●

●●

● ● ● ● ●●

●

●●

●● ●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●

●●

●

● ● ●●

●

● ●

●

●● ●

●●

0.0

00.0

10.0

20.0

30.0

4

Component 1

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●●

● ● ● ● ● ● ● ● ●● ● ●

●● ● ● ● ● ● ●

●● ● ● ● ● ● ● ● ●

● ●

●

●● ●

●

● ●●

●

● ●●

●

●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

●

●

● ●● ●

● ●●

● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ● ●

0.0

00.0

50.1

00.1

50.2

0

Component 2

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●

● ●●

●

●●

●●

● ● ●●

● ● ●● ●

●●

●

●● ●

● ● ● ●● ●

●

●

●

●

●

●

●

● ●

●

●

●●

●

●

●

● ● ● ●● ● ● ● ● ● ● ● ● ● ● ●

●

●

●

●●

●

●●

● ● ● ●●

●●

●● ● ● ● ● ● ● ●

● ● ● ●● ● ● ●

0.0

00.0

20.0

40.0

60.0

80.1

00.1

2

Component 3

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

●

● ●

●

●● ●

●

●

●

●

●

●●

●

● ● ●

●

●●

●●

●●

●

●

● ● ●

●●

●

●

●

●● ●

●

●●

●

●

●

●

●

●

●

●●

●● ● ● ● ●

●●

● ● ● ● ● ●

●

●

●

●

●●

●●

●

● ●●

● ● ●●

● ●● ● ● ● ● ●

●

●

●

●

● ●●

●

0.0

00.0

20.0

40.0

60.0

80.1

0

Component 4

Pro

port

ion o

f m

uta

tions

AC

A.A

AC

C.A

AC

G.A

AC

T.A

CC

A.A

CC

C.A

CC

G.A

CC

T.A

GC

A.A

GC

C.A

GC

G.A

GC

T.A

TC

A.A

TC

C.A

TC

G.A

TC

T.A

AC

A.G

AC

C.G

AC

G.G

AC

T.G

CC

A.G

CC

C.G

CC

G.G

CC

T.G

GC

A.G

GC

C.G

GC

G.G

GC

T.G

TC

A.G

TC

C.G

TC

G.G

TC

T.G

AC

A.T

AC

C.T

AC

G.T

AC

T.T

CC

A.T

CC

C.T

CC

G.T

CC

T.T

GC

A.T

GC

C.T

GC

G.T

GC

T.T

TC

A.T

TC

C.T

TC

G.T

TC

T.T

ATA

.A

AT

C.A

AT

G.A

AT

T.A

CTA

.A

CT

C.A

CT

G.A

CT

T.A

GTA

.A

GT

C.A

GT

G.A

GT

T.A

TTA

.A

TT

C.A

TT

G.A

TT

T.A

ATA

.C

AT

C.C

AT

G.C

AT

T.C

CTA

.C

CT

C.C

CT

G.C

CT

T.C

GTA

.C

GT

C.C

GT

G.C

GT

T.C

TTA

.C

TT

C.C

TT

G.C

TT

T.C

ATA

.G

AT

C.G

AT

G.G

AT

T.G

CTA

.G

CT

C.G

CT

G.G

CT

T.G

GTA

.G

GT

C.G

GT

G.G

GT

T.G

TTA

.G

TT

C.G

TT

G.G

TT

T.G

PCA3

PC

A2

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA4

PC

A1

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA2

PC

A4

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

PCA1

PC

A3

Cell lines

Other

●

●

●

●

●

●

●

EastAsia

Africa

WestEurasia

America

Oceania

SouthAsia

CentralAsiaSiberia

A

Signature2,4 1 Signature2,4 3

Sign

atur

e 2,42

Sign

atur

e 2,4 4


http://dx.doi.org/10.1101/063578


variation in mutation rates among human...

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