Understanding Human Evolution throughGenetic Data

Daniel P. HowriganMatthew A. SimonsonMatthew C. KellerDepartment of Psychology, University ofColorado at Boulder, U.S.A.Institute of Behavioral Genetics,University of Colorado at Boulder, U.S.A.

An overview of…• What our current genetic variation can tell us

about

• Directional Selection

• Balancing Selection

• Mutation-Selection Balance

Genetic Variation• Unrelated individuals share roughly 99% of their DNA

with each other (although slowly falling)

• Yet almost every trait studied to date is heritable tosome degree

• Main question: How does evolution explain existinggenetic variation?

Genetic Variation• Single Nucleotide Polymorphisms (SNPs)

www.science.marshall.edu

• Allele = Variant

• Locus (loci) = Location

• Common and rare variants

• Genome-wide coverage ofcommon variants (GWAS)

• Deletions and duplications

Inferring Directional Selectionfrom genetic variation• Fisherʼs fundamental theorem (1930) - any trait under selection pressure

should become fixed and show no variation

• But…

• In general, more recent selection seen in patterns of genetic variation atthe population level. After the the variant reaches 100%, the patterns startto disappear

Evidence of recent selection• Variant under

positive selection

• High frequency

• Long “Haplotype”

• High homozygosity Sabeti, Varilly et al., Nature, 2007

Findings so far

• Skin pigmentation (Sabeti, Varilly et al., 2007, Pickrell et al., 2009)• Lactose tolerance (Bersaglieri et al., 2004)• Hypertension and Alcohol susceptibility (Voight et al., 2006)• Numerous others with little or no known function….

Population differentiationSLC24A5 skin pigmentation variant

anthropology.net

Directional SelectionBut beware…

Multiple confounding demographic variables

• Population Bottlenecks

• Population Expansion

• Genetic drift within sub-populations

Multiple tests and exceptionally strong signals needed to overcomefalse positives

Inferring Balancing Selectionfrom genetic variation• Balancing selection occurs when common variants are

maintained at equilibrium via selection

• The fitness of the variant depends on its frequency

Candidate Examples• Immune system genes (MHC) - host-pathogen defense

• Sickle-cell / Malaria resistance - ex. of heterozygote advantage

Balancing Selection

• Indirect evidence - Common variants not explaining a largeproportion of susceptibility in complex disease

Confounds and difficulties• Weak balancing-selection hard to distinguish from neutral drift• Recent balancing selection may just be a snapshot of directional

selection• High-standards of evidence to infer antagonistic pleiotropy

Inferring Mutation-SelectionBalance from genetic variation• Fisherʼs fundamental theorem again…

• But complex traits rely on a multitude of genes

• New mutations arising (Keighley Keighley & Eyre-Walker, 2000& Eyre-Walker, 2000)

• Old mutations yet to disappear (Fay et al, 2001; Fay et al, 2001; Sunyaev Sunyaev et al, 2001)et al, 2001)

• Genetic variation is a result of mutations appearing and being selected out

• What we expect• Common variation explains little or no individual differences• Genome-wide burden of rare variants, most of small effect, will

correlate to trait variation

Transcription factors

Cortical neural firing

Pre-frontal cortex function

intelligence

• Upstream processes directly affected

• Downstream processes altered

• Complex emergent trait shows heritable continuous distribution

Extended Homozygosityburden on IQ

• Recessive mutation

• Ex. Inbreeding depression

• Genome-wide burden

M.C. Keller, unpublished data

Mutations and Schizophrenia• Schizophrenia - high heritability, but no strong candidate genes

• Walsh et al., Science, 2008

• Other rare deletions found in large case/control studies (ISC, 2008;Stefansson et al., 2008; Xu et al., 2008)

Mutation-Selection balance• Large scale studies of common variants (GWAS) and

disease have not ruled out role of mutation-selectionbalance

Issues• Mutation is a factor in all heritable traits, so the effect of mutation-

selection balance is a matter of degree• Sequencing data from large sample (e.g. 1000 genomes project)

necessary to fully test mutation-selection predictions

The future…• More sequencing data• Gene expression studies• Epigenetics• Proteomics

This presentation is a precis to an upcoming chapter for Evolution ofPersonality and Individual Differences (Eds. Patricia Hawley and DavidBuss)

The author is supported by NIH training grant 5 T32 HD007289 andthe Institute for Behavioral Genetics

Youʼll be able to download this presentationat: http://ibgwww.colorado.edu/~howrigan

Or just google: Daniel Howrigan

References

Positive selection

References

Mutation-selection balance

References

Schizophrenia