sources of variation. mutation produces variation at multiple scales:
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Larger mutations in alleles
• Microsatellites
Examples:AGTCCTGAGATTGGATATATATATATGTAGTACGGTACC
AGTCCTGAGATTGGATATATATATATATGTAGTACGGTACC
Chromosomal mutationsLarge-scale chromosomal rearrangements:
Inversions
Transpositions/Translocations
Consequences of inversions
• Keep favorable allele combinations from recombining
Could selection favor inversions? Perhaps.
New genes: gene duplications
Alu AluGene1
crossover
Gene2
Alu AluGene1 Gene2Alu Gene1’
Alu Gene2
Duplicate
Deletion
Fate of duplicated genes: change in expression
gestation (weeks) postnatal age (weeks)
perc
ent
of t
otal
glo
bin
synt
hesi
s
Fig 4.8
Approaches to studying mutation
• Classical: study of loss of function
• Comparative: sequence from two species
• Experimental: mutation accumulation
Mutation rates for single-celled, asexual organisms (estimated from
loss of function)
0.0015 to 0.0030 mutations per genome per generation (2.2 to 5.4 x 10-10 per nucleotide)
Multi-cellular, sexual organisms
Organism
Mutations per genome per generation
Mutations per nucleotide per
generation
C. elegans (worm) 0.036 2.0 x 10-9
D. melanogaster (fruit fly)
0.14 8.5 x 10-9
M. musculus (mouse) 0.9 1.1 x 10-9
H. sapiens 1.6 2.3 x 10-8
Species comparisons
G HPan (chimps)
Pongo pygmaeus
(orangutan) H. sapiensGorilla gorillaP
Common ancestor
Species comparisons
Divergence time?
Which sequences?
Gorilla: AGTCCTAGGTGTTACTGATGGGCATHuman: AGTGCTAGGTGTTAATGATGGCCATChimp: AGTCTTAGGAGTTAC–GATGGGCAT
Mutation accumulation
Attempt to limit effects of selection
Caenorhabditis elegans
Hermaphrodite – can self-fertilize
Nematode
Mutation accumulation: experimental design
generation 0
reproduce
generation 1
transfer one individual
reproduce
Repeat 500 generations; 74 replicate lines
Start with single inbred strain
Mutation accumulation
• Compare DNA sequences
Generation 0: AACTAGCGTACCG
Generation 50: AATTAGCGTACCG
Generation 100: AAT- AGCGTACCG
Selection – Mutation balance
A new deleterious mutation is completely recessive
Mutations will be removed by selection, but added each generation at rate p.
At equilibrium, mutations added will equal deleterious alleles removed.
Then, p(t+1) = p(t)
Mutation selection balance II
p(t + 1) – p(t) = -p
If we use selection coefficients, this is easierAA Aa aa
Fitness
Solve for q:
We can do the same if the deleterious allele is partially recessive (but this requires some approximations)
Mutation selection balance III
If a new deleterious mutation is completely recessive (h = 1) then
qeq = squareroot(-/s)
If a new deleterious mutation is partially recessive (1 > h > 0.5) then
qeq = - / hs
Example
spinal muscular atrophy: lethal, autosomal recessive
Frequency in human population: 0.01
Selection coefficient: -0.9
What is the mutation rate under mutation –selection balance?
Quantifying variation: Polymorphism & Heterozygosity
• Populations with higher allele variability will be more heterozygous
• Heterozygosity:
Genetic variation is rampant
• but varies among groups– vertebrates: mode 3-
5%– invertebrates: mode 8-
15%– plants: varies
depending on mating system
Mutations and Variation
•Big questions–How do genes change?–How do new genes come about?
•What we need to know–How much variation exists, and why? –What types of mutation are important? How often do they occur? –What are their effects?
Readings and questionsDenver, D. et al. 2000. High direct estimate of the mutation rate of the
mitochondrial genome of Caenorhabditis elegans. Science 289: 2342-2344.
Denver, D. et al. 2004. High mutation rate and predominance of insertions in the Caenorhabditis elegans nuclear genome. Nature 430: 679-682.
Drake, J. W. et al. 1998. Rates of spontaneous mutation. Genetics 148:1667-1686.
Vassilieva, L. et al. 2000. The fitness effects of spontaneous mutations in Caenorhabditis elegans. Evolution 54: 1234-1246.
Chapter 5, particularly 5.1-5.3 (chapter 4 in 3rd edition)Questions 1, 5, 6, 1and 14, and . . .
In mammals, sperm cells are produced by constant cell division, while egg cells are produced only during fetal development. Given this, which gametes are likely to contribute more mutations to the next generation? Which gametes are more likely to show increasing number of mutations due to increasing age?