Sources of variation

Mutation produces variation at multiple scales:

Larger mutations in alleles

• Microsatellites

Examples:AGTCCTGAGATTGGATATATATATATGTAGTACGGTACC

AGTCCTGAGATTGGATATATATATATATGTAGTACGGTACC

Larger mutations in alleles

• Transposons

Chromosomal mutationsLarge-scale chromosomal rearrangements:

Inversions

Transpositions/Translocations

Consequences of inversions

• Keep favorable allele combinations from recombining

Could selection favor inversions? Perhaps.

Selection favoring inversions

Figure 4.11

New genes: gene duplications

Alu AluGene1

crossover

Gene2

Alu AluGene1 Gene2Alu Gene1’

Alu Gene2

Duplicate

Deletion

Fate of duplicated genes

Fate of gene duplicates: globins

Fig 4.9

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

Gene families

Family Number of duplicates

actin

Histones

Immunoglobins

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

A puzzle: mutation rates

Why do some mutation rates differ?

Effects of mutations

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?

Mutations are random!

Levels of variation

How much variation is there? Prediction?

Allozymes (= alternate alleles of metabolic enzymes)

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

Larger populations have higher genetic diversity

Gillespie, 1992

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?