Sources of variation

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Sources of variation
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Mutation produces variation at multiple scales
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Larger mutations in alleles

• Microsatellites
• Examples

AGTCCTGAGATTGGATATATATATATGTAGTACGGTACC
AGTCCTGAGATTGGATATATATATATATGTAGTACGGTACC
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Larger mutations in alleles

• Transposons

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Chromosomal mutations
Large-scale chromosomal rearrangements
Inversions
Transpositions/Translocations
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Consequences of inversions

• Keep favorable allele combinations from
  recombining

Could selection favor inversions? Perhaps.
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Selection favoring inversions
Figure 4.11
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New genes gene duplications
Duplicate
Deletion
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Fate of duplicated genes
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Fate of gene duplicates globins
Fig 4.9
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Fate of duplicated genes change in expression
percent of total globin synthesis
postnatal age (weeks)
gestation (weeks)
Fig 4.8
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Gene families

• Family Number of duplicates
• actin
• Histones
• Immunoglobins

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Approaches to studying mutation

• Classical study of loss of function
• Comparative sequence from two species
• Experimental mutation accumulation

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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)
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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

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Species comparisons

Common ancestor
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Species comparisons
Divergence time?
Which sequences?
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Mutation accumulation

• Attempt to limit effects of selection

Caenorhabditis elegans Hermaphrodite can
self-fertilize Nematode
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Mutation accumulation experimental design
Start with single inbred strain
reproduce
generation 0
Repeat 500 generations 74 replicate lines
transfer one individual
reproduce
generation 1
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Mutation accumulation

• Compare DNA sequences
• Generation 0 AACTAGCGTACCG
• Generation 50 AATTAGCGTACCG
• Generation 100 AAT- AGCGTACCG

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A puzzle mutation rates

• Why do some mutation rates differ?

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Effects of mutations
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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(t1) p(t)

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Mutation selection balance II

• p(t 1) p(t) -?p
• If we use selection coefficients, this is easier
• AA Aa aa
• Fitness
• Solve for q
• We can do the same if the deleterious allele is
  partially recessive (but this requires some
  approximations)

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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 gt h gt 0.5) then
• qeq -? / hs

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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?

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Mutations are random!
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Levels of variation

• How much variation is there? Prediction?

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Allozymes ( alternate alleles of metabolic
enzymes)
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Quantifying variation Polymorphism
Heterozygosity

• Populations with higher allele variability will
  be more heterozygous
• Heterozygosity

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Genetic variation is rampant

• but varies among groups
• vertebrates mode 3-5
• invertebrates mode 8-15
• plants varies depending on mating system

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Larger populations have higher genetic diversity
Gillespie, 1992
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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?

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Readings and questions

• Denver, 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 1481667-1686.
• 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?