Sex and molecular evolution

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Sex and molecular evolution
Brian Charlesworth
Institute of Evolutionary Biology School
of Biological Sciences University of Edinburgh
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• Sex is the most prevalent mode of reproduction
  among the great division of life (the eukaryotes)
  that includes the animals, green plants, algae,
  fungi and protozoa.
• All mammals and all birds reproduce sexually, and
  there are only a few dozen examples of asexually
  reproducing species among reptiles, amphibia and
  fish.
• Only about 0.1 of the over 300,000 species of
  flowering plants are thought to reproduce
  asexually.

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An exception to the recent origin of asexual
species
The Bdelloid rotifer Philodina roseola
(Meselson laboratory)
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• A regular cycle of sexual reproduction is absent
  from the other division of life (prokaryotes
  bacteria and viruses).
• There is, however, often detectable exchange of
  pieces of genetic information between individuals
  within prokaryote populations, involving a
  variety of processes that act as a substitute for
  sex.

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• The essence of sexual reproduction is the
  reshuffling of genetic information derived from
  the two parents of an individual (genetic
  recombination).
• To understand the evolutionary significance of
  sex, we need to understand the significance of
  recombination.

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Structure of DNA
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How evolution works

• Evolution involves the transformation of
  variation between members of a population into
  differences between ancestral and descendant
  populations
• At the level of DNA sequences, this variation can
  be studied by comparing the sequences of the same
  region of the genome in different individuals

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The gene for glucose-6-phosphate dehydrogenase
The set of basepairs for a given DNA sequence is
known as a haplotype
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• The most general description of the state of a
  population would thus be a list of the
  frequencies of all possible haplotypes.
• We could then characterise evolutionary change in
  terms of the rates of change of the frequency of
  each haplotype, ?xi , where xi is the frequency
  of the ith haplotype.
• In practice, we usually collect data on, or model
  the evolution of, only limited portions of the
  genome, the simplest level being that of a single
  basepair.

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The genetic processes of evolution

• Mutation changes in the sequence of DNA that
  occur during transmission of a chromosome from
  parent to offspring.
• Natural selection differences in fitness
  (survival and reproductive success) between
  individuals with different genetic make-ups
• Recombination reshuffling of genetic material
  between the chromosomes derived from different
  parents
• Genetic drift random fluctuations in the
  frequencies of genetic variations, caused by the
  finite size of the population

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R. A. Fisher
Sewall Wright
J.B.S. Haldane
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Mutation rates

• The most common type of mutation is a change from
  one basepair to another, e.g. GC mutates to AT.
• Direct estimates have recently been done in
  several species of animals and plants, and show
  that probability that a given site in the DNA
  changes its state is of the order of 10-9 to 10-8
  per generation this is the mutation rate per
  basepair.
• This means that mutation is a very weak force,
  operating on a timescale of hundreds of millions
  of generations.
• Nevertheless, it is crucial for evolutionary
  change to happen.

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Measuring the mutation rate
Initial isogenic stock
x
Many separate single-pair mated lines
200 generations to allow mutations to arise
DNA extracted and sequenced, or mutations
detected by special methods
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Selection

• The simplest form of selection is when two
  alternative variants at a given site in the
  genome confer differences in fitness on the their
  carriers.
• Let one variant be called A1 and the other A2.
• Let the ratio of the fitnesses of A2 and A1
  individuals be 1 s .
• The quantity s measures the intensity of
  selection, and is called the selection
  coefficient.
• If q is the frequency of A2, the change in q is
  ?q, given approximately by sq(1 q).

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The peppered moth Biston betularia, with melanic
(dark) and non-melanic forms
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Genetic recombination
A T A G C T T G A C C T A T G
Parental combinations of two variants
A A A G C C T G A G C T A T A
Recombination between A and B sites or between
polymorphic sites in a DNA sequence
A A A G C C T G A C C T A T G
Recombinant haplotypes
A T A G C T T G A G C T A T A
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Genetic drift

• The frequencies of genetic variants in one
  generation are a random draw from the frequencies
  of the parents in the previous generation.
• This cause variant frequencies to experience a
  random walk (genetic drift).
• The state of the population must then be
  charaterised by a probability distribution of
  variant frequencies, e.g. the probability that
  variant A2 at a site takes frequency q at time t
• The rate at which the scatter of this
  distribution occurs is measured by the inverse of
  the effective size of the population, Ne.
• The timescale of genetic drift is of the order of
  Ne generations.

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Drift in lab populations of the fruitfly
Drosophila melanogaster
Generations
Numbers of copies of the bw eyecolour variant
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The general equation of evolution (forward
diffusion equation)
Here, x is the vector of haplotype frequencies,
?(x, t) is the probability density of x at time
t, ?xi is the deterministic change in the
frequency of the ith haplotype, Cij is the
covariance between the random changes in
frequencies of haplotypes i and j. The Cij are
all proportional to 1/Ne this means that we can
multiply both sides by Ne, and work with Net as a
time unit and with Ne ?xi instead of ?xi.
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What has all this got to do with the evolution of
sex and recombination?

• In order to understand how sexual reproduction
  and genetic recombination influence the
  evolutionary process, we need to have
  well-formulated models that can be related to
  data.
• To produce these models, we need to include
  processes that are likely to be operating in the
  real world.
• Before introducing them, lets look at some
  patterns that are revealed by studying DNA
  sequence variation and evolution.
• Differences within different regions of the
  genome that experience different levels of
  genetic recombination have proved particularly
  useful for revealing these patterns.

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The Drosophila melanogaster genome (heterochromati
n in black)
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Some correlates of low versus high recombination

• Regions of the genome with unusually low rates of
  genetic recombination often seem to have low
  levels of within-species DNA sequence
  variability.
• Species with low levels of genome-wide
  recombination, such as largely self-fertilizing
  plants and animals, also show reduced
  variability.
• 3. The level of adaptation at the protein and DNA
  sequence level is often reduced in
  non-recombining genomic regions.

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The fourth/dot chromosome in D. melanogaster
1.2 million basepairs (Mb) / 80 genes
Low recombination
No crossing over under normal lab conditions
Characteristics of the dot chromosome Low
silent site variability (about 10 of genomewide
mean)
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Divergence between D. melanogaster and D. yakuba
P. Haddrill et al. 2007 Genome Biology 8R18
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Drosophila miranda neo-sex chromosomes
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Polymorphisms on the two neo-sex chromosomes
Neo-X Neo-Y
Mean silent diversities neo-X 0.39 , neo-Y
0.004
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• A general feature of low recombination
• genome regions
• A lack of recombination among a set of genes
  in a genome or genomic region means that the
  evolutionary fates of mutations at different
  sites are not independent of each other, so that
  they can interfere with each others evolution.
• This is the Hill-Robertson effect.
• (Hill and Robertson 1966 Genetical Research 8
  269-294)

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The Hill-Robertson effect
A1 B1
Fitness 0.9
Mutation B1 ? B2
Mutation A1 ? A2
A2 B1

Fitness 0.95
A1 B2
Fitness 1
Maximum fitness possible with both advantageous
mutations A2 and B2

A2 B2
Fitness 1.05
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• The effective population size (Ne) of large
  non-recombining portions of the genome is
  substantially reduced by such interference among
  genes subject to selection.
• This leads to a reduction in the level of neutral
  variability in DNA sequences
• Genes in low recombination genomic regions are
  more likely to accumulate deleterious mutations,
  and less likely to fix selectively advantageous
  mutations, than genes in regions with normal or
  high recombination rates, since the chance of
  spread of mutation with selection coefficient s
  is determined by the magnitude of Nes.

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Selection against deleterious mutationswith low
recombination (background selection)

• 10 different sequences 7 different sequences
  

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Does background selection have important effects?

• To answer this, we need to know
• The rate of input of deleterious mutations into
  the population each generation
• The frequency distribution of the sizes of
  effects of these mutations on fitness (i.e. their
  selection coefficients)

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• Our previous theoretical work showed that, using
  estimates of the selection intensities against
  amino-acid mutations, background selection wildly
  over-estimates the reduction in neutral
  variability on the dot chromosome and neo-Y
  chromosome.
• (Loewe and Charlesworth 2007 Genetics 175
  1381-1393.)
• What is going on?

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Weak Selection Hill-Robertson Effects

• These models assumed that selection is
  sufficiently strong relative to drift that
  deleterious mutations are mostly held close to
  their equilibrium values for an infinitely large
  population.
• If a large number of sites with low
  recombination are under selection, this does not
  hold because of their mutual H-R interference,
  which means that deleterious variants can drift
  to intermediate frequencies.
• This reduces the strength of their HR effects.

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• The Model
• Population of 500 diploid individuals
• 2 selected sites alternating with one neutral
  site
• 00101000010100111001011100010101
• 01110100111011000101001001110001
• mutation 0 ? 1 or 1 ? 0 (equal rates) red
  sites are under selection against amino-acid
  mutations (0 is good, 1 is bad), black sites have
  no fitness effects
• crossing over/gene conversion
• 0011000111000011111001 0011000111000011000000
• 1111000000010111000000 1111000000010111111001
• multiplicative effects on fitness of mutations
  at different sites

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• Results
• Compare observed reduction in neutral diversity
  (p/p0) to expectation under background selection
  model

? formula overpredicts reduction in p if
recombination rates are low and chromosomes long
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Results Exponential decline of neutral diversity
with chromosome length
D. miranda neo-Y
Drosophila dot chromosome
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Conclusions

• Many features of variability in the
  non-recombining regions of the Drosophila genome
  are captured by models involving mutations at a
  large number of selected sites, corresponding to
  the amino-acid coding sites in genes.
• This suggests that the reduction in effectiveness
  of selection resulting from Hill-Robertson
  interference of this kind may be a major player
  in the evolutionary significance of recombination
  and sexual reproduction.

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ACKNOWLEDGEMENTS

• THEORY Deborah Charlesworth, Isabel Gordo, Vera
  Kaiser, Laurence Loewe, Martin Morgan, Magnus
  Nordborg
• DATA AND ANALYSES Andrea Betancourt, Doris
  Bachtrog, Penny Haddrill, John Welch
• MONEY BBSRC, NSF, Royal Society

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