SOME PATTERNS OF MOLECULAR EVOLUTION AND VARIATION

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SOME PATTERNS OF MOLECULAREVOLUTION AND
VARIATION

• 1. Regions of the genome with unusually low
  rates of genetic recombination seem to have low
  levels of within-species DNA sequence
  variability.
• 2. Species with low levels of genome-wide
  recombination, such as largely self-fertilizing
  plants and animals, also show reduced variability.

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• 3. The level of adaptation in non-recombining
  genomic regions is often reduced.
• 4. Repetitive DNA sequences (satellite DNA,
  transposable elements) often accumulate in
  genomic regions with low rates of genetic
  recombination.

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Diversity on the D. melanogaster X
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Comparing within-population diversity of A.
lyrata and total A. thaliana diversity Data of
Stephen Wright and Béatrice Lauga

• kS/kT
• petraea 1
• A. thaliana 0

Roughly twofold reduction in the inbreeder, but
some outbreeding populations also have low
diversity. This suggests importance of historical
processes.
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Drosophila miranda Neo-Sex Chromosomes
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• A GENERAL FEATURE OF LOW
• RECOMBINATION 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 (the
  Hill-Robertson effect).
• unless advantageous mutations occur so
  seldom that each has had time to become
  predominant before the next appears, they can
  only come to be simultaneously in the same gamete
  by means of recombination
• (Fisher 1930)

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Present
Fitness
0 . 95
Fitness
1
Fitness
0 . 9
Absent
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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
• Loci in low recombination genomic regions are
  more likely to accumulate deleterious mutations,
  and less likely to fix selectively advantageous
  mutations, than in regions with normal or high
  recombination rates.

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POSSIBLE FORCES INVOLVED

• Hitchhiking by favourable mutations (selective
  sweeps)
• Hitchhiking by deleterious mutations (background
  selection)
• Stochastic accumulation of deleterious mutations
  (Mullers ratchet)
• Mutual interference among weakly selected sites
  (weak selection Hill-Robertson effects)

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• MUTATION-SELECTION BALANCE
• Assume a very large population size, so that the
  loci under selection are approximately at
  deterministic equilibrium.
• Assume a mean number of new deleterious
  mutations per haploid genome per generation of U,
  and a harmonic mean selection coefficient against
  heterozygous mutations of t.
• The equilibrium mean number of deleterious
  mutations per haploid genome is
• n U/t

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• With independent effects on fitness of mutations
  at different loci, the frequencies of gametes
  carrying i deleterious mutations are
  Poisson-distributed with mean n U/t.
• The frequency of the mutation-free class is
• f0 exp - n
• e.g. with n 5, f0 0.007.

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• Hitchhiking by Favourable Mutations
• The spread of a favourable mutation in a
  non-recombining genome will drag to fixation any
  (sufficiently weakly selected) mutant alleles
  initially associated with it (a selective sweep).
  
• Successive adaptive substitutions on
  non-recombining chromosome can lead to the
  fixation of deleterious mutations at other loci,
  contributing to its degeneration. There is an
  associated loss of variability at neutral sites
  on the chromosome.

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• For deleterious mutations which are sufficiently
  strongly selected that they are near
  mutation-selection equilibrium in the absence of
  selective sweeps, a succession of S selective
  sweeps changes the expected fitness of a
  population by a factor of at most approximately
• exp - SU/h
• where h is the harmonic mean reduction in
  fitness to mutant heterozygotes compared with
  heterozygotes (the dominance coefficient).

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• Background Selection
• A neutral or weakly selected mutation that
  arises in a large non-recombining population has
  a non-zero chance of survival only if it arises
  on a chromosome free of strongly deleterious
  mutations.
• This accelerates the fixation of weakly
  deleterious mutations, and retards the fixation
  of advantageous mutations.
• Neutral variability is also reduced.

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• it will only be the best adapted genotypes
  which can become the ancestors of future
  generations, and the beneficial mutations which
  occur will have only the minutest chance of not
  appearing in types of organisms so inferior to
  some of their competitors, that their offspring
  will certainly be supplanted by those of the
  latter
• (Fisher 1930)

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• The net effect of background selection is that
  the effective population size, Ne, is reduced to
  f0Ne (in the absence of recombination). This
  means that the equilibrium level of neutral or
  nearly-neutral within-population variability will
  be reduced accordingly.
• The chance of fixation of deleterious mutations
  can be greatly increased, and the chance of
  fixation of advantageous mutations reduced, due
  to this reduction in Ne.

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• This effect can be very large e.g. if f0
  0.007, and Ne 500,000, a deleterious mutation
  with a heterozygous effect on fitness of 10-5 has
  a probability of fixation on the neo-Y of 98 of
  the value for a neutral mutation, whereas the
  probability in the absence of background
  selection is only 3 of the neutral value.
• Similarly, the rate of fixation of advantageous
  mutations is reduced by a factor of approximately
  f0, unless their selection coefficients are
  larger than those of the deleterious mutations in
  the background (as is required for the selective
  sweep model to work).

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• Mullers Ratchet
• This involves the stochastic loss from a finite
  population of the class of chromosomes carrying
  the fewest deleterious mutations. In the absence
  of recombination and back mutation, this class of
  chromosome cannot be restored. The next best
  class then replaces it and is in turn lost, in a
  process of successive irreversible steps.
• Each click of the ratchet is quickly
  followed by the fixation of one mutation in the
  whole population, unless mutations are strongly
  selected and highly recessive.

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Mutation
Drift
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• SPEED OF MULLERS RATCHET
• N U t Time between
  Clicks Mean Fitness
• Sims.
  Theory (at 5 x105gens)
• 5 x105 0.04 0.0075 3912 5910 0.38
• 5 x105 0.015 0.0015 732 1343 0.36
• 5 x105 0.015 0.0025 4924 7785 0.77

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Weak Selection Hill-Robertson Effects

• The previous models assume that selection is
  sufficiently strong relative to drift that
  deleterious mutations are mostly held close to
  their equilibrium value for an infinitely large
  population, if recombination is frequent.
• If selection coefficients against deleterious
  mutations are of the order of 1/ Ne, or less,
  this does not hold, and deleterious variants can
  drift to intermediate frequencies, even with free
  recombination

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Testing Hypotheses

• Can the various models quantitatively explain the
  general patterns seen in the data?
• When two or more models produce similar
  predictions about patterns, can we discriminate
  among them?

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Nucleotide Diversity in Drosophila as a Test-Case

• This is the problem for which it is easiest to
  make quantitative predictions about expected
  patterns i.e., how should variability in a gene
  relate to its position on a chromosome?
• In addition, the different models make somewhat
  different predictions about the extent of
  departures of the distribution of variant
  frequencies from those expected in the absence of
  Hill-Robertson effects

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Testing for Departures from Neutrality

• Various statistical tests for departures from the
  distribution of nucleotide variants expected in a
  population at statistical equilibrium have been
  devised, mostly concerned with detecting an
  excess/deficiency of rare variants.
• Different types of Hill-Robertson effects, as
  well as other factors such as population size
  changes, have different effects on departures
  from neutral expectation.

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Patterns of Codon Usage Bias

• The theory suggests that background selection and
  selective sweeps should produce a regional
  pattern of codon usage bias across the genome
  that parallels that for neutral diversity.
• The data on Drosophila melanogaster contradict
  this codon usage (after correcting for local
  base composition) is reduced only in regions of
  the genome with very low rates of crossing over.

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ACKNOWLEDGEMENTS

• THEORY Deborah Charlesworth, Isabel Gordo,
  Gabriel Marais, Martin Morgan, Magnus Nordborg
• DATA Peter Andolfatto, Doris Bachtrog, Carolina
  Bartlomomé, Mark Jensen, Xulio Maside, Soojin Yi
• MONEY BBSRC, EMBO, NSF, Royal Society