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Recombination and genome evolution – Recombination and selection

Recombination and genome evolution – Recombination and selection. Sylvain Glémin Institut des Sciences de l’Evolution - Montpellier glemin@univ-montp2.fr. Introduction. Recombination: (mostly) universal Key role in genetic process  genome evolution Variations in patterns of recombination

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Recombination and genome evolution – Recombination and selection

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  1. Recombination and genome evolution – Recombination and selection Sylvain Glémin Institut des Sciences de l’Evolution - Montpellier glemin@univ-montp2.fr

  2. Introduction • Recombination: (mostly) universal • Key role in genetic process  genome evolution • Variations in patterns of recombination • Between species (sexual/asexual, outcrossing/selfing,…) • Between genomic compartments (nuclear/organelles) • Between chromosomes (sexual/autosomes, size,…) • Along chromosomes (recombination gradients, hotspots,…)

  3. Introduction • Direct effects of recombination • Possible mutagenic effects • Genic conversion • At the initiation sites (see Hotspot paradox, Boulton et al. 1997) • At flanking regions [gBGC, see L. Duret’ lecture] • Indirect effects of recombination • Crossing-over: mixing alleles between genes

  4. Outline • I. Effects of genetic linkage on selection: general predictions • II. Evolution of non-recombining genomic regions: the example of mtDNA • III. The surprising effects of gBGC on selection • IV. Using genomes to study breeding system evolution

  5. I. Effects of genetic linkage on selection: general predictions I.1 Recombination and linkage disequilibrium I.2 Genetic hitch-hiking effects I.3 Consequences for genomic patterns

  6. LD: non-random association between alleles at two (or more) loci f(AB) = f(A)f(B) +D f(Ab) = f(A)f(b) – D f(aB) = f(a)f(B) – D f(ab) = f(a)f(b) + D I.1 Recombination and linkage disequilibrium A B A b a B a b

  7. LD: non-random association between alleles at two (or more) loci Created by Drift Selection Population structure … Removed by Recombination (Mutation) f(AB) = f(A)f(B) +D f(Ab) = f(A)f(b) – D f(aB) = f(a)f(B) – D f(ab) = f(a)f(b) + D I.1 Recombination and linkage disequilibrium A B A b a B a b

  8. Genomic patterns of linkage disequilibrium Arabidopsis thaliana (selfer) (Nordborg et al. 2005) Maize (Outcrosser) (Remington et al. 2001)

  9. I.2. Genetic hitch-hiking effects • “The hitch-hiking effect of a favorable gene” (Maynard-smith and Haig, 1974) • Two-locus dynamics • Genotypes: AA Aa aa BB Bb bb Fitness: 1 1+s 1+2s 1 1 1

  10. The different forms of genetic hitch-hiking effects Hill-Robertson interference (Hill & Robertson 1966) Genetic drift of haplotypes Loss of advantageous mutations Strongly advantageous Weakly advantageous Mildly deleterious Weakly deleterious Neutral

  11. The different forms of genetic hitch-hiking effects Selective sweep Hill-Robertson interference (Maynard-Smith & Haig 1974) (Hill & Robertson 1966) Selection of strongly advantageous mutations Genetic drift of haplotypes Loss of polymorphism and fixation of weakly deleterious mutations Loss of advantageous mutations Strongly advantageous Weakly advantageous Mildly deleterious Weakly deleterious Neutral

  12. The different forms of genetic hitch-hiking effects Selective sweep Muller’s ratchet Hill-Robertson interference (Maynard-Smith & Haig 1974) (Muller 1932) (Hill & Robertson 1966) Random loss (by drif) of crhomosomes free of mutation Selection of strongly advantageous mutations Genetic drift of haplotypes Loss of polymorphism and fixation of weakly deleterious mutations Loss of advantageous mutations Accumulation of deleterious mutations Strongly advantageous Weakly advantageous Mildly deleterious Weakly deleterious Neutral

  13. The different forms of genetic hitch-hiking effects Selective sweep Muller’s ratchet Background selection Hill-Robertson interference (Maynard-Smith & Haig 1974) (Muller 1932) (Charlesworth et al. 1993) (Hill & Robertson 1966) Random loss (by drif) of crhomosomes free of mutation Selection against deleterious mutations Selection of strongly advantageous mutations Genetic drift of haplotypes Loss of polymorphism and fixation of weakly deleterious mutations Loss of advantageous mutations Accumulation of deleterious mutations Loss of neutral and weakly advantageous variants Strongly advantageous Weakly advantageous Mildly deleterious Weakly deleterious Neutral

  14. Hitch-hiking effects: formalisation • Roughly equivalent to reducing effective size

  15. time Hitch-hiking effects: formalisation Background selection Deleterious allele Neutral alleles

  16. Hitch-hiking effects: formalisation • Roughly equivalent to reducing effective size • Background selection (Charlesworth et al. 1993) • Ne = Nf0avec f0 = exp(-U/s) (haploid)

  17. time time Hitch-hiking effects: formalisation Background selection Selective sweep Deleterious allele Advantageous allele Neutral alleles Neutral alleles

  18. Hitch-hiking effects: formalisation • Roughly equivalent to reducing effective size • Background selection (Charlesworth et al. 1993) • Ne = Nf0avec f0 = exp(-U/s) (haploid) • Recurrent selective sweep (genetic draft) (Gillespie 2000) • Ne = N/(1+2Nρ) • Rq: for some processes the effect of draft cannot be simply summarized by an effect on Ne

  19. I.3 Consequences for genomic patterns • Neutral mutations (synonymous, introns,…) • Polymorphism π = 4Neµ • Divergence D = µT Indirect effects Direct effects

  20. I.3 Consequences for genomic patterns • Neutral mutations (synonymous, introns,…) • Polymorphism π = 4Neµ • Divergence D = µT • Selected mutations (non-synonymous, regulatory sequences,…) • Polymorphism π = 4Nefnµ + πweak selection • Divergence D = µTfn+ Dweak selection + Dadvantageous Indirect effects Direct effects Indirect effects

  21. Interaction between selection and drift Dn/Ds Substitution rate pn/ps S = 4Nes High rec Low rec High rec

  22. Summary of predictions πn/πS πS/DS rec Dn/DS Stabilizing selection Positive selection rec rec

  23. Recombination and genomic patterns: polymorphism C. elegans A. thaliana Significant effect after controlling for divergence (Nordborg et al. 2005) (Cutter et al. 2003)

  24. Recombination and genomic patterns: polymorphism Human: an example of the confounding effects of recombination (Hellmann et al. 2003)

  25. Recombination and genomic patterns: Dn/Ds Dn/Ds per classes Human/chimp divergence Recombination classes (Bullaughey et al. 2008)

  26. Recombination and genomic patterns: Dn/Ds D. melanogaster/ D. yacuba divergence • ~ 7600 genes • Recombination classes • High • Intermediate • Low • NA: no recombination • N4: 4th chromosome NO (Haldrill et al. 2007)

  27. Summary • Globally: weak effects of recombination gradients • Strong contrast between recombining and non-recombining regions • Weak recombination is sufficient to counteract Hill-Robertson effects (if c/u > 1)

  28. II. Evolution of non-recombining genomic regions:the example of mtDNA II.1 mtDNA characteristics and classical assumptions II.2 Patterns of mtDNA polymorphism in animals II.3 The genetic draft hypothesis

  29. II.1 mtDNA characteristics and classical assumptions • Mitochondrial genome in animals • Small genome ~13 to 20 kb • Non-recombining • High gene density • High mutation rates • Classical assumptions • Strong purifying selection • Observed polymorphism ~neutral • Good marker for molecular biodiversity

  30. II.1 mtDNA characteristics and classical assumptions • Tests of these assumptions • Does mtDNA polymorphism correlate with Nethrough life history/ecological traits effects demography Life history traits Ecological traits p ~ Ne . m structure selection

  31. II.2 Patterns of mtDNA polymorphism in animals • The Polymorphix data base (Bazin et al. 2005) • Homologous sequences within species + outgroups • Several homology criteria • Database cleaning • Remove genome projects, transposons, specific genes (MHC, rRNA,…) • Manually check highly polymorphic genes

  32. II.2 Patterns of mtDNA polymorphism in animals • Data set available in Polymorphix • mtDNA ~1350 species • nucDNA ~100 species • Allozyme diversity (Nevo et al. 1984) • ~750 species • Computation of ps • Average over loci within species • Average over species within taxa / ecological groups • Comparison with allozimic diversity

  33. Global comparison Vertebrates Invertebrates nucDNA psynonymous Allozyme heterozygosity (Bazin et al. 2006)

  34. Global comparison Vertebrates Invertebrates mtDNA nucDNA psynonymous Allozyme heterozygosity (Bazin et al. 2006)

  35. Life history traits and diversity continent marine Branch. Dec. 0.40 0.30 H H * ** Allozymes Allozymes Molluscs Crustaceans Fresh-water marine 0.08 * H Allozymes (Bazin et al. 2006) Fishes

  36. Life history traits and diversity Branch. Dec. continent marine continent marine Branch. Dec. 0.40 0.30 0.08 0.10 ps H ps H * ** Allozymes ADNmt Allozymes mtDNA Molluscs Crustaceans Fresh-water marine Fresh-water marine 0.08 0.08 * ps H Allozymes ADNmt (Bazin et al. 2006) Fishes

  37. temps II.3 The genetic draft hypothesis(Gillespie 2000, 2001) Recurrent selective sweeps Ne Pure drift Continuous adaptation N Advantageous mutations Ne = N / (1+ 2Nr) Neutral alleles

  38. Signature of positive selection on mtDNA Neutrality index: NI = (pN / pS) / (dN / dS) 10 5 NI (log scale) purifying 1 neutral adaptative 0 Vert. Invert. Vert. Invert. mtDNA nuclear DNA (Bazin et al. 2006)

  39. Signature of positive selection on mtDNA Neutrality index: NI = (pN / pS) / (dN / dS) 10 5 NI (log scale) purifying 1 neutral adaptative 0 Vert. Invert. Vert. Invert. mtDNA nuclear DNA (Bazin et al. 2006)

  40. Signature of positive selection on mtDNA Neutrality index: NI = (pN / pS) / (dN / dS) 10 5 NI (log scale) purifying 1 neutral adaptative 0 Vert. Invert. Vert. Invert. mtDNA nuclear DNA (Bazin et al. 2006)

  41. The effect of draft on the whole mtDNA genome Complete mitochondrial genomes: Groups of closely related species (max dS < 50%) (Bazin et al. 2006)

  42. Patterns of selection on the whole mtDNA genome Selective sweep • Recurrent selective sweeps in large population •  Fixation of weakly deleterious alleles (dN/dS) (Maynard-Smith & Haig 1974) Selection of strongly advantageous mutations Loss of polymorphism and fixation of weakly deleterious mutations

  43. Summary • Importance of linkage in the evolution of mtDNA • Classical assumptions • Strong purifying selection + recurrent positive selection • Observed polymorphism ~neutral but not related to global Ne • Good Bad marker for molecular biodiversity • What is mtDNA (in large populations) adapting to ? • Metabolism adaptations? • Selfish genes? (two-level selection) • Cyto-nuclear interactions • Association with maternal-inherited endosymbionts (Wolbachia,…) • …?

  44. III. The surprising effect of gBGC on selection III.1 The population genetics of gBGC/selection interference III.2 The fitness consequences of gBGC

  45. II.1 The population genetics of gBGC/selection interference • gBGC ~ meiotic distortion: formally equivalent to genic selection for GC alleles (Nagylaki 1983) • DpGC = pGC(1 – pGC)b • Selection: Dp = p(1 – p)s / W (W ~ 1) • (Normalized) substitution rates • Selection alone • gBGC alone B = 4Neb • gBGC + selection Indirect effects Direct effects

  46. gBGC/selection: substitution rates 4 3 2 1 S = 4Ne s - 3 - 2 - 1 1 2

  47. gBGC/selection: substitution rates GC  AT mutations (B < 0) gBGC helps purging deleterious mutations 4 3 2 1 S = 4Ne s - 3 - 2 - 1 1 2

  48. gBGC/selection: substitution rates AT  GC mutations (B > 0) gBGC contribute to fixing deleterious mutations 4 3 2 1 S = 4Ne s - 3 - 2 - 1 1 2

  49. gBGC/selection: substitution rates • Fixation > purging • Achilles’ heel (Galtier and Duret 2007) 4 3 2 1 S = 4Ne s - 3 - 2 - 1 1 2

  50. gBGC/selection: from dominance to overdominance • (Partially) recessive deleterious ATGC mutations • Genotypes: WW WS SS • Fitness: 1 1- hs 1 – s • gBGC: 1 - b 1 1 + b • Total effects: 1 – b 1 – hs 1 + b – s • If hs < b <(1 – h)s : overdominance-like dynamics

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