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The Evolution of Sex Chromosomes: from Humans to Non-model Organisms

The Evolution of Sex Chromosomes: from Humans to Non-model Organisms. Gabriel Marais Laboratoire Biométrie et Biologie Evolutive (LBBE) Eq. Bioinformatique et Génomique Evolutive (BGE) CNRS, Université Claude Bernard - Lyon 1. The human sex chromosomes. Why to study sex chromosomes?

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The Evolution of Sex Chromosomes: from Humans to Non-model Organisms

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  1. The Evolution of Sex Chromosomes: from Humans to Non-model Organisms Gabriel Marais Laboratoire Biométrie et Biologie Evolutive (LBBE) Eq. Bioinformatique et Génomique Evolutive (BGE) CNRS, Université Claude Bernard - Lyon 1

  2. The human sex chromosomes • Why to study sex chromosomes? • Ideal system for understanding the effect of recombination on genome evolution • Key players in sex determination and sex dimorphism • Infertility in man (Y), genetic diseases (X) X Y PAR1 PAR1 NRY or MSY XSR PAR2 PAR2

  3. Sry Sry Sry Sox3 Sox3 Sox3 Sox3 Sox3 Monotremes and birds 130-170 Mya Placentals and marsupials 80 -130 Mya Placentals Sox3/Sry pair Non-recombining Y (degenerated) Evolution region by region of dosage compensation on the X following the degeneration of the homologous regions on the Y Scenario for the evolution of the human sex chromosomes PAR1 Sry Sry PAR2 Sox3 Sox3 30-50 Mya Simian Primates ~5 Mya Humans, Chimps? Marais & DuretBiofutur 2009

  4. Syn. X-Y Divergence X 0 20 40 60 80 100 5 4 3 2 Y • Lahn & Page Science 1999 • Skaletskyet al.Nature 2003 • Ross et al.Nature 2005 SRY 1 106 (28) (PAR genes) SOX3 1098 (28) Glémin & Marais in BiologieEvolutive, Ed de Boeck Recombination suppression and evolutionary strata

  5. Why is recombination between the sex chromosomes suppressed? M1 f “proto-Y” 1- Recombination suppression at the sex determining region “proto-X” m1 F M = male fertility gene m = male sterility gene F = female fertility gene f = female sterility gene Charlesworth, Charlesworth, Marais Heredity 2005

  6. 2- Addition of Y genes that are ‘good’ for males and ‘bad’ for females M2 M1 f “proto-Y” “proto-X” 3- Recombination suppression between males ‘good’ genes and male determining genes m2 m1 F M2 M1 f Y 4- Y degeneration Why is recombination between the sex chromosomes suppressed? M1 f “proto-Y” 1- Recombination suppression at the sex determining region “proto-X” m1 F Charlesworth, Charlesworth, Marais Heredity 2005

  7. The Y chromosome is degenerated Skaletsky et al. Nature 2003 Ross et al.Nature 2005 ( ) PARs

  8. The Y chromosome is degenerated  98% of the Y genes have been lost…

  9. Y degeneration: Evolution of dosage compensation on the X • Because of Y gene loss, males and females should have differences in sex-linked gene expression • In female somatic tissues, one of the two X chromosomes is inactivated (Barr body) • X inactivation makes X gene expression the same in males (XY) and females (XX) Vicoso & BachtrogChrom. Res. 2009 Chow & Heard Curr. Opin. Cell Biol. 2009

  10. Y degeneration: lack of recombination and dosage compensation on the X X Skaletskyet al. Nature 2003 Ross et al. Nature 2005 Carrel & Willard Nature 2005

  11. A1 A1 B1 B1 Advantageous alleles C1 Wild-type alleles Deleterious alleles A2 B1 C2 + 10 % - 0.1 % A1 B2 C1 Without Crossing over With Crossing over + 0.1 % C2 C1 A2 B1 A2 B2 B2 is lost, C2 is fixed A2 and B2 are fixed, C2 is eliminated Y degeneration:Example of Hill-Robertson effects Marais & CharlesworthCurr. Biol. 2003

  12. Selective sweeps (strong advantageous mutations) • Hill-Robertson interference (many weak advantageous mutations) • Background selection (moderately deleterious mutations) • Muller’s ratchet (small Ne, slightly deleterious mutations) • Reduced fixation of beneficial mutations • Increased fixation of deleterious mutations • Reduced polymorphism • More insertions of transposable elements • More chromosomal rearrangements Y degeneration:the different Hill-Robertson effects Glémin & Marais in BiologieEvolutive, Ed de Boeck

  13. Questions on sex chromosomes • How was X-Y recombination suppressed (Y inversions)? • Was the X a passive player during sex chromosomes evolution? 3) How is survival on the Y possible? 4) Is this scenario correct for other species with sex chromosomes?

  14. ? ? Data obtained with GRIMM 1) Were strata formed by Y inversions? Collaboration with Marie-France Sagot’s group (LBBE) Lemaitre*, Braga*,…, Marais Genome Biol. Evol. 2009

  15. Footprints of inversions at present and past pseudo-autosomal boundaries Div < Div Lemaitre et al.GBE 2009

  16. The recent strata 4 and 5 have been formed by two inversions on the Y Stratum 4 Stratum 5 Lemaitre et al.GBE 2009

  17. 2) Was the X a passive player in the evolution of sex chromosomes? • Accumulation of genes involved in male functions because X hemizygosity in males increases the probability of recessive male-beneficial mutations [1,2] • “Out of X”: excess of X->A retrogenes because of X silencing during male meiosis (MSCI) [3,4,5] [1] Ross et al. Nature 2005 [2] Ellegren & Parsch Nat. Rev. Genet. 2007 [3] Emerson et al. Science 2004 [4] Khil et al. Nat Genet. 2004 [5] Portzebowski et al.PLoS Biol. 2008

  18. Burst of duplicates on the human and rodent X Collaboration withManyuan Long group (Chicago, USA) • Identifying duplicate genes in 13 mammalian genomes + outgroups • Mapping on the phylogeny of mammals Two Burst of X genes expressed in testis • Accumulation of male-beneficial genes on the X Zhang, …, Marais, Long PLoSBiol. 2010

  19. Burst of X duplicates and the evolutionary strata Collaboration withManyuan Long group (Chicago, USA) The accumulation of X duplicates occurs in already formed strata, where the X is actually hemizygous in males as predicted by the theory • Accumulation of male-beneficial genes on the X Zhang, …, Marais, Long PLoSBiol. 2010

  20. 3) How is survival on the Y possible? 98% of the Y genes have been lost… What about the remaining 2% that survived?

  21. A big surprise from the Y complete sequence Rozenet al. Nature 2003 • + Comments: • Nature • Cell • Genome Biology • Survival by Y-Y gene conversion? • MSY have 9 gene families (with 2-35 copies) = ampliconic genes, many involved in spermatogenesis • They experience a very high rate of gene conversion (x1000 genome average); large palindromes, inverted repeats or tandem arrays may promote such a high rate • Most of these genes amplified specifically in primates from single-copy ancestors (Bhowmicket al.Genome Res. 2007)

  22. Y … 1 2a 2b 2c 3 4 5 6 7 L duplicates Haploid population of Y chromosomes evolving under the Wright-Fisher model Humans 2500 Introduction of a mutant with gene conversion to study its fate by Monte Carlo simulations Fate??? Y Y 27 Y Y Y Y 1/3 Y Y Y 7 Y Y Y Y 0.4 Y Y Y 0.01 Y Y Y Gamma distributiona=0.2b=2.5 Modelling Y-Y gene conversion Marais, Campos, GordoGBE 2010 Isabel Gordo Instituto Gulbenkian de Ciência Portugal Effect of deleterious mutations on duplicated gene divided by 1/C • Population size • Genes number • % of duplicate genes • Copy number • Gene conversion rate • Deleterious mutation rate • Selection coefficients

  23. Study of gene conversion modifiers Population: N Y chromosomes resembling the human Y (no gene conversion) Introduced variant: Y with gene conversion within duplicated copies nb of fixations events/nb of runs Pfixo/e= 1/N Human parameters 20.N replicates Threshold • Gene conversion is advantageous in humans, this advantage increases with increasing gene conversion rate

  24. Evolution of fitness over time for weak and strong modifiers Weak modifier • Fitness increases over time for strong modifiers only, weak modifiers are fixed by drift Strong modifier

  25. Study of gene conversion modifiers Population: N Y chromosomes resembling the human Y (no gene conversion) Introduced variant: Y with gene conversion within duplicated copies nb of fixations events/nb of runs Pfixo/e= 1/N Human parameters 20.N replicates • We see an advantage for a wide range of values for population sizes, deleterious mutation rates, duplication configurations • Ampliconic regions should exist in other species, which is in agreement with the data (Hughes et al. Nature 2010) Threshold • Gene conversion is advantageous in humans, this advantage increases with increasing gene conversion rate

  26. Muller’s ratchet and Y-Y gene conversion * * * * * * * * Loss of mutation free chromosomes by drift Loss of mutation free chromosomes by drift * * * * * * * * Gene conversion restoring mutation free multicopy genes * * Single-copy gene Multi-copy gene * * * Slightly deleterious mutations * * Marais, Campos, GordoGBE 2010 *

  27. Silene latifolia, a dioecious plant X Y PAR PAR OPA OPA Xp SlX6b SlY6b SlX1 SlY1 SlCypX Yq SlY3 SlssX DD44X Xq SlY7 MFF SlY4 SPF SlX3 DD44Y SlssY Yp SlCypY SlX7 GSF SlX6a SlY6a SlX4 4) How is the evolution of sex chromosomes in other species?

  28. XY XY Evolution of sex chromosomes and dioecy in the Silene genus Collaboration with Deborah Charlesworth’s group 13 nuclear genes Hermaphrodite Gynodioecious Dioecious and Vincent Daubin (LBBE) • Young sex chromosomes (~ 10 my) Early steps of XY evolution • Plant model Plant XY vs. animal XY • Non-dioecious closely related species Comparative analysis Bernasconi, …, Marais, et al. Heredity 2009 Marais et al. submitted

  29. Collaborative project: D. Charlesworth(Univ. Edinburgh) N. Negrutiu(ENS Lyon) B. Vyskot(Brno, Czech Rep.) 30 1.8 x 10-8 syn. substitutions / syn. site / year 25 ~10 My 20 15 ~4 My 10 ~2.5 My 5 0 0 10 20 30 40 50 60 Genetic distance (cM) Evolutionary strata in S. latifolia dSX-Y (%) X PAR p q SlX1 SlX6b DD44X OPA SlssX SlX3 SlX7 SlX6a SlX4 SlCypX Nicolas*, Marais* et al.Plos Biol. 2005

  30. Evidence for the degeneration of the Y chromosome in S. latifolia XY Collaborative project: D. Charlesworth(Univ. Edinburgh) B. Vyskot(Brno, Czech Rep.) A. Widmer(ETH Zurich) dN = non-synonymous substitutions rate dS = synonymous substitutions rate dN/dS = form and intensity of selection (PAML) • Silene Y genes evolve faster, have lower expression and more transposable element insertions than their X counterparts Marais et al.Curr. Biol. 2008

  31. Sry Sry Sry Sry Sox3 Sox3 Sox3 Sox3 Sox3 Sox3 Monotremes and birds 130-170 Mya Placentals and marsupials 80-130 Mya Placentals The evolution of sex chromosomes PAR1 Sry PAR2 Sox3 30-50 Mya Simian Primates ~5 Mya Humans, Chimps? ZW Chicken XY Medaka XY Silene Papaya Young AND heteromorphic sex chromosomes XY XY Drosophila Marais & Duret Biofutur 2009 X0 C. elegans

  32. Conclusions • The human Y chromosome is a clear example on how recombination can affect genome evolution • The scenario for the evolution of the human sex chromosomes has been repeated many times in different taxa • There are still many unanswered questions!!!!

  33. Acknowledgements Sex chromosomes in Lyon: AlineMuyle (M2) EugéniePessia (PhD) JosKafer (Postdoc) Raquel Tavares Sylvain Mousset Collaborators: Deborah Charlesworth (U. Edinburgh) Alex Widmer (ETH, Zurich) Boris Vyskot (IBP, Brno, Czech Rep.) Manyuan Long (U. Chicago) Isabel Gordo (IGC, Portugal) Marie-France Sagot (LBBE) LaboratoireBiométrie et BiologieEvolutive CNRS, Université Lyon 1

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