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Sex chromosome evolution in Vertebrates

Sex chromosome evolution in Vertebrates. Frédéric VEYRUNES. Institut des Sciences de l’Evolution Department Genome Team Sex & Speciation CNRS / University Montpellier 2 . frederic.veyrunes@univ-montp2.fr. email:. Comparative Genomics Lyon 2011.

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Sex chromosome evolution in Vertebrates

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  1. Sex chromosome evolution in Vertebrates Frédéric VEYRUNES Institut des Sciences de l’Evolution Department Genome Team Sex & Speciation CNRS / University Montpellier 2 frederic.veyrunes@univ-montp2.fr email: Comparative Genomics Lyon 2011

  2. I. Origin and Evolution of sex chromosomes in Vertebrates. II. The “weird” sex chromosome system of the platypus. III. New data from the complete sequencing genome of the platypus IV. Sex chromosomes and sex determination in African pygmy mice.

  3. X X X Y 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 X Y

  4. X > 1000 genes Y >45 genes (SRY) X and Y chromosomes evolved from an ancestral pair of autosomes SRY proto-X -Y Y X

  5. Y = by-product of perverse evolution leading to its extinction ? Well… Human Y may disappear, but probably not males Ellobius lutescens, a species without Y, nor SRY (Just et al Nature Genet 1995) The ancestral Y of D. pseudoobcura has been lost, and a novel Y has arisen de novo (Carvalho & Clarck Science 2005) The Human Y chromosome rapidly degenerates. Graves Cell 2006

  6. Z W Non-recombining region has remained small Ratite bird sex chromosomes are not evolving at the same rate than other birds(Nanda et al Cytogenet Genome Res 2008) Large non-recombining region FOUR active genes in human and gorilla became pseudogenes in chimpanzee, suggesting a faster Y degrading process in the chimp than in the other lineages(Goto et al J Mol Evol 2009) No genes shared between Z and W (W has lost most genes) 11/11 genes shared between Z and W (small sex-determining region) 3/11 genes shared between Z and W Gradual degeneration of snake W chromosome (Matsubara et al PNAS 2006) Pythonidae Colubridae Viperidae

  7. Most of the gametologues present on the human Y are found in the youngest strata (3 and 4) of the X • This indicates that the older strata are genetically degenerated and have lost most of the genes that were once on the Y Lahn & Page Science 1999

  8. BUT… The Ychromosome is a by-product of perverse evolution leading to its degeneration AT CONTRARY: The Xchromosome is gene-rich, and notably with an over-representation of genes involved in sex, reproduction, and cognitive (“intelligence genes”) functions. IN FACT, Rapid Selection for: - male-advantage recessive mutations on the X chromosome (hemizygous males) - female-advantage dominant mutations on the X chromosome (ratio 2:1) The Y chromosome determines the male sex, regardless of which other chromosomes are present Female development: « default pathway »

  9. Environmental Sex Determination Genetic Sex Determination Male heterogametic: X X X Y Female heterogametic : Z Z W Z In Vertebrates, sex is determined by many different strategies

  10. Platyfish Silverside sp. with Genetic SD sp. with Environmental SD sp. hermaphrodite Conover et al Evolution 1992 Volff & Schartl Genetica 2001 Polyfactorial Genetic Sex Determination Females: XX, XW or ZW Males: XY or YY Nile Tilapia XX/XY species But temperature induces sex reversal Stickleback Ross et al PLoS Genet 2009 sp. with XX/XY sp. with ZZ/ZW Baroiller & D’Cotta Comp Biochem Phys C 2001

  11. Pogona vitticeps Rana rugosa Uno et al Chrom Res 2008 In the Japanese frog, some populations are XY and others ZW Quinn et al Science 2007 Temperature induces sex reversal in a ZZ/ZW lizard The XY pair switched into a ZW pair

  12. Sex determining systems mapped onto a molecular phylogeny of Squamates - Numerous transitions from TSD to GSD (but GSD > TSD ??) - A few XY  ZW Pokorna & Kratochvil Zool J Linn Soc 2009

  13. All Therian mammals have the same sex chromosomes

  14. Heteromorphic sex chromosomes, with a highly degraded and specialized Y chromosome, are a strong barrier to transitions between sex-determining systems. Due to formation of lethal genotypes (YY) Vs. The potential adverse effects of Y-specific genes on the feminization process of neo-XY females YY YY And conversely, the lack of necessary Y-specificgenes in neo-XX males But some exceptions exist… Why?

  15. Any modifications generally lead to infertility/sterility The X and Y are extremely conserved • Human patients with Klinefelter syndrom (XXY) • or Turner (XO) The X and Y are very ancient Murphy et al Genome Res 1999

  16. Recent autosomal addition on the Eutherian X chromosome Origin of sex chromosomes in Mammals. Large-scale gene-mapping comparisons 5 Graves 1995 BioEssays X X

  17. 1 4 12 X Z 4 5 8 2 Matsubara et al 2006 PNAS 9 18 Nanda et al 1999 Nature Genet Independent origin of sex chromosomes in mammals, birds, and snakes Fridolfsson et al 1998 PNAS

  18. Differentiation of mammalian X-Y started 310 Mya, just after mammal / reptile split (Lahn & Page Science 1999) Origin of sex chromosomes in Mammals.

  19. ? Mammals Monotremes: pivotal position for genomic comparisons/origin of mammal XY …But their sex chromosome system remained a long mystery until recently Amniote sex chromosomes systems Snakes Birds Crocodilians Turtles Monotremes Marsupials Eutherians Lizards XY XY ZW ZW X Y W X W Z Y Z 245mya 150mya 220mya 165mya 270mya 285mya 310mya

  20. I. Origin and Evolution of sex chromosomes in Vertebrates. II. The “weird” sex chromosome system of the platypus. III. New data from the complete sequencing genome of the platypus IV. Sex chromosomes and sex determination in African pygmy mice.

  21. 10 sex chromosomes !! X1Y1X2Y2X3Y3X4Y4X5Y5 5 Ys: male-specific 5 Xs: in pairs in female Unprecedented sex chromosome system X1 Y1 X2 Y2 X3 Y3 X4 Y4 X5 Y5 Karyotype Rens et al PNAS 2004

  22. 5Xs 5Ys An exceptional system (1) Extraordinary meiotic chain: Grutzner et al Nature 2004

  23. absence SRY orthologues Mammalian X DMRT1 gene Avian Z X5 DMRT1 X5 DMRT1 Watson et al PNAS 1990 Grutzner et al Nature 2004 El Morghabel et al Genomics 2007 An exceptional system (2) Déterminisme du sexe inconnu X1 Y1 X2 Y2 X3 Y3 X4 Y4 X5 Y5

  24. DAX1 DAX1 15 SOX9, DAX1, SF1, WT1, etc… Mapped on autosomes GATA4 Y1/X2 GATA4 X2 BUT… On the pseudo-autosomal region (same dose between sexes) GATA4 Sex determining gene remains unknown Search for the sex determining switch in Monotremes absent SRY X5, but in opposite dosage than in birds (2:1 in : ) DMRT1 Graphodatskaya et al Chrom Res 2007 unpublished data

  25. Chromosome Painting allows to establish the chromosomal homologies according to the DNA content, by fluorescence in situ hybridization And the Echidna ? Need a comparative sex chromosome map between Echidna and Platypus

  26. Flow-sorted chromosomes are separated Pics are isolated Amplification by DOP-PCR Labelling with fluorochrome Chromosome probe Human chromosome 1 Human chromosome 19 How does it work? Genomic comparison Human/Pangolin Yang et al Chrom Res 2006

  27. Echidna = “only” 9 sex chromosomes Platypus X5 and Y5 are not the last chromosomes in echidna chain Sex chromosome system still evolved after platypus-echidna divergence Cross-species Chromosome Painting Echidna Y2 Echidna X5 Rens et al. Genome Biol 2007

  28. proto X -Y A link between the bird ZW and mammal XY systems ? Amniote sex chromosomes systems Mammals Snakes Birds Crocodilians Turtles Monotremes Marsupials Eutherians Lizards XY XY ZW ZW X Y W X W Z Y Z 245mya 150mya 220mya 165mya 270mya 285mya 310mya Ezaz et al Current Biol 2006

  29. I. Origin and Evolution of sex chromosomes in Vertebrates. II. The “weird” sex chromosome system of the platypus. III. New data from the complete sequencing genome of the platypus IV. Sex chromosomes and sex determination in African pygmy mice.

  30. Physical map of the platypus genome Y2 X2 correspondence « karyotype – genotype » X3 Warren et al Nature 2008

  31. miRNAs Some are shared with others mammals but not birds (mammal-specific), and others are bird-specific Egg - Only one vitellogenin gene, whereas chicken has 3, but other mammals 0 - Formation of zona pellucida: 4 genes shared with other mammals + 2 ZPAX genes present only in birds, fishes, amphibians Milk Duplication/Cluster of 5 casein genes Venom Like in reptiles, cocktail of variations of 3 peptide families, but arose from duplications of different set of genes convergence with snake venom. Platypus genome: a patchwork of mammalian, reptilian and avian characters

  32. human X chicken Z X1 Y1 X2 Y2 X3 Y3 X4 Y4 X5 Y5 1 3 6 15 18 Sex chrom autosomes Sex Chromosomes Comparative Genomic : Platypus – Human - Chicken Veyrunes et al Genome Res 2008

  33. the 10 sex chromosomes of the platypus(5 Xs and 5 Ys) had no gene homology with the “mammalian” XY, while they did have substantial homology with the bird Z chromosome.

  34. W Z Gekko hokouensis 145My + jeune proto-X -Y Kawai et al Chromosoma 2008 proto-Z -W Sex chromosome evolution Mammals Snakes Birds Crocodilians Turtles Monotremes Marsupials Eutherians Lizards XY XY ZW ZW X Y W X W Z Y Z 245mya 150mya 220mya 165mya 270mya 285mya 310mya Veyrunes et al Genome Res 2008

  35. Is homology a relic of shared ancestry or just convergence? Do particular portions of genome make better sex chromosomes? Graves & Peichel Genome Biol 2010

  36. In Vertebrates, DMRT1 is expressed specifically in male gonads just after sex determination DMRT1 is homolog of the genes doublesex in Drosophila and mab-3 in C. elegans, both involved in the downstream events of sex differentiation DMRT1 is a critical gene near the top of the sex determination cascade in both vertebrates and invertebrates Mutations on DMRT1 induce sex reversal in human Review in Ferguson-Smith Sex Dev 2007

  37. In addition to DMRT1 (birds) and SRY (mammals) Smith et al Nature 2009 Sinclair et al Nature 1990 Only two other vertebrate sex determining genes are known: Both homologs of DMRT1 ! - DMY a duplicated copy of DMRT1 in the Medaka fish Matsuda et al. Nature 2002 Nanda et al PNAS 2002 - DM-W a truncated copy of DMRT1 in the frog Xenopus laevis Yoshimoto et al PNAS 2008 Repeated use of the same gene for sex determination Some parts of the genome may make better sex chromosomes

  38. The 10 platypus’ sex chromosomes do not share gene homology with the “mammal” X, but with the bird Z chromosome Two independent sex chromosome systems among mammals The human XY are 145My younger than previously thought. Consequences on rates of gene evolution and Y degeneration Platypus genome: genomic features of two separate lineages (mammals and sauropsids) coexist in a single organism Platypus sex determining gene remains unknown Conclusions Warren et al Nature 2008 Veyrunes et al Genome Res 2008

  39. I. Origin and Evolution of sex chromosomes in Vertebrates. II. The “weird” sex chromosome system of the platypus. III. New data from the complete sequencing genome of the platypus IV. Sex chromosomes and sex determination in African pygmy mice.

  40. Dicrostonyx torquatus Microtus oregoni Myopus schistocolor XO / XY XX, XY / XY Akodon sp. Mus minutoides Ellobius lutescens Ellobius tancrei XO / XO XX / XX Tokudaia osimensis

  41.  Genus :Mus (40 sp.) Laboratory mouse • Mus sensu stricto • Coelomys • Pyromys • Nannomys  Subgenera 19 sp. Sub-Saharan Africa Very low morphological differentiation (species-complexes) Chromosomal radiation involving in particular the sex chromosomes Biological Model: African pygmy mice

  42. The sex chromosomes of the African pygmy mice show three extraordinary deviations from the norm: Unusual meiotic behaviour Addition of genetic material on the sex chromosomes (multiple sex-autosome fusions) Modifications of sex determination systems

  43. During male meiosis, sex chromosomes must pair to ensure balanced gamete formation. However, in a very few species, the sex chromosomes do not pair (asynaptic). X X Y Y Mus mattheyi Mus minutoides 1 1 Y X Unusual meiotic behaviour Loss of the Pseudo-Autosomal Region ? How these species manage to ensure a proper segregation is still under discussion

  44. Extremely diverse among the Nannomys rare and deleterious among the mammals but… - Gametogenesis disruptions - Spreading of X-inactivation to autosome (silencing autosomal genes) X X Y Y 7 1 7 1 autosome Genome modif/plasticity allowing a higher rate of appearance/fixation of these fusions X chromosome 15 15 X X Human pathologic cases: 13 Y-autosome = azoospermia X-autosome = sterility + other symptoms (congenital malformations …) 13 Y 16 16 1 1 X Multiple sex-autosome fusions Sex-autosome fusions : a paradox … Multiple formations Neo-sex chromosomes Veyrunes et al Chrom Res 2004, 2007

  45. deleted X? Y XY XX XY Y mouse probe X X Y Very high proportion of fertile sex-reversed females Y 1 1 1 1 Mutanda 15 4 14 Belfast Kuruman Sandveld NR Sterkfontein NR Caledon NR Willem Pretorius NR Stellenbosch 24 11 23 Unexplained strong bias in favor of the XY females Modification of sex determining systems (1) Mus minutoides: Veyrunes et al Proc R Soc B 2010

  46. … but rather on a X-linked mutation Two morphologically different X chromosomes, one always associated to sex-reversed females Females are XX, XX* or X*Y, and Males only XY Male XY Female XX Female XX* Female X*Y asterisk designates the still unknown mutation converting X*Y individuals into females Novel sex determination system in a Therian species X X X X* X* Y Y 1 female XX female XX* female X*Y male XY Modification of sex determining systems (2) Sex reversal is probably not due to a mutation on SRY gene SRY sequencing = male & female have the same haplotype Veyrunes et al Proc R Soc B 2010

  47. + ovulation? Meiotic drive? Loss YY Reproductive Cost BREEDING PROGRAM Litter sizes & Offspring sex-ratio Consequences on mating system ? Evolutionary Processes: Impact on sex-ratio Population Dynamics, etc… Modification of sex determining systems (3) TEST ON CANDIDATE GENES Identification of the Mutation FIELD TRIPS Temporal survey in natural pop.

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