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Sex chromosome evolution in Vertebrates Institut des Sciences de lEvolution Department Genome Team Sex & Speciation CNRS / University Montpellier 2 Frédéric.

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Presentation on theme: "Sex chromosome evolution in Vertebrates Institut des Sciences de lEvolution Department Genome Team Sex & Speciation CNRS / University Montpellier 2 Frédéric."— Presentation transcript:

1 Sex chromosome evolution in Vertebrates Institut des Sciences de lEvolution Department Genome Team Sex & Speciation CNRS / University Montpellier 2 Frédéric VEYRUNES email: frederic.veyrunes@univ-montp2.fr 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 1 1091186 2345 12 15 7 1413161817 19222120XY X Y X X

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

5 The Human Y chromosome rapidly degenerates. Graves Cell 2006 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)

6 11/11 genes shared between Z and W (small sex-determining region) 3/11 genes shared between Z and W No genes shared between Z and W (W has lost most genes) PythonidaeColubridae Gradual degeneration of snake W chromosome (Matsubara et al PNAS 2006) Viperidae Z W Non-recombining region has remained small Large non- recombining region Ratite bird sex chromosomes are not evolving at the same rate than other birds (Nanda et al Cytogenet Genome Res 2008) 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)

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 The Y chromosome determines the male sex, regardless of which other chromosomes are present Female development: « default pathway » AT CONTRARY: The X chromosome 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 is a by-product of perverse evolution leading to its degeneration BUT…

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

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

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

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

13 All Therian mammals have the same sex chromosomes

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

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

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

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

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

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

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.

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23 Rens et al PNAS 2004 X1X4X2Y2Y3X3Y1Y5X5Y4 Karyotype 10 sex chromosomes !! X 1 Y 1 X 2 Y 2 X 3 Y 3 X 4 Y 4 X 5 Y 5 5 Ys: male-specific 5 Xs: in pairs in female Unprecedented sex chromosome system

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

25 absence SRY X1X4X2Y2Y3X3Y1Y5X5Y4 orthologues Mammalian X Watson et al PNAS 1990 An exceptional system (2) Déterminisme du sexe inconnu Grutzner et al Nature 2004 El Morghabel et al Genomics 2007 DMRT1 gene Avian Z X5 DMRT1 X5 DMRT1

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

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

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

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

30 Eutherians MarsupialsMonotremesBirdsCrocodiliansTurtlesSnakes Lizards 150mya 245mya 270mya 220mya 285mya 310mya 165mya Z W Z W X Y XY ZW XY ZW X Y proto X-Y Amniote sex chromosomes systems Mammals A link between the bird ZW and mammal XY systems ? Ezaz et al Current Biol 2006

31 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.

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

33 Platypus genome: a patchwork of mammalian, reptilian and avian characters 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.

34 Comparative Genomic : Platypus – Human - Chicken Veyrunes et al Genome Res 2008 Sex Chromosomes

35 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.

36 Eutherians MarsupialsMonotremesBirdsCrocodiliansTurtlesSnakes Lizards 150mya 245mya 270mya 220mya 285mya 310mya 165mya Z W Z W X Y XY ZW XY ZW X Y proto-Z-W proto-X-Y 145My + jeune Mammals Sex chromosome evolution Veyrunes et al Genome Res 2008 Z W Gekko hokouensis Kawai et al Chromosoma 2008

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

38 DMRT1 is homolog of the genes doublesex in Drosophila and mab-3 in C. elegans, both involved in the downstream events of sex differentiation Review in Ferguson-Smith Sex Dev 2007 In Vertebrates, DMRT1 is expressed specifically in male gonads just after sex determination 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

39 In addition to DMRT1 (birds) and SRY (mammals) Sinclair et al Nature 1990 Smith et al Nature 2009 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

40 Conclusions 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 Warren et al Nature 2008 Veyrunes et al Genome Res 2008

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42 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.

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

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

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

46 How these species manage to ensure a proper segregation is still under discussion Unusual meiotic behaviour 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 Loss of the Pseudo-Autosomal Region ? Mus minutoides X Y 1 1

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

48 deleted X? Y Y mouse probe Y 1 1 X Y X 1 1 Modification of sex determining systems (1) Mus minutoides: XY XX XY Very high proportion of fertile sex-reversed females Unexplained strong bias in favor of the XY females Stellenbosch Caledon NR Kuruman Belfast Willem Pretorius NR Mutanda Sterkfontein NR Sandveld NR 14 15 4 241123 Veyrunes et al Proc R Soc B 2010

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

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

51 Modification of sex determining systems (4) XXXX*X*Y 50% XX females 50% XY males 25% XX females 25% XX* females 25% X*Y females 25% XY males 25% XX* females 25% X*Y females 25% XY males 25% dead embryos 1:13:12:1 Complex meiotic configurations bivalent Ring of 4 Chain of 4 Y 1 13 16 X* 1616 13 1 1 X 1 X X 1 1 16 X* Selective pressures favouring such system? Different fitness for each type of female? Y 1 1 X 1 X 1 X 16 X* 16 X* Sex chromosomes How could explain the high prevalence of X*Y females ? In addition, in one pop., the X* has been translocated to another autosome 1 X* 16

52 Modification of sex determining systems (5) Mus triton in Burundi has been described with an XO / XO sex chromosome system (Jotterand-Bellomo 1988) Mus indutus, among five : three were XX, and two XO In addition to the standard XX / XY, and the new sex determining system described here: Maybe four different sex chromosome systems recorded within the African pygmy mice !!

53 But all new variants restricted to only one species Evolutionary cul-de-sac species ? Finally, a few mammal species have evolved to escape convention, and present aberrant sex chromosome systems


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