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Chromosome Res
2012 Jan 01;201:139-51. doi: 10.1007/s10577-011-9265-9.
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Molecular evolution of vertebrate sex-determining genes.
Mawaribuchi S
,
Yoshimoto S
,
Ohashi S
,
Takamatsu N
,
Ito M
.
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Y-linked Dmy (also called dmrt1bY) in the teleost fish medaka, W-linked Dm-W in the African clawed frog (Xenopus laevis), and Z-linked Dmrt1 in the chicken are all sex chromosome-linked Dmrt1 homologues required for sex determination. Dmy and Dm-W both are Dmrt1 palalogues evolved through Dmrt1 duplication, while chicken Dmrt1 is a Z-linked orthologue. The eutherian sex-determining gene, Sry, evolved from an allelic gene, Sox3. Here we analyzed the exon-intron structures of the Dmrt1 homologues of several vertebrate species through information from databases and by determining the transcription initiation sites in medaka, chicken, Xenopus, and mouse. Interestingly, medaka Dmrt1 and Dmy and Xenopus Dm-W and Dmrt1 have a noncoding-type first exon, while mouse and chicken Dmrt1 do not. We next compared the 5'-flanking sequences of the Dmrt1 noncoding and coding exons 1 of several vertebrate species and found conservation of the presumptive binding sites for some transcription factors. Importantly, based on the phylogenetic trees for Dmrt1 and Sox3 homologues, it was implied that the sex-determining gene Dmy, Dm-W, and Sry have a higher substitution rate than thier prototype genes. Finally, we discuss the evolutionary relationships between vertebrate sex chromosomes and the sex-determining genes Dmy/Dm-W and Sry, which evolved by neofunctionalization of Dmrt1 and Sox3, respectively, for sex determining function. We propose a coevolution model of sex determining gene and sex chromosome, in which undifferentiated sex chromosomes easily allow replacement of a sex-determining gene with another new one, while specialized sex chromosomes are restricted a particular sex-determining gene.
Fig. 1. Exon–intron structures of Dmrt1 orthologues and its paralogous sex-determining genes Dmy and Dm-W in vertebrates. The number shows the size (bp) of each exon. Noncoding exon 1 is shown as a blue box; other noncoding and coding regions in exons are shown as white and gray boxes, respectively. The locations of DM domains, male-specific motifs, and P/S (proline/serine)-rich regions are indicated by orange, green, and purple boxes, respectively. Medaka, Oryzias latipes; Frog (Xl), Xenopus laevis; Frog (Xt), Xenopus (Silurana) tropicalis; Chicken, Gallus gallus; Platypus, Ornithorhynchus anatinus; Opossum, Monodelphis domestica; Mouse, Mus musculus; Human, Homo sapiens
Fig. 2. Comparisons of the 5′-flanking regions among several vertebrate Dmrt1 homologues using mVISTA. Graphs were constructed using the AVID alignment program. Numbers with minus sign correspond to bp upstream of the transcription start site (+1). a Comparison of the first 500 bp of the mouse or chicken Dmrt1 promoter sequence, located upstream of the coding exon 1, with that of human DMRT1. b Comparison of the first 500 bp of the frog (Xl) Dmrt1α, frog (Xl) Dm-W, medaka Dmrt1, or medaka Dmy promoter sequence, located upstream of the noncoding exon 1, with that of frog (Xt) Dmrt1. c Comparison of the medaka Dmy 5′-flanking region with the first 500 bp of medaka Dmrt1. The 8-kb 5′-flanking region of the transcription initiation site of medaka Dmy was used, and the homologous regions are shown. d Comparison of the 2-kb region between the 3′-flanking region of kank1 and the 5′-flanking region of Dmrt1, a region conserved in several vertebrate species. The graph was constructed in comparison to the human 2-kb sequence. The locations of the conserved regions are shown in Supplementary Table 1. Dog, Canis lupus familiaris; Lizard, Anolis carolinensis
Fig. 3. Comparisons of substitution rates among Dmy, Dm-W, and their prototype gene Dmrt1. The phylogenetic trees were constructed from three groups of medaka and O. marmoratus (Om) as an outgroup (a) or three species of Xenopus and Bufo marinus (Bm) as an outgroup (b), using the maximum likelihood method based on the Tamura 3-parameter model with 4 discrete gamma distribution categories (a) or Kimura 2-parameter model (b). The three trees of each panel were derived from the DM domain region (upper), the non-DM domain region (middle), and their combined region (lower). The number shows the branch length, which was defined as the number of nucleotide substitutions per site for the branch. The substitution rates of Dmy or Dm-W and their prototype gene Dmrt1 (right side of each panel) were calculated using the branch lengths from the position of their common ancestor (white block) to the branch tip corresponding to each gene (gray block). Bootstrap percentage values of 500 replications are shown in bold above the node. Dmy and Dm-W diverged from the their prototype genes 10 and 13–64 million years ago, respectively (Kondo et al. 2004; Bewick et al. 2011). *An average of the substitution rates of sex-determining genes or thier prototype gene. Ol, O. latipes; Xl, X. laevis; Xa, X. andrei; Xi, X. itombwensis
Fig. 4. Comparisons of substitution rates among a sex-determining gene Sry and its prototype gene Sox3. The phylogenetic trees were constructed from the HMG domain regions of Sox3 and Sry (a) in four species of primates and Ornithorhynchus anatinus (Oa) as an outgroup, Sox3 (b) or Sry (c) in three species of primates and Macaca mulatta (Mm) as an outgroup, using the maximum likelihood method based on the Kimura 2-parameter model (a), Hasegawa-Kishino-Yano model (b), or the Kimura 2-parameter model (c). The three trees in (b) and (c) were derived from the HMG domain region (upper), the non-HMG domain region (middle), and their combined region (lower). Calculations of the substitution rates were performed as described in Fig. 3. Sry diverged from the prototype genes 148â166 million years ago (Marques-Bonet et al. 2009). A common ancestor of Homo. sapiens, Pan. troglodytes, and Nomascus leucogenys diverged from M. mulatta 18 million years ago (Marques-Bonet et al. 2009). Hs, H. sapiens; Pt, Pan troglodytes; Nl, Nomascus leucogenys
Fig. 5. Proposed model for evolutionary relationships between the appearance of sex-determining genes (SDGs) and sex chromosomes in vertebrates. First, a candidate SDG emerges or evolves on one chromosome of a pair of autosomes by insertion or mutation. Then, the candidate gene may be established as an SDG during species divergence with few morphological changes in the two chromosomes, in cases like that of the heterogametic XY or ZW sex chromosomes in the teleost fish medaka (O. latipes) carrying the Y-linked SDG Dmy, or the African clawed frog (X. laevis) carrying the W-linked SDG Dm-W, respectively. If the new SDG emerges as a stronger regulator for sex determination, the original SDG or its candidate might degenerate into a psuedogene, as in the case of sex determination in O. luzonensis, which is closely related to the medaka species. In contrast, if an SDG strongly contributes to the stability of a sex-determining system during species divergence, differentiation of the sex chromosomes might be allowed, leading to specialization of the heterogametic sex chromosomes and to stabilization of the SDG. This might be the case for the heterogametic XY sex chromosomes in eutherian mammals carrying the Y-linked SDG, Sry
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