The origin and evolution of vertebrate sex chromosomes and dosage compensation

Abstract

In mammals, birds, snakes and many lizards and fish, sex is determined genetically (either male XY heterogamy or female ZW heterogamy), whereas in alligators, and in many reptiles and turtles, the temperature at which eggs are incubated determines sex. Evidently, different sex-determining systems (and sex chromosome pairs) have evolved independently in different vertebrate lineages. Homology shared by Xs and Ys (and Zs and Ws) within species demonstrates that differentiated sex chromosomes were once homologous, and that the sex-specific non-recombining Y (or W) was progressively degraded. Consequently, genes are left in single copy in the heterogametic sex, which results in an imbalance of the dosage of genes on the sex chromosomes between the sexes, and also relative to the autosomes. Dosage compensation has evolved in diverse species to compensate for these dose differences, with the stringency of compensation apparently differing greatly between lineages, perhaps reflecting the concentration of genes on the original autosome pair that required dosage compensation. We discuss the organization and evolution of amniote sex chromosomes, and hypothesize that dosage insensitivity might predispose an autosome to evolving function as a sex chromosome.

Figure 1

Evolution of the eutherian sex chromosome differentiation and dosage compensation (X-chromosome inactivation). (a) One member of a pair of autosomes (the proto-Y) acquires a testis-determining factor (TDF). Male beneficial genes accumulate near this new TDF and recombination (represented by crosses) with the proto-X is suppressed. Most genes (two represented here; brown) remain in the pseudoautosomal region (PAR) and are expressed equally from the X and Y (brown ovals and diamonds represent products from different genes). In females, the two X-chromosome pair and recombine normally. (b) Recombination is further suppressed between the X and Y. In the absence of recombination, the proto-Y degrades, resulting in the loss of function of Y genes that can tolerate some haploinsufficiency (here represented by the gene expressing diamonds). In males, there is selection for upregulation of this gene from the single X (light green box behind the X) giving a gene dose of four. In females, the two X chromosomes express at this upregulated level, resulting in a gene dose of eight. The gene represented by the ovals cannot tolerate any decreased dosage, so is retained on the Y as a functional copy. (c) More upregulation of X genes in males occurs to restore gene dose to its original level of 6 (green box behind chromosome). In females, this gene is also upregulated on the X, which results in selection to downregulate the other X (pink box behind the chromosome). The gene that cannot tolerate dosage change (ovals) remains functional from its Y allele, but its prolonged retention on the Y gives it a chance to begin to acquire a male-specific function (light brown). (d) Further restriction of recombination leads to further degeneration of the Y and insertion of heterochromatin (grey). The Y copy of the gene producing ovals has gained a male-specific role (orange), and loses its original function. Overexpression of X genes in females (green box behind chromosome) results in complete transcriptional inactivation of homologous regions of the other X (red box behind chromosome). (e) An autosomal segment is added to both sex chromosomes (added to one and recombined onto the other), extending the PAR and contributing additional genes (gene product represented by brown hexagons). (f) Genes on the added segment are then differentiated or lost on the Y and the X copy is upregulated. The established inactivation mechanism can rapidly spread into the added region to compensate for Y gene loss and upregulation of the X in males.

Figure 2

Vertebrate relationships with estimated divergence dates (branch lengths not to scale). The sex chromosome systems observed in each lineage are shown (TSD=temperature-dependent sex determination). Orthology of sex chromosomes and autosomes is represented by different colours for representative mammals and birds. The orange regions represent an original ZW system in amniotes that has been retained on sex chromosomes in birds, a gekko and monotremes, or independently selected for sex chromosome function in these lineages. The green region became X and Y chromosomes only recently in therian mammals (marsupials and eutherians). The black region remains autosomal, except for eutherian mammals, in which it was added to the X and Y. A full color version of this figure is available at the Heredity journal online.