Induction of testis development in mammals requires the presence of the Y-chromosome gene SRY. This gene must exert its effect by interacting with other genes in the sex-determination pathway. Cloning of a translocation chromosome breakpoint from a sex-reversed patient with campomelic dysplasia, followed by mutation analysis of an adjacent gene, indicates that SOX9, an SRY-related gene, is involved in both bone formation and control of testis development.

The (9). The relationships between the SR Y and SOX genes are obviously of interest in considering the origin and evolution of the SRY gene in mammals.Marsupials diverged from eutherian (placental) mammals 120-150 million years ago and monotremes (egg-laying mammals) diverged even earlier, so that comparisons between these three major mammalian groups may provide information about the function and early evolution of mammalian sex chromosomes and sex-determining genes. Eutherian, marsupial, and monotreme sex chromosomes have been found to differ in size and gene content, enabling the different evolutionary origins of regions of the human sex chromosomes to be deduced. The genes on the long arm and proximal short arm of the human X chromosome are present on the X chromosome in marsupial and monotreme mammals, and this region, therefore, represents a conserved, probably original, mammalian X chromosome (10,11). The marsupial and monotreme X chromosome lacks genes borne on the short arm of the human X chromosome, suggesting that this region was originally autosomal and was added later to the eutherian X chromosome. The presence of several genes in this region with homologues on the Y chromosome implies that the region was added to both X and Y chromosomes, probably by recombination within an original pseudoautosomal region (10,12). In marsupials, as in eutherian mammals, the Y chromosome is testis determining, but at least some sexual dimorphisms are sex hormone independent and seem to be a function of X chromosome dosage, rather than the presence or absence of a Y chromosome (13).We have isolated an SR Y-related sequence from the marsupial X chromosome, which is closely homologous to the mouse and human SOX3 gene. This raises the possibility that X chromosome inactivation or gene dosage may play a role in sex determination in marsupials. However, we suggest that a more likely explanation for the presence of SR Y homologues on marsupial, mouse, and human X chromosomes is that SOX3 and SRY were originally alleles of a developmentally important gene shared by partly differentiated ancestral X and Y chromosomes. MATERIALS AND METHODSWe used two marsupial species, representing the two major Australian orders that diverged about 50 million years ago, the striped-faced dunnart Sminthopsis macroura (Order Polyprotodonta, Family Dasyuridae) and the Tammar wallaby Macropus eugenii (Order Diprotodonta, Family Macropodidae). Tissue was originally provided by

In mammals, testis determination is under the control of the testis-determining factor borne by the Y chromosome. SRY, a gene cloned from the sex-determining region of the human Y chromosome, has been equated with the testis-determining factor in man and mouse. We have used a human SRY probe to identify and clone related genes from the Y chromosome of two marsupial species. Comparisons of eutherian and metatherian Y-located SRY sequences suggest rapid evolution of these genes, especially outside the region encoding the DNA-binding HMG box. The SRY homologues, together with the mouse Ube1y homologues, are the first genes to be identified on the marsupial Y chromosome.

The island of Sardinia shows a unique high incidence of several autoimmune diseases with multifactorial inheritance, particularly type 1 diabetes and multiple sclerosis. The prior knowledge of the genetic structure of this population is fundamental to establish the optimal design for association studies in these diseases. Previous work suggested that the Sardinians are a relatively homogenous population, but some reports were contradictory and data were largely based on variants subject to selection. For an unbiased assessment of genetic structure, we studied a combination of neutral Y-chromosome variants, 21 biallelic and 8 short tandem repeats (STRs) in 930 Sardinian males. We found a high degree of interindividual variation but a homogenous distribution of the detected variability in samples from three separate regions of the island. One haplogroup, I-M26, is rare or absent outside Sardinia and is very common (0.37 frequency) throughout the island, consistent with a founder effect. A Bayesian full likelihood analysis (BATWING) indicated that the time from the most recent common ancestor (TMRCA) of I-M26, was 21.0 (16.0–25.5) thousand years ago (KYA) and that the population began to expand 14.0 (7.8–22.0) KYA. These results suggest a largely pre-Neolithic settlement of the island with little subsequent gene flow from outside populations. Consequently, Sardinia is an especially attractive venue for case-control genome wide association scans in common multifactorial diseases. Concomitantly, the high degree of interindividual variation in the current population facilitates fine mapping efforts to pinpoint the aetiologic polymorphisms.

Sexual differentiation in placental mammals results from the action of a testis-determining gene encoded by the Y chromosome. This gene causes the indifferent gonad to develop as a testis, thereby initiating a hormonal cascade which produces a male phenotype. Recently, a candidate for the testis-determining gene (ZFY, Y-borne zinc-finger protein) has been cloned. The ZFY probe detects a male-specific (Y-linked) sequence in DNA from a range of eutherian mammals, as well as an X-linked sequence (ZFX) which maps to the human X chromosome. In marsupials it is also the Y chromosome that seems to determine the fate of the gonad, but not all sexual dimorphisms. Using the ZFY probe we find, surprisingly, that the ZFY homologous sequences are not on either the X or the Y chromosome in marsupials, but map to the autosomes. This implies ZFY is not the primary sex-determining gene in marsupials. Either the genetic pathways of sex determination in marsupials and eutherians differ, or they are identical and ZFY is not the primary signal in human sex determination.

The human testis determining factor (SRY) has been cloned from the Y chromosome. This gene is a dominant inducer of male differentiation. Mutations in the SRY gene result in an XY individual developing as a sex reversed phenotypic female. Sex reversal in humans can also be caused by mutations located in autosomal or X-linked loci. One such sex-reversing locus (SRAI) is associated with the developmental disorder campomelic dysplasia (CD). Both these syndromes were mapped to human chromosome 17q by the identification of balanced reciprocal translocations in five unrelated patients. The translocation breakpoint of one such XY-female CD patient was mapped and the region surrounding it cloned. The closest distal marker used to map the translocation breakpoint was the SOX9 gene. Because of the close proximity of this gene to the breakpoint, it was subjected to mutation analysis in patients without overt chromosome rearrangements. Analysis of DNA from these patients and their parents identitied de novo mutations in the SOX9 gene in patients with both autosomal sex reversal and CD. This showed that mutations in the SOX9 gene are responsible for both syndromes.

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