MinireviewThe evolution of the search for novel genes in mammalian sex determination: From mice to men
Introduction
Identifying the genetic origins of testis and ovarian determination is no easy task. Traditional linkage approaches for mapping disease genes required large families with multiple affected members. However, patients with disorders of sex development are sub- or infertile and therefore most families are too small to perform genetic linkage analysis. Some of the major breakthroughs relied on identification of karyotype abnormalities followed by positional cloning to identify the disrupted gene. Using this approach, SRY was identified as the gene responsible for initiating male sex determination in humans. As the human genome project evolved, it provided the tools to identify many of the important genes in sex development.
Disorders of sex development (DSD) constitute a rare set of genetic disorders in which the chromosomal, gonadal, and phenotypic sexes are incongruous. These disorders are extraordinarily stressful for both the child and parents and in the majority of cases the genetic etiology of the DSD remain unknown. To date, there exists little evidence-based data by which parents can make the difficult decisions regarding gender assignment, medical management, and surgery. The advent of next generation sequencing has identified many of the genes responsible for a variety of Mendelian traits, including those responsible for DSD. Genome sequencing will ultimately be central in the development of novel diagnostic tools and allow clinicians to personalize disease management. This review will cover the history of novel gene identification in sex determination and the future role of sequencing technology in personalized medicine for patients with DSD.
Section snippets
Mouse models of mammalian sex determination
Beyond the initial discovery of the testis-determination gene, SRY, in humans, the discovery of other novel sex determination genes was still limited by the size of the families, the rareness of these conditions, and access to fetal gonad tissue. To elucidate the complex interactions that result in the formation of a testis or an ovary, much of the work in identifying novel genes and understanding their interactions was done in inbred mouse strains. In the developing mouse there is easy access
The role of the human genome project on disorders of sex development
The early history of novel gene identification in sex development relied heavily on karyotype and in situ hybridization to identify regions of interest within the genome from which a gene could be positionally cloned. Through positional cloning of Yp translocations to the X-chromosome, the testis-determining gene on the Y-chromosome was identified as SRY, a homeobox gene [8]. This initial discovery paved the way for the discovery of a second gene in the SOX gene family, SOX9, in patients with
The future of sex determination research
Strategies to identify sex development genes have evolved alongside genomic technologies. Next generation sequencing is just the beginning of a new chapter in personalized medicine and sex development research. Sequencing the entire exome, and even the whole genome, in unexplained cases of DSD will continue to enlighten and broaden our understanding about both normal testis and ovarian development and patients who have disorders of sex development. However, the future of sex determination
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