The evolution of the search for novel genes in mammalian sex determination: From mice to men

Abstract

Disorders of sex determination are a genetically heterogeneous group of rare disorders, presenting with sex-specific phenotypes and variable expressivity. Prior to the advent of the Human Genome Project, the identification of novel mammalian sex determination genes was hindered by the rarity of disorders of sex determination and small family sizes that made traditional linkage approaches difficult, if not impossible. This article reviews the revolutionary role of the Human Genome Project in the history of sex determination research and highlights the important role of inbred mouse models in elucidating the role of identified sex determination genes in mammalian sex determination. Next generation sequencing technologies has made it possible to sequence complete human genomes or exomes for the purpose of providing a genetic diagnosis to more patients with unexplained disorders of sex determination and identifying novel sex determination genes. However, beyond novel gene discovery, these tools have the power to inform us on more intricate and complex regulation-taking place within the heterogeneous cells that make up the testis and ovary.

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.