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The Origins of Sexual Dimorphism in the Mammalian Genome and Germline

Research Summary

David Page studies the genetic and developmental foundations of mammalian reproduction and sexual dimorphism. The two broad goals of his laboratory are to understand sex chromosome biology and evolution through comparative genomic sequencing in nine vertebrates and to elucidate the early development of eggs and sperm.

Most eukaryotes reproduce sexually: two haploid cells, or gametes, fuse to form a diploid that, through meiosis, gives rise to another generation of haploid cells, completing the life cycle. In most animals, including all mammals and birds, the gametes are of two types: large gametes, or oocytes, produced by diploids called females; and small gametes, or sperm, produced by diploids called males. In many animal species, the two diploid forms, or sexes, differ by one chromosome. In mammals, females are XX and males are XY. In birds, which are the closest living relatives of mammals, females are ZW and males are ZZ.

The ongoing, long-term objectives of our laboratory's research fall into three broad categories: sex chromosome genomics, evolution, and biology; germ cell development and sexual differentiation; and human reproductive disorders.

Sex Chromosome Genomics, Evolution, and Biology
Our goal is to better understand vertebrate sex chromosomes, including the male-specific Y chromosome of mammals, the female-specific W chromosome of birds, and their meiotic partners, the X and Z chromosomes, respectively. In 2003, in collaboration with the Genome Institute at Washington University, our lab completed the sequencing of the human MSY (male-specific region of the Y chromosome). This was the first sex-specific chromosome to be sequenced from any organism.

Because of the complex nature of the MSY, we developed a novel strategy, which we termed single-haplotype iterative mapping and sequencing (SHIMS), to assemble such intricately repetitive genomic regions. This exacting approach enabled us to produce an accurate and complete picture of the MSY's repetitive regions, which has yielded tremendous biological and medical insights. We recognized, however, that in order to more fully understand the nature of sex chromosomes, we must also similarly analyze the sex chromosomes of other mammals and birds. Therefore, we are in the process of sequencing the sex-specific chromosomes of seven other mammals and one bird, and we have expanded our team to include the Human Genome Sequencing Center at Baylor College of Medicine. Our ultimate goal is to systematically and comprehensively compare the human X and Y chromosomes with the sex chromosomes of these eight other species. This will enable us to reconstruct the course of sex chromosome evolution and gain further insight into the biological functions of Y chromosomes.

Germ Cell Development and Sexual Differentiation
Our goal is to learn, through genetic and molecular analysis of germ cell differentiation in the mammalian ovary and testis, how germ cells initiate the meiotic program and acquire a female or male identity (ultimately oocyte or sperm). Whether germ cells develop as oocytes or sperm appears to depend on the timing of meiotic initiation, which occurs embryonically in females and during puberty in males. Starting in the late 1990s, we have used the mouse as an experimental model to genetically dissect the process of meiotic initiation, which is a critical juncture in mammalian development, both female and male.

Our initial genetic insight came from the discovery that the Stra8 gene is required for meiotic initiation in germ cells of fetal ovaries. Rapid progress followed, including (1) the identification of retinoic acid (RA) as an extrinsic inducer of Stra8, (2) the discovery that RA and Stra8 govern meiotic initiation in postnatal testes, and (3) the discovery that the Dazl gene encodes a meiotic competence factor, enabling fetal germ cells to respond to the RA signal, express Stra8, and enter meiosis. Now that we have identified the critical players and a genetic regulatory network is beginning to emerge, we will probe meiotic initiation more deeply and test its connection to germ cell sexual identity.

Human Reproductive Disorders
Our goal is to translate basic knowledge gained through our analyses of sex chromosomes and germ cell development into a new understanding of human reproductive disorders, including male infertility, Turner syndrome, and sex reversal. Our analysis of the human MSY, together with our ongoing studies of human MSY variation, has brought a reassessment of the chromosome's architecture and genetic content and of its biological and medical significance. Knowledge of the MSY's elaborately mirrored structures, including eight massive palindromes, enabled the identification of five different interstitial MSY deletions, each recurring at different frequencies, that cause spermatogenic failure. We have also found that a high degree of MSY structural polymorphism exists among men, and one of these polymorphisms reduces sperm production and increases the risk of spermatogenic failure. At the most extreme end, aberrant recombination within the MSY's massive palindromes can generate mirror-image "isodicentric" Y chromosomes that contribute to not only spermatogenic failure but also Turner syndrome and sex reversal.

A grant from the National Human Genome Research Institute provides partial support for genomic studies of mammalian sex chromosomes.

As of November 05, 2012

Scientist Profile

Investigator
Whitehead Institute for Biomedical Research
Developmental Biology, Genetics