The genomic and genetic basis of mammalian sexual reproduction : sequence of the mouse Y chromosome, and a gene regulatory program for meiotic prophase

Abstract

Mammalian sexual reproduction requires sexual determination, sexual differentiation, and the production of haploid gametes. In this thesis, I examined the genomic evolution of the mouse Y chromosome, which instructs sexual determination, and genetic regulation of a program of gene expression for meiosis, a specialized cell cycle which gives rise to haploid gametes. Chapter 2 describes the study of the mouse Y chromosome. Contrary to popular theory that Y chromosomes should be degenerate and gene poor, we find that the mouse male-specific region of the Y chromosome (MSY) is almost entirely euchromatic and contains about 700 protein-coding genes. Almost all of these genes belong to three acquired, massively amplified gene families that have no homologs on primate MSYs but do have acquired, amplified homologs on the mouse X chromosome. We propose that lineage-specific convergent acquisition and amplification of X-Y gene families is a result of sex-linked meiotic drive. Chapter 3 describes the gene regulatory program of meiotic prophase. Meiotic prophase comprises a complex chromosomal program results in the production of haploid gametes. This must be supported by a program of gene expression via which the required genes are induced. We interrogated gene expression in fetal ovaries over time and space, and in mutants of Dazl and Stra8 - key genes required for meiotic initiation. We determined that genes are regulated in three classes. Class 1 genes are expressed independently of Stra8, class 2 genes are expressed partially independently of Stra8, and Class 3 genes are dependent on Stra8 to be expressed. All genes require Dazl to be expressed. We propose that the Stra8-independent genes may represent genes required to be expressed prior to or early during meiotic initiation. Following initiation of meiosis, we found that Stra8 is required to induce down-regulation of its own expression. We propose that induction of down-regulation of the initiating signal by itself serves to ensure timely cessation of and one-time activation of the chromosomal program of meiotic prophase.