Function of the sex chromosomes in mammalian fertility

Abstract

The sex chromosomes play a highly specialized role in germ cell development in mammals, being enriched in genes expressed in the testis and ovary. Sex chromosome abnormalities (e.g., Klinefelter [XXY] and Turner [XO] syndrome) constitute the largest class of chromosome abnormalities and the commonest genetic cause of infertility in humans. Understanding how sex-gene expression is regulated is therefore critical to our understanding of human reproduction. Here, we describe how the expression of sex-linked genes varies during germ cell development; in females, the inactive X chromosome is reactivated before meiosis, whereas in males the X and Y chromosomes are inactivated at this stage. We discuss the epigenetics of sex chromosome inactivation and how this process has influenced the gene content of the mammalian X and Y chromosomes. We also present working models for how perturbations in sex chromosome inactivation or reactivation result in subfertility in the major classes of sex chromosome abnormalities.

Figure 1.

The mechanisms by which errors in meiosis give rise to chromosome abnormalities. (A) During normal male meiosis, the X and Y chromosomes synapse and crossover within the distal pseudoautosomal region; this crossover is essential in ensuring normal homologous segregation during the first meiotic division (MI). The resulting secondary spermatocytes then enter the second meiotic division (MII), during which sister chromatids segregate, thereby generating four haploid products each containing a single sex chromosome. (B) Nondisjunction of the two Y sisters to segregate at MII results in YY spermatids; these give rise to XYY sons at fertilization. (C) Nondisjunction of X and Y homologs to segregate at MI, either because of failed establishment or maintenance of crossing over, followed by normal sister separation at MII results in XY spermatids; these give rise to XXY sons at fertilization. (D) Formation of a DNA double-strand break in one of two Y sister chromatids followed by crossing over between palindromes of sisters results in an isodicentric Y chromosome. This forms a bipolar attachment during cell division and is subsequently broken and lost. In principle, this form of recombination could take place during spermatogonial mitosis, meiosis, or even in the early embryo; all of which will give rise to XO daughters. (E) During normal female meiosis, synapsis and crossover formation are followed by dictyate arrest. The first meiotic division at puberty generates a polar body and a secondary oocyte; the second at fertilization generates a second polar body and a single haploid product. (F) Nondisjunction of either homologs at MI or sisters at MII has similar effect, with haploid products with no sex chromosome (“O” gametes) generated. These generate XO daughters at fertilization. (G) Similar meiotic errors give rise to XX haploid products and thereafter XXY sons; the outcome depends on whether the nondisjoined chromosomes end up in the oocyte or the polar body. Although not detailed here, some cases of XXY and XYY arise during embryogenesis as a result of mitotic nondisjunction of the maternally inherited X and paternally inherited Y, respectively.

Figure 2.

Sex chromosome activity during female and male germ cell development. Female PGCs have one inactive and one active X chromosome. X chromosome reactivation occurs during migration of PGCs to the genital ridge between E7.5 and E9.5; full reactivation is achieved after colonization of the genital ridge between E10 and E11.5 in response to an unknown secreted factor/s. Female germ cells then enter meiosis. Meiotic DNA replication (S-phase) is followed by leptotene (E13.5) when DNA DSBs are formed. Chromosomes initiate synapsis during zygotene (E14) and the completion of synapsis heralds the onset of pachytene (E15.5). Throughout and after meiosis the X chromosomes remain active. In males, the X and Y are active in male throughout early germ cell development. In contrast to females, male germ cells undergo mitotic arrest from E13.5 to E14.5 until shortly after birth, when the spermatogonial divisions begin. The X and Y remain active until pachytene, when meiotic sex chromosome inactivation (MSCI) takes place. After meiosis, mean expression from the X chromosome remains low compared to autosomes, but at this stage genes are not silenced as completely as they are during pachytene.

Figure 3.

A model for germ cell arrest in sex chromosome aneuploid conditions. In XO females, XCI does not take place during early development, the X chromosome is therefore active until pachytene. At this stage, the unsynapsed state of the X chromosome triggers meiotic silencing; the resulting inactivation of X-linked genes leads to pachytene arrest. In XXY males, the presence of two X chromosomes initiates random XCI in the epiblast; PGCs therefore have one inactive X. The exact timing of X chromosome reactivation during germ cell development is unclear, but may follow similar kinetics to that in XX females. The resulting double dose of X-linked gene expression causes spermatogonial arrest. In XYY males, all three sex chromosomes are active until pachytene. At this stage, the X chromosome undergoes MSCI because it is unsynapsed. However, the two Y chromosomes undergo synapsis and therefore escape silencing; the resulting sustained expression of Y-linked genes is toxic and leads to pachytene arrest.