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Prophase 2 definition4/6/2023 Data from these cases indicate that all except trisomy 16 (the most common chromosomal cause of miscarriage) occur at very low frequency (<5%) up until the age of ∼35 yr and then increase to varying extents thereafter ( Nagaoka et al. Some segregation errors, notably those resulting in trisomy 13, 15, 16, 18, or 21, can develop to later stages. These manifest clinically as failed implantation, resulting in infertility. 2013), most errors are not compatible with development of embryos beyond the earliest stages. Although all autosomal chromosomes are susceptible to missegregation during female meiosis ( Handyside 2012 Fragouli et al. The vast majority of meiotic errors detected in human pregnancies result from errors in female meiosis, whereas <5% are a result of errors in male meiosis ( Hassold and Hunt 2001). This necessitates a specialized cell division known as meiosis, in which haploid gametes are generated from diploid precursors. The formation of a diploid embryo requires that sperm and egg contribute exactly one copy of each chromosome. This has major implications for human reproductive health, especially in developed economies in which there is an increasing trend for women to delay childbearing until after the age of 35 ( Schmidt et al. However, menopause is preceded by a sharp increase in the incidence of infertility, miscarriage, and birth defects (notably Down’s syndrome, trisomy 21) from the mid-30s onward ( Hassold and Hunt 2001 Nagaoka et al. Menopause typically occurs around the age of 50 yr and is remarkably consistent among diverse populations ( Lambalk et al. This culminates in the menopause when the population of oocytes dwindles to ∼1000 and the hormonal triggers controlling the reproductive cycle cease to function, resulting in cessation of ovulation ( te Velde et al. First, the stock of germ cells (oocytes) present in the ovary at birth (approximately one million) becomes depleted throughout life. According to our current understanding, female reproductive lifespan is curtailed by two forces. ![]() ![]() Human female fertility declines markedly during the fourth decade of life, resulting in an extended postreproductive lifespan. Here, we propose a mechanistic framework to reconcile data from genetic studies on human trisomy and oocytes with recent advances in our understanding of the molecular mechanisms of chromosome segregation during meiosis in model organisms. Consistent with this, premature loss of centromeric cohesion is a major source of aneuploidy in oocytes from older women. In mouse oocytes, cohesin becomes depleted from chromosomes during female aging. ![]() Bivalent chromosomes are stabilized by cohesion between sister chromatids, which is mediated by the cohesin complex. Extending this period beyond ∼35 years greatly increases the risk of aneuploidy in human oocytes, resulting in a dramatic increase in infertility, miscarriage, and birth defects, most notably trisomy 21. In female mammals, bivalents are formed during fetal life and remain intact until shortly before ovulation. These are resolved to their four constituent chromatids during two meiotic divisions. In most organisms, genome haploidization requires reciprocal DNA exchanges (crossovers) between replicated parental homologs to form bivalent chromosomes.
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