title: Meiosis and maternal aging: insights from aneuploid oocytes and trisomy births.
abstract: In most organisms, genome haploidization requires reciprocal DNA exchanges (crossovers) between replicated parental homologs to form bivalent chromosomes. These are resolved to their four constituent chromatids during two meiotic divisions. In female mammals, bivalents are formed during fetal life and remain intact until shortly before ovulation. 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. Bivalent chromosomes are stabilized by cohesion between sister chromatids, which is mediated by the cohesin complex. In mouse oocytes, cohesin becomes depleted from chromosomes during female aging. Consistent with this, premature loss of centromeric cohesion is a major source of aneuploidy in oocytes from older women. 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.
authors.affiliation: Newcastle Fertility Centre, Centre for Life, Times Square, Newcastle upon Tyne NE1 4EP, United Kingdom Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom.
authors.forename: Mary
authors.initials: M
authors.lastname: Herbert
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Kalleas
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom.
authors.forename: Daniel
authors.initials: D
authors.lastname: Cooney
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom.
authors.forename: Mahdi
authors.initials: M
authors.lastname: Lamb
authors.affiliation: Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom.
authors.forename: Lisa
authors.initials: L
authors.lastname: Lister
mesh_terms: D000375:Aging / Q000502:physiology*; D000782:Aneuploidy; D000818:Animals; D020090:Chromosome Segregation; D022004:Chromosome Structures / Q000502:physiology; D006801:Humans; D008423:Maternal Age; D008540:Meiosis; D009865:Oocytes / Q000502:physiology*; D009866:Oogenesis; D014314:Trisomy
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