Crossover recombination reshuffles genes and prevents errors in segregation that lead to extra or missing chromosomes (aneuploidy) in human eggs, a major cause of pregnancy failure and congenital disorders. Here, we generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female meioses. Genotyping > 4 million informative single-nucleotide polymorphisms (SNPs) from 23 complete meioses allowed us to map 2,032 maternal and 1,342 paternal crossovers and to infer the segregation patterns of 529 chromosome pairs. We uncover a novel reverse chromosome segregation pattern in which both homologs separate their sister chromatids at meiosis I; detect selection for higher recombination rates in the female germline by the elimination of aneuploid embryos; and report chromosomal drive against non-recombinant chromatids at meiosis II. Collectively, our findings reveal that recombination not only affects homolog segregation at meiosis I but also the fate of sister chromatids at meiosis II.

Chromosome errors, or aneuploidy, affect an exceptionally high number of human conceptions, causing pregnancy loss and congenital disorders. Here, we have followed chromosome segregation in human oocytes from females aged 9 to 43 years and report that aneuploidy follows a U-curve. Specific segregation error types show different age dependencies, providing a quantitative explanation for the U-curve. Whole-chromosome nondisjunction events are preferentially associated with increased aneuploidy in young girls, whereas centromeric and more extensive cohesion loss limit fertility as women age. Our findings suggest that chromosomal errors originating in oocytes determine the curve of natural fertility in humans.

Crossing over establishes connections between homologous chromosomes that promote their proper segregation at the first meiotic division. However, there exists a backup system to ensure the correct segregation of those chromosome pairs that fail to cross over. We have found that, in budding yeast, a mutation eliminating the synaptonemal complex protein, Zip1, increases the meiosis I nondisjunction rate of nonexchange chromosomes (NECs). The centromeres of NECs become tethered during meiotic prophase, and this tethering is disrupted by the zip1 mutation. Furthermore, the Zip1 protein often colocalizes to the centromeres of the tethered chromosomes, suggesting that Zip1 plays a direct role in holding NECs together. Zip3, a protein involved in the initiation of synaptonemal complex formation, is also important for NEC segregation. In the absence of Zip3, both the tethering of NECs and the localization of Zip1 to centromeres are impaired. A mutation in the MAD3 gene, which encodes a component of the spindle checkpoint, also increases the nondisjunction of NECs. Together, the zip1 and mad3 mutations have an additive effect, suggesting that these proteins act in parallel pathways to promote NEC segregation. We propose that Mad3 promotes the segregation of NECs that are not tethered by Zip1 at their centromeres.

SummaryDefects in segregation lead to missing or lacking chromosomes (aneuploidy) in human eggs, a major cause of pregnancy failure and congenital disorders. Physical exchanges (crossovers) between homologous chromosomes are formed during foetal development and ensure that the pair remains tethered until their separation decades later in the meiotic divisions in adult oocytes. Here, we generate genome-wide maps of crossovers and chromosome segregation patterns by recovering all three products of single female meioses (embryo or oocytes and corresponding polar bodies). Genotyping > 4 million informative single-nucleotide polymorphisms (SNPs) from 23 complete meioses allowed us to map 2,032 maternal and 1,342 paternal crossovers and to infer the segregation patterns from 529 chromosome pairs.We uncover a novel reverse chromosome segregation pattern in which both homologs separate their sister chromatids at meiosis I; detect selection for higher recombination rates in the female germline by the elimination of aneuploid embryos; and report chromosomal drive against non-recombinant chromatids at meiosis II. Collectively, our findings reveal that recombination not only affects homolog segregation at meiosis I but also the fate of sister chromatids at meiosis II.3 Main text.Errors in chromosome segregation during the meiotic divisions in human female meiosis are a major cause of aneuploid conceptions, leading to implantation failure, pregnancy loss, and congenital disorders 1 . The incidence of human trisomies increases exponentially in women from ~ 35 years of age, but despite conservative estimates that 10-30% of natural conceptions are aneuploid 2 , the underlying causes and their relative contributions are still unclear. In addition to maternal age, one important factor that is hypothesized to predispose to missegregation in both sexes is altered recombination. Recombinant chromosomes in the offspring are the result of crossovers, the reciprocal exchange of DNA between homologous chromosomes (homologs). Together with sister chromatid cohesion, crossovers physically link the homolog pair together during the prophase stage of meiosis (Fig. 1a), which takes place during foetal development in females. The linkages have to be maintained for decades, because the two rounds of chromosome segregation only occur in the adult woman. By following the pattern of genetic markers such as single nucleotide polymorphisms (SNPs) on the two chromosomes inherited from the mother in trisomic conceptions, it has been inferred that some crossovers occur too close to centromeres 1,3-6 , where they may disrupt the cohesion between the two sister chromatids 7,8 . Other crossovers have been suggested to be too far from the centromeres to mediate correct attachment, or to be lacking altogether (non-exchange, E 0 ) 1,3-6 . If these inferences are correct, it follows that events that shape the recombination landscape in oocytes during foetal development of women affect their risk of having an aneuploid conception decades later in adult lif...