Genome-Wide Maps of Recombination and Chromosome Segregation in Human Oocytes and Embryos Show Selection for Maternal Recombination Rates

Abstract

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...

Meiotic Recombination: The Essence of Heredity

“…Diminished centromeric cohesion weakens the normally tight association of sister kinetochores, increasing the frequency and stability of aberrant sister biorientations on the meiosis-I spindle, thereby elevating the risk of premature separation of sister chromatids (Watanabe 2012;TachibanaKonwalski et al 2013). Angell inferred that premature separation of sister chromatids is the major route to nondisjunction (Angell 1991;Angell et al 1994), a proposal that is strongly supported by more recent studies (Pellestor et al 2003;Fragouli et al 2011;Handyside et al 2012;Hou et al 2013;Ottolini et al 2015). Unexpectedly, it appears that achiasmate homologs, which were predicted to undergo canonical meiosis-I nondisjunction, instead tend to biorient their sister chromatids on the meiosis-I spindle, thereby evading the spindle-assembly checkpoint (LeMaire-Adkins and Hunt 2000; Kouznetsova et al 2007;Nagaoka et al 2011;Ottolini et al 2015).…”

“…Angell inferred that premature separation of sister chromatids is the major route to nondisjunction (Angell 1991;Angell et al 1994), a proposal that is strongly supported by more recent studies (Pellestor et al 2003;Fragouli et al 2011;Handyside et al 2012;Hou et al 2013;Ottolini et al 2015). Unexpectedly, it appears that achiasmate homologs, which were predicted to undergo canonical meiosis-I nondisjunction, instead tend to biorient their sister chromatids on the meiosis-I spindle, thereby evading the spindle-assembly checkpoint (LeMaire-Adkins and Hunt 2000; Kouznetsova et al 2007;Nagaoka et al 2011;Ottolini et al 2015). The ensuing separation of sister chromatids at meiosis I is followed by segregation of nonsister chromatids at meiosis II in a process termed reverse meiosis (Ottolini et al 2015).…”

“…Mouse studies indicate that cohesion is not replenished during dictyotene (Revenkova et al 2010;Tachibana-Konwalski et al 2010) and that both cohesion subunits and factors that function to protect centromeric cohesion until meiosis II are depleted in older animals (Hodges et al 2005;Liu and Keefe 2008;Chiang et al 2010;Lister et al 2010;Shomper et al 2014;Yun et al 2014). Although definitive proof of analogous "cohesion exhaustion" in aging human oocytes has been harder to obtain, the weight of evidence suggests that this is the case (Angell 1991;Angell et al 1994;Pellestor et al 2003;Garcia-Cruz et al 2010;Fragouli et al 2011;Tsutsumi et al 2014;Ottolini et al 2015).…”

“…Moreover, the crossover rate appears to increase with advancing maternal age. Specifically, more crossovers are detected in children born to older mothers, implying that oocytes that give rise to viable offspring in older mothers tend to have more crossovers (Kong et al 2004;Coop et al 2008;Campbell et al 2015;Ottolini et al 2015). Extra crossovers are proposed to buffer against the effects of advancing maternal age, in particular, the erosion of sister-chromatid cohesion (discussed below).…”

“…Unexpectedly, it appears that achiasmate homologs, which were predicted to undergo canonical meiosis-I nondisjunction, instead tend to biorient their sister chromatids on the meiosis-I spindle, thereby evading the spindle-assembly checkpoint (LeMaire-Adkins and Hunt 2000; Kouznetsova et al 2007;Nagaoka et al 2011;Ottolini et al 2015). The ensuing separation of sister chromatids at meiosis I is followed by segregation of nonsister chromatids at meiosis II in a process termed reverse meiosis (Ottolini et al 2015). Aneuploidy may result from nondisjunction of the nonsister chromatids in meiosis II, whereas successful disjunction effectively rescues the original defect, producing a euploid ovum.…”