Aging Predisposes Oocytes to Meiotic Nondisjunction When the Cohesin Subunit SMC1 Is Reduced Vijayalakshmi V. Subramanian, Sharon E. Bickel* Department of Biological Sciences, Dartmouth College, Hanover, New Hampshire, United States of America Abstract In humans, meiotic chromosome segregation errors increase dramatically as women age, but the molecular defects responsible are largely unknown. Cohesion along the arms of meiotic sister chromatids provides an evolutionarily conserved mechanism to keep recombinant chromosomes associated until anaphase I. One attractive hypothesis to explain age- dependent nondisjunction (NDJ) is that loss of cohesion over time causes recombinant homologues to dissociate prematurely and segregate randomly during the first meiotic division. Using Drosophila as a model system, we have tested this hypothesis and observe a significant increase in meiosis I NDJ in experimentally aged Drosophila oocytes when the cohesin protein SMC1 is reduced. Our finding that missegregation of recombinant homologues increases with age supports the model that chiasmata are destabilized by gradual loss of cohesion over time. Moreover, the stage at which Drosophila oocytes are most vulnerable to age-related defects is analogous to that at which human oocytes remain arrested for decades. Our data provide the first demonstration in any organism that, when meiotic cohesion begins intact, the aging process can weaken it sufficiently and cause missegregation of recombinant chromosomes. One major advantage of these studies is that we have reduced but not eliminated the SMC1 subunit. Therefore, we have been able to investigate how aging affects normal meiotic cohesion. Our findings that recombinant chromosomes are at highest risk for loss of chiasmata during diplotene argue that human oocytes are most vulnerable to age-induced loss of meiotic cohesion at the stage at which they remain arrested for several years. Citation: Subramanian VV, Bickel SE (2008) Aging Predisposes Oocytes to Meiotic Nondisjunction When the Cohesin Subunit SMC1 Is Reduced. PLoS Genet 4(11): e1000263. doi:10.1371/journal.pgen.1000263 Editor: R. Scott Hawley, Stowers Institute for Medical Research, United States of America Received July 14, 2008; Accepted October 16, 2008; Published November 14, 2008 Copyright: 2008 Subramanian, Bickel. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Funding for this work was initially provided by March of Dimes (5-FY98-738) and continued with funding from National Institutes of Health (GM-59354) awarded to SEB. These sponsors made only financial contributions. Competing Interests: The authors have declared that no competing interests exist. * E-mail: sharon.e.bickel@dartmouth.edu Introduction In humans, meiotic chromosome segregation errors that give rise to aneuploid gametes are the leading cause of fetal loss and birth defects [1]. Approximately 30% of miscarriages result from aneuploidy and at least 5% of all clinically recognized pregnancies and 0.3% of live-borns are aneuploid [1]. Female meiosis in humans is especially error-prone and the majority of segregation errors in oocytes originate during meiosis I [1,2]. The link between increased maternal age and meiotic segregation defects in humans is well established. At maternal age 25, the risk of a trisomic pregnancy is approximately 2% but increases to approx- imately 35% for a woman at age 42 [3]. Despite its clinical importance, the specific mechanisms that give rise to age-dependent meiotic nondisjunction (NDJ) are not understood. The prevailing theory is that segregation errors in older oocytes arise in large part because of the protracted prophase I arrest at which human oocytes remain suspended for decades [1,4]. Accurate segregation during meiosis I requires that homologous chromosomes undergo recombination and remain physically attached to one another until they segregate to opposite poles during anaphase I. In the absence of a stable connection, homologues will segregate randomly resulting in meiosis I NDJ. Cohesion between the arms of sister chromatids provides an evolutionarily conserved mechanism for maintaining the associa- tion of recombinant homologues (Figure 1). Normally, the release of arm cohesion at anaphase I allows recombinant homologues to segregrate to opposite poles [5,6]. In the absence of cohesion, chiasmata are not maintained and homologous chromosomes missegregate during meiosis I [5,7,8]. Given that human oocytes undergo meiotic recombination during fetal development and remain suspended in a prolonged dictyate (diplotene) arrest until ovulation, the continuous associ- ation of homologous chromosomes demands that meiotic sister- chromatid cohesion remain intact for decades. One attractive hypothesis to explain age-dependent NDJ is that deterioration of cohesion with age causes recombinant homologues to dissociate prematurely and segregate randomly during the first meiotic division (Figure 1). However, testing this hypothesis in humans presents several insurmountable challenges. Using Drosophila as a model system, we have developed an experimental regimen to study the mechanisms that contribute to increased levels of meiotic NDJ in oocytes as a result of aging [9]. The Drosophila ovary is composed of several ovarioles, each of which contains a linear array of oocytes at progressive stages of development (Figure 2A). Throughout the lifetime of the female, germline stem cells at the tip of each ovariole continuously generate a steady stream of newly formed oocytes that enter meiotic prophase and grow and develop as they move posteriorly; as mature oocytes pass through the oviduct they complete meiosis and are fertilized. Under normal conditions (continuous egg laying), Drosophila oogenesis is an uninterrupted process with only PLoS Genetics | www.plosgenetics.org 1 November 2008 | Volume 4 | Issue 11 | e1000263