New insights into human nondisjunction of chromosome 21 in oocytes

• Type of Material: Article
• Authors: Tiffany Renee Oliver, Emory University; Eleanor Feingold, University of Pittsburgh; Kai Yu, National Cancer Institute, Bethesda; Vivian Cheung, University of Pennsylvania; Stuart Tinker, Emory University; Maneesha Yadav-Shah, Emory University; Nirupama Masse, Emory University; Stephanie Sherman, Emory University
• Language: English
• Date: 2008-03-01
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: Copyright Oliver et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.pgen.1000033
• Title of Journal or Parent Work: PLoS Genetics
• ISSN: 1553-7390
• Volume: 4
• Issue: 3
• Start Page: e1000033
• End Page: e1000033
• Grant/Funding Information: This work was funded by NIH R01 HD38979, by NIH MO-1-RR00039 that supports the General Clinical Research Center at Emory University which provided laboratory support for establishment of cell lines and by NIH R01 HG01880 (VC), which supported genotype of the CEPH families.; NIH 5F31GM078751-02 also provided support for analyses performed.
• Keywords: DNA POLYMORPHISMS; TRISOMY-21; Science & Technology; Genetics & Heredity; DROSOPHILA; SEGREGATION; AGE; ORIGIN; MATERNAL MEIOSIS I; DOWN-SYNDROME; MEIOTIC RECOMBINATION; PATTERNS; Life Sciences & Biomedicine; GENETICS & HEREDITY
• Research Categories: Health Sciences, Human Development; Biology, Genetics

Abstract

Nondisjunction of chromosome 21 is the leading cause of Down syndrome. Two risk factors for maternal nondisjunction of chromosome 21 are increased maternal age and altered recombination. In order to provide further insight on mechanisms underlying nondisjunction, we examined the association between these two well established risk factors for chromosome 21 nondisjunction. In our approach, short tandem repeat markers along chromosome 21 were genotyped in DNA collected from individuals with free trisomy 21 and their parents. This information was used to determine the origin of the nondisjunction error and the maternal recombination profile. We analyzed 615 maternal meiosis I and 253 maternal meiosis II cases stratified by maternal age. The examination of meiosis II errors, the first of its type, suggests that the presence of a single exchange within the pericentromeric region of 21q interacts with maternal age-related risk factors. This observation could be explained in two general ways: 1) a pericentromeric exchange initiates or exacerbates the susceptibility to maternal age risk factors or 2) a pericentromeric exchange protects the bivalent against age-related risk factors allowing proper segregation of homologues at meiosis I, but not segregation of sisters at meiosis II. In contrast, analysis of maternal meiosis I errors indicates that a single telomeric exchange imposes the same risk for nondisjunction, irrespective of the age of the oocyte. Our results emphasize the fact that human nondisjunction is a multifactorial trait that must be dissected into its component parts to identify specific associated risk factors. © 2008 Oliver et al.