Human chromosome nondisjunction leads to an extraordinary frequency of aneuploidy: an estimated 10-25% of all human conceptions have too many or too few chromosomes. This chromosome error is the leading cause of pregnancy loss, intellectual disabilities and birth defects. We propose to continue the study of trisomy 21, the cause of Down syndrome (DS), as a model to understand nondisjunction. We have built an unprecedented resource of infants with DS and their parents, including biological samples, epidemiological and clinical data. We have shown that altered recombination patterns along the nondisjoined chromosome are a risk for nondisjunction, and for the first time, have shown that the position of susceptible recombinants differ by the age of the oocyte. Our data have generated new hypotheses that focus on the importance of the genetic architecture of meiotic recombination. We will harness the use of the public genotyping data from genome-wide association studies (GWAS) and our DS repository to gain insight into mechanisms that lead to nondisjunction. First, we will narrow possible mechanism of recombination-based nondisjunction by better understanding recombination patterns in normal meiosis. Second, we will determine the interaction between recombination patterns and environmental and genomic/epigenomic factors that have been associated with nondisjunction, and 3) conduct a GWAS study to identify susceptibility genes for nondisjunction of chromosome 21. Our strategy will ensure progress toward understanding nondisjunction and its consequent impact on the length of woman's reproductive life span.

Public Health Relevance

Human chromosome nondisjunction is the leading cause of pregnancy loss, intellectual disabilities and birth defects. In this competitive renewal, we will focus on uncovering the genetic architecture of meiotic recombination, one important molecular risk factor for nondisjunction. Our strategy to identify recombination-related susceptibility genes will ensure progress toward understanding nondisjunction and its consequent impact on the length of woman's reproductive life span.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD038979-12
Application #
8301482
Study Section
Special Emphasis Panel (ZRG1-PSE-H (03))
Program Officer
Oster-Granite, Mary Lou
Project Start
2000-06-22
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
12
Fiscal Year
2012
Total Cost
$613,617
Indirect Cost
$156,008
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Ramachandran, Dhanya; Mulle, Jennifer G; Locke, Adam E et al. (2015) Contribution of copy-number variation to Down syndrome-associated atrioventricular septal defects. Genet Med 17:554-60
Middlebrooks, Candace D; Mukhopadhyay, Nandita; Tinker, Stuart W et al. (2014) Evidence for dysregulation of genome-wide recombination in oocytes with nondisjoined chromosomes 21. Hum Mol Genet 23:408-17
Kermany, Amir R; Segurel, Laure; Oliver, Tiffany R et al. (2014) TroX: a new method to learn about the genesis of aneuploidy from trisomic products of conception. Bioinformatics 30:2035-42
Hollis, NaTasha D; Allen, Emily G; Oliver, Tiffany Renee et al. (2013) Preconception folic acid supplementation and risk for chromosome 21 nondisjunction: a report from the National Down Syndrome Project. Am J Med Genet A 161A:438-44
Hunter, Jessica Ezzell; Allen, Emily Graves; Shin, Mikyong et al. (2013) The association of low socioeconomic status and the risk of having a child with Down syndrome: a report from the National Down Syndrome Project. Genet Med 15:698-705
Tseng, George C; Ghosh, Debashis; Feingold, Eleanor (2012) Comprehensive literature review and statistical considerations for microarray meta-analysis. Nucleic Acids Res 40:3785-99
Oliver, Tiffany Renee; Tinker, Stuart W; Allen, Emily Graves et al. (2012) Altered patterns of multiple recombinant events are associated with nondisjunction of chromosome 21. Hum Genet 131:1039-46
Begum, Ferdouse; Ghosh, Debashis; Tseng, George C et al. (2012) Comprehensive literature review and statistical considerations for GWAS meta-analysis. Nucleic Acids Res 40:3777-84
Locke, Adam E; Dooley, Kenneth J; Tinker, Stuart W et al. (2010) Variation in folate pathway genes contributes to risk of congenital heart defects among individuals with Down syndrome. Genet Epidemiol 34:613-23
Arnold, Stacey; Pelet, Anna; Amiel, Jeanne et al. (2009) Interaction between a chromosome 10 RET enhancer and chromosome 21 in the Down syndrome-Hirschsprung disease association. Hum Mutat 30:771-5

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