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 #
5R01HD038979-13
Application #
8486456
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
2013-06-01
Budget End
2014-05-31
Support Year
13
Fiscal Year
2013
Total Cost
$576,744
Indirect Cost
$144,820
Name
Emory University
Department
Genetics
Type
Schools of Medicine
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
Oliver, Tiffany Renee; Middlebrooks, Candace; Harden, Ariel et al. (2016) Variation in the Zinc Finger of PRDM9 is Associated with the Absence of Recombination along Nondisjoined Chromosomes 21 of Maternal Origin. J Down Syndr Chromosom Abnorm 2:
Begum, Ferdouse; Sharker, Monir H; Sherman, Stephanie L et al. (2016) Regionally Smoothed Meta-Analysis Methods for GWAS Datasets. Genet Epidemiol 40:154-60
Begum, Ferdouse; Chowdhury, Reshmi; Cheung, Vivian G et al. (2016) Genome-Wide Association Study of Meiotic Recombination Phenotypes. G3 (Bethesda) 6:3995-4007
Zeng, Zhen; Weeks, Daniel E; Chen, Wei et al. (2016) A Pipeline for Classifying Relationships Using Dense SNP/SNV Data and Putative Pedigree Information. Genet Epidemiol 40:161-71
Visootsak, Jeannie; Huddleston, Lillie; Buterbaugh, Allison et al. (2016) Influence of CHDs on psycho-social and neurodevelopmental outcomes in children with Down syndrome. Cardiol Young 26:250-6
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
Ramachandran, Dhanya; Zeng, Zhen; Locke, Adam E et al. (2015) Genome-Wide Association Study of Down Syndrome-Associated Atrioventricular Septal Defects. G3 (Bethesda) 5:1961-71
Albizua, I; Rambo-Martin, B L; Allen, E G et al. (2015) Association between telomere length and chromosome 21 nondisjunction in the oocyte. Hum Genet 134:1263-70
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
Oliver, Tiffany Renee; Middlebrooks, Candace D; Tinker, Stuart W et al. (2014) An examination of the relationship between hotspots and recombination associated with chromosome 21 nondisjunction. PLoS One 9:e99560

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