The goal of this study is to gain an understanding of genomic copy number variants in humans and other primates. Copy number variants are large stretches of DNA sequence repeated a different number of times among the genomes of normal humans, which can influence transcriptional and translational levels (the amount of mRNA and protein created for a particular gene) and therefore susceptibility to diseases such as HIV infection. We will characterize the relationship between copy number variants and gene expression variation within and between humans and other primates, which will allow us to identify copy number variants that may be of considerable functional and biomedical significance. Narrative: The goal of this study is to gain an understanding of the structure and evolution of genomic copy number variation in primates and its impact on gene expression. Specifically, we will (i) assess whether levels and patterns of copy number variation in non-human primates are similar to those for humans and test for heterogeneity in the inter-specific fixation rate for copy number gains and losses, and (ii) characterize the relationship between copy number variants (CNVs) and gene expression variation across different timescales of primate evolution. Our work will provide the most comprehensive understanding to date of the relationship between copy number and gene expression variation in primates, allowing us to identify specific CNVs that may be of considerable evolutionary and biomedical significance. Our research team, which includes leaders in both the primate copy number variation and gene expression fields, is well positioned to collaboratively address these important issues.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM081533-02
Application #
7620976
Study Section
Genetic Variation and Evolution Study Section (GVE)
Program Officer
Krasnewich, Donna M
Project Start
2008-05-15
Project End
2012-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
2
Fiscal Year
2009
Total Cost
$511,678
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
030811269
City
Boston
State
MA
Country
United States
Zip Code
02115
Falchi, Mario; El-Sayed Moustafa, Julia Sarah; Takousis, Petros et al. (2014) Low copy number of the salivary amylase gene predisposes to obesity. Nat Genet 46:492-7
Gokcumen, Omer; Tischler, Verena; Tica, Jelena et al. (2013) Primate genome architecture influences structural variation mechanisms and functional consequences. Proc Natl Acad Sci U S A 110:15764-9
Gokcumen, Omer; Zhu, Qihui; Mulder, Lubbertus C F et al. (2013) Balancing selection on a regulatory region exhibiting ancient variation that predates human-neandertal divergence. PLoS Genet 9:e1003404
Iskow, Rebecca C; Gokcumen, Omer; Lee, Charles (2012) Exploring the role of copy number variants in human adaptation. Trends Genet 28:245-57
Iskow, Rebecca C; Gokcumen, Omer; Abyzov, Alexej et al. (2012) Regulatory element copy number differences shape primate expression profiles. Proc Natl Acad Sci U S A 109:12656-61
Fernando, Michelle M A; de Smith, Adam J; Coin, Lachlan et al. (2011) Investigation of the HIN200 locus in UK SLE families identifies novel copy number variants. Ann Hum Genet 75:383-97
Mills, Ryan E; Walter, Klaudia; Stewart, Chip et al. (2011) Mapping copy number variation by population-scale genome sequencing. Nature 470:59-65
Gokcumen, Omer; Babb, Paul L; Iskow, Rebecca C et al. (2011) Refinement of primate copy number variation hotspots identifies candidate genomic regions evolving under positive selection. Genome Biol 12:R52
Lee, Charles (2010) The future of prenatal cytogenetic diagnostics: a personal perspective. Prenat Diagn 30:706-9
Conrad, Donald F; Pinto, Dalila; Redon, Richard et al. (2010) Origins and functional impact of copy number variation in the human genome. Nature 464:704-12

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