Copy number variants (CNVs) are large insertions, duplications, or deletions of DNA sequence. CNVs can be common in human populations and are known as copy number polymorphisms (CNPs). Serval lines of evidence suggest that CNPs are important in human biology. First, CNPs have been associated with human diseases such as Crohn's disease and psoriasis. Second, CNPs with large population differences in frequency have been described suggesting that copy number changes may have occurred in response to population-specific selective pressures. However, several important questions remain to be answered. First, the full range of CNPs have not been thoroughly tested for population differences. Additionally, the recurrence and mutation rate of CNPs has not been well studied. Unstanding these issues will give a more complete picture of the dynamic forces acting on the human genome. The broad objectives of this proposal is to perform a more complete analysis of population differentiation by including CNPs in duplication-rich regions of the genome and insertions of sequence not in the reference genome assembly as these CNPs are understudied in previous analyses. A further objective of the proposed research is to estimate the mutation rate of CNPs. These goals are focused on testing the hypothesis that there will be differences between CNP loci in terms of both population differentiation and mutation rate. Because many CNPs are not well assayed by currently available platforms, I have developed and tested a custom microarray targeted to CNP loci defined at high resolution. I will hybridize over one thousand individuals from multiple populations to this microarray to discover population differentiated CNPs. To study CNP mutation rate, I will analyze individuals selected from a multigeneration pedigree of Hutterites. This cohort offers a unique oppurtunity to study individuals with a high degreee of allele sharing, due to inbreeding, but who are separated by an average of eight meioses. These characteristics should make these samples powerful for discovering mutated or recurrent CNPs and estimating the frequency of these events. Finally, to understand the role of paralogous variants in CNP loci, I will fully sequence population differentiated CNPs and CNPs with high mutation rates. These sequence data will allow for a better understanding of the interplay between copy number and sequence content. The experiments proposed here will provide a better understanding of this type of genetic variation and may influence the design of future studies involving CNPs.

Public Health Relevance

This study of the population genetics of copy-number polymorphisms, differencs in the number of copies of certain regions of the genome between individuals, aims to gain a better understanding of genetic variation among humans. The knowledge gained here has the potential to influence studies of the genetics of human diseases.

National Institute of Health (NIH)
National Human Genome Research Institute (NHGRI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1-F08-E (20))
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Graham, Bettie
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University of Washington
Schools of Medicine
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Campbell, Catarina D; Eichler, Evan E (2013) Properties and rates of germline mutations in humans. Trends Genet 29:575-84
Girirajan, Santhosh; Dennis, Megan Y; Baker, Carl et al. (2013) Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder. Am J Hum Genet 92:221-37
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Campbell, Catarina D; Sampas, Nick; Tsalenko, Anya et al. (2011) Population-genetic properties of differentiated human copy-number polymorphisms. Am J Hum Genet 88:317-32