Mobile DNA elements are DNA segments that can mobilize from one genomic location to another, some making copies of themselves during the process. Mobile elements are ubiquitous in eukaryotic genomes, and roughly 50% of the human genome consists of mobile, repetitive DNA sequences such as Alu and LINE1 elements. Mobile elements have profoundly influenced primate genomic evolution, and alterations caused by mobile elements have been identified in more than 100 human genetic disorders. In addition, mobile elements are highly useful as genetic markers in tracing relationships of populations and species because of their unique manner of propagating in the genome. Therefore, it is of great interest to understand the biology of mobile elements in human populations. Currently available genotyping methods, however, provide only limited insight into the distribution of Alu and L1 elements in the human genome. In this proposal, I will first describe a novel, high-throughput method to genotype a large number of individuals for Alu insertion polymorphisms. Implementation of this method will permit, for the first time, rapid, inexpensive genotyping of whole families of mobile elements not only in humans but in any organism. Next, I outline my plans to construct a computational pipeline that can efficiently handle and analyze the high- throughput genomic data generated by my genotyping method. Finally I describe my plan to apply the genotyping procedure to 540 HapMap samples and use my computational pipeline to analyze the results. Specifically, I will use the insertion polymorphism data to assess the genomic diversity associated with mobile element insertions, as well as to answer questions related to mobile element biology and to reconstruct ancient human demographic history. In addition, the Alu insertion polymorphism dataset generated in this project will provide a valuable supplementary resource of structural variants for the HapMap and 1000 Genomes Projects. My long-term goal is to pursue a career in human genomic variation and population genetics research with an emphasis on mobile elements. Using a combination of computational and experimental tools, I will study the impact of mobile DNA elements on the human genome and on genetic diversity among human populations. This award will provide the necessary training for me to become an independent investigator on two fronts: I will acquire essential training in computational biology and bioinformatics to handle large-scale genomic data, including data generated from next-generation sequencing technology. In addition, research training offered by the institution and my mentor will allow me to acquire knowledge about research resources, grant writing, responsible conduct in research, and other information necessary to become a successful, independent investigator.
Mobile DNA elements have had profound and widespread effects on the human genome, and they have been implicated in the causation of dozens of human diseases. This proposal will develop a low-cost, high-throughput technology that can be used to genotype mobile element insertions in humans and other organisms. This technology will greatly enhance our understanding of mobile element biology in human populations and provide a valuable structural variant data resource for the 1000 Genomes Project.
| Lorenzo, Felipe R; Huff, Chad; Myllymäki, Mikko et al. (2014) A genetic mechanism for Tibetan high-altitude adaptation. Nat Genet 46:951-6 |
| Marmoset Genome Sequencing and Analysis Consortium (2014) The common marmoset genome provides insight into primate biology and evolution. Nat Genet 46:850-7 |
| Stringham, Sydney A; Mulroy, Elisabeth E; Xing, Jinchuan et al. (2012) Divergence, convergence, and the ancestry of feral populations in the domestic rock pigeon. Curr Biol 22:302-8 |
| Watkins, W Scott; Xing, Jinchuan; Huff, Chad et al. (2012) Genetic analysis of ancestry, admixture and selection in Bolivian and Totonac populations of the New World. BMC Genet 13:39 |
| Ge, Ri-Li; Simonson, Tatum S; Cooksey, Robert C et al. (2012) Metabolic insight into mechanisms of high-altitude adaptation in Tibetans. Mol Genet Metab 106:244-7 |
| Huff, Chad D; Witherspoon, David J; Zhang, Yuhua et al. (2012) Crohn's disease and genetic hitchhiking at IBD5. Mol Biol Evol 29:101-11 |
| Yandell, Mark; Huff, Chad; Hu, Hao et al. (2011) A probabilistic disease-gene finder for personal genomes. Genome Res 21:1529-42 |
| Stewart, Chip; Kural, Deniz; Strömberg, Michael P et al. (2011) A comprehensive map of mobile element insertion polymorphisms in humans. PLoS Genet 7:e1002236 |
| Huff, Chad D; Witherspoon, David J; Simonson, Tatum S et al. (2011) Maximum-likelihood estimation of recent shared ancestry (ERSA). Genome Res 21:768-74 |
| Roos, Christian; Zinner, Dietmar; Kubatko, Laura S et al. (2011) Nuclear versus mitochondrial DNA: evidence for hybridization in colobine monkeys. BMC Evol Biol 11:77 |
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