Genomes evolve and diversify through di?erent mechanisms, including small point mutations, but also larger, structural variations (SV). SVs can be mediated by simple repeats and microhomology based recombination (termed 'progressive SVs' in this proposal). However, progressive SV mechanisms cannot explain all forms of large genomic variation; sometimes, more 'complex mechanisms' are needed; examples include Breakage Fusion Bridge, and Chromothripsis. Moreover, there is little understanding of the genetic mechanisms of genome instability that lead to complex SV formation. It is suspected that random viral genome insertions into the genome can on occasion disrupt key genes, causing genome instability and hyper-variability. To address these problems, the proposal will design and implement computational methods to (a) reconstruct and validate episomal structures of viral genome insertions; (b) determine if genomic sequence sampled from tumor genomes has a signature of complex variation; and, (b) phase and sub-type regions with complex SV including KIR and HLA; As clinical/translational applications of genomics come to the forefront, the impact of complex SVs on the phenotype of an individual become increasingly important. Understanding the computational signatures of BFB and Chromothripsis will help sub-type and characterize cancers. The knowledge of KIR/HLA sub-type will be correlated with immune related phenotypes, and the reconstruction of viral episomes will help clarify the etiology of virus mediated cancers. Thus, the proposed set of computational tools will directly impact the translational/medical aspect of genomics.

Public Health Relevance

The proposed computational tools will be used to detect complex structural variations in human genomes, and will provide a starting point for understanding their role in disease. The development of computational signatures of BFB and Chromothripsis will help sub-type and characterize cancers; similarly, the knowledge of KIR/HLA sub- type could be correlated with immune related phenotypes, and the reconstruction of viral episomes will help clarify the etiology of virus mediated cancers. Thus, the proposed set of computational tools will have an immediate and long term impact on human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM114362-03
Application #
9406494
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Krasnewich, Donna M
Project Start
2016-01-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of California, San Diego
Department
Biostatistics & Other Math Sci
Type
Schools of Arts and Sciences
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Nguyen, Nam-Phuong D; Deshpande, Viraj; Luebeck, Jens et al. (2018) ViFi: accurate detection of viral integration and mRNA fusion reveals indiscriminate and unregulated transcription in proximal genomic regions in cervical cancer. Nucleic Acids Res 46:3309-3325
Akbari, Ali; Vitti, Joseph J; Iranmehr, Arya et al. (2018) Identifying the favored mutation in a positive selective sweep. Nat Methods 15:279-282
Beyter, Doruk; Lin, Miin S; Yu, Yanbao et al. (2018) ProteoStorm: An Ultrafast Metaproteomics Database Search Framework. Cell Syst 7:463-467.e6
Bakhtiari, Mehrdad; Shleizer-Burko, Sharona; Gymrek, Melissa et al. (2018) Targeted genotyping of variable number tandem repeats with adVNTR. Genome Res 28:1709-1719
Azad, Priti; Stobdan, Tsering; Zhou, Dan et al. (2017) High-altitude adaptation in humans: from genomics to integrative physiology. J Mol Med (Berl) 95:1269-1282
Chu, Wai Keung; Edge, Peter; Lee, Ho Suk et al. (2017) Ultraaccurate genome sequencing and haplotyping of single human cells. Proc Natl Acad Sci U S A 114:12512-12517
Stobdan, Tsering; Akbari, Ali; Azad, Priti et al. (2017) New Insights into the Genetic Basis of Monge's Disease and Adaptation to High-Altitude. Mol Biol Evol 34:3154-3168
Edge, Peter; Bafna, Vineet; Bansal, Vikas (2017) HapCUT2: robust and accurate haplotype assembly for diverse sequencing technologies. Genome Res 27:801-812
Cha, Seong Won; Bonissone, Stefano; Na, Seungjin et al. (2017) The Antibody Repertoire of Colorectal Cancer. Mol Cell Proteomics 16:2111-2124
Turner, Kristen M; Deshpande, Viraj; Beyter, Doruk et al. (2017) Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature 543:122-125

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