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The genomic architecture of segmental duplications and associated copy number variants in dogs.

ABSTRACT: Structural variation is an important and abundant source of genetic and phenotypic variation. Here we describe the first systematic and genome-wide analysis of segmental duplications and associated copy number variants (CNVs) in the modern domesticated dog, Canis familiaris, which exhibits considerable morphological, physiological, and behavioral variation. Through computational analyses of the publicly available canine reference sequence, we estimate that segmental duplications comprise approximately 4.21% of the canine genome. Segmental duplications overlap 841 genes and are significantly enriched for specific biological functions such as immunity and defense and KRAB box transcription factors. We designed high-density tiling arrays spanning all predicted segmental duplications and performed aCGH in a panel of 17 breeds and a gray wolf. In total, we identified 3583 CNVs, approximately 68% of which were found in two or more samples that map to 678 unique regions. CNVs span 429 genes that are involved in a wide variety of biological processes such as olfaction, immunity, and gene regulation. Our results provide insight into mechanisms of canine genome evolution and generate a valuable resource for future evolutionary and phenotypic studies.

SUBMITTER: Nicholas TJ

PROVIDER: S-EPMC2661811 | biostudies-literature | 2009 Mar

REPOSITORIES: biostudies-literature

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The genomic architecture of segmental duplications and associated copy number variants in dogs.

Nicholas Thomas J TJ Cheng Ze Z Ventura Mario M Mealey Katrina K Eichler Evan E EE Akey Joshua M JM

Genome research 20090107 3

Structural variation is an important and abundant source of genetic and phenotypic variation. Here we describe the first systematic and genome-wide analysis of segmental duplications and associated copy number variants (CNVs) in the modern domesticated dog, Canis familiaris, which exhibits considerable morphological, physiological, and behavioral variation. Through computational analyses of the publicly available canine reference sequence, we estimate that segmental duplications comprise approxi ...[more]

PMID: 19129542

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Project description:The human genome contains numerous blocks of highly homologous duplicated sequence. This higher-order architecture provides a substrate for recombination and recurrent chromosomal rearrangement associated with genomic disease. However, an assessment of the role of segmental duplications in normal variation has not yet been made. On the basis of the duplication architecture of the human genome, we defined a set of 130 potential rearrangement hotspots and constructed a targeted bacterial artificial chromosome (BAC) microarray (with 2,194 BACs) to assess copy-number variation in these regions by array comparative genomic hybridization. Using our segmental duplication BAC microarray, we screened a panel of 47 normal individuals, who represented populations from four continents, and we identified 119 regions of copy-number polymorphism (CNP), 73 of which were previously unreported. We observed an equal frequency of duplications and deletions, as well as a 4-fold enrichment of CNPs within hotspot regions, compared with control BACs (P < .000001), which suggests that segmental duplications are a major catalyst of large-scale variation in the human genome. Importantly, segmental duplications themselves were also significantly enriched >4-fold within regions of CNP. Almost without exception, CNPs were not confined to a single population, suggesting that these either are recurrent events, having occurred independently in multiple founders, or were present in early human populations. Our study demonstrates that segmental duplications define hotspots of chromosomal rearrangement, likely acting as mediators of normal variation as well as genomic disease, and it suggests that the consideration of genomic architecture can significantly improve the ascertainment of large-scale rearrangements. Our specialized segmental duplication BAC microarray and associated database of structural polymorphisms will provide an important resource for the future characterization of human genomic disorders.

Dataset Information

The genomic architecture of segmental duplications and associated copy number variants in dogs.

Publications

The genomic architecture of segmental duplications and associated copy number variants in dogs.

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