| 1. |
- Conrad, Donald F., et al.
(author)
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Origins and functional impact of copy number variation in the human genome
- 2010
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 704-712
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Journal article (peer-reviewed)abstract
- Structural variations of DNA greater than 1 kilobase in size account for most bases that vary among human genomes, but are still relatively under-ascertained. Here we use tiling oligonucleotide microarrays, comprising 42 million probes, to generate a comprehensive map of 11,700 copy number variations (CNVs) greater than 443 base pairs, of which most (8,599) have been validated independently. For 4,978 of these CNVs, we generated reference genotypes from 450 individuals of European, African or East Asian ancestry. The predominant mutational mechanisms differ among CNV size classes. Retrotransposition has duplicated and inserted some coding and non-coding DNA segments randomly around the genome. Furthermore, by correlation with known trait-associated single nucleotide polymorphisms (SNPs), we identified 30 loci with CNVs that are candidates for influencing disease susceptibility. Despite this, having assessed the completeness of our map and the patterns of linkage disequilibrium between CNVs and SNPs, we conclude that, for complex traits, the heritability void left by genome-wide association studies will not be accounted for by common CNVs.
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| 2. |
- Pang, Andy Wing Chun, et al.
(author)
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Mechanisms of Formation of Structural Variation in a Fully Sequenced Human Genome
- 2013
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In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 34:2, s. 345-354
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Journal article (peer-reviewed)abstract
- Even with significant advances in technology, few studies of structural variation have yet resolved to the level of the precise nucleotide junction. We examined the sequence of 408,532 gains, 383,804 losses, and 166 inversions from the first sequenced personal genome, to quantify the relative proportion of mutational mechanisms. Among small variants (<1kb), we observed that 72.6% of them were associated with nonhomologous processes and 24.9% with microsatellites events. Medium-size variants (<10kb) were commonly related to minisatellites (25.8%) and retrotransposons (24%), whereas 46.2% of large variants (>10kb) were associated with nonallelic homologous recombination. We genotyped eight new breakpoint-resolved inversions at (3q26.1, Xp11.22, 7q11.22, 16q23.1, 4q22.1, 1q31.3, 6q27, and 16q24.1) in human populations to elucidate the structure of these presumed benign variants. Three of these inversions (3q26.1, 7q11.22, and 16q23.1) were accompanied by unexpected complex rearrangements. In particular, the 16q23.1 inversion and an accompanying deletion would create conjoined chymotrypsinogen genes (CTRB1 and CTRB2), disrupt their gene structure, and exhibit differentiated allelic frequencies among populations. Also, two loci (Xp11.3 and 6q27) of potential reference assembly orientation errors were found. This study provides a thorough account of formation mechanisms for structural variants, and reveals a glimpse of the dynamic structure of inversions.
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