Origins and functional impact of copy number variation in the human genome

By D. Conrad, D. Pinto, R. Redon, L. Feuk, O. Gokcumen, Yujun Zhang, Jan Aerts, T. Daniel Andrews, Chris P. Barnes, P. Campbell and 21 more. Nature, 2009

1,997 citations recorded by the source corpus.

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.

Subfields: Genetics, Plant Science

View Paper: https://www.semanticscholar.org/paper/b3b4871e5c4b4e04f371ab6c6563c4c6b6ad379b

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Genetics

In Plant Science

Citations in the corpus

Dynamic Changes in the Copy Number of Pluripotency and Cell Proliferation Genes in Human ES and iPS Cells during Reprogramming and Time in Culture (2011, background): “set and the common CNVs observed in 450 reference HapMap samples (Conrad et al., 2010) when the common region of the CNVs exceeded both 20% of the CNV identified in our samples and 20% of the common CNV in”
The Intolerance of Regulatory Sequence to Genetic Variation Predicts Gene Dosage Sensitivity (2015, methodology): “We used Ensembl 73 to define the UTR sequence of CCDS genes that did not overlap with CCDS protein coding regions of the same or overlapping genes [45].”
CNVnator: an approach to discover, genotype, and characterize typical and atypical CNVs from family and population genome sequencing. (2011, methodology): “Furthermore, the population genotyping approach using arrays can be misled in determining the absolute CN as the range of log2 ratios for high-frequency duplications is expected to overlap in the range of low frequency deletions, e.g., rare and de novo events (Conrad et al. 2010).”
Genome evolution across 1,011 Saccharomyces cerevisiae isolates (2018, positive): “The high number of associated CNVs is consistent with the notion that these variants can contribute to a large amount of phenotypic variation 47 .”
Progress and Promise of Genome-Wide Association Studies for Human Complex Trait Genetics (2011, background): “…well-documented examples of CNV association with complex traits (e.g., deletion of CCL3L1 in HIV susceptibility; Gonzalez et al. 2005), common CNVs will not likely contribute substantially to unexplained heritability, as common CNVs are in LD with SNPs (Conrad et al. 2010; Craddock et al. 2010).”
Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. (2010, background): “9 kb, and that 95% of CNVs are less than 100 kb.(66) These smaller CNVs were previously undetectable because of technological limitations, and CNV sizes from previous studies have often been overestimated for the majority of CNVs.”