Diversity of Human Copy Number Variation and Multicopy Genes

Abstract

Copy number variants affect both disease and normal phenotypic variation, but those lying within heavily duplicated, highly identical sequence have been difficult to assay. By analyzing short-read mapping depth for 159 human genomes, we demonstrated accurate estimation of absolute copy number for duplications as small as 1.9 kilobase pairs, ranging from 0 to 48 copies. We identified 4.1 million “singly unique nucleotide” positions informative in distinguishing specific copies and used them to genotype the copy and content of specific paralogs within highly duplicated gene families. These data identify human-specific expansions in genes associated with brain development, reveal extensive population genetic diversity, and detect signatures consistent with gene conversionin the human species. Our approach makes ~1000 genes accessible to genetic studies of disease association.

Expansion of a 12-kb VNTR containing the REXO1L1 gene cluster underlies the microscopically visible euchromatic variant of 8q21.2

“…5 Interphase FISH has been used to determine relative haploid copy numbers but becomes impractical when amplicon size is small and copy number very high. 32 Further investigations will be needed of EV and non-EV carriers in larger families using quantitative allele-specific copy number techniques 33 to confirm or exclude our proposal.…”

A genetic model for neurodevelopmental disease

“…We posit that this reflects both a technological limitation and an ascertainment bias as a result of the mutation severity. Affordable whole-genome sequencing [29] has revealed a plethora of uncharacterized genetic variation below the lower limits of arrayCGH and SNP array platforms, which rapidly lose genome-wide sensitivity below 50 kbp for most commercial arrays [30]. The number of CNVs per individual increases linearly as sizes approach 100 kbp (closely related to the de novo rate and matching observations of selection against large CNVs), but then begins to increase exponentially for CNVs less than 10 kbp in size ( Figure 1B) [31].…”

“…The analysis of copy number and structural variation is frequently an afterthought requiring specialized and computationally intensive methods [4, 29,30]. No method is comprehensive and each differs in its sensitivity as a function of size and class of CNVs.…”

“…Read-pair methodologies, for example, are most sensitive to events between 40 bp and 1 kbp (depending on library insert sizes and consistency) [30][31][32][33]. Readdepth methodologies are powerful for detecting copy number changes greater than 10 kbp and are dependent on sequence coverage, which limits the number of genomes that can be analyzed [29,30,[34][35][36][37]. This leaves a gap in our detection abilities between about 1 kbp and 50 kbp where performance is suboptimal ( Figure 1B).…”

A commentary on Implication of gene copy number variation in health and diseases

“…More recently, CNV studies have become more precise to the level of nucleotide resolution and have allowed the discovery of rare CNVs by resequencing personal genomes using the next-generation sequencer. [8][9][10] The Structural Variation Group of the 1000 Genomes Project constructed a map of CNVs on the basis of whole genome DNA sequencing data from 185 human genomes, which were resequenced using next-generation sequencer. 10 The map encompassed 22 035 deletions and 6000 additional structural variations, including insertions and tandem duplications.…”