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A copy number variation map of the human genome

Key Points

  • The copy number variation (CNV) map of the human genome documents the extent and characteristics of CNV among healthy populations.

  • Depending on the level of stringency of the map, 4.8–9.7% of the human genome contributes to CNVs.

  • CNVs are distributed unevenly in the genome; the pericentromeric and subtelomeric regions of chromosomes show a particularly high rate of variation.

  • Various gene groups are affected differently by copy number variants. Genes that are associated with disease are the least affected by copy number variants, whereas paralogous genes have the most copy number variants.

  • More than 100 genes can be completely removed from the genome without producing apparent phenotypic consequences.

  • The CNV map will aid the interpretation of copy number variants of medical importance.

Abstract

A major contribution to the genome variability among individuals comes from deletions and duplications — collectively termed copy number variations (CNVs) — which alter the diploid status of DNA. These alterations may have no phenotypic effect, account for adaptive traits or can underlie disease. We have compiled published high-quality data on healthy individuals of various ethnicities to construct an updated CNV map of the human genome. Depending on the level of stringency of the map, we estimated that 4.8–9.5% of the genome contributes to CNV and found approximately 100 genes that can be completely deleted without producing apparent phenotypic consequences. This map will aid the interpretation of new CNV findings for both clinical and research applications.

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Figure 1: Proportion of each human chromosome that is copy number variable based on the inclusive and stringent maps.
Figure 2: Distribution of copy number variable regions in pericentromeric and subtelomeric regions of human chromosomes.
Figure 3: Copy number variations that involve regulatory elements or exons of specified gene lists.
Figure 4: Copy number variations that involve genes with or without disease association.
Figure 5: Gene function enrichment map for the inclusive and stringent maps of copy number variation losses.

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Acknowledgements

The authors thank R. Ziman and G. Pellecchia for computational support, as well as J. Buchanan, J. Stavropoulos, C. Marshall, R. Yuen, B. Thiruvahindrapuram, M. Uddin, M. Mohammed and L. Feuk for discussions. They thank The Centre for Applied Genomics Science and Technology Innovation Centre (funded by Genome Canada and the Ontario Genomics Institute) for computational support. The Database of Genomic Variants and our research are supported by grants from Genome Canada, the Canada Foundation of Innovation, the Canadian Institute for Advanced Research, the government of Ontario, the Canadian Institutes of Health Research (CIHR), The Hospital for Sick Children, and the University of Toronto McLaughlin Centre. S.W.S. holds the GlaxoSmithKline–CIHR Endowed Chair in Genome Sciences at The Hospital for Sick Children and the University of Toronto.

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Glossary

Copy number variation

(CNV). A genomic segment of at least 50 bp that differs in copy number based on the comparison of two or more genomes.

Unbalanced rearrangements

Genomic variants that involve loss (deletion) or gain (duplication) of segments of the genome.

Database of Genomic Variants

(DGV). A curated catalogue of copy number and structural variations in the human genomes of healthy control individuals.

Copy number variable regions

(CNVRs). Regions containing at least two copy number variations that overlap and that may have different breakpoints.

Next-generation sequencing

(NGS). A high-throughput DNA sequencing technology that typically generates shorter reads than Sanger sequencing-based methods and that can sequence billions of bases in parallel. NGS minimizes the need for fragment cloning.

Comparative genomic hybridization

(CGH). An array-based technique that interrogates the genome for signs of deletion or duplication in relation to a reference.

SNP-based arrays

Single-nucleotide polymorphism (SNP)-based microarrays that contain SNP probes to genotype human DNA at the single-base level. However, through dosage signals in adjacent regions, they can be used to recognize copy number variations.

Segmental duplications

(Also known as low-copy repeats). Highly homologous duplicated segments of DNA that are >1 kb in length and that show >90% sequence similarity.

International Standards for Cytogenomic Arrays

(ISCA). A consortium of clinical cytogeneticists who work together to standardize the use of array-based approaches in clinical genetic testing.

Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources

(DECIPHER). A database that documents phenotype information in patients with observed chromosome abnormalities and that aids the interpretation of genomic variants.

DECIPHER critical genes

Genes located in the critical regions that are associated with the 70 syndromes defined in Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources (DECIPHER).

Essential genes

Orthologues of mouse genes for which homozygous loss-of-function mutations cause embryonic or neonatal lethality. They are necessary for cellular viability and organism development. They are evolutionarily more conserved than non-essential genes.

Copy number stable

(CNS). Pertaining to regions of the genome without any detected copy number variation in healthy individuals.

Genic intolerance score

An index of intolerance to rare, non-synonymous variation.

Haploinsufficiency

Reduction in the amount of gene product owing to functional loss of an allele that leads to an abnormal or a disease state.

Long intergenic non-coding RNAs

(lincRNAs). Non-coding RNAs that are thought to be key regulators of diverse cellular processes. Their expression seems to be more tissue-specific than that of coding genes.

PhastCons elements

Evolutionarily conserved elements that were identified by modelling substitution rates in multiple genome alignments.

Ultra-conserved elements

Regions of DNA that are conserved across mammalian genomes and that mostly consist of non-protein-coding regions (that is, regions with little or no evolutionary changes since the divergence of mammals and birds).

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Zarrei, M., MacDonald, J., Merico, D. et al. A copy number variation map of the human genome. Nat Rev Genet 16, 172–183 (2015). https://doi.org/10.1038/nrg3871

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