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Patterns of genic intolerance of rare copy number variation in 59,898 human exomes

Abstract

Copy number variation (CNV) affecting protein-coding genes contributes substantially to human diversity and disease. Here we characterized the rates and properties of rare genic CNVs (<0.5% frequency) in exome sequencing data from nearly 60,000 individuals in the Exome Aggregation Consortium (ExAC) database. On average, individuals possessed 0.81 deleted and 1.75 duplicated genes, and most (70%) carried at least one rare genic CNV. For every gene, we empirically estimated an index of relative intolerance to CNVs that demonstrated moderate correlation with measures of genic constraint based on single-nucleotide variation (SNV) and was independently correlated with measures of evolutionary conservation. For individuals with schizophrenia, genes affected by CNVs were more intolerant than in controls. The ExAC CNV data constitute a critical component of an integrated database spanning the spectrum of human genetic variation, aiding in the interpretation of personal genomes as well as population-based disease studies. These data are freely available for download and visualization online.

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Figure 1: Distribution of the number and amount of CNV across 59,898 exome-sequenced individuals.
Figure 2: Genic summary of rare deletions and duplications in the ExAC sample.
Figure 3: Brain-relevant genes demonstrate the greatest intolerance to dosage changes from CNVs.

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Acknowledgements

We would like to acknowledge E. Fluder and K. Shakir for their help in running XHMM at the large scale required for over 60,000 samples. Work at the Icahn School of Medicine at Mount Sinai was supported by the Institute for Genomics and Multiscale Biology (including computational resources and staff expertise provided by the Department of Scientific Computing) and NIH grants R01-HG005827 and R01-MH099126 (to S.M.P.).

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Authors and Affiliations

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Contributions

D.M.R., M.F., and S.M.P. designed the study. M.L., K.J.K., and D.G.M. handled sample and data management. D.M.R., T.H., K.E.S., M.F., and S.M.P. contributed to statistical analyses. D.K., D.M.R., and K.J.K. designed and implemented website visualizations. D.M.R., M.J.D., D.G.M., M.F., and S.M.P. contributed to primary interpretations. D.M.R., M.F., and S.M.P. performed the primary drafting of the manuscript. All authors contributed to, read, and approved the final manuscript.

Corresponding authors

Correspondence to Douglas M Ruderfer or Shaun M Purcell.

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Competing interests

M.F. is now an employee at Verily Life Sciences.

Additional information

A list of members and affiliations appears in the Supplementary Note.

Integrated supplementary information

Supplementary Figure 1 Histogram showing the proportion of genotyping array–based CNV calls that were also called by exome sequencing in 10,091 samples where CNVs from both platforms existed.

The histogram is stratified by the number of exome sequencing targets in which the array-based CNV overlapped.

Supplementary Figure 2 Histogram showing the number of CNVs called by exome sequencing and the number that were also called by genotyping arrays in 10,091 samples where CNVs from both platforms existed.

The histogram is stratified by the number of exome sequencing targets in which the CNV overlapped.

Supplementary Figure 3 Correlation of number of CNVs and average read depth by ExAC cohort.

ExAC cohorts stratified by sample and population (corresponding to colors) with mean read depth on the x axis and mean number of CNVs on the y axis.

Supplementary Figure 4 Average number of CNVs by population and ExAC cohort.

Mean number of CNVs, stratified by ethnicity on the x axis. Each point corresponds to an ExAC cohort (as denoted by its color), and the size of the point is proportional to the size of the subcohort from a particular ethnicity group.

Supplementary Figure 5 CNV frequency mediated by the number of pairs of segmental duplications within which a gene occurs.

Number of CNVs for each gene, binned by the number of pairs of segmental duplications between which the gene is found; note that 6+ denotes 6 or more pairs.

Supplementary Figure 6 Distribution of CNV intolerance scores.

Histogram of the CNV intolerance score for each gene before and after winsorizing the most tolerant end of the distribution.

Supplementary Figure 7 Correlation of CNV intolerance scores and loss-of-function constraint scores.

The violin plots show that increase in CNV intolerance score tracks with increase in both missense and loss-of-function SNV constraint scores stratified by decile.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–7 and Supplementary Note. (PDF 1195 kb)

Supplementary Table 1

Summary of the number of CNVs and genes affected by CNVs, stratified by ethnicity and gender. (XLSX 10 kb)

Supplementary Table 2

Output of the full linear regression model used to create CNV intolerance scores for the seven main variables included. (XLSX 8 kb)

Supplementary Table 3

Results from t tests of highly expressed genes from a given tissue versus the remaining genes, stratified by all CNV, deletions, and duplications. (XLSX 12 kb)

Supplementary Table 4

Results from t tests of disease-related gene sets versus the remaining genes, stratified by all CNV, deletions, and duplications. (XLSX 11 kb)

Supplementary Table 5

Summary of gene set enrichment results from the 5% most intolerant genes (n = 787) from ToppFun. (XLSX 16 kb)

Supplementary Table 6

List of genes among the top 5% of intolerance (most intolerant) that were present in at least one group of significant pathways, along with the CNV intolerance score, the number of pathways in each group, and the number of groups. (XLSX 39 kb)

Supplementary Table 7

Summary of gene set enrichment results for the 5% most tolerant genes (n = 787) from ToppFun. (XLSX 17 kb)

Supplementary Table 8

List of genes among the bottom 5% of intolerance (most tolerant) that were present in at least one group of significant pathways, along with the CNV intolerance score, the number of pathways in each group, and the number of groups. (XLSX 15 kb)

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Ruderfer, D., Hamamsy, T., Lek, M. et al. Patterns of genic intolerance of rare copy number variation in 59,898 human exomes. Nat Genet 48, 1107–1111 (2016). https://doi.org/10.1038/ng.3638

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