Structural variants exhibit widespread allelic heterogeneity and shape variation in complex traits

Mahul Chakraborty,J J Emerson,Stuart J Macdonald,Anthony D Long

doi:10.1038/s41467-019-12884-1

Mahul Chakraborty, J J Emerson + Show 2 more

Open Access

https://doi.org/10.1038/s41467-019-12884-1

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Abstract

It has been hypothesized that individually-rare hidden structural variants (SVs) could account for a significant fraction of variation in complex traits. Here we identified more than 20,000 euchromatic SVs from 14 Drosophila melanogaster genome assemblies, of which ~40% are invisible to high specificity short-read genotyping approaches. SVs are common, with 31.5% of diploid individuals harboring a SV in genes larger than 5kb, and 24% harboring multiple SVs in genes larger than 10kb. SV minor allele frequencies are rarer than amino acid polymorphisms, suggesting that SVs are more deleterious. We show that a number of functionally important genes harbor previously hidden structural variants likely to affect complex phenotypes. Furthermore, SVs are overrepresented in candidate genes associated with quantitative trait loci mapped using the Drosophila Synthetic Population Resource. We conclude that SVs are ubiquitous, frequently constitute a heterogeneous allelic series, and can act as rare alleles of large effect.

Highlights

It has been hypothesized that individually-rare hidden structural variants (SVs) could account for a significant fraction of variation in complex traits
Despite claims that a significant proportion of complex trait variation in humans, model organisms, and agriculturally important animals and plants is likely due to rare SVs of large effect[11], systematic inquiry of this hypothesis has been impeded by genotyping approaches attuned to SNP detection[21]
The value of comprehensive SV detection is underscored by the presence of SVs in ~50% of the candidate genes underlying mapped Drosophila quantitative trait locus (QTL), and by the observation that a large fraction of Drosophila genes harbor multiple rare SV alleles

Summary

Introduction

It has been hypothesized that individually-rare hidden structural variants (SVs) could account for a significant fraction of variation in complex traits. We assembled the genome of Oregon-R, an outbred stock widely used as a “wild-type” strain both by Drosophila geneticists and by large scale community projects like modENCODE26–28 Using these reference quality genome assemblies, we show that SVs are common in D. melanogaster genes, with almost one third of diploid individuals harboring an SV in genes larger than 5 kb, and more than a third of burdened genes carrying multiple SVs. The site frequency spectrum (SFS) of SV alleles relative to amino acid polymorphisms suggests that SVs are under stronger purifying selection, and are more likely to impact phenotype than nonsynonymous SNPs. We further show that a number of functionally important genes harbor previously hidden SVs likely to affect complex phenotypes (e.g., Cyp6g1, Drsl[5], Cyp28d1, Cyp28d2, InR, and Gss1&2). We conclude that SVs are pervasive in genomes, frequently manifest as heterogeneous allelic series affecting the same gene, and exhibit all the properties that make them prime candidates for being rare alleles of large effect

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