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

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.

Topologically associating domains and their role in the evolution of genome structure and function in Drosophila

“…Thus, our results from a genus-wide genome dataset demonstrate that at least a considerable fraction of TAD structure, if not most, in the Drosophila genome is preserved and chromosomal arrangements resulting in their disruption is constrained. polymorphic SVs that detected within 14 D. melanogaster strains (Chakraborty et al 2019(Chakraborty et al , 2018 and 2) between species and/or divergent (~3 million years) SVs that detected in the three species ( D. simulans, D. sechellia, and D. mauritiana ) of the Drosophila simulans clade (Chakraborty et al 2020) . Both are relative to the reference genome assembly of D.…”

“…We also compared the gene expression pattern across 7 tissus in both sexes between D. melanogaster and D. pseudoobscura to see whether evolutionary TAD arrangements were associated with gene expression divergence. Finally, we used high-confident structural variants identified from reference-quality genome assemblies in both intraspecies (14 D. melanogaster strains) (Chakraborty et al 2019(Chakraborty et al , 2018 and…”

Generating high quality assemblies for genomic analysis of transposable elements

“…Long reads usually have high error rates, and assemblies based on these reads may thus also contain appreciable amounts of errors (Sović et al, 2016;Vaser et al, 2017). Following recommendations of previous works (Solares et al, 2018;Chakraborty et al, 2019;Ellison and Cao, 2020), we aimed to reduce the error rate by polishing the assembly with Racon (long reads) (Vaser et al, 2017) and Pilon (short reads) (Walker et al, 2014). Polishing algorithms align reads to an assembly and infer the consensus sequence Assemblies were either based on a random subset of the reads (random) or on the longest reads (longest).…”

“…To illustrate this, we estimated CUSCO values for several publicly available assemblies of different D. melanogaster strains (supplementary fig. 10; (McCoy et al, 2014;Vicoso and Bachtrog, 2015;Anreiter et al, 2017;Singhal et al, 2017;Chakraborty et al, 2019;Ellison and Cao, 2020)). Assemblies based on ONT and PacBio long reads have a similar quality than our assemblies of Pi2 and Canton-S (supplementary fig.…”

“…10). Interestingly, an assembly based on synthetic long reads (Illumina TruSeq) has a much lower CUSCO value than the other long-read based assemblies ( supplementary fig 10; ( McCoy et al, 2014;Ellison and Cao, 2020;Chakraborty et al, 2019)). As expected, assemblies based on Illumina short reads have much smaller CUSCO values than assemblies based on long reads (supplementary fig.…”