Structural variants exhibit allelic heterogeneity and shape variation in complex traits

Abstract

Despite extensive effort to reveal the genetic basis of complex phenotypic variation, studies typically explain only a fraction of trait heritability. It has been hypothesized that individually rare hidden structural variants (SVs) could account for a significant fraction of variation in complex traits. To investigate this hypothesis, we assembled 14Drosophila melanogaster genomes and systematically identified more than 20,000 euchromatic SVs, of which ~40% are invisible to high specificity short read genotyping approaches. SVs are common in Drosophila genes, with almost one third of diploid individuals harboring an SV in genes larger than 5kb, and nearly a quarter harboring multiple SVs in genes larger than 10kb. We show that SV alleles are rarer than amino acid polymorphisms, implying that they are more strongly deleterious. A number of functionally important genes harbor previously hidden structural variants that likely affect complex phenotypes (e.g., Cyp6g1, Drsl5, Cyp28d1&2, InR, and Gss1&2).Furthermore, SVs are overrepresented in quantitative trait locus candidate genes from eight Drosophila Synthetic Population Resource (DSPR) mapping experiments. We conclude that SVs are pervasive in genomes, are frequently present as heterogeneous allelic series, and can act as rare alleles of large effect.

Polygenic adaptation to an environmental shift: temporal dynamics of variation under Gaussian stabilizing selection and additive effects on a single trait

“…It may also be of interest to explore non-additive genetic models in future work. In particular, models of non-complementing recessive effects within genes are a specific class of models with epistasis that deserve consideration due to their connection with observations of allelic heterogeneity underlying variation in complex traits (C lark , 1998; T hornton et al , 2013; S anjak et al , 2017; G ruber and L ong , 2009; K ing et al , 2014; L ong et al , 2014; M cClellan and K ing , 2010; C hakraborty et al , 2018). Acknowledging the focus on the standard additive model, the current work is best viewed as an investigation of a central concern in molecular population genetics (the effect of natural selection on linked neutral variation) having replaced the standard model of that sub-discipline with the standard model of evolutionary quantitative genetics.…”

A high-quality genome assembly from a single, field-collected spotted lanternfly (Lycorma delicatula) using the PacBio Sequel II system

“…The ability to generate genomes de novo from field-collected arthropods makes high-quality genomes accessible for many more species. This approach also enables comprehensive comparisons of genetic diversity within and between populations without the bias from previous single reference-based studies [16] and allows generation of a diploid genome assembly that more closely captures the organism's biology [23].…”

A High-Quality Genome Assembly from a Single, Field-collected Spotted Lanternfly (Lycorma delicatula) using the PacBio Sequel II System

“…The ability to generate genomes de novo from field-collected arthropods makes high-quality genomes accessible for many more species. This approach also enables comprehensive comparisons of genetic diversity within and between populations without the bias from single reference-based studies [15] and allows generation of a diploid genome assembly that more closely captures the organism's biology [22]. Library preparation and sequencing.…”

“…Arthropod genome assembly projects face unique challenges stemming from their small body size and high heterozygosity. Due to the limited quantities of genomic DNA that can be extracted from a small-bodied animal, researchers may pool multiple individuals, such as by generating NGS libraries of different insert sizes, each from a different individual [10,13], or by pooling multiple individuals for a single long-read sequencing library from an iso-female laboratory strain [14][15][16][17][18] or colony [5,19]. Pooling introduces multiple haplotypes into the sample and complicates the assembly and curation process [19], and while this issue may be ameliorated by inbreeding it is not always an option for organisms that cannot be cultured in the laboratory.…”