Cosmopolitan inversions have a major impact on trait variation and the power of different GWAS approaches to identify associations

The ability of genomic inversions to reduce recombination and generate linkage can have a major impact on genetically based phenotypic variation in populations. However, the increase in linkage associated with inversions can create hurdles for identifying associations between loci linked to inversions and the traits they impact. Therefore, the role of inversions in mediating genetic variation of complex traits remains to be fully understood. This study uses the fruit fly Drosophila melanogaster to investigate the impact of inversions on trait variation. We tested the effects of common inversions among a diverse assemblage of traits including aspects of behavior, morphology, and physiology, and identified that the cosmopolitan inversions In(2L)t and In(3R)Mo are associated with many traits. We compared the ability of different approaches of accounting for relatedness and inversion presence during genome-wide association to identify signals of association with SNPs. We report that commonly used association methods are underpowered within inverted regions, while alternative approaches such as leave-one-chromosome-out improve the ability to identify associations. In all, our research enhances our understanding of inversions as components of trait variation and provides insight into approaches for identifying genomic regions driving these associations.Author summary: Genomic inversions are large mutations that flip the orientation of sections of DNA, and the presence of inversions has the potential to impact many traits at once. Inversions exist in many organisms, including humans and the fruit fly Drosophila melanogaster. We take existing knowledge on Drosophila trait variation and identify several inversions which impact many kinds of traits. Approaches such as GWAS can be used to identify the DNA mutations most associated with variation in a trait of interest, but many GWAS methods do not perform well when inversions contribute to variation in phenotype. We show that a common GWAS approach in Drosophila is not only unable to find association within inversions, but is overall underpowered. In contrast, we show a different approach is better able to identify mutations within inversions that are potentially associated with fruit fly traits. These findings help scientists studying a wide range of organisms to better understand the phenotypic impact of inversions, and support the broad research of identifying gene associations within these regions of inversion.