Towards a complete characterization of common human polymorphic inversions and their functional effects

Structural variants (SVs) contribute substantially to genetic and phenotypic diversity, but their characterization is far from complete. Inversions are particularly interesting because they affect recombination and could have negative consequences on fertility. However, they are often missed due to their balanced nature, the repetitive sequences at their breakpoints and the fact that many are recurrent. Here, thanks to an in-depth analysis of >350 predictions from different studies, manual annotation, and accurate validation and genotyping in diverse populations, we have generated the largest and most reliable dataset of human polymorphic inversions to date, making it finally possible to determine their real functional and evolutionary impact. This unique resource totals 134 inversions, which in many cases consist of more complex rearrangements with additional insertions and deletions, and 61 inverted duplications that were used as a control. In particular, by rigorous imputation in available functional data, we have shown that many of the studied variants act as lead expression QTLs (eQTL) for different genes in multiple tissues. Moreover, several inversions are associated with epigenetic changes in chromatin accessibility, DNA methylation or histone marks. Finally, ~20% of inversions are in high linkage disequilibrium (LD) with GWAS signals, including an inversion showing frequency differences across continents that is associated with body shape and height. Remarkably, when compared to SNPs, inversions tend to be enriched in functional effects, especially the largest ones that have already been proposed to act as supergenes, which could compensate for their potential fertility costs. Therefore, these findings highlight the important role that inversions can play in many organisms and reveal previously missing variants responsible for human phenotype variability.