Genomic architecture and functional effects of potential human inversion supergenes

Supergenes are involved in adaptation in multiple organisms, but they are little known in humans. Genomic inversions are the most common mechanism of supergene generation and maintenance. Here, we review the information about two large inversions that are the best examples of potential human supergenes. In addition, we do an integrative analysis of the newest data to understand better their functional effects and underlying genetic changes. We have found that the highly divergent haplotypes of the 17q21.31 inversion of approximately 1.5 Mb have multiple phenotypic associations, with consistent effects in brain-related traits, red and white blood cells, lung function, male and female characteristics and disease risk. By combining gene expression and nucleotide variation data, we also analysed the molecular differences between haplotypes, including gene duplications, amino acid substitutions and regulatory changes, and identify CRHR1, KANLS1 and MAPT as good candidates to be responsible for these phenotypes. The situation is more complex for the 8p23.1 inversion, where there is no clear genetic differentiation. However, the inversion is associated with several related phenotypes and gene expression differences that could be linked to haplotypes specific of one orientation. Our work, therefore, contributes to the characterization of both exceptional variants and illustrates the important role of inversions.This article is part of the theme issue 'Genomic architecture of supergenes: causes and evolutionary consequences'.

Automated summary

Supergenes play important roles in adaptation in various organisms, but their understanding in humans is limited. Genomic inversions are the main mechanism for generating and maintaining supergenes. This review focuses on two large inversions that serve as potential examples of human supergenes. The highly divergent haplotypes resulting from the 17q21.31 inversion of approximately 1.5 Mb are associated with multiple phenotypic effects, including brain-related traits, blood cells, lung function, and disease risk. By analyzing gene expression and nucleotide variation data, several candidate genes, such as CRHR1, KANLS1, and MAPT, have been identified to be responsible for these phenotypes. The 8p23.1 inversion is more complex, with no clear genetic differentiation, but it is associated with related phenotypes and gene expression differences. This study contributes to the understanding of exceptional variants and highlights the importance of inversions in human genomes.