Genomic architecture and functional effects of potential human inversion supergenes

Abstract

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’.

Rescue of the increased susceptibility to Mild Chronic Oxidative Stress of iNeurons carrying the MAPT Chromosome 17q21.3 H1/H1 risk allele by FDA-approved compounds

“…GWAS have consistently identified the MAPT-17q21.31 locus (H1 -H2) haplotypes as a common risk factor for NDD, including tauopathies such as PSP, CBD and AD (Rademakers et Campoy et al, 2022). Therefore, we performed a combinatory study of genetic variation within the context of cellular oxidative stress, another major risk factor in many NDD (Andersen, 2004;Shukla et al, 2011;Salim, 2017).…”

“…This locus occurs in humans as two haplotypes, H1 (direct orientation) and H2 (inverted orientation) which show no recombination between them over a region approximately 1.8 Mb and contains several genes including, MAPT , KAT8 regulatory NSL complex subunit 1 ( KANLS1 ), Corticotropin releasing hormone receptor 1 ( CRHR1 ), Saitohin ( STH ) and N-ethylmaleimide sensitive factor vesicle fusing ATPase ( NSF ) genes (Pittman et al ., 2004; Caffrey and Wade-Martins 2007; Bowles et al ., 2022). The major H1 haplotype is considered as the ancestral haplotype while the minor H2 allele is present in 20 % of individuals of European ancestry, is rare in Africans and almost absent in East Asians (Stefansson et al ., 2005; Hardy et al ., 2005 ; Campoy et al ., 2022).…”

“…The H2 haplotype has been subject to recurrent microdeletions associated with the 17q21.31 microdeletion syndrome (Rao et al ., 2010). Initial studies focused largely on the differential expression of MAPT (Rademakers et al ., 2005; Caffrey et al ., 2006; Caffrey et al ., 2007; Allen et al ., 2014) and identified the SNPs rs17651213, rs1800547 (Lai et al ., 2017) and rs242561 (Wang et al ., 2016) as modulators of MAPT expression, evidence is emerging that other genes at the locus also showed differential expression between the haplotypes (de Jong et al ., 2012; Bowles et al ., 2022 Campoy et al ., 2022). Despite the strong genetic correlation of the MAPT 17q21.31 locus haplotypes with NDD, up until now there is no conclusive functional experimental evidence linking the MAPT 17q21.31 locus haplotypes with distinct molecular consequences leading to neurodegeneration.…”

Genomic architecture of supergenes: connecting form and function

“…Campoy et al . [ 64 ] review and analyse data from both GWAS and functional analyses to understand the phenotypic effects of two large inversions in humans that might likely represent supergenes. One of these inversions, 17q21.31, is associated with multiple complex phenotypes, including brain-related traits, red and white blood cells, lung function, male and female-specific traits, and disease risk.…”

Environmental profiles of urban living relate to regional brain volumes and symptom groups of mental illness through distinct genetic pathways

“…These moderating genes are located in two genomic loci of chromosome 17q21.3 and 18q21.2. Notably, the chromosome 17q21.3 genomic locus is the site of a human supergene candidate, a cluster of tightly linked functional genetic elements spanning approximately 900 kb that control balanced phenotypes and are inherited as a unit 61 . Haplotypes of this cluster have been associated with brain morphology and different cognitive and behavioural traits, including depressive behaviour, neuroticism and risk taking behaviour 62,63 .…”