Haplotype-resolved inversion landscape reveals hotspots of mutational recurrence associated with genomic disorders

Abstract

Unlike copy number variants (CNVs), inversions remain an underexplored genetic variation class. By integrating multiple genomic technologies, we discover 729 inversions in 41 human genomes. Approximately 85% of inversions <2 kbp form by twin-priming during L1-retrotransposition; 80% of the larger inversions are balanced and affect twice as many base pairs as CNVs. Balanced inversions show an excess of common variants, and 72% are flanked by segmental duplications (SDs) or mobile elements. Since this suggests recurrence due to non-allelic homologous recombination, we developed complementary approaches to identify recurrent inversion formation. We describe 40 recurrent inversions encompassing 0.6% of the genome, showing inversion rates up to 2.7*10-4 per locus and generation. Recurrent inversions exhibit a sex-chromosomal bias, and significantly co-localize to the critical regions of genomic disorders. We propose that inversion recurrence results in an elevated number of heterozygous carriers and structural SD diversity, which increases mutability in the population and predisposes to disease-causing CNVs.

Modeling the stepwise extension of recombination suppression on sex chromosomes and other supergenes through deleterious mutation sheltering

“…At the start of each simulation, we randomly sampled k genomic positions that could be used as inversion breakpoints, with k being 10, 100, 1000 or 10,000. These genomic positions represent inversion hotspots, such as those that can be generated by repeats in genomes ( 45 ). In each generation, we introduced j inversions, j being sampled from a Poisson distribution.…”

“…The number of genomic positions at which inversions can occur in natural conditions is unknown, but this number is likely to be high given the chaos of rearrangements observed in some sex and mating-type chromosomes with hundreds of different breakpoints (16,45,53,54). A recent study reported the recurrent appearance of inversions at the same positions, but also the existence of numerous potential breakpoints of inversions in human genomes (45). Moreover, chromosomal rearrangements rapidly accumulate in recently established regions of non-recombination (53) and overlapping inversions are observed on many sex chromosomes, which should prevent the restoration of recombination by reversions (16,(55)(56)(57)(58).…”

“…Given the lack of knowledge about inversion rates in natural conditions and the computation challenge represented by the simulation of complex patterns of recombination, we used reasonably high inversion rates in our sexchromosome evolution simulations, making it possible to observe the stepwise extension of a nonrecombining region within 100,000 generations. A recent study suggested that inversions may not be too rare and that inversion breakpoints may be widely distributed throughout the genome ( 45 ). The use of different inversion rates might result in much shorter or much longer times for the stepwise extension of the non-recombining region, but should not change the final outcome.…”

“…The reversion of inversions has been reported only in very rare cases in which inversions occur at specific breakpoints rich in repeated elements ( 51, 52 ), as in our simulations in which only a few possible breakpoints were present in the genome. The number of genomic positions at which inversions can occur in natural conditions is unknown, but this number is likely to be high given the chaos of rearrangements observed in some sex and mating-type chromosomes with hundreds of different breakpoints ( 16, 45, 53, 54 ). A recent study reported the recurrent appearance of inversions at the same positions, but also the existence of numerous potential breakpoints of inversions in human genomes ( 45 ).…”

“…For instance, the mean distance between two heterozygous positions is ~1000 bp in primates ( 59 ), and it has been estimated that most of mutations are probably partially recessive and deleterious ( 22, 60 ). Chromosomal rearrangements spanning hundreds of kilobases are frequently observed ( 45, 61, 62 ), and would, therefore, be expected to capture several deleterious variants.…”