Discovery of human inversion polymorphisms by comparative analysis of human and chimpanzee DNA sequence assemblies

Abstract

With a draft genome-sequence assembly for the chimpanzee available, it is now possible to perform genome-wide analyses to identify, at a submicroscopic level, structural rearrangements that have occurred between chimpanzees and humans. The goal of this study was to investigate chromosomal regions that are inverted between the chimpanzee and human genomes. Using the net alignments for the builds of the human and chimpanzee genome assemblies, we identified a total of 1,576 putative regions of inverted orientation, covering more than 154 mega-bases of DNA. The DNA segments are distributed throughout the genome and range from 23 base pairs to 62 mega-bases in length. For the 66 inversions more than 25 kilobases (kb) in length, 75% were flanked on one or both sides by (often unrelated) segmental duplications. Using PCR and fluorescence in situ hybridization we experimentally validated 23 of 27 (85%) semi-randomly chosen regions; the largest novel inversion confirmed was 4.3 mega-bases at human Chromosome 7p14. Gorilla was used as an out-group to assign ancestral status to the variants. All experimentally validated inversion regions were then assayed against a panel of human samples and three of the 23 (13%) regions were found to be polymorphic in the human genome. These polymorphic inversions include 730 kb (at 7p22), 13 kb (at 7q11), and 1 kb (at 16q24) fragments with a 5%, 30%, and 48% minor allele frequency, respectively. Our results suggest that inversions are an important source of variation in primate genome evolution. The finding of at least three novel inversion polymorphisms in humans indicates this type of structural variation may be a more common feature of our genome than previously realized.

A chromosome 10 variant with a 12 Mb inversion [inv(10)(q11.22q21.1)] identical by descent and frequent in the Swedish population

“…The proximal breakpoint is located in a long terminal repeat. Previous analysis of cytogenetic and submicroscopic inversion breakpoint regions show that repetitive elements, high sequence similarity to the opposite breakpoint, pseudogenes, gene desserts, segmental duplications and co-localization with fragile sites are over-represented [Feuk et al, 2005;Schmidt et al, 2005;Tuzun et al, 2005]. Although both breakpoints identified in our study are located within or adjacent to repeats, they showed no strong homologies to each other from sequence analysis.…”

“…Detailed structural analysis of submicroscopic inversion variants indicates that they frequently origin from non-allelic homologous rearrangements between repeated and re-iterated sequences or duplicons [Shaw and Lupski, 2004;Bansal et al, 2007]. Recent progress in genomics indicates that most polymorphic inversions span minor regions down to a few kilobases of DNA [Feuk et al, 2005;Tuzun et al, 2005]. These inversions constitute a large part of the normal genomic variation among humans and may occur frequently as somatic events [Flores et al, 2007].…”

Characterizing polymorphic inversions in human genomes by single-cell sequencing

“…Other than sequence variants, structural polymorphisms such as copy number variants (including insertions, deletions, and duplications) and copy-neutral genomic rearrangements (such as translocations and inversions) play major roles in human biology and health (Stankiewicz and Lupski 2010;Alkan et al 2011). Indeed, polymorphic rearrangements are a common feature of the human genome (Pang et al 2010) and are implicated in speciation (Feuk et al 2005;Zody et al 2008), population diversification (Stefansson et al 2005;Alves et al 2014), and many complex diseases, including neurological disorders and cancers (Antonarakis et al 1995;Bondeson et al 1995;Koolen et al 2006;Shaw-Smith et al 2006;Sharp et al 2008;Tam et al 2008;Antonacci et al 2009;Salm et al 2012). However, few human inversions have been studied comprehensively to date, and the phenotypic consequences and clinical relevance of most remain undefined (Feuk 2010;Alkan et al 2011;Alves et al 2012;Martinez-Fundichely et al 2014).…”

The discovery of human genetic variations and their use as disease markers: past, present and future

“…However, their results were not placed in the DGV. 100 This, together with the study by Feuk et al (2005) 99 , also provided some supporting evidence that a considerable portion of their detected inversions were flanked by highly homologous repeats or segmental duplications. This suggests that segmental duplications could be the favorite spots mediating the chromosomal rearrangements that generate inversions.…”

“…Rather, several different strategies and approaches have been taken to try to identify inversions in the human genome. For example, Feuk et al 99 discovered regions that are inverted between the chimpanzee and human genomes by performing comparative analysis of their DNA sequence assemblies. In the study, they identified about 1600 putative regions of inverted orientation in the genomes that covered 4150 megabases of DNA sequence.…”