Abstract
In recent years different types of structural variants (SVs) have been discovered in the human genome and their functional impact has become increasingly clear. Inversions, however, are poorly characterized and more difficult to study, especially those mediated by inverted repeats or segmental duplications. Here, we describe the results of a simple and fast inverse PCR (iPCR) protocol for high-throughput genotyping of a wide variety of inversions using a small amount of DNA. In particular, we analyzed 22 inversions predicted in humans ranging from 5.1 kb to 226 kb and mediated by inverted repeat sequences of 1.6–24 kb. First, we validated 17 of the 22 inversions in a panel of nine HapMap individuals from different populations, and we genotyped them in 68 additional individuals of European origin, with correct genetic transmission in ∼12 mother-father-child trios. Global inversion minor allele frequency varied between 1% and 49% and inversion genotypes were consistent with Hardy-Weinberg equilibrium. By analyzing the nucleotide variation and the haplotypes in these regions, we found that only four inversions have linked tag-SNPs and that in many cases there are multiple shared SNPs between standard and inverted chromosomes, suggesting an unexpected high degree of inversion recurrence during human evolution. iPCR was also used to check 16 of these inversions in four chimpanzees and two gorillas, and 10 showed both orientations either within or between species, providing additional support for their multiple origin. Finally, we have identified several inversions that include genes in the inverted or breakpoint regions, and at least one disrupts a potential coding gene. Thus, these results represent a significant advance in our understanding of inversion polymorphism in human populations and challenge the common view of a single origin of inversions, with important implications for inversion analysis in SNP-based studies.
Highlights
Different types of structural variants (SVs), including deletions, duplications, insertions, inversions, and translocations, have been recently discovered in the human genome and there is growing evidence of their importance in human diseases, complex traits, and evolution [1,2,3,4]
We have optimized a technique for high-throughput validation and genotyping of inversions mediated by inverted repeats
The results of our study indicate that a high proportion of these inversions are recurrent and have occurred multiple times during evolution
Summary
Different types of structural variants (SVs), including deletions, duplications, insertions, inversions, and translocations, have been recently discovered in the human genome and there is growing evidence of their importance in human diseases, complex traits, and evolution [1,2,3,4]. The knowledge of human inversions has lagged behind This is reflected in the fact that several hundred inversions have been reported in humans [4], few (,15) inversions have been characterized in greater detail [4,11,12,14,15,16,17,18,19,20,21,22]. These and other studies [23,24,25] have shown that inversions
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