Abstract
Despite many years of study into inversions, very little is known about their functional consequences, especially in humans. A common hypothesis is that the selective value of inversions stems in part from their effects on nearby genes, although evidence of this in natural populations is almost nonexistent. Here we present a global analysis of a new 415-kb polymorphic inversion that is among the longest ones found in humans and is the first with clear position effects. This inversion is located in chromosome 19 and has been generated by non-homologous end joining between blocks of transposable elements with low identity. PCR genotyping in 541 individuals from eight different human populations allowed the detection of tag SNPs and inversion genotyping in multiple populations worldwide, showing that the inverted allele is mainly found in East Asia with an average frequency of 4.7%. Interestingly, one of the breakpoints disrupts the transcription factor gene ZNF257, causing a significant reduction in the total expression level of this gene in lymphoblastoid cell lines. RNA-Seq analysis of the effects of this expression change in standard homozygotes and inversion heterozygotes revealed distinct expression patterns that were validated by quantitative RT-PCR. Moreover, we have found a new fusion transcript that is generated exclusively from inverted chromosomes around one of the breakpoints. Finally, by the analysis of the associated nucleotide variation, we have estimated that the inversion was generated ~40,000–50,000 years ago and, while a neutral evolution cannot be ruled out, its current frequencies are more consistent with those expected for a deleterious variant, although no significant association with phenotypic traits has been found so far.
Highlights
Polymorphic inversions have been known for a long time to segregate in the genomes of multiple species, ranging from insects to plants and animals, and constitute one of the most studied paradigms in evolutionary biology [1,2,3]
We have carried out a complete characterization of a new human polymorphic inversion and determined that it is specific to East Asian populations
We describe a new polymorphic inversion found at a 4.7% frequency in East Asians, which represents one of the few inversions genotyped in several worldwide populations that show a limited geographical distribution
Summary
Polymorphic inversions have been known for a long time to segregate in the genomes of multiple species, ranging from insects to plants and animals, and constitute one of the most studied paradigms in evolutionary biology [1,2,3] Given that they just change the orientation of a chromosomal segment and often do not result in gain or loss of DNA, inversions could be considered neutral variants, but far from this, their adaptive value and phenotypic effects are becoming increasingly clear. This suppression can occur both through the reduced pairing and crossing over due to the formation of inversion loops in heterozygotes, and by selection against the unbalanced gametes resulting from unique crossovers within the inverted segment In this case, the advantage of an inversion could be caused by the capture of a favorable combination of alleles maintained together in strong linkage disequilibrium (LD) due to the reduction of recombination [2,11,12]. Very few cases of position effects have been identified for polymorphic inversions in natural populations [18,21]
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