Functional Impact and Evolution of a Novel Human Polymorphic Inversion That Disrupts a Gene and Creates a Fusion Transcript

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 ~40,00050,000 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.

.... 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

... could affect genes and modify gene expression levels, although evidence of this came only from laboratory mutants. In humans, a few inversions have been shown to associate with expression differences, but in all cases the molecular causes have remained elusive. Here, we have carried out a complete characterization of a new human polymorphic inversion and determined that it is specific to East Asian populations. In addition, we demonstrate that it disrupts the ZNF257 gene and, through the

... complete LD with the inversion ( r 2 = 1). For these three SNPs, which span 400.8 kb, all Std chromosomes carry the ancestral reference alleles ( Fig 1 ) while the five heterozygote individuals are the only ones with the alternative alleles, also in heterozygosis. Two tag SNPs are located within the inverted sequence in intergenic regions and the third one right outside, in an intron of gene ZNF257 ( Fig 1 ). The analysis of the recently released SNP calls for 2,535 genomes included in 1000GP Phase 3

... in Table 1 . Functional consequences of the inversion The HsInv0379 inverted segment contains three protein-coding genes: ZNF100 , ZNF43 and ZNF208 and at least one long intergenic non-coding RNA (reported in GENCODE v19 gene annotation). A fourth protein-coding gene, ZNF257 , appears to be disrupted by BP2 ( Fig 1 ). ZNF257 encodes a transcription factor with a Krppel -associated box (KRAB) repressor domain and 13 zinc fingers. This gene has two main transcripts of 3,520 and 3,641 nucleotides, which are transcribed from the same promoter but differ in the presence of an extra non-coding second exon ( Fig 3 ). The inversion removes the first two exons as well as the promoter of this gene, which are relocated 415 kb away in the Inv chromosomes. Thus, total ZNF257 expression (both isoforms included) was quantified by quantitative PCR (qPCR) in lymphoblastoid cell lines (LCLs) of 15 Std / Std and 11 Std / Inv individuals from the CHB and JPT populations, plus the Inv/Inv homozygote (CDX). A 2.9-fold decrease ( P = 0.0047) was found in the inversion carriers compared to the homozygote Std individuals and no expression was detected in the Inv/Inv individual ( Fig 3 and S2 Fig ), indicating that, as expected, this gene is not expressed from the Inv chromosomes. However, five Std / Std individuals showed an extremely low ZNF257 expression, comparable to the levels in inversion carriers ( S2 Fig ). These individuals are all from the CHB population and most likely carry some regulatory variant in cis or trans that causes a lower expression of ZNF257 not related to the presence of the inversion. In fact, an analysis of Geuvadis RNA-Seq data [ 36 ] in LCLs from European and YRI populations (which include only Std/Std homozygotes) indicates that ZNF257 is among the top 10% genes with highest variation in expression among those with similar low expression levels ( S3 Fig ). In addition, several studies including the recent results from the GTEx project [ 36 , 37 ] suggest the existence

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Gene: ZNF257 - zinc finger protein 257 - (NCBI)

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