Human gephyrin is encompassed within giant functional noncoding yin-yang sequences.

Sharlee Climer,Weixiong Zhang,Alan R Templeton

doi:10.1038/ncomms7534

Sharlee Climer, Weixiong Zhang + Show 1 more

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https://doi.org/10.1038/ncomms7534

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Abstract

Gephyrin is a highly-conserved gene that is vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis, and other diverse functions. Its specific function is intricately regulated and its aberrant activities have been observed for a number of human diseases. Here we report a remarkable yin-yang haplotype pattern encompassing gephyrin. Yin-yang haplotypes arise when a stretch of DNA evolves to present two disparate forms that bear differing states for nucleotide variations along their lengths. The gephyrin yin-yang pair consists of 284 divergent nucleotide states and both variants vary drastically from their mutual ancestral haplotype, suggesting rapid evolution. Several independent lines of evidence indicate strong positive selection on the region and suggest these high-frequency haplotypes represent two distinct functional mechanisms. This discovery holds potential to deepen our understanding of variable human-specific regulation of gephyrin while providing clues for rapid evolutionary events and allelic migrations buried within human history.

Highlights

Gephyrin is a highly conserved gene that is vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis and other diverse functions
Gephyrin is indispensable for molybdenum cofactor (MoCo) biosynthesis, as it is necessary for the insertion of molybdenum during this essential process[3]
In their 2010 paper, Curtis and Vine[16] determined 20 genomic regions that had the largest number of subjects showing an region of homozygosity (ROH) and studied the haplotypes of the 9 single-nucleotide polymorphisms (SNPs) at the centre of each of these regions, observing that the haplotypes showed significant excess disparity, that is, a tendency for pairs to simultaneously differ at multiple SNPs

Summary

Introduction

Gephyrin is a highly conserved gene that is vital for the organization of proteins at inhibitory receptors, molybdenum cofactor biosynthesis and other diverse functions. ROHs are correlated with linkage disequilibrium (LD) and have been observed to sometimes bear markedly disparate haplotypes[17] In their 2010 paper, Curtis and Vine[16] determined 20 genomic regions that had the largest number of subjects showing an ROH and studied the haplotypes of the 9 single-nucleotide polymorphisms (SNPs) at the centre of each of these regions, observing that the haplotypes showed significant excess disparity, that is, a tendency for pairs to simultaneously differ at multiple SNPs. The term yin–yang haplotypes was coined to capture the polarity of such structures when a 24-SNP pattern for which two haplotypes with differing states at each site and a combined frequency of 0.50 was discovered by Zhang et al.[18] Curtis and Vine[16] noted that the ten most common haplotypes for the nine SNPs in the gephyrin region had a combined frequency of 0.67, indicating surprisingly little diversity of haplotypes. Park[19] noted the uniqueness of this region, but the underlying yin–yang pattern went undetected

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