The human RIT2 core promoter short tandem repeat predominant allele is species-specific in length: a selective advantage for human evolution?

Abstract

Evolutionary analyses of the critical core promoter interval support a selective advantage for expanding the length of certain short tandem repeats (STRs) in humans. We recently reported genome-wide data on human core promoter STRs that are "exceptionally long" (≥6-repeats). Near the top of the list, the neuron-specific gene, RIT2, contains one of the longest GA-STRs at 11-repeats. In the present study, we analyzed the evolutionary implications of this STR across species. We also studied this STR in a sample of 2,143 Iranian human subjects that encompassed a number of neuropsychiatric disorders and controls. We report that this GA repeat is functional and different lengths of the repeat result in significant alteration in gene expression activity. The 11-repeat allele was human specific and the sole allele detected in 110 unrelated Iranian individuals randomly selected and sequenced from our control pool. Remarkably, homozygosity for a 5-repeat allele was detected in a consanguineous, hospitalized case of schizophrenia, which significantly decreased gene expression activity (p < 5 × 10). The frequency of the 5-repeat allele in the Iranian population was calculated at <0.0001, putting this allele in the deleterious mutations category based on allele frequency. The 5-repeat allele is annotated in the Ensembl database in the heterozygous status (5/11) in one of four indigenous hunter-gatherer men sequenced from southern Africa (BUSHMAN KB1: rs113265205). The present findings indicate for the first time, selective advantage for a human-specific allele at an STR locus, and a phenomenon in which genotypes and alleles at the extreme length of STRs occur with disease only. This is a pilot study that warrants large-scale sequencing of the RIT2 core promoter STR in diseases and characteristics that are linked to the brain function.

Editorial: “Disease-Only” alleles and genotypes in complex disorders?

“…The Ras like without CAAX 2 gene (RIT2) is regulated by one of the longest STRs identified in a human gene core promoter, expansion of which may be of selective advantage in human-specific characteristics. In line with the above notion, the predominant allele of the RIT2 core promoter STR is human-specific in length [2].…”

Regulatory Architecture of the Neuronal Cacng2/Tarpγ2 Gene Promoter: Multiple Repressive Domains, a Polymorphic Regulatory Short Tandem Repeat, and Bidirectional Organization with Co-regulated lncRNAs

“…With respect to promoter dinucleotide polymorphisms in general, these are recognized to be correlated with gene expression (Bilgin Sonay et al 2015 ), being observed in numerous promoters (Sugiyama et al 2011 ; Ohadi et al 2012 ; Nikkhah et al 2015 ; Liu et al 2015 ; Emamalizadeh et al 2017 ), and forming potential “tuning knobs” of gene expression (Abe and Gemmell 2016 ; Sawaya et al 2012 , 2013 ; Vinces et al 2009 ). The reported effects of STR variation are gene-specific, resulting in either enhanced (e.g., Sugiyama et al 2011 ) or reduced (e.g., Liu et al 2015 ; Chen et al 2016 ) promoter activity, as a function of increasing dinucleotide repeat length.…”

Mapping the landscape of tandem repeat variability by targeted long read single molecule sequencing in familial X-linked intellectual disability

“…CT-repeats (or GA-repeats in complement), also known as GAGA-elements, act as chromatin remodelling mediators by disrupting and displacing pre-assembled nucleosomes [56–58]. Emamalizadeh and colleagues [59] suggested that the (GA) 11 repeat length in the promoter of RIT2 is crucial for obtaining the correct dosage of RIT2, important in regulating the neuronal function. A shorter allele (GA) 5 in homozygous state has been detected only in a proband with schizophrenia thus linking it to the disease state.…”