title: 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 × 10-6). 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.
authors.affiliation: Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.|Department of Medical Genetics, Medical Faculty, Tabriz University of Medical Sciences, Tabriz, Iran.
authors.forename: Babak
authors.initials: B
authors.lastname: Emamalizadeh
authors.affiliation: Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Abofazl
authors.initials: A
authors.lastname: Movafagh
authors.affiliation: Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Darvish
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Science, Tehran, Iran.
authors.forename: Somayeh
authors.initials: S
authors.lastname: Kazeminasab
authors.affiliation: Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
authors.forename: Monavvar
authors.initials: M
authors.lastname: Andarva
authors.affiliation: Shahid Chamran University of Ahvaz, Ahvaz, Iran.
authors.forename: Pegah
authors.initials: P
authors.lastname: Namdar-Aligoodarzi
authors.affiliation: Iranian Research Center on Aging, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran. mi.ohadi@uswr.ac.ir.
authors.forename: Mina
authors.initials: M
authors.lastname: Ohadi
mesh_terms: D000818:Animals; D019143:Evolution, Molecular; D005787:Gene Frequency / Q000235:genetics; D005838:Genotype; D006801:Humans; D007492:Iran; D018895:Microsatellite Repeats / Q000235:genetics*; D020559:Monomeric GTP-Binding Proteins / Q000235:genetics*; D010865:Pilot Projects; D011323:Primates / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012559:Schizophrenia / Q000235:genetics*; D013045:Species Specificity
chemical_list: D020559:Monomeric GTP-Binding Proteins; C583559:RiT2 protein, human
keywords: Human specific; RIT2; Schizophrenia; Short tandem repeat