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

• Published in: Molecular genetics and genomics : MGG Vol. 292; no. 3; pp. 611 - 617
• Main Authors: Emamalizadeh, Babak, Movafagh, Abofazl, Darvish, Hossein, Kazeminasab, Somayeh, Andarva, Monavvar, Namdar-Aligoodarzi, Pegah, Ohadi, Mina
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.06.2017; Springer Nature B.V
• Subjects: Alleles; Animal Genetics and Genomics; Animals; Biochemistry; Biomedical and Life Sciences; brain; Evolution; Evolution, Molecular; Gene expression; gene expression regulation; Gene frequency; Gene Frequency - genetics; Genomes; Genotype; Genotypes; heterozygosity; homozygosity; Human Genetics; Humans; Iran; Life Sciences; loci; men; Mental disorders; Microbial Genetics and Genomics; microsatellite repeats; Microsatellite Repeats - genetics; Monomeric GTP-Binding Proteins - genetics; mutation; Original Article; Pilot Projects; Plant Genetics and Genomics; Population genetics; Primates - genetics; promoter regions; Promoter Regions, Genetic - genetics; Schizophrenia; Schizophrenia - genetics; Short tandem repeats; Southern Africa; Species Specificity; Iran; Southern Africa; Schizophrenia; RIT2; Human specific; Short tandem repeat
• ISSN: 1617-4615; 1617-4623
• DOI: 10.1007/s00438-017-1294-4

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.