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.
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Abbreviations
- NHP:
-
Non-human primate
- PAGE:
-
Polyacrylamide gel electrophoresis
- RIT2:
-
Ras-like without CAAX 2
- STR:
-
Short tandem repeat
- TSS:
-
Transcription start site
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This research was jointly funded by the Shahid Beheshti University of Medical Sciences and the University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
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The following authors declare that there is no conflict of interest: Babak Emamalizadeh, Abolfazl Movafagh, Hossein Darvish, Somayeh Kazeminasab, Monavvar Andarva, Pegah Namdar-Aligoodarzi, and Mina Ohadi.
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All procedures performed in studies involving human participants were conducted in accordance with the ethical standards of the institutional and/or national research committee and the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
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Communicated by S. Hohmann.
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Emamalizadeh, B., Movafagh, A., Darvish, H. et al. The human RIT2 core promoter short tandem repeat predominant allele is species-specific in length: a selective advantage for human evolution?. Mol Genet Genomics 292, 611–617 (2017). https://doi.org/10.1007/s00438-017-1294-4
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DOI: https://doi.org/10.1007/s00438-017-1294-4