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
References
Abe H, Gemmell NJ (2016) Evolutionary footprints of short tandem repeats in avian promoters. Scientific reports 6:19421. doi:10.1038/srep19421
Aghajanirefah A, Nguyen LN, et al (2016) BEND3 is involved in the human-specific repression of calreticulin: Implication for the evolution of higher brain functions in human. Gene 576(1 Pt 3):577–580. doi:10.1016/j.gene.2015.10.040
Berger N, Dubreucq B (2012) Evolution goes GAGA: GAGA binding proteins across kingdoms. Biochim Biophys Acta 1819(8):863–868. doi:10.1016/j.bbagrm.2012.02.022
Bodmer W, Bonilla C (2008) Common and rare variants in multifactorial susceptibility to common diseases. Nat Genet 40(6):695–701. doi:10.1038/ng.f.136
Bouquillon S, Andrieux J et al (2011) A 5.3 Mb deletion in chromosome 18q12.3 as the smallest region of overlap in two patients with expressive speech delay. Eur J Med Genet 54(2):194–197. doi:10.1016/j.ejmg.2010.11.009
Cooper DN, Bacolla A et al (2011) On the sequence-directed nature of human gene mutation: the role of genomic architecture and the local DNA sequence environment in mediating gene mutations underlying human inherited disease. Hum Mutat 32(10):1075–1099. doi:10.1002/humu.21557
Darvish H, Nabi MO et al (2011) Exceptional human core promoter nucleotide compositions. Gene 475(2):79–86. doi:10.1016/j.gene.2010.12.013
Darvish H, Heidari A et al (2013) Biased homozygous haplotypes across the human caveolin 1 upstream purine complex in Parkinson’s disease. Journal of molecular neuroscience : MN 51(2):389–393. doi:10.1007/s12031-013-0021-9
Eckert KA, Hile SE (2009) Every microsatellite is different: intrinsic DNA features dictate mutagenesis of common microsatellites present in the human genome. Mol Carcinog 48(4):379–388. doi:10.1002/mc.20499
Emamalizadeh B, Movafagh A et al (2014) RIT2, a susceptibility gene for Parkinson’s disease in Iranian population. Neurobiol Aging 35(12):e27–e28. doi:10.1016/j.neurobiolaging.2014.07.013
Emamalizadeh B, Jamshidi J, et al (2016) RIT2 polymorphisms: is there a differential association? Mol Neurobiol. doi:10.1007/s12035-016-9815-4
Esmaeilzadeh-Gharehdaghi E, Banan M, et al (2011) Support for down-tuning of the calreticulin gene in the process of human evolution. Progress Neuro-Psychopharmacol Biol Psychiatry 35(7):1770–1773. doi:10.1016/j.pnpbp.2011.06.009
Farashi S, Ohadi M et al Decreased gene expression activity as a result of a mutation in the calreticulin gene promoter in a family case of schizoaffective disorder. Cognitive Neurodynamics: 1–6
Farokhashtiani T, Mirabzadeh A, et al (2011) Reversion of the human calreticulin gene promoter to the ancestral type as a result of a novel psychosis-associated mutation. Progress Neuro-psychopharmacol Biol Psychiatry 35(2): 541–544. doi:10.1016/j.pnpbp.2010.12.012
Faurie C, Mettling C, Ali Bchir M, Hadmoko DS, Heitz C, Lestari ED, Raymond M, Willinger M (2016) Evidence of genotypic adaptation to the exposure to volcanic risk at the dopamine receptor DRD4 locus. Sci Rep 1(6):37745
Fondon JW 3rd, Hammock EA et al (2008) Simple sequence repeats: genetic modulators of brain function and behavior. Trends Neurosci 31(7):328–334. doi:10.1016/j.tins.2008.03.006
Glessner JT, Reilly MP et al (2010) Strong synaptic transmission impact by copy number variations in schizophrenia. Proc Natl Acad Sci USA 107(23):10584–10589. doi:10.1073/pnas.1000274107
Gymrek M, Willems T et al (2016) Abundant contribution of short tandem repeats to gene expression variation in humans. Nat Genet 48(1):22–29. doi:10.1038/ng.3461
Hammock EA, Young LJ (2005) Microsatellite instability generates diversity in brain and sociobehavioral traits. Science 308(5728):1630–1634. doi:10.1126/science.1111427
Heidari A, Nariman Saleh Fam Z et al (2012) Core promoter STRs: novel mechanism for inter-individual variation in gene expression in humans. Gene 492(1):195–198. doi:10.1016/j.gene.2011.10.028
Kashi Y, King DG (2006) Simple sequence repeats as advantageous mutators in evolution. Trends Genet TIG 22(5): 253–259. doi:10.1016/j.tig.2006.03.005
Kayser M, Brauer S, Stoneking M (2013) A genome scan to detect candidate regions influenced by localnatural selection in human populations. Mol Biol Evol 20(6):893–900
Lee CH, Della NG et al (1996) Rin, a neuron-specific and calmodulin-binding small G-protein, and Rit define a novel subfamily of ras proteins. J Neurosci Off J Soc Neurosci 16(21):6784–6794
Legendre M, Pochet N et al (2007) Sequence-based estimation of minisatellite and microsatellite repeat variability. Genome Res 17(12):1787–1796. doi:10.1101/gr.6554007
Lehmann M (2004) Anything else but GAGA: a nonhistone protein complex reshapes chromatin structure. Trends Genet TIG 20(1): 15–22. doi:10.1016/j.tig.2003.11.005
Liu ZH, Guo JF, et al (2015) Assessment of RIT2 rs12456492 association with Parkinson’s disease in Mainland China. Neurobiology of aging 36(3):1600 e1609–1600 e1611. doi:10.1016/j.neurobiolaging.2014.12.012
Lu Y, Liu W et al (2015) Genetic association of RIT2 rs12456492 polymorphism and Parkinson’s disease susceptibility in Asian populations: a meta-analysis. Scientific reports 5:13805. doi:10.1038/srep13805
Lynch VJ, Wagner GP (2008) Resurrecting the role of transcription factor change in developmentalevolution. Evolution 62(9):2131–2154. doi:10.1111/j.1558-5646.2008.00440.x. (Epub 2008 Jun 28)
Melnikova L, Juge F et al (2004) Interaction between the GAGA factor and Mod(mdg4) proteins promotes insulator bypass in Drosophila. Proc Natl Acad Sci USA 101(41):14806–14811. doi:10.1073/pnas.0403959101
Mohammadparast S, Bayat H et al (2014) Exceptional expansion and conservation of a CT-repeat complex in the core promoter of PAXBP1 in primates. Am J Primatol 76(8):747–756. doi:10.1002/ajp.22266
Navaroli DM, Stevens ZH et al (2011) The plasma membrane-associated GTPase Rin interacts with the dopamine transporter and is required for protein kinase C-regulated dopamine transporter trafficking. J Neurosci Off J Soc Neurosci 31(39):13758–13770. doi:10.1523/JNEUROSCI.2649-11.2011
Nikkhah M, Rezazadeh M, et al (2016). An exceptionally long CA-repeat in the core promoter of SCGB2B2 links with the evolution of apes and Old World monkeys. Gene 576(1 Pt 1):109–114. doi:10.1016/j.gene.2015.09.070
Oh H, Slattery M et al (2013) Genome-wide association of Yorkie with chromatin and chromatin-remodeling complexes. Cell reports 3(2):309–318. doi:10.1016/j.celrep.2013.01.008
Ohadi M, Mirabzadeh A, et al (2012) Novel evidence of the involvement of calreticulin in major psychiatric disorders. Progress Neuro-Psychopharmacol Biol Psychiatry 37(2):276–281. doi:10.1016/j.pnpbp.2012.02.007
Ohadi M, Mohammadparast S et al (2012) Evolutionary trend of exceptionally long human core promoter short tandem repeats. Gene 507(1):61–67. doi:10.1016/j.gene.2012.07.001
Ohadi M, Valipour E et al (2015) Core promoter short tandem repeats as evolutionary switch codes for primate speciation. Am J Primatol 77(1):34–43. doi:10.1002/ajp.22308
Omelina ES, Baricheva EM et al (2011) Analysis and recognition of the GAGA transcription factor binding sites in Drosophila genes. Comput Biol Chem 35(6):363–370. doi:10.1016/j.compbiolchem.2011.10.008
Rezazadeh M, Gharesouran J, et al (2015a) A primate-specific functional GTTT-repeat in the core promoter of CYTH4 is linked to bipolar disorder in human. Progress Neuro-Psychopharmacol Biol Psychiatry 56:161–167. doi:10.1016/j.pnpbp.2014.09.001
Rezazadeh M, Gharesouran J et al (2015b) Dominant and protective role of the CYTH4 primate-specific GTTT-repeat longer alleles against neurodegeneration. J Mol Neurosci MN 56(3):593–596. doi:10.1007/s12031-015-0542-5
Richards AL, Leonenko G et al (2016) Exome arrays capture polygenic rare variant contributions to schizophrenia. Hum Mol Genet 25(5):1001–1007. doi:10.1093/hmg/ddv620
Schuster SC, Miller W et al (2010) Complete Khoisan and Bantu genomes from southern Africa. Nature 463(7283):943–947. doi:10.1038/nature08795
Shimojima T, Okada M, et al (2003) Drosophila FACT contributes to Hox gene expression through physical and functional interactions with GAGA factor. Genes Dev 17(13): 1605–1616. doi:10.1101/gad.1086803
Srivastava S, Puri D, et al (2013) Vertebrate GAGA factor associated insulator elements demarcate homeotic genes in the HOX clusters. Epigenet Chromatin 6(1):8. doi:10.1186/1756-8935-6-8
Tsukiyama T, Becker PB et al (1994) ATP-dependent nucleosome disruption at a heat-shock promoter mediated by binding of GAGA transcription factor. Nature 367(6463):525–532. doi:10.1038/367525a0
Valipour E, Kowsari A et al (2013) Polymorphic core promoter GA-repeats alter gene expression of the early embryonic developmental genes. Gene 531(2):175–179. doi:10.1016/j.gene.2013.09.032
Vasanthi D, Anant M, et al (2010) A functionally conserved boundary element from the mouse HoxD locus requires GAGA factor in Drosophila. Development 137(24): 4239–4247. doi:10.1242/dev.058701
Zhang X, Niu M et al (2015) RIT2 rs12456492 polymorphism and the risk of Parkinson’s disease: a meta-analysis. Neurosci Lett 602:167–171. doi:10.1016/j.neulet.2015.07.004
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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