Support for “Disease-Only” Genotypes and Excess of Homozygosity at the CYTH4 Primate-Specific GTTT-Repeat in Schizophrenia

Khademi, Ehteram; Alehabib, Elham; Shandiz, Ehsan Esmaili; Ahmadifard, Azadeh; Andarva, Monavvar; Jamshidi, Javad; Rahimi-Aliabadi, Simin; Pouriran, Ramin; Nejad, Farhad R; Mansoori, Nader; Shahmohammadibeni, Neda; Taghavi, Shaghyegh; Shokraeian, Parasto; Akhavan‐Niaki, Haleh; Paisán-Ruı́z, Coro; Darvish, Hossein; Ohadi, Mina

doi:10.1089/gtmb.2016.0422

Cited by 18 publications

(13 citation statements)

References 28 publications

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“…Recent findings of a link between the low-frequency alleles at the extreme short and long ends of "exceptionally long" STRs with human disorders [5][6][7] Fig. 8.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously reported that approximately 2% of the human protein-coding genes contain STRs of ≥6 repeats in the critical core promoter region [3]. Preliminary findings indicate that expansion of a number of these STRs may be linked to adaptive evolutionary processes in human, and also endure the burden of certain human disorders such as schizophrenia, bipolar disorder, and Alzheimer's disease [4][5][6][7].…”

Section: Introductionmentioning

confidence: 93%

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Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

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Background: Approximately 2% of the human core promoter short tandem repeats (STRs) reach lengths of ≥6 repeats, which may in part be a result of adaptive evolutionary processes and natural selection. A single-exon transcript of the human nescient helix loop helix 2 (NHLH2) gene is flanked by the longest CA-repeat detected in a human protein-coding gene core promoter (Ensembl transcript ID: ENST00000369506.1). NHLH2 is involved in several biological and pathological pathways, such as motivated exercise, obesity, and diabetes. Methods: The allele and genotype distribution of the NHLH2 CA-repeat were investigated by sequencing in 655 Iranian subjects, consisting of late-onset neurocognitive disorder (NCD) as a clinical entity (n = 290) and matched controls (n = 365). The evolutionary trend of the CA-repeat was also studied across vertebrates. Results: The allele range was between 9 and 25 repeats in the NCD cases, and 12 and 24 repeats in the controls. At the frequency of 0.56, the 21-repeat allele was the predominant allele in the controls. While the 21-repeat was also the predominant allele in the NCD patients, we detected significant decline of the frequency (p < 0.0001) and homozygosity (p < 0.006) of this allele in this group. Furthermore, 12 genotypes were detected across 16 patients (5.5% of the entire NCD sample) and not in the controls (disease-only genotypes; p < 0.0003), consisting of at least one extreme allele. The extreme alleles were at 9, 12, 13, 18, and 19 repeats (extreme short end), and 23, 24, and 25 repeats (extreme long end), and their frequencies ranged between 0.001 and 0.04. The frequency of the 21-repeat allele significantly dropped to 0.09 in the disease-only genotype compartment (p <

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“…Recent findings of a link between the low-frequency alleles at the extreme short and long ends of "exceptionally long" STRs with human disorders [5][6][7] Fig. 8.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Afshar¹,

Adelirad²,

Kowsari³

et al. 2020

Gerontology

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“…A number of the identified STRs such as GTTT have established repressor activity [ 6 , 28 , 29 ] and are differentially expanded in certain genes in the Old World monkeys and Apes [ 14 ]. Purine STRs such as GAAA repeats are also functional in gene expression regulation, and their link to certain diseases unique to humans were previously reported [ 30 , 31 ].…”

Section: Discussionmentioning

confidence: 99%

“…Human specificity of the predominant allele of the RIT2 core promoter STR in the human species, the presence of the shortest allele of this STR (5-repeat) in hunter-gatherer humans (BUSHMAN KB1: rs113265205), the lack of this allele in the agricultural modern humans (Genome Aggregation database: gnomad.broadinstitute.org ), and its co-occurrence with schizophrenia provide the first indication of STR allele selection in humans [ 13 ]. A link between the CYTH4 core promoter STR (the longest tetranucleotide STR identified in a human gene core promoter) with the Old World monkeys and Apes and evidence of extreme “disease-only” genotypes at this STR with schizophrenia [ 14 ] provide the first link between a primate-specific STR and higher-order brain functions in human. The “exceptionally long” CA-repeat in the core promoter of SCGB2B2 is another example of directional STR expansion in the Old World monkeys and Apes [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

Genome-scale portrait and evolutionary significance of human-specific core promoter tri- and tetranucleotide short tandem repeats

et al. 2018

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BackgroundWhile there is an ongoing trend to identify single nucleotide substitutions (SNSs) that are linked to inter/intra-species differences and disease phenotypes, short tandem repeats (STRs)/microsatellites may be of equal (if not more) importance in the above processes. Genes that contain STRs in their promoters have higher expression divergence compared to genes with fixed or no STRs in the gene promoters. In line with the above, recent reports indicate a role of repetitive sequences in the rise of young transcription start sites (TSSs) in human evolution.ResultsFollowing a comparative genomics study of all human protein-coding genes annotated in the GeneCards database, here we provide a genome-scale portrait of human-specific short- and medium-size (≥ 3-repeats) tri- and tetranucleotide STRs and STR motifs in the critical core promoter region between − 120 and + 1 to the TSS and evidence of skewing of this compartment in reference to the STRs that are not human-specific (Levene’s test p < 0.001). Twenty-five percent and 26% enrichment of human-specific transcripts was detected in the tri and tetra human-specific compartments (mid-p < 0.00002 and mid-p < 0.002, respectively).ConclusionOur findings provide the first evidence of genome-scale skewing of STRs at a specific region of the human genome and a link between a number of these STRs and TSS selection/transcript specificity. The STRs and genes listed here may have a role in the evolution and development of characteristics and phenotypes that are unique to the human species.

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“…Genome-scale findings of the evolutionary trend of a number of STRs has begun to unfold their implications in respect with speciation and species-specific characteristics/phenotypes (Yuan et al 2018;Emamalizadeh et al 2017;Abe and Gemmell 2016;Bushehri et al 2016;Namdar-Aligoodarzi et al 2016;Nikkhah et al 2016;Bilgin Sonay et al 2015;Rezazadeh et al 2014;Khademi et al 2017;Mohammadparast et al 2014;Ohadi et al 2012;King et al 2012). The hypermutable nature of STRs and their large unascertained reservoir of functionality make them an ideal source of evolutionary adaptation, speciation, and disease (Hannan et al 2018;Bagshaw et al 2017;Press et al 2017;Ohadi et al2015;Valipour et al 2013;Heidari et al 2012).…”

Section: Introductionmentioning

confidence: 99%

Link Between Short tandem Repeats and Translation Initiation Site Selection

Arabfard

Kavousi

Delbari

et al. 2018

Preprint

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Recent work in yeast and humans suggest that evolutionary divergence in cis-regulatory sequences impact translation initiation sites (TISs). Cis-elements can also affect the efficacy and amount of protein synthesis. Despite their vast biological implication, the landscape and relevance of short tandem repeats (STRs)/microsatellites to the human protein-coding gene TISs remain largely unknown. Here we characterized the STR distribution at the 120 bp cDNA sequence upstream of all annotated human protein-coding gene TISs based on the Ensembl database. Furthermore, we performed a comparative genomics study of all annotated orthologous TIS-flanking sequences across 47 vertebrate species (755,956 transcripts), aimed at identifying human-specific STRs in this interval. We also hypothesized that STRs may be used as genetic codes for the initiation of translation. The initial five amino acid sequences (excluding the initial methionine) that were flanked by STRs in human were BLASTed against the initial orthologous five amino acids in other vertebrate species (2,025, in order to compare the number of events in which human-specific and non-specific STRs occurred with homologous and non-homologous TISs (i.e. ≥50% and <50% similarity of the five amino acids). We characterized human-specific STRs and a bias of this compartment in comparison to the overall (human-specific and non-specific) distribution of STRs (Mann Whitney p=1.4 x 10 -11 ). We also found significant enrichment of non-homologous TISs flanked by human-specific STRs (p<0.00001). In conclusion, our data indicate a link between STRs and TIS selection, which is supported by differential evolution of the human-specific STRs in the TIS upstream flanking sequence.

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Support for “Disease-Only” Genotypes and Excess of Homozygosity at the CYTH4 Primate-Specific GTTT-Repeat in Schizophrenia

Abstract: This indicates that STR genotypes that are absent in the control group may be risk factors for SCZ. Future studies are warranted to test the significance of our findings.

Cited by 18 publications

References 28 publications

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Natural Selection at the NHLH2 Core Promoter Exceptionally Long CA-Repeat in Human and Disease-Only Genotypes in Late-Onset Neurocognitive Disorder

Genome-scale portrait and evolutionary significance of human-specific core promoter tri- and tetranucleotide short tandem repeats

Link Between Short tandem Repeats and Translation Initiation Site Selection

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