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

Abstract Background While 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. Results Following 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). Conclusion Our 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

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

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 < 0.0001). Evolutionarily, while the maximum length of the NHLH2 CA-repeat was 11 repeats in non-primates, this CA-repeat was �14 repeats in primates and reached maximum length in human. Conclusion: We propose a novel locus for late-onset NCD at the NHLH2 core promoter exceptionally long CA-STR and natural selection at this locus. Furthermore, there was indication of genotypes at this locus that unambiguously linked to late-onset NCD. This is the first instance of natural selection in favor of a predominantly abundant STR allele in human and its differential distribution in late-onset NCD. © 2020 The Author(s) Published by S. Karger AG, Basel

Evaluation of a Persian version of the Adelaide driving self-efficacy scale among Iranian older adults

Objective: Our aim in the present study was to estimate the psychometric properties of the full-length Adelaide driving self-efficacy scale (ADSES) for use among community-based resident older adults in Tehran, Iran. Methods: We recruited older adults (60+ years) from various sampling units nested in the Tehran district�s general urban population (20 subjects/questionnaire-item). The questionnaire was translated and back-translated by using recommended pathways. Multiple forms of validity and reliability, including Cronbach alpha, were estimated. Also, we measured intra-class correlation coefficient, and did confirmatory factor analysis (CFA). Results: A total of 243 participants (mean age: 65.8, 95CI 65.4�66.3) met our inclusion criteria. For ADSES, the alpha coefficient was 0.77, the intraclass correlation coefficient was 0.97 (95 CI: 0.95�0.98), and the average item-test correlation was 0.67. Upon CFA, we found a 0.95 comparative fit index, a coefficient of determination = 92.6, and standardized size of the residual = 0.04. Conclusion: Our Persian language ADSES was found to have adequate validity and factor structure parameters for evaluating driving self-efficacy among community-based older adults in a non-western context. Our questionnaire is an essential first step toward evaluating driving self-efficacy among older adults, especially where no such tool is available, to help develop driving self-efficacy as a healthy aging measure. © 2021 Taylor & Francis Group, LLC