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

Abstract

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 <

Natural selection at the RASGEF1C (GGC) repeat in human and divergent genotypes in late-onset neurocognitive disorder.

“…A number of divergent genotypes were detected in the NCD group only. Evidence of natural selection for an abundant allele has been previously reported by our group in the instance of the exceptionally long CA-repeat in the core promoter of the human NHLH2 gene, and enrichment of genotypes lacking the predominantly abundant allele (the 21-repeat) in patients a icted with late-onset NCD 1 . It is commonly assumed that genes in uencing health in later life are not subject to natural selection.…”

Directional Decremental Abundance of (GA)9 and (GA)11 Blocks in Primate Speciation

“…The emerging comparative and functional analyses support adaptive evolutionary patterns for the expansion of a number of STRs, and the co-occurrence of alleles at the extreme ends of these STRs with major human cognitive disorders (10,12,(29)(30)(31). Recent reports indicate that STR length in uences expression quantitative trait loci (eQTL) associations (32).…”

Novel biological implication of a strictly monomorphic GCC repeat in the human PRKACB gene

“…Significant divergence has also been observed with various CA-repeat lengths in the case of the human NHLH2 gene 9 . The above findings indicate that exceptionally long GCC/GGC repeats might have evolved to exert epigenetic effects (epigenetic knobs) without changing the structure of the region.…”

“…Because of their polymorphic nature and plasticity, these elements provide an efficient source of variation at the inter-and intraspecies levels [1][2][3][4][5][6] . Accumulating evidence indicates that certain STRs may be associated with selective advantage in human and other species [7][8][9][10] . Among the exceptionally long STRs spanning the core promoter and 5′ untranslated region (UTR) of human protein-coding genes, the protein kinase cAMP-activated catalytic subunit beta (PRKACB) gene contains one of the longest GCC-repeats, at 7-repeats 5 .…”