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

Afshar, Hossein; Adelirad, Fatemeh; Kowsari, Ali; Kalhor, Neda; Delbari, Ahmad; Najafipour, Reza; Foroughan, Mahshid; Bozorgmehr, Ali; Khamse, Safoura; Nazaripanah, Neda; Ohadi, Mina

doi:10.1159/000509471

Cited by 21 publications

(15 citation statements)

References 38 publications

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“…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.…”

Section: Discussionsupporting

confidence: 61%

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

Jafarian

Khamse

Afshar

et al. 2021

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Expression dysregulation of the neuron-specific gene, RASGEF1C (RasGEF Domain Family Member 1C), occurs in late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GGC)13, spanning its core promoter and 5′ untranslated region (RASGEF1C-201 ENST00000361132.9). Here we sequenced the (GGC)-repeat in a sample of human subjects (N=269), consisting of late-onset NCDs (N=115) and controls (N=154). We also studied the status of this STR across various primate and non-primate species based on Ensembl 103. The 6-repeat allele was the predominant allele in the controls (frequency=0.85) and NCD patients (frequency=0.78). The NCD genotype compartment consisted of an excess of genotypes that lacked the 6-repeat (divergent genotypes) (Mid-P exact=0.004). A number of those genotypes were not detected in the control group (Mid-P exact=0.007). The RASGEF1C (GGC)-repeat expanded beyond 2-repeats specifically in primates, and was at maximum length in human. We conclude that there is natural selection for the 6-repeat allele of the RASGEF1C (GGC)-repeat in human, and significant divergence from that allele in late-onset NCDs. STR alleles that are predominantly abundant in human and genotypes that deviate from those alleles are underappreciated features, which may have deep evolutionary and pathological consequences in human.

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Section: Discussionsupporting

confidence: 61%

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

Jafarian

Khamse

Afshar

et al. 2021

Preprint

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“…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).…”

Section: Discussionmentioning

confidence: 93%

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

Khamse

Arabfard

Salesi

et al. 2021

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Background: Recent evidence indicates that expansion of a number of short tandem repeats (STRs) may be a result of natural selection. The human neuron-specific genes, RIT2 and GPM6B, contain two of the longest GA-STRs at 11 and 9-repeats, respectively, the length ranges of which are functional, and exceedingly rare repeats at the extreme end of those STRs occur with major human disorders. To examine the evolutionary trend of (GA)11 and (GA)9 blocks, two sets of chromosomal regions (each spanning 10 Mb of genomic DNA) across all chromosomes, were searched for those blocks across rodent and primate orders. We also sequenced the RIT2 and GPM6B STRs in 600 human subjects, consisting of late-onset neurocognitive disorder (n=200), multiple sclerosis (n=100), and controls (n=200). Results: We detected a directional decremental abundance of (GA)11 and (GA)9 blocks, matching the phylogenetic distance of the selected species as follows: mouse>macaque>great apes (p=0.000006). The RIT2 and GPM6B GA-repeats were at strict lengths of 11 and 9-repeats in human, respectively, and were predominantly human-specific in formula. Exception included a 9/11 genotype of the RIT2 GA-STR in an isolate case of multiple sclerosis. Conclusion: We report the first evidence of massive directional trend of STRs linking to speciation. Genes such as RIT2 and GPM6B may be suitable candidates to explore the evolutionary impact of STR blocks.

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“…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.…”

Section: Discussionmentioning

confidence: 96%

“…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 .…”

Section: Introductionmentioning

confidence: 99%

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

Khamse¹,

Jafarian²,

Bozorgmehr³

et al. 2021

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Across human protein-coding genes, PRKACB (Protein Kinase CAMP-Activated Catalytic Subunit Beta) contains one of the longest GCC-repeats, and is predominantly expressed in the brain. Here we studied this STR in 300 human subjects, consisting of late-onset neurocognitive disorder (NCD) (N = 150) and controls (N = 150). We also studied the impact of this STR on the three-dimensional structure of DNA. While the PRKACB GCC-STR was strictly monomorphic at 7-repeats, we detected two 7/8 genotypes only in the NCD group. In comparison to all other lengths, (GCC)7 had the least effect on the three-dimensional structure of DNA, evidenced by minimal divergence between 0 and 7-repeats (divergence score = 0.04) and significant divergence between 0 and 8 repeats (divergence score = 0.50). A similar inert effect to the GCC-repeat was not detected in other classes of STRs such as GA and CA repeats. In conclusion, we report monomorphism of an exceptionally long GCC repeat in the PRKACB gene in human, its inert effect on DNA structure, and divergence in two cases of late-onset NCD. This is the first indication of natural selection for an exceptionally long monomorphic GCC-repeat, which probably evolved to function as an “epigenetic knob”, without changing the regional DNA structure.

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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

Cited by 21 publications

References 38 publications

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

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

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

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

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