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

Bernhart

et al. 2022

Preprint

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Across numerous primate species and tissues, SMAD9 (SMAD Family Member 9) reaches the highest level of expression in the human brain. This gene contains a (GCC) short tandem repeat (STR) at the interval between + 1 and + 60 of the transcription start site, which is in the 1st percent of high-ranking (GCC)-repeats in respect of length. Here we sequenced this (GCC)-repeat in 396 Iranian individuals, consisting of late-onset neurocognitive disorder (NCD) (N = 181) and controls (N = 215). We detected two predominantly abundant alleles of 7 and 9 repeats, forming 96.2% of the allele pool. The ratio of the (GCC)7 and (GCC)9 alleles was in the reverse order in the NCD group versus controls (p = 0.005), resulting from excess of (GCC)7 in the NCD group (p = 0.003) and the 9-repeat in the controls (p = 0.01). Five genotypes, predominantly consisting of (GCC)7 and lacking (GCC)9 were detected in the NCD group only (p = 0.008). Those patients received probable diagnoses of Alzheimer’s disease and/or cerebrovascular dementia. Five genotypes consisting of (GCC)9 and lacking (GCC)7 were detected in the control group only (p = 0.002). The group-specific genotypes formed approximately 4% of the genotype pool in human samples studied. In conclusion, we propose natural selection and a novel locus for late-onset NCD at the SMAD9 (GCC)-repeat in humans. Although the percentage of individuals harboring the specific genotypes in each group was modest, those genotypes represent an underappreciated feature, which may enhance the perspective of disorders that are considered to be complex, and yet may be linked to unambiguous genotypes at certain STR loci.

Section: Discussionmentioning

confidence: 72%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A primate-specific (GCC) repeat in SMAD9 undergoes natural selection in humans and harbors unambiguous genotypes in late-onset neurocognitive disorder.

Bernhart

et al. 2022

Preprint

Self Cite

“…The secondary structure and accessibility effect of the 5/6 genotype were dramatically divergent, and the 5-repeat allele length was not detected in the control group. It is possible that low frequency alleles at the extreme ends of the allele distribution curve are subject to negative natural selection 8,12,35 .…”

Section: Discussionmentioning

confidence: 99%

“…Among various categories of STRs, CGG/GCC repeats are overrepresented in the exons of the human genome, and are mainly focused on because of their involvement in neurological disorders [11][12][13][14] . The human gene, SBF1 (SET binding factor 1), also known as MTMR5 (Myotubularin-related protein 5) contains an annotated (GCC)repeat of 9-repeats in the 5′ untranslated region (UTR), between + 1 to + 60 of the transcription start site (TSS) (SBF1-202 ENST00000380817.8), which is in the top 1 percentile of (GCC)-repeats with respect to length 15 .…”

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confidence: 99%

A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder

Bernhart

et al. 2022

Sci Rep

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The human SBF1 (SET binding factor 1) gene, alternatively known as MTMR5, is predominantly expressed in the brain, and its epigenetic dysregulation is linked to late-onset neurocognitive disorders (NCDs), such as Alzheimer’s disease. This gene contains a (GCC)-repeat at the interval between + 1 and + 60 of the transcription start site (SBF1-202 ENST00000380817.8). We sequenced the SBF1 (GCC)-repeat in a sample of 542 Iranian individuals, consisting of late-onset NCDs (N = 260) and controls (N = 282). While multiple alleles were detected at this locus, the 8 and 9 repeats were predominantly abundant, forming > 95% of the allele pool across the two groups. Among a number of anomalies, the allele distribution was significantly different in the NCD group versus controls (Fisher’s exact p = 0.006), primarily as a result of enrichment of the 8-repeat in the former. The genotype distribution departed from the Hardy–Weinberg principle in both groups (p < 0.001), and was significantly different between the two groups (Fisher’s exact p = 0.001). We detected significantly low frequency of the 8/9 genotype in both groups, higher frequency of this genotype in the NCD group, and reverse order of 8/8 versus 9/9 genotypes in the NCD group versus controls. Biased heterozygous/heterozygous ratios were also detected for the 6/8 versus 6/9 genotypes (in favor of 6/8) across the human samples studied (Fisher’s exact p = 0.0001). Bioinformatics studies revealed that the number of (GCC)-repeats may change the RNA secondary structure and interaction sites at least across human exon 1. This STR was specifically expanded beyond 2-repeats in primates. In conclusion, we report indication of a novel biological phenomenon, in which there is selection against certain heterozygous genotypes at a STR locus in human. We also report different allele and genotype distribution at this STR locus in late-onset NCD versus controls. In view of the location of this STR in the 5′ untranslated region, RNA/RNA or RNA/DNA heterodimer formation of the involved genotypes and alternative RNA processing and/or translation should be considered.

A primate-specific (CCG) repeat in DISP2 is subject to natural selection in human and harbors unambiguous genotypes in late-onset neurocognitive disorder

et al. 2022

Preprint

Intact blocks of (CCG)-repeats are among the top short tandem repeats (STRs), which have undergone natural selection. The above stems from the facts that these STRs are mutation hotspots for C to T truncating substitutions, and are predominantly enriched in the exons. The human DISP2 (dispatched RND transporter family member 2) has the highest level of expression in the brain, and contains a (CCG)-repeat at the interval between + 1 and + 60 of the transcription start site (ENST00000267889.5 DISP2-201), which ranks in the top 1 percent of (CCG) STRs in respect of length. Here we sequenced this STR in a sample of 448 Iranian individuals, consisting of late-onset NCDs (N = 203) and controls (N = 245). While the region spanning the (CCG)-repeat was highly mutated and contained several C to T transitions, which resulted in several (CCG)-residues, a 8-repeat of the (CCG)-STR was the predominantly abundant allele (frequency = 0.92) across the two groups. The overall distribution of alleles was not different between the two groups (p > 0.05). However, we detected four genotypes that belonged to the NCD group only (2% of the NCD genotypes, Mid-p = 0.02), and consisted of allele lengths that were not detected in the control group. We also found six genotypes that were detected in the control group only (2.5% of the control genotypes, Mid p = 0.01). While the group-specific genotypes formed a small percentage of the overall genotypes, they unveil an underappreciated feature, in which complex disorders such as late-onset NCDs may be linked with unambiguous genotypes.