Predominant monomorphism of the RIT2 and GPM6B exceptionally long GA blocks in human and enriched divergent alleles in the disease compartment

et al. 2022

Preprint

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). Sequencing of the SBF1 (GCC)-repeat in a sample of 542 Iranian individuals, consisting of late-onset NCDs (N=260) and controls (N=282) revealed a predominantly bi-allelic locus for this STR, consisting of 8 and 9 repeats, with allele frequencies ranging from 0.39 to 0.55, and four other alleles with frequencies of <0.03 across the two groups. Overall heterozygosity for the observed alleles was significantly less than expected in the NCD and control groups, at 22.3% and 16.31%, respectively (p=0.000). Specifically, the heterozygous 8/9 genotype was significantly less than expected in both case and control groups (Hardy-Weinberg disequilibrium, p=0.000), and significantly enriched in the NCD group (Yates corrected p=0.001). Skewed heterozygous genotypes were also detected for other allele combinations, such as 6/8 vs 6/9 across groups (p=0.000). Bioinformatics studies revealed that the number of (GCC)-repeats may change the RNA secondary structure and interaction sites across human exon 1. This STR was specifically expanded beyond 2-repeats in primates. In conclusion, we report a novel biological phenomenon in which there is indication of purifying selection against heterozygous genotypes at a STR locus in human, and skewed genotype compartment in late-onset NCD vs. controls. In view of the location of this STR in the 5′ UTR, RNA/RNA or RNA/DNA heterodimer formation of the involved genotypes and possible deleterious downstream events should be considered.

Section: Discussionsupporting

confidence: 68%

A (GCC) Repeat in the Untranslated Region of Human SBF1 Departs from Hardy-Weinberg Equilibrium in Human and Links to Late-onset Neurocognitive Disorder.

Ohadi

et al. 2022

Preprint

“…Another interesting feature at this locus and a number of other previously reported instances are the lowfrequency alleles, which might have been subject to negative natural selection [8, 14,34]. In human SMAD9, examples of those alleles are (GCC)8 and (GCC)10.…”

Section: Discussionmentioning

confidence: 73%

“…Reported instances of STR allelic natural selection at non-coding loci in humans are rare [8, 14,34], and the SMAD9 (GCC)-repeat provides a potentially valuable locus to further test this phenomenon.…”

Section: Discussionmentioning

confidence: 99%

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

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.

“…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%

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

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.