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

Khamse, Safoura; Arabfard, Masoud; Salesi, Mahmood; Behmard, Esmaeil; Jafarian, Zahra; Afshar, Hossein; Khazaei, Maryam; Ohadi, Mina

doi:10.1007/s10709-021-00143-5

Cited by 14 publications

(15 citation statements)

References 41 publications

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“…SBF1 is predominantly expressed in the brain and skeletal muscle, and the protein encoded by this gene is a member of the myotubularin family. Myotubularin-related proteins, namely MTMR2, MTMR13/SBF2 and MTMR5/SBF1 are mainly involved in regulating endolysosomal tra cking [33] and mitochondrial functioning [34]. Dysregulation of SBF1 is linked to late-onset NCDs such as AD [17], which is also indicated by the observed genotype anomalies in the NCD group vs. controls in our study.…”

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

Khamse

Alizadeh

et al. 2022

Preprint

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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). 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.

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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

Khamse

Alizadeh

et al. 2022

Preprint

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“…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.

Alizadeh

Khamse

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.

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“…For example, some colonies are a mechanism for the emergence of CG-rich STRs, which may be order-or species-speci c. This follows from our observations that the pure and intermediate units necessary for the emergence of the STRs were detectable in the same colonies or their orthologous colonies, such as in C96. CG-rich STRs are widely linked to evolution and speciation [6], as well as neurodevelopmental and neurological disorders [7,9,10,35,36]. Example of another evolutionary relevance is envisioned in C266, which is speci c to great apes, and hosts several Piwi-interacting RNAs (piRNAs) (https://genome.ucsc.edu/) (Suppl.…”

Section: Discussionmentioning

confidence: 99%

CG-rich trinucleotide two-repeats signify novel recombination hotspots conserved across primates and mouse

Ohadi,

Tajeddin,

Arabfard

et al. 2024

Preprint

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We previously reported colonies of GGC and GCC two-repeat units (dyads) across the human genome, which were conserved across great apes. On a genome-wide scale, here we extended our methodology, and mapped the two-repeat units of all combinations of C and G trinucleotides in human, consisting of CCG, CGG, CGC, GGC, GCG, and CGC. The majority of the units coincided in 81,118 colonies (distance between consecutive units < 500 bp). We detected pure units and units that were overlaps of those pure units across the colonies, signifying unequal crossover and recombination at those units. Subsequently, we performed a comparative genomics study of several large and medium-size colonies in other primates and mouse. We found that several of those colonies were conserved, yet with extensive dynamicity, as phylogenetically distant as in mouse. In conclusion, CG-rich two-repeat units signify novel unequal crossover and recombination hotspots of the finest molecular resolution, conserved across primates and mouse.

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

Cited by 14 publications

References 41 publications

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

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

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

CG-rich trinucleotide two-repeats signify novel recombination hotspots conserved across primates and mouse

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