A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder
Abstract 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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2022-09-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-19878-y |
| _version_ | 1797994932154138624 |
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| author | Safoura Khamse Samira Alizadeh Stephan H. Bernhart Hossein Afshar Ahmad Delbari Mina Ohadi |
| author_facet | Safoura Khamse Samira Alizadeh Stephan H. Bernhart Hossein Afshar Ahmad Delbari Mina Ohadi |
| author_sort | Safoura Khamse |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-04-11T09:53:35Z |
| format | Article |
| id | doaj.art-024b2eb0ebeb492da5d5899a5e1ea369 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-11T09:53:35Z |
| publishDate | 2022-09-01 |
| publisher | Nature Portfolio |
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| spelling | doaj.art-024b2eb0ebeb492da5d5899a5e1ea3692022-12-22T04:30:42ZengNature PortfolioScientific Reports2045-23222022-09-011211910.1038/s41598-022-19878-yA (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorderSafoura Khamse0Samira Alizadeh1Stephan H. Bernhart2Hossein Afshar3Ahmad Delbari4Mina Ohadi5Iranian Research Center on Aging, University of Social Welfare and Rehabilitation SciencesIranian Research Center on Aging, University of Social Welfare and Rehabilitation SciencesIZBI, Interdisciplinary Centre for Bioinformatics, Universität LeipzigIranian Research Center on Aging, University of Social Welfare and Rehabilitation SciencesIranian Research Center on Aging, University of Social Welfare and Rehabilitation SciencesIranian Research Center on Aging, University of Social Welfare and Rehabilitation SciencesAbstract 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.https://doi.org/10.1038/s41598-022-19878-y |
| spellingShingle | Safoura Khamse Samira Alizadeh Stephan H. Bernhart Hossein Afshar Ahmad Delbari Mina Ohadi A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder Scientific Reports |
| title | A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder |
| title_full | A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder |
| title_fullStr | A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder |
| title_full_unstemmed | A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder |
| title_short | A (GCC) repeat in SBF1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder |
| title_sort | gcc repeat in sbf1 reveals a novel biological phenomenon in human and links to late onset neurocognitive disorder |
| url | https://doi.org/10.1038/s41598-022-19878-y |
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