Department of Medical Genetics, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.
Department of Neuroscience, Faculty of Advanced Technologies in Medicine, Iran University of Medical Sciences, Tehran, Iran.
Mol Genet Genomics. 2018 Jun;293(3):747-752. doi: 10.1007/s00438-018-1415-8. Epub 2018 Jan 13.
Differential expansion of a number of human short tandem repeats (STRs) at the critical core promoter and 5' untranslated region (UTR) support the hypothesis that at least some of these STRs may provide a selective advantage in human evolution. Following a genome-wide screen of all human protein-coding gene 5' UTRs based on the Ensembl database ( http://www.ensembl.org ), we previously reported that the longest STR in this interval is a (GA), which belongs to the X-linked zinc finger MYM-type containing 3 (ZMYM3) gene. In the present study, we analyzed the evolutionary implication of this region across evolution and examined the allele and genotype distribution of the "exceptionally long" STR by direct sequencing of 486 Iranian unrelated male subjects consisting of 196 cases of schizophrenia (SCZ) and 290 controls. We found that the ZMYM3 transcript containing the STR is human-specific (ENST00000373998.5). A significant allele variance difference was observed between the cases and controls (Levene's test for equality of variances F = 4.00, p < 0.03). In addition, six alleles were observed in the SCZ patients that were not detected in the control group ("disease-only" alleles) (mid p exact < 0.0003). Those alleles were at the extreme short and long ends of the allele distribution curve and composed 4% of the genotypes in the SCZ group. In conclusion, we found skewing of the genetic architecture at the ZMYM3 STR in SCZ. Further, we found a bell-shaped distribution of alleles and selection against alleles at the extreme ends of this STR. The ZMYM3 STR sets a prototype, the evolutionary course of which determines the range of alleles in a particular species. Extreme "disease-only" alleles and genotypes may change our perspective of adaptive evolution and complex disorders. The ZMYM3 gene "exceptionally long" STR should be sequenced in SCZ and other human-specific phenotypes/characteristics.
多种人类短串联重复序列（STRs）在关键核心启动子和 5'非翻译区（UTR）的差异扩张支持了以下假设：至少其中一些 STRs 可能在人类进化中提供了选择性优势。在基于 Ensembl 数据库（http://www.ensembl.org）对所有人类蛋白编码基因 5'UTR 进行全基因组筛查后，我们之前报道了该区间内最长的 STR 是一个（GA），它属于 X 连锁锌指 MYM 型 3（ZMYM3）基因。在本研究中，我们分析了该区域在进化过程中的进化意义，并通过直接对 486 名伊朗无关男性受试者（包括 196 例精神分裂症（SCZ）患者和 290 名对照）的测序，检查了“异常长”STR 的等位基因和基因型分布。我们发现含有 STR 的 ZMYM3 转录物是人类特有的（ENST00000373998.5）。病例组和对照组之间观察到 ZMYM3 基因座的 STR 存在显著的等位基因方差差异（方差相等的 Levene 检验 F=4.00，p<0.03）。此外，在对照组中未检测到的 6 个等位基因在 SCZ 患者中观察到（“仅疾病”等位基因）（中 p 确切值<0.0003）。这些等位基因位于等位基因分布曲线的极端短端和长端，在 SCZ 组的基因型中占 4%。总之，我们发现 SCZ 中 ZMYM3 STR 的遗传结构存在偏斜。此外，我们发现该 STR 极端端的等位基因存在钟形分布和选择。ZMYM3 STR 建立了一个原型，其进化过程决定了特定物种的等位基因范围。极端的“仅疾病”等位基因和基因型可能会改变我们对适应性进化和复杂疾病的看法。ZMYM3 基因“异常长”STR 应在 SCZ 和其他人类特异性表型/特征中进行测序。
