Iranian Research Center on Aging, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
Personalized Medicine and Genometabolomics Research Center, Hope Generation Foundation, Tehran, Iran.
Mol Neurobiol. 2024 Nov;61(11):8777-8786. doi: 10.1007/s12035-024-04155-y. Epub 2024 Apr 2.
(CCG) short tandem repeats (STRs) are predominantly enriched in genic regions, mutation hotspots for C to T truncating substitutions, and involved in various neurological and neurodevelopmental disorders. However, intact blocks of this class of STRs are widely overlooked with respect to their link with natural selection. The human neuron-specific gene, DISP2 (dispatched RND transporter family member 2), contains a (CCG) repeat in its 5' untranslated region. Here, we sequenced this STR in a sample of 448 Iranian individuals, consisting of late-onset neurocognitive disorder (NCD) (N = 203) and controls (N = 245). We found that the region spanning the (CCG) repeat was highly mutated, resulting in several flanking (CCG) residues. However, an 8-repeat of the (CCG) repeat was predominantly abundant (frequency = 0.92) across the two groups. While the overall distribution of genotypes was not different between the two groups (p > 0.05), we detected four genotypes in the NCD group only (2% of the NCD genotypes, Mid-p = 0.02), consisting of extreme short alleles, 5- and 6-repeats, that were not detected in the control group. The patients harboring those genotypes received the diagnoses of probable Alzheimer's disease and vascular dementia. We also found six genotypes in the control group only (2.5% of the control genotypes, Mid-p = 0.01) that consisted of the 8-repeat and extreme long alleles, 9- and 10-repeats, of which the 10-repeat was not detected in the NCD group. The (CCG) repeat specifically expanded in primates. In conclusion, we report an indication of natural selection at a novel hypermutable region in the human genome and divergent alleles and genotypes in late-onset NhCDs and controls. These findings reinforce the hypothesis that a collection of rare alleles and genotypes in a number of genes may unambiguously contribute to the cognition impairment component of late-onset NCDs.
（CCG）短串联重复序列（STRs）主要富集在基因区域，是 C 到 T 截断突变的热点，与各种神经和神经发育障碍有关。然而，由于与自然选择有关，这种 STR 类的完整块被广泛忽视。人类神经元特异性基因 DISP2（Dispatcher RND 转运蛋白家族成员 2）在其 5'非翻译区含有一个（CCG）重复序列。在这里，我们对 448 名伊朗个体样本中的这个 STR 进行了测序，其中包括迟发性神经认知障碍（NCD）（N=203）和对照组（N=245）。我们发现，跨越（CCG）重复序列的区域高度突变，导致几个侧翼（CCG）残基。然而，8 个（CCG）重复序列的重复在两组中都占主导地位（频率=0.92）。虽然两组之间的基因型总体分布没有差异（p>0.05），但我们只在 NCD 组中检测到四种基因型（NCD 基因型的 2%，中 p=0.02），包括极端短等位基因、5-和 6-重复，在对照组中未检测到。携带这些基因型的患者被诊断为可能的阿尔茨海默病和血管性痴呆。我们还只在对照组中发现了六种基因型（对照组基因型的 2.5%，中 p=0.01），包括 8 个重复和极端长等位基因、9-和 10-重复，其中 10-重复在 NCD 组中未检测到。（CCG）重复序列在灵长类动物中特异性扩增。总之，我们报告了在人类基因组中一个新的高突变区域和迟发性 NhCDs 和对照组中不同的等位基因和基因型的自然选择迹象。这些发现加强了这样一种假设，即许多基因中的一系列罕见等位基因和基因型可能明确导致迟发性 NCDs 的认知障碍成分。
