Iranian Research Center on Aging, University of Social Welfare and Rehabilitation Sciences, Daneshjoo Blvd. Koodakyar St, Tehran, 1985713871, Iran.
IZBI, Interdisciplinary Centre for Bioinformatics, Universität Leipzig, Härtelstr. 16-18, 04107, Leipzig, Germany.
Neurol Sci. 2024 Nov;45(11):5241-5251. doi: 10.1007/s10072-024-07637-y. Epub 2024 Jun 14.
Whereas (GCC)-repeats are overrepresented in genic regions, and mutation hotspots, they are largely unexplored with regard to their link with natural selection. Across numerous primate species and tissues, SMAD9 (SMAD Family Member 9) reaches highest level of expression in the human brain. This gene contains a (GCC)-repeat in the interval between + 1 and + 60 of the transcription start site, which is in the high-ranking (GCC)-repeats with respect to 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 (GCC)7/(GCC)9 ratio 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 (GCC)9 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). The patients harboring those genotypes received the diagnoses of Alzheimer's disease (AD) and vascular dementia (VD). 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 the human samples studied.
We propose natural selection and a novel locus for late-onset AD and VD at the SMAD9 (GCC)-repeat in humans.
虽然 (GCC)-重复序列在基因区域和突变热点中过度表达，但它们与自然选择的联系在很大程度上尚未得到探索。在许多灵长类物种和组织中，SMAD9（SMAD 家族成员 9）在人类大脑中表达水平最高。该基因在转录起始位点的+1 到+60 之间的区间内含有一个 (GCC)-重复序列，该重复序列在长度上属于高排名 (GCC)-重复序列。
我们对 396 名伊朗个体进行了该 (GCC)-重复序列的测序，其中包括迟发性神经认知障碍（NCD）患者（N=181）和对照组（N=215）。
我们检测到两种主要的 7 个和 9 个重复序列的等位基因，占等位基因池的 96.2%。在 NCD 组中，（GCC）7/（GCC）9 的比值与对照组相反（p=0.005），这是由于 NCD 组中（GCC）7 的过剩（p=0.003）和对照组中（GCC）9 的过剩（p=0.01）所致。在 NCD 组中仅检测到五种主要由（GCC）7 组成且缺乏（GCC）9 的基因型（p=0.008）。那些基因型的患者被诊断为阿尔茨海默病（AD）和血管性痴呆（VD）。在对照组中仅检测到五种主要由（GCC）9 组成且缺乏（GCC）7 的基因型（p=0.002）。在研究的人类样本中，组特异性基因型占基因型池的约 4%。
我们提出了在人类 SMAD9（GCC）-重复序列中存在自然选择和新的迟发性 AD 和 VD 位点。
