Division of Functional Breeding, Department of Animal Sciences, Georg-August-Universität Göttingen, Burckhardtweg 2, 37077, Göttingen, Germany.
Hum Genomics. 2023 Oct 23;17(1):94. doi: 10.1186/s40246-023-00543-y.
With the first complete draft of a human genome, the Telomere-to-Telomere Consortium unlocked previously concealed genomic regions for genetic analyses. These regions harbour nearly 2000 potential novel genes with unknown function. In order to uncover candidate genes associated with human neurological pathologies, a comparative transcriptome study using the T2T-CHM13 and the GRCh38 genome assemblies was conducted on previously published datasets for eight distinct human neurological disorders.
The analysis of differential expression in RNA sequencing data led to the identification of 336 novel candidate genes linked to human neurological disorders. Additionally, it was revealed that, on average, 3.6% of the differentially expressed genes detected with the GRCh38 assembly may represent potential false positives. Among the noteworthy findings, two novel genes were discovered, one encoding a pore-structured protein and the other a highly ordered β-strand-rich protein. These genes exhibited upregulation in multiple epilepsy datasets and hold promise as candidate genes potentially modulating the progression of the disease. Furthermore, an analysis of RNA derived from white matter lesions in multiple sclerosis patients indicated significant upregulation of 26 rRNA encoding genes. Additionally, putative pathology related genes were identified for Alzheimer's disease, amyotrophic lateral sclerosis, glioblastoma, glioma, and conditions resulting from the m.3242 A > G mtDNA mutation.
The results presented here underline the potential of the T2T-CHM13 assembly in facilitating the discovery of candidate genes from transcriptome data in the context of human disorders. Moreover, the results demonstrate the value of remapping sequencing data to a superior genome assembly. Numerous potential pathology related genes, either as causative factors or related elements, have been unveiled, warranting further experimental validation.
随着人类基因组的第一个完整草图的公布，端粒到端粒联盟解锁了以前隐藏的遗传分析基因组区域。这些区域拥有近 2000 个具有未知功能的潜在新基因。为了发现与人类神经病理相关的候选基因，我们对 T2T-CHM13 和 GRCh38 基因组组装进行了比较转录组研究，使用了以前发表的八个不同人类神经障碍数据集。
对 RNA 测序数据的差异表达分析导致鉴定出 336 个与人类神经障碍相关的新候选基因。此外，研究结果表明，使用 GRCh38 组装检测到的差异表达基因中，平均有 3.6%可能代表潜在的假阳性。在值得注意的发现中，发现了两个新基因，一个编码孔状蛋白，另一个编码高度有序的β-折叠丰富蛋白。这些基因在多个癫痫数据集上调，作为可能调节疾病进展的候选基因具有潜力。此外，对多发性硬化症患者白质病变的 RNA 分析表明，26 个 rRNA 编码基因显著上调。此外，还确定了阿尔茨海默病、肌萎缩性侧索硬化症、胶质母细胞瘤、神经胶质瘤以及 m.3242A>G mtDNA 突变引起的病症的潜在病理相关基因。
本文的结果强调了 T2T-CHM13 组装在人类疾病转录组数据中发现候选基因方面的潜力。此外，研究结果还表明了将测序数据重新映射到更优的基因组组装上的价值。已经揭示了许多潜在的病理相关基因，无论是作为致病因素还是相关因素，都需要进一步的实验验证。
