Evolutionary Neurogenomics, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands.
Genomics of Neurodegenerative Diseases and Aging, Department of Human Genetics, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam UMC, 1081 HV Amsterdam, The Netherlands.
Genome Res. 2022 Apr;32(4):656-670. doi: 10.1101/gr.275515.121. Epub 2022 Mar 24.
Genome-wide association studies (GWAS) have been highly informative in discovering disease-associated loci but are not designed to capture all structural variations in the human genome. Using long-read sequencing data, we discovered widespread structural variation within SINE-VNTR- (SVA) elements, a class of great ape-specific transposable elements with gene-regulatory roles, which represents a major source of structural variability in the human population. We highlight the presence of structurally variable SVAs (SV-SVAs) in neurological disease-associated loci, and we further associate SV-SVAs to disease-associated SNPs and differential gene expression using luciferase assays and expression quantitative trait loci data. Finally, we genetically deleted SV-SVAs in the and Alzheimer's disease-associated risk loci and in the Parkinson's disease-associated risk locus and assessed multiple aspects of their gene-regulatory influence in a human neuronal context. Together, this study reveals a novel layer of genetic variation in transposable elements that may contribute to identification of the structural variants that are the actual drivers of disease associations of GWAS loci.
全基因组关联研究（GWAS）在发现与疾病相关的基因座方面非常有价值，但并不能捕获人类基因组中的所有结构变异。我们使用长读测序数据，在 SINE-VNTR-（SVA）元件内发现了广泛的结构变异，SVA 是一类具有基因调控作用的类人猿特异性转座元件，代表了人类群体结构可变性的主要来源。我们强调了在与神经疾病相关的基因座中存在结构可变的 SVA（SV-SVA），并使用荧光素酶测定和表达数量性状基因座数据进一步将 SV-SVA 与疾病相关的 SNP 和差异基因表达相关联。最后，我们在与阿尔茨海默病相关的风险基因座和与帕金森病相关的风险基因座中基因敲除了 SV-SVA，并在人类神经元环境中评估了它们在基因调控方面的多个方面的影响。总之，这项研究揭示了转座元件中一种新的遗传变异层，这可能有助于确定 GWAS 基因座疾病关联的实际驱动因素的结构变异。
