The motif composition of variable number tandem repeats impacts gene expression.
The motif composition of variable number tandem repeats impacts gene expression.
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DOI：
10.1101/gr.276768.122
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发表时间：
2023-04
期刊：
影响因子：
7
通讯作者：
Chaisson, Mark J P
中科院分区：
文献类型：
--
作者：
Lu, Tsung-Yu;Smaruj, Paulina N;Fudenberg, Geoffrey;Mancuso, Nicholas;Chaisson, Mark J P
了解DNA变异对人类特征的影响是人类遗传学的一个基本问题。可变数目串联重复序列（VNTRs）占人类基因组的约3%，但由于读取映射性差或重复序列内容不同，经常被排除在关联分析之外。虽然存在从短读数据估计VNTR长度的方法，但已知VNTR在长度和重复（基序）组成上都是不同的。在这里，我们使用了一个由35个单倍型分解的片段构建的重复泛基因组图（RPGG）来检测VNTR长度和重复组成的变化。我们整理了来自基因型组织表达（GTEx）联盟的群体规模数据，以研究序列组成的变化如何与表达相关，包括与VNTR总长度无关的病例。我们发现，在39125个VNTRs中，有9422个通过基序变异与附近基因表达相关，其中只有23.4%可以从长度上获得。精细定位鉴定出174个基因可能是由某些VNTR基序的变异驱动的，而不是由总长度驱动的。我们强调了两个基因，CACNA1C和RNF213，它们的表达与基序变异相关，显示了RPGG分析作为多等位基因和高可变位点性状关联的新方法的实用性。
Understanding the impact of DNA variation on human traits is a fundamental question in human genetics. Variable number tandem repeats (VNTRs) make up ∼3% of the human genome but are often excluded from association analysis owing to poor read mappability or divergent repeat content. Although methods exist to estimate VNTR length from short-read data, it is known that VNTRs vary in both length and repeat (motif) composition. Here, we use a repeat-pangenome graph (RPGG) constructed on 35 haplotype-resolved assemblies to detect variation in both VNTR length and repeat composition. We align population-scale data from the Genotype-Tissue Expression (GTEx) Consortium to examine how variations in sequence composition may be linked to expression, including cases independent of overall VNTR length. We find that 9422 out of 39,125 VNTRs are associated with nearby gene expression through motif variations, of which only 23.4% are accessible from length. Fine-mapping identifies 174 genes to be likely driven by variation in certain VNTR motifs and not overall length. We highlight two genes, CACNA1C and RNF213, that have expression associated with motif variation, showing the utility of RPGG analysis as a new approach for trait association in multiallelic and highly variable loci.