Department of Molecular Biosciences, Northwestern University, Evanston, IL.
Mol Biol Evol. 2023 Apr 4;40(4). doi: 10.1093/molbev/msad067.
Short tandem repeats (STRs) have orders of magnitude higher mutation rates than single nucleotide variants (SNVs) and have been proposed to accelerate evolution in many organisms. However, only few studies have addressed the impact of STR variation on phenotypic variation at both the organismal and molecular levels. Potential driving forces underlying the high mutation rates of STRs also remain largely unknown. Here, we leverage the recently generated expression and STR variation data among wild Caenorhabditis elegans strains to conduct a genome-wide analysis of how STRs affect gene expression variation. We identify thousands of expression STRs (eSTRs) showing regulatory effects and demonstrate that they explain missing heritability beyond SNV-based expression quantitative trait loci. We illustrate specific regulatory mechanisms such as how eSTRs affect splicing sites and alternative splicing efficiency. We also show that differential expression of antioxidant genes and oxidative stresses might affect STR mutations systematically using both wild strains and mutation accumulation lines. Overall, we reveal the interplay between STRs and gene expression variation by providing novel insights into regulatory mechanisms of STRs and highlighting that oxidative stress could lead to higher STR mutation rates.
短串联重复序列（STRs）的突变率比单核苷酸变异（SNVs）高出几个数量级，并且已经被提出可以在许多生物中加速进化。然而，只有少数研究探讨了 STR 变异对生物体和分子水平上表型变异的影响。STR 高突变率的潜在驱动因素在很大程度上仍然未知。在这里，我们利用最近生成的野生秀丽隐杆线虫品系之间的表达和 STR 变异数据，进行了全基因组分析，以研究 STRs 如何影响基因表达变异。我们鉴定出数千个具有调节作用的表达 STR（eSTRs），并证明它们可以解释基于 SNV 的表达数量性状基因座之外的遗传缺失。我们举例说明了特定的调节机制，例如 eSTRs 如何影响剪接位点和可变剪接效率。我们还表明，抗氧化基因的差异表达和氧化应激可能会使用野生菌株和突变积累系系统地影响 STR 突变。总的来说，我们通过提供 STR 调节机制的新见解，并强调氧化应激可能导致更高的 STR 突变率，揭示了 STRs 和基因表达变异之间的相互作用。
