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Background <p>Short tandem repeat (STR) length is a known determinant of pathogenicity in a variety of human disorders. The repeat sequence itself can modulate disease severity and penetrance; however, the broader impact of STR sequence variation on gene expression in the general population remains poorly understood.</p> Results <p>Here, we analyze the sequence composition of STRs across two general population cohorts of unrelated individuals (<i>n</i> = 3,150) and report that ~ 7% of STRs exhibit sequence variability, with distinct patterns observed among different ethnic groups. These variable repeats are more prone to expansion and are frequently found in proximity to <i>Alu</i> elements. Notably, STRs with variable motifs are often found near splice junctions of genes involved in brain and neuronal functions. This is supported by the differential expression of genes associated with neuron and cellular projection functions, driven by the presence of distinct STR sequences.</p> Conclusions <p>Our findings underscore the previously unrecognized role of STR sequence variability in modulating gene expression and contributing to human phenotypic diversity.</p>

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Diverse short tandem repeat sequences influence gene regulation in human populations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月12日

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  • Aleksandra Mitina,
  • Worrawat Engchuan,
  • Brett Trost,
  • Giovanna Pellecchia,
  • Stephen W. Scherer,
  • Ryan K. C. Yuen

摘要

Background

Short tandem repeat (STR) length is a known determinant of pathogenicity in a variety of human disorders. The repeat sequence itself can modulate disease severity and penetrance; however, the broader impact of STR sequence variation on gene expression in the general population remains poorly understood.

Results

Here, we analyze the sequence composition of STRs across two general population cohorts of unrelated individuals (n = 3,150) and report that ~ 7% of STRs exhibit sequence variability, with distinct patterns observed among different ethnic groups. These variable repeats are more prone to expansion and are frequently found in proximity to Alu elements. Notably, STRs with variable motifs are often found near splice junctions of genes involved in brain and neuronal functions. This is supported by the differential expression of genes associated with neuron and cellular projection functions, driven by the presence of distinct STR sequences.

Conclusions

Our findings underscore the previously unrecognized role of STR sequence variability in modulating gene expression and contributing to human phenotypic diversity.