Scholarlink

Background <p>The 17q21.31 locus is structurally complex, harbouring a common H1/H2 inversion and dense regulatory variation; one of the two SNPs studied lies within the inversion and the other outside it. Disentangling the effects of individual non-coding variants in this context remains challenging. We used reciprocal double-editing in isogenic human iPSCs as a cross-background validation strategy, together with multi-clone replication and a three-way intersection filter (WT-anchored edit and the two reciprocal edit configurations) to resolve variant-linked transcriptional effects for rs77692262 (A &gt; G) and rs79724577 (A &gt; C).</p> Results <p>rs77692262 affected two TGF-β/SMAD-responsive genes, with <i>ANKRD1</i> replicating across reciprocal and independent contexts, while <i>ACTA2</i> showed context-dependent effects. By contrast, rs79724577 yielded seven candidates (<i>ANKRD1</i>, <i>CUZD1</i>, <i>GJA5</i>, <i>PRICKLE1</i>, RAB17, <i>RSPO4</i>, <i>SNPH</i>). Independent validation refined these sets: four discovery-set genes, <i>ANKRD1</i>, <i>CUZD1</i>, <i>PRICKLE1</i>, <i>RAB17</i>, replicated for rs79724577 across edited clones/reciprocal contexts, defining a compact, reproducible signature; <i>ANKRD1</i> also replicated for rs77692262 and was recovered as the sole consistent DEG when rs77692262 was retested in the reciprocal configuration, making it the most clone-invariant target across both variants. <i>GJA5</i> appeared in discovery but did not replicate and is treated as hypothesis-generating.</p> <p>Motif analyses were consistent with disrupted T-box/SMAD input at rs77692262 and loss of RFX-family recognition at rs79724577. Long-read CpG methylation profiling detected no significant differences at promoters/gene bodies or at/near the SNP sites, supporting a methylation-independent mechanism involving altered transcription-factor occupancy.</p> Conclusions <p>These data identify reproducible, variant-linked transcriptional effects at 17q21.31 within a fixed H1/H1 haplotypic background, centered on <i>ANKRD1</i> and a validated four-gene signature for rs79724577, and outline a generalizable, replication-first strategy for variant-to-function dissection in structurally polymorphic regions.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Variant-to-function dissection of the 17q21.31 locus resolves ANKRD1 as a convergent regulatory target

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月30日

查看全文
  • Oyedele J. Olaoye,
  • Sophie L. Farrow,
  • Antony A. Cooper,
  • Denis M. Nyaga,
  • Justin M. O’Sullivan

摘要

Background

The 17q21.31 locus is structurally complex, harbouring a common H1/H2 inversion and dense regulatory variation; one of the two SNPs studied lies within the inversion and the other outside it. Disentangling the effects of individual non-coding variants in this context remains challenging. We used reciprocal double-editing in isogenic human iPSCs as a cross-background validation strategy, together with multi-clone replication and a three-way intersection filter (WT-anchored edit and the two reciprocal edit configurations) to resolve variant-linked transcriptional effects for rs77692262 (A > G) and rs79724577 (A > C).

Results

rs77692262 affected two TGF-β/SMAD-responsive genes, with ANKRD1 replicating across reciprocal and independent contexts, while ACTA2 showed context-dependent effects. By contrast, rs79724577 yielded seven candidates (ANKRD1, CUZD1, GJA5, PRICKLE1, RAB17, RSPO4, SNPH). Independent validation refined these sets: four discovery-set genes, ANKRD1, CUZD1, PRICKLE1, RAB17, replicated for rs79724577 across edited clones/reciprocal contexts, defining a compact, reproducible signature; ANKRD1 also replicated for rs77692262 and was recovered as the sole consistent DEG when rs77692262 was retested in the reciprocal configuration, making it the most clone-invariant target across both variants. GJA5 appeared in discovery but did not replicate and is treated as hypothesis-generating.

Motif analyses were consistent with disrupted T-box/SMAD input at rs77692262 and loss of RFX-family recognition at rs79724577. Long-read CpG methylation profiling detected no significant differences at promoters/gene bodies or at/near the SNP sites, supporting a methylation-independent mechanism involving altered transcription-factor occupancy.

Conclusions

These data identify reproducible, variant-linked transcriptional effects at 17q21.31 within a fixed H1/H1 haplotypic background, centered on ANKRD1 and a validated four-gene signature for rs79724577, and outline a generalizable, replication-first strategy for variant-to-function dissection in structurally polymorphic regions.