美国哈佛大学Alkes L. Price研究组探明了通过整合单细胞多组方法和基因组距离将调控变异体与靶基因联系起来。这一研究成果于2025年6月12日发表在国际顶尖学术期刊《自然—遗传学》上。

该研究组提出了pgBoost，这是一个综合建模框架，它训练表达数量性状位点（eQTL）数据上现有连接策略（包括基因组距离）的非线性组合，为每个候选单核苷酸多态性-基因链接分配概率分数。与现有的基于eQTL、接触活性、CRISPR和全基因组关联研究（GWAS）数据的评估集相比，pgBoost获得了更高的富集度。研究人员进一步确定，将pgBoost限制在聚焦细胞类型的特征上，可以提高识别与该细胞类型相关的链接的能力。该研究团队强调了几个例子，在这些例子中，pgBoost将精细定位的GWAS变异与实验验证或生物学上可移植的靶基因联系起来，而其他方法没有涉及这些基因。总之，连接策略的非线性组合提高了识别GWAS关联的靶基因的能力。

据了解，分析单细胞配对RNA测序（RNA-seq）和转座酶可及染色质主题化测序（ATAC-seq）多组数据的方法已经显示出将调控元件与基因联系起来的希望。然而，现有的方法显示低一致性，并没有捕捉到基因组距离的影响。

附：英文原文

Title: Linking regulatory variants to target genes by integrating single-cell multiome methods and genomic distance

Author: Dorans, Elizabeth, Jagadeesh, Karthik, Dey, Kushal, Price, Alkes L.

Issue&Volume: 2025-06-12

Abstract: Methods that analyze single-cell paired RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) multiome data have shown promise in linking regulatory elements to genes. However, existing methods exhibit low concordance and do not capture the effects of genomic distance. We propose pgBoost, an integrative modeling framework that trains a non-linear combination of existing linking strategies (including genomic distance) on expression quantitative trait locus (eQTL) data to assign a probabilistic score to each candidate single-nucleotide polymorphism–gene link. pgBoost attained higher enrichment than existing methods for evaluation sets derived from eQTL, activity-by-contact, CRISPR and genome-wide association study (GWAS) data. We further determined that restricting pgBoost to features from a focal cell type improved power to identify links relevant to that cell type. We highlight several examples in which pgBoost linked fine-mapped GWAS variants to experimentally validated or biologically plausible target genes that were not implicated by other methods. In conclusion, a non-linear combination of linking strategies improves power to identify target genes underlying GWAS associations.

DOI: 10.1038/s41588-025-02220-3

Source: https://www.nature.com/articles/s41588-025-02220-3