荷兰伊拉斯谟大学Tahsin Stefan Barakat小组的一项最新研究开发出了BRAIN-MAGNET：用于解释非编码变体的功能基因组图谱。该项研究成果发表在2025年11月19日出版的《细胞》上。
该团队将染色质免疫沉淀与自转录活性调控区测序（ChIP-STARR-seq）结合，对人类大脑发育细胞模型中的非编码调控元件（NCREs）进行功能性注释。这为神经干细胞提供了基因调控的见解，并证明NCRE已经在胚胎干细胞中启动，用于后期的神经活动。基于这个功能基因组图谱，课题组研究人员开发了BRAIN-MAGNET（以大脑为主题的人工智能方法，用于分析基因组中的非编码调控元件突变靶点），这是一个功能验证的卷积神经网络，可以从DNA序列组成预测NCRE活性，并识别NCRE功能所需的核苷酸。BRAIN-MAGNET允许对常见神经特征的全基因组关联研究（GWAS）位点进行精细定位，并优先考虑候选疾病-在遗传原因不明的神经遗传疾病个体中引导罕见的非编码变异。NCRE图谱和BRAIN-MAGNET共同代表了对非编码遗传变异解释的强大抵抗，可能有助于识别以前未被识别的增强病。
据悉，遗传变异的全基因组评估正在成为遗传学的常规，但对常见和罕见疾病中非编码单核苷酸变异的功能解释仍然是一个主要挑战。
附：英文原文
Title: BRAIN-MAGNET: A functional genomics atlas for interpretation of non-coding variants
Author: Ruizhi Deng, Elena Perenthaler, Anita Nikoncuk, Soheil Yousefi, Kristina Lanko, Rachel Schot, Michela Maresca, Eva Medico-Salsench, Leslie E. Sanderson, Michael J. Parker, Wilfred F.J. van Ijcken, Joohyun Park, Marc Sturm, Tobias B. Haack, Gennady V. Roshchupkin, Eskeatnaf Mulugeta, Tahsin Stefan Barakat
Issue&Volume: 2025-11-19
Abstract: Genome-wide assessment of genetic variation is becoming routine in genetics, yet functional interpretation of non-coding single nucleotide variants in both common and rare diseases remains a major challenge. Here, we used chromatin immunoprecipitation coupled to self-transcribing active regulatory region sequencing (ChIP-STARR-seq) to functionally annotate non-coding regulatory elements (NCREs) in cellular models of human brain development. This provides gene regulatory insights into neural stem cells and evidence of NCRE priming already in embryonic stem cells for later neural activity. Based on this functional genomics atlas, we developed BRAIN-MAGNET (brain-focused artificial intelligence method to analyze genomes for non-coding regulatory element mutation targets), a functionally validated convolutional neural network that predicts NCRE activity from DNA sequence composition and identifies nucleotides required for NCRE function. BRAIN-MAGNET allows fine-mapping of genome-wide association study (GWAS) loci for common neurological traits and prioritizing candidate disease-causing rare non-coding variants in genetically unexplained individuals with neurogenetic disorders. Together, this NCRE atlas and BRAIN-MAGNET represent a powerful resource for the interpretation of non-coding genetic variation, possibly aiding the identification of previously unrecognized enhanceropathies.
DOI: 10.1016/j.cell.2025.10.029
Source: https://www.cell.com/cell/abstract/S0092-8674(25)01234-6