美国芝加哥大学Marcelo A. Nóbrega等研究人员合作发现，广泛的基因多效性和等位基因异质性介导IRX3和IRX5的代谢效果。2021年6月4日出版的《科学》杂志发表了这项成果。

研究人员分析了与肥胖风险密切相关FTO基因内基因组区域的遗传和功能结构。结果表明，常见单倍型上的多个变体可从兆碱基距离改变几种针对IRX3和IRX5的增强子的调节特性。研究人员证明，这些增强子影响多种组织中的基因表达，包括脂肪和大脑，并在有限的时间窗口内传递调节作用。这些数据表明，疾病相关位点的遗传结构可能涉及广泛的多效性、等位基因异质性、跨组织共享等位基因效应和时间限制效应。

据悉，编码变体通常在多个组织中具有多效性，而非编码变体被认为通过特定组织和基因表达的时间调节来介导它们的表型效应。 

附：英文原文

Title: Extensive pleiotropism and allelic heterogeneity mediate metabolic effects of IRX3 and IRX5

Author: Débora R. Sobreira, Amelia C. Joslin, Qi Zhang, Iain Williamson, Grace T. Hansen, Kathryn M. Farris, Noboru J. Sakabe, Nasa Sinnott-Armstrong, Grazyna Bozek, Sharon O. Jensen-Cody, Kyle H. Flippo, Carole Ober, Wendy A. Bickmore, Matthew Potthoff, Mengjie Chen, Melina Claussnitzer, Ivy Aneas, Marcelo A. Nóbrega

Issue&Volume: 2021/06/04

Abstract: Whereas coding variants often have pleiotropic effects across multiple tissues, noncoding variants are thought to mediate their phenotypic effects by specific tissue and temporal regulation of gene expression. Here, we investigated the genetic and functional architecture of a genomic region within the FTO gene that is strongly associated with obesity risk. We show that multiple variants on a common haplotype modify the regulatory properties of several enhancers targeting IRX3 and IRX5 from megabase distances. We demonstrate that these enhancers affect gene expression in multiple tissues, including adipose and brain, and impart regulatory effects during a restricted temporal window. Our data indicate that the genetic architecture of disease-associated loci may involve extensive pleiotropy, allelic heterogeneity, shared allelic effects across tissues, and temporally restricted effects.

DOI: 10.1126/science.abf1008

Source: https://science.sciencemag.org/content/372/6546/1085