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

Obesity genes working together

The biological causes of obesity are not well understood. Sobreira et al. examined the chromatin interactions between key genes in a locus known for its associations with obesity in human patients. In addition to directly interrogating the connections between these genes and examining the mechanisms that regulate their activity, the authors used mouse models to study the target genes’ effects on both adipose tissue and brain cells that play a role in regulating dietary preferences.

Science, abf1008, this issue p. 1085


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.

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