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Genetic variations underlying susceptibility to complex autoimmune and allergic diseases are concentrated within noncoding regulatory elements termed enhancers(1). The functions of a large majority of disease-associated enhancers are unknown, in part owing to their distance from the genes they regulate, a lack of understanding of the cell types in which they operate, and our inability to recapitulate the biology of immune diseases in vitro. Here, using shared synteny to guide loss-of-function analysis of homologues of human enhancers in mice, we show that the prominent autoimmune and allergic disease risk locus at chromosome 11q13.5(2-7) contains a distal enhancer that is functional in CD4(+) regulatory T (T-reg) cells and required for T-reg-mediated suppression of colitis. The enhancer recruits the transcription factors STAT5 and NF-kappa B to mediate signal-driven expression of Lrrc32, which encodes the protein glycoprotein A repetitions predominant (GARP). Whereas disruption of the Lrrc32 gene results in early lethality, mice lacking the enhancer are viable but lack GARP expression in Foxp3(+) T-reg cells, which are unable to control colitis in a cell-transfer model of the disease. In human T-reg cells, the enhancer forms conformational interactions with the promoter of LRRC32 and enhancer risk variants are associated with reduced histone acetylation and GARP expression. Finally, functional fine-mapping of 11q13.5 using CRISPR-activation (CRISPRa) identifies a CRISPRa-responsive element in the vicinity of risk variant rs11236797 capable of driving GARP expression. These findings provide a mechanistic basis for association of the 11q13.5 risk locus with immune-mediated diseases and identify GARP as a potential target in their therapy.

Shared synteny guides loss-of-function analysis of human enhancer homologues in mice, identifying a distal enhancer at the autoimmune and allergic disease risk locus at chromosome 11q13.5 whose function in regulatory T cells provides a mechanistic basis for its role in disease.

The pectoral fin of an Elpistostege watsoni specimen from the Upper Devonian period of Canada combines digits and fin rays, blurring the line between the appendages of fish and land vertebrates.

The evolution of fishes to tetrapods (four-limbed vertebrates) was one of the most important transformations in vertebrate evolution. Hypotheses of tetrapod origins rely heavily on the anatomy of a few tetrapod-like fish fossils from the Middle and Late Devonian period (393-359 million years ago)(1). These taxa-known as elpistostegalians-include Panderichthys(2), Elpistostege(3,4) and Tiktaalik(1,5), none of which has yet revealed the complete skeletal anatomy of the pectoral fin. Here we report a 1.57-metre-long articulated specimen of Elpistostege watsoni from the Upper Devonian period of Canada, which represents-to our knowledge-the most complete elpistostegalian yet found. High-energy computed tomography reveals that the skeleton of the pectoral fin has four proximodistal rows of radials (two of which include branched carpals) as well as two distal rows that are organized as digits and putative digits. Despite this skeletal pattern (which represents the most tetrapod-like arrangement of bones found in a pectoral fin to date), the fin retains lepidotrichia (fin rays) distal to the radials. We suggest that the vertebrate hand arose primarily from a skeletal pattern buried within the fairly typical aquatic pectoral fin of elpistostegalians. Elpistostege is potentially the sister taxon of all other tetrapods, and its appendages further blur the line between fish and land vertebrates.