Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk

Abstract

Variants in GDF5 are associated with human arthritis and decreased height, but the causal mutations are still unknown. We surveyed the Gdf5 locus for regulatory regions in transgenic mice and fine-mapped separate enhancers controlling expression in joints versus growing ends of long bones. A large downstream regulatory region contains a novel growth enhancer (GROW1), which is required for normal Gdf5 expression at ends of developing bones and for normal bone lengths in vivo. Human GROW1 contains a common base-pair change that decreases enhancer activity and colocalizes with peaks of positive selection in humans. The derived allele is rare in Africa but common in Eurasia and is found in Neandertals and Denisovans. Our results suggest that an ancient regulatory variant in GROW1 has been repeatedly selected in northern environments and that past selection on growth phenotypes explains the high frequency of a GDF5 haplotype that also increases arthritis susceptibility in many human populations.

Recapitulating evolutionary divergence in a singlecis-regulatory element is sufficient to cause expression changes of the lens geneTdrd7

“…Strikingly, replacing the sequence of this single regulatory element is sufficient to cause a more than two-fold increase in expression, which reveals that this repressor element has a major effect on Tdrd7 expression. This result contrasts previous findings that perturbations of individual regulatory elements generally have no measurable or only a small effect on gene expression (47)(48)(49)(50)(51)(52)(53). Previously-observed robustness at the transcriptional level can be attributed to functional redundancy, whereby multiple regulatory elements control the expression of a gene and a substantial change in gene expression can only be achieved by perturbations of multiple elements (50).…”

“…While perturbations or deletions of single regulatory elements can result in drastic (55)(56)(57) or subtle phenotypic changes (47,49,52), often they do not result in detectable phenotypic changes (48,50,51,58). Even in the absence of detectable phenotypes when perturbing a single regulatory element, mutations in several regulatory elements can collectively account for phenotypic differences.…”

Genetics of scapula and pelvis development: An evolutionary perspective

“…Several recent studies have demonstrated that regulatory elements such as enhancers, promoters, and repressors allow for fine-tuned, modular control of gene expression in time and space to mediate specific anatomical outcomes (Serfling, Jasin, & Schaffner, 1985; Spitz & Furlong, 2012). This research has identified distinct enhancer sequences that act as key musculoskeletal regulators, including specific long bone and joint regulatory sequences for genes such as Gdf5 (Capellini et al, 2017), Gdf6 (Mortlock, Guenther, & Kingsley, 2003), Bmp5 (Guenther, Pantalena-Filho, & Kingsley, 2008), Fgf8 (Marinić, Aktas, Ruf, & Spitz, 2013), and Myf5 and Myf6 (Summerbell et al, 2000; Vinagre et al, 2010). However, aside from the developmental work on the biochemical and genetic interaction of Pbx1 and Emx2 on an Alx1 regulatory element during scapula patterning (Capellini et al, 2010) and studies on the cisregulatory structure of the Pitx1 locus (Chan et al, 2010; Sarro et al, 2018; Spielmann et al, 2012), few tissue-specific regulatory elements have been identified so far during scapula and pelvic development.…”

Histone ChIP-Seq identifies differential enhancer usage during chondrogenesis as critical for defining cell-type specificity

“…Mutations in enhancers of collagen genes are also associated with chondrodysplasias [11,12]. Osteoarthritis (OA), an age-related cartilage degenerative disease, has a strong genetic component and to date, the vast majority of polymorphisms that confer an increased risk are located in non-coding regions of the genome, including enhancers [13,14]. There is evidence that the OA phenotype may be linked to the re-activation of developmental pathways [15].…”