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.
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The authors thank M. Hiller and G. Renaud for assistance with Neandertal and Denisovan sequence data; E. Eichler and M. Malig (University of Washington) for human fosmids; C. Lowe and F. Jones for assistance with 1000 Genomes data analysis; P. Arlotta, H.H. Chen, L. Wu, E. Brown, and M. Guo for assistance with CRISPR–Cas9 gene targeting; M. Bouxsein, D. Brooks, and M. Armanini (MGH Center for Skeletal Research Imaging and Biomechanical Testing Core (NIH P30 AR066261)) for assistance with μCT experiments; and G. Bejerano, K. Guenther, D. Mortlock, A. Pollen, and members of the laboratories of D.M.K. and T.D.C. for useful scientific discussions. This work was funded in part by grants from NSERC (RGPIN-435973-2013, A.C.D.), the Arthritis Foundation (H.C. and M.S.), the NIH (AR42236, D.M.K.), the Milton Fund of Harvard (T.D.C.), the China Scholarship Council (J.C.), and the Jason S. Bailey Fund of Harvard (J.C.). D.M.K. is supported an investigator of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
Supplementary Figures 1–10, 14 and 15, and Supplementary Note. (PDF 13966 kb)
Allele frequencies for 1000 Genomes SNPs across 400-kb interval centered on the GDF5 locus. (XLSX 436 kb)
r2 linkage calculations between rs4911178 and other SNPs within 400-kb interval for all populations and continents. (XLSX 177 kb)
Phased 1000 Genomes haplotypes for individuals used in this study including haplotypes for archaic hominins, chimpanzee reference (panTro3) and human reference (hg19). (XLSX 7353 kb)
Total counts of the different 1000 Genomes population haplotypes within clades identified through phylogenetic analyses based on reduced tree used in Figure 6. (XLSX 39 kb)
1000 Genomes SNP frequencies in different clades for the major height and osteoarthritis GWAS variants addressed in this study based on reduced tree used in Figure 6. (XLSX 46 kb)
Divergence calculations for Neandertal versus all haplotypes within A, B, and B* identified in this study. (XLSX 165 kb)
Transcription factor binding site analysis of rs4911178. (XLSX 126 kb)
Primer locations, sequences, and source DNA used for constructs and genotyping in this study. (XLSX 41 kb)
Maximum-likelihood analysis of 1000 Genomes, Neandertal, Denisovan, and chimpanzee haplotypes using phased variants. (PDF 3086 kb)
Maximum-likelihood analysis and visual genotyping of human 1000 Genomes, Neandertal, Denisovan, and chimpanzee haplotypes using all 1,489 phased variants at MAF ≥0.05. (PDF 871 kb)
Maximum-likelihood analysis and visual genotyping of human 1000 Genomes, Neandertal, Denisovan, and chimpanzee haplotypes using all 1,489 phased variants at MAF ≥0.01. (PDF 1851 kb)
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Capellini, T., Chen, H., Cao, J. et al. Ancient selection for derived alleles at a GDF5 enhancer influencing human growth and osteoarthritis risk. Nat Genet 49, 1202–1210 (2017) doi:10.1038/ng.3911
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