Positive selection on the osteoarthritis-risk and decreased-height associated variants at the GDF5 gene in East Asians

Abstract

GDF5 is a member of the bone morphogenetic protein (BMP) gene family, and plays an important role in the development of the skeletal system. Variants of the gene are associated with osteoarthritis and height in some human populations. Here, we resequenced the gene in individuals from four geographically separated human populations, and found that the evolution of the promoter region deviated from neutral expectations, with the sequence evolution driven by positive selection in the East Asian population, especially the haplotypes carrying the derived alleles of 5' UTR SNPs rs143384 and rs143383. The derived alleles of rs143384 and rs143383, which are associated with a risk of osteoarthritis and decreased height, have high frequencies in non-Africans and show strong extended haplotype homozygosity and high population differentiation in East Asian. It is concluded that positive selection has driven the rapid evolution of the two osteoarthritis osteoarthritis-risk and decreased height associated variants of the human GDF5 gene, and supports the suggestion that the reduction in body size during the terminal Pleistocene and Holocene period might have been an adaptive process influenced by genetic factors.

Figure 1. Structure of the human GDF5 gene structure.

The human GDF5 gene is composed of two exons. The two regions sequenced in this study are denoted by the two rectangles.

Figure 2. SNP allele frequencies in the GDF5 gene.

(A) Allele frequencies of haplotypes constructed using SNP rs143384 and rs143383 in four separate populations and the whole population. (B) Derived allele frequencies of the two SNPs in the four populations and the whole population.

Figure 3. World-wide allele frequency distribution of the two SNPs rs143384 and rs143383.

The data were downloaded from http://hgdp.uchicago.edu/.

Figure 4. Median-joining phylogenetic network of the 16 haplotypes at at the exon 1 region.

Each haplotype is represented by a circle with its area proportional to its frequency. The ancestral haplotype is outlined by a black line. The two haplotypes in the ellipse are the haplotypes that carry the derived allele at SNPs rs143383 and rs143384.

Figure 5. Fst distribution of SNPs across chromosome 20 gene regions.

(A): Fst among the three populations vs minor allele frequencies (MAF). Big green dot and triangle represent SNPs rs143383 and rs143384. (B) Fst between East Asians and Europeans vs minor allele frequencies (MAF). (C) Fst between East Asians and Africans vs minor allele frequencies (MAF). (D) Fst between Africans and Europeans vs minor allele frequencies (MAF). (E) Sliding window analysis of Fst. Purple, black, brown and gray lines represent Fst among the three populations, Fst between East Asians and Africans, Fst between Africans and Europeans, Fst between East Asians and Europeans, respectively. The vertical line represents the position of GDF5 gene. Black and brown horizontal lines represent the 95% percentile rank values of Fst values between East Asians and Africans and Fst between Africans and Europeans, respectively.

Figure 6. REHH of the core haplotypes on chromosome 20 and GDF5.

REHH distributions at (A) 300 kb, (B) 500 kb, and (C) 1000 kb upstream and downstream of the core haplotypes. The two lines represent the 99% and 95% percentile rank values. Big dots are the major haplotype at the GDF5 gene. (D) REHH of the major core haplotype at the GDF5 gene at varying physical distances (kb).

Figure 7. Evaluation of the ages of the derived alleles of SNPs rs143383 and rs143384 by linear regression of −ln(EHH) and 2r.

Figure 8. Positive natural selection operated upon the derived alleles of SNPs rs143384 and rs143383.