On the left: Figure 5. Worldwide distribution of the allele frequency of the SNP rs3733549 (Arg192Gln) genotyped in this study.From the paper:
There is a high degree of divergence of haplotype composition between African and Non-Africans. Two major clades account for ~78.3% haplotypes for CEU, and these are also the major haplotypes in East Asians (HCB+JPT) but are rare (only ~5.3%) in Africans (YRI).
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The adaptive evolution of BMP3 is consistent with the rapid evolution of the human skeletal system, although we do not have data that explains the mechanism for the selective advantage of the BMP3 variant. BMP3, is an antagonist of several osteogenic BMPs, and is a negative determinant of bone density [19]. Lacking the BMP3, mice have increased bone mass [19]. Potentially, the antagonistic activity of human BMP3 to osteogenic acting factors, and even the level of BMP signal, was adaptively changed via many amino acid substitutions during human evolution, which may diverge functionally from chimpanzee accounting for the skeletal differences [2], [30]. It still needs test by further functional experiment. The targets of selection operated on the BMP3 are different between European and East Asian evidenced by long-range haplotype test (Fig. 2). Within modern human populations, BMP3 may also diverge in the activity, expression level, accounting for the skeletal variation, such as body mass, because of the key function of BMP3 in the skeletal system [19], [31], [32].
PLoS ONE doi:10.1371/journal.pone.0010959
Evidence for Positive Selection on the Osteogenin (BMP3) Gene in Human Populations
Dong-Dong Wu et al.
Abstract
Background
Human skeletal system has evolved rapidly since the dispersal of modern humans from Africa, potentially driven by selection and adaptation. Osteogenin (BMP3) plays an important role in skeletal development and bone osteogenesis as an antagonist of the osteogenic bone morphogenetic proteins, and negatively regulates bone mineral density.
Methodology/Principal Findings
Here, we resequenced the BMP3 gene from individuals in four geographically separated modern human populations. Features supportive of positive selection in the BMP3 gene were found including the presence of an excess of nonsynonymous mutations in modern humans, and a significantly lower genetic diversity that deviates from neutrality. The prevalent haplotypes of the first exon region in Europeans demonstrated features of long-range haplotype homogeneity. In contrast with findings in European, the derived allele SNP Arg192Gln shows higher extended haplotype homozygosity in East Asian. The worldwide allele frequency distribution of SNP shows not only a high-derived allele frequency in Asians, but also in Americans, which is suggestive of functional adaptation.
Conclusions/Significance
In conclusion, we provide evidence for recent positive selection operating upon a crucial gene in skeletal development, which may provide new insight into the evolution of the skeletal system and bone development.