Evidence for Positive Selection on the Osteogenin (BMP3) Gene in Human Populations

Dong-Dong Wu,Nelson Leung Sang Tang,Ya-Ping Zhang,Xiao-Dan Hao,Wei Jin,Lyle Konigsberg

doi:10.1371/journal.pone.0010959

Abstract

BackgroundHuman 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 FindingsHere, 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/SignificanceIn 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.

Highlights

Humans are characterized by dramatic skeletal anatomic differences from the chimpanzee, our closest neighbor in evolution
We examined the sequences for these signatures of BMP3 variation in human populations for evidence of positive selection operating on BMP3
Positive selection could increase the numbers of nonsynonymous mutations, such deviation from neutrality could be attributable to a recent relaxation of the selective constraint in the human population

Summary

Introduction

Humans are characterized by dramatic skeletal anatomic differences from the chimpanzee, our closest neighbor in evolution. Modern human populations demonstrate substantial phenotypic diversity, which can be illustrated by differences in body mass, height, and craniofacial dimensions that are all shaped by the skeletal system. The rapid evolution of the skeletal system during modern human evolution has previously been reviewed [3]. Genes that regulate bone development are good potential targets for positive selection, and the identification of genes that were the subject of adaptive evolution should be a good strategy to investigate the mechanisms of gene evolution in skeletal development, and associated diseases. We concluded that skeletal genes demonstrated high population differentiation driven by positive selection, supporting the rapid evolution of skeletal system [17]. 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

Methods

Results

Conclusion