June 08, 2010

Osteogenin (BMP3) selection in humans

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).


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.


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.

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.



Maju said...

Sincerely, it looks a case of acute academic publicatitis, which I understand has some particular severe incidence in China for curriculary reasons.

I may be missing something (you tell me what) but the paper is full of vagueness, a clear symptom of this epidemic. This can well be illustrated by the (technically ok but in this case rather indicative of wishful thinking) decision to agree that P=0.0479 (in relation to orangutan) is significant while admitting that P=0.0517 is not (in relation with chimpanzee). A safer decision would have been using a more strict value for statistical significance such as P=0.01 and leave the whole research as probably meaningless. But guess much work was already invested and they decided to publish anyhow.

To me it looks in fact more like founder effects produced by the pseudo-bottleneck at the OoA migratory episode. Coincident with this expectation are the facts that diversity values are highest in Yorubas, lower in East Asians and lowest among Utahpeans.

As you can probably infer from my comment so far I'm both amused and slightly irritated (p<0.0001).


Andrew Oh-Willeke said...

One way to check for selective advantage would be to see if there are Asia only Y-DNA or mtDNA haplotypes whose frequencies correlate closely with this trait (suggesting founder effect).

Another would be to measure bone density related traits between people with and without the gene to see if it is expressing itself in a meaningful way.

Maju said...

Agree, Andrew.

I would say that we trace that parallel even if this gene is autosomal. I already said why above: the diversity patterns are roughly coincident with those of haploid DNA.

For the second part, the authors acknowledge once and again in the paper that they have no idea what specific trait is the gene in question related with.

terryt said...

Fascinating. At first glance it could be taken as supporting German's idea of America being an important early contributor to the human geneome. The non-African version is most strongly represented in some Mexican Indian tribe. From where it virtually diminishes across Eurasia to Africa.

"the authors acknowledge once and again in the paper that they have no idea what specific trait is the gene in question related with".

But that doesn't automatically mean it wasn't subject to selection.

"To me it looks in fact more like founder effects produced by the pseudo-bottleneck at the OoA migratory episode".

I know exactly why you prefer this explanation, and why you so readily dismiss the authors' claim, 'we provide evidence for recent positive selection operating upon a crucial gene'. You use the same concepts you've used here to explain the distribution of modern human haplogroups. You're uncomfortable with the idea that at times certain haplogroups, for one reason or another, have been able to expand and replace previous ones. To me this latter explanation more readily accounts for the many gaps in modern human haplogroup distribution than does the idea that virtually all the haplogroups diversified in India and then expand together around the world, losing that diversity as they went.

You're also uncomfortable with the idea that modern human regional phenotypic diversity might be a product of selection. You prefer to view it as a product of drift.

Maju said...

I don't see modern phenotype diversity only as product of drift and/or founder effects.

For example I have defended often that skin color variation is largely caused by selection. However American Natives (who have not de-evolved into black pigmentation yet, even if at the tropics) are proof that selection and adaptative evolution may need some long time even with such traits so strongly related to fitness and health. And it also depends on whether the genes involved were readily available in the original population or not, something that is determined more by founder effects and such than anything else.

I have even hinted recently that thinly curled "Afro" hair (non-existent among our semi-arboreal cousins) may have got an adaptative value for hot tropical climate, maybe by creating an isolating layer of air between the scorching sun and the head.

But I don't have any reason to think that such traits expanded by demic replacement but much more probably by slow gradual infiltration (introgression) between populations and within them, as well as within the coalescent episodes of the several regional populations (founder effect plus drift and/or selective pressure within intra-population diversity).

"But that doesn't automatically mean it wasn't subject to selection".

What I say is that the authors seem to fail to provide a single piece of evidence that selection, and not normal quasi-random demographic events, was the force acting in this case.