Primate genomics: the Duffy (FY) gene, malaria, and baboons

Jenny Tung of Duke University and colleagues report in Nature (online early) that yellow baboons have evolved a Duffy antigen-related defense against a baboon relative of malaria.

Most Africans carry a null allele for the Duffy antigen, coded by the DARC gene, which functions to protect them from vivax malaria. It’s not the worst kind of malaria (that would be falciparum), but it is a major cause of disease outside those regions where the Fy*O allele is near fixation.

The baboon version of DARC is not convergent with the human null allele; the paper reports that it actually increases the gene activity, whereas the baboon variant allele actually increases the activity.

Presumably, the different defense in baboons is because they’re fighting a different parasite:

Baboons are not generally infected by Plasmodium in the wild, but are vulnerable to infection by several closely related haematoprotozoans (4, 5) including Hepatocystis kochi, a blood parasite nested within the paraphyletic Plasmodium genus (15). Hepatocystis parasites do not produce the cyclical fever spikes typical of malaria in humans, but do produce anaemia and visible merocyst formation, followed by scarring on the liver (4).

They were able to show that the infection rate with Hepatocystis is significantly lower in baboons that cary the protective allele.

Based on their comparisons, the locus looks like a case of balancing selection:

We detected an increased level of population differentiation among East African baboon populations around FY, by comparing a FY-linked microsatellite with 35 neutral microsatellites (Fst = 0.31, P<0.029; range of Fst for the neutral markers was 0.0080.346; Fst is a metric describing genetic divergence between populations based on allele frequency differences at variable sites; Supplementary Fig. 3). We also detected a higher value for the Tajima's D statistic (D = 1.26) in this region relative to nine of nine other resequenced putative cis-regulatory regions in the Amboseli population and 11 of 12 resequenced transcribed regions (range of D for all other loci was -1.60 to 2.12). The only locus with a higher value of D, a transcribed portion of the gene MSR1, exhibited an even more extreme value than that identified for the MHC DQA1 promoter in baboons (22), which is known to evolve under strong trans-specific balancing selection (20).

A balance really would be necessary for them to be likely to have any evidence of selection. There’s no reason to think that baboons are in the kind of demographic and disease transient that humans are in, so if a protective allele were always beneficial, it would likely be fixed. Still, it’s not obvious what the disadvantage of the protective allele would be, although in humans it has been suggested that altering Duffy expression may impair immune response by reducing white blood cell count (Reich et al. 2009). Considering the high stress and cortisol levels of wild baboons, it may be that changes in immune activity have even more disadvantages.

One important aspect of the study is that the allele affects the cis-regulatory region of the gene; that’s the general research topic covered by Gregory Wray’s research group. I think that it’s important because it raises the prospect that targeted sequencing of cis-regulatory elements in primate genomes might lead to the discovery of more adaptive variations within primate species. In their concluding paragraph, the authors emphasize the strengths of a combined field and in vitro approach to characterizing functional variants:

In vivo gene expression measurements are complicated by variation in genetic background and in the environment, both of which can modify functional cis-regulatory effects (25, 26). Indeed, our results show that even baboons that are homozygotes at the C/T site sometimes exhibit allelic imbalance in FY expression, suggesting that other, unidentified functional cis-regulatory variants are also segregating in the population. In contrast, in the in vitro comparisons, only a single cis-regulatory site differed between the experimental constructs, thus controlling for both environment and genetic backgrounds. Using both approaches in tandem can be synergistic: while in vitro experiments can help pin down specific functional sites, in vivo results demonstrate that these effects are relevant to the biology of individuals in the wild.

When it comes to primate genetics, looking for defenses to infectious diseases should be low-hanging fruit. Just take human genes that have alleles that defend against diseases, and sequence them for variations. Hopefully we’ll find many others – and in a few cases, those variations may prove useful in human health contexts, as they may reveal new pathways to deter or defeat pathogen infections.

References:

Tung J, Primus A, Bouley AJ, Severson TF, Alberts SC, Wray GA. 2009. Evolution of a malaria resistance gene in wild primates. Nature (advance online publication) doi:10.1038/nature08149

Reich D, Nalls MA, Kao WHL, Akylbekova EL, Tandon A, et al. 2009. Reduced Neutrophil Count in People of African Descent Is Due To a Regulatory Variant in the Duffy Antigen Receptor for Chemokines Gene. PLoS Genet 5(1): e1000360. doi:10.1371/journal.pgen.1000360