microRNAs punch Plasmodium parasites in the face

This is the first time I’m teaching Introduction to Biological Anthropology here at Nazarbayev University. It’s exciting and curious that for nearly every class session, I’m able to find a very recent outside article or blog post that’s relevant to the field and/or something we’re talking about at the moment. For instance, the 30-paper barrage of the ENCODE project came out right as we were beginning the unit focused on evolution and genetics. Serendipity!

Recently in this first unit, we covered one of the classic anthro examples illustrating principles of both genetics and evolution: sickle-cell anemia and malaria resistance. And right on cue, a brief review about the actual molecular basis for this phenomenon was just published in Nature Genetics (Feliciano, 2012, reviewing LaMonte et al., 2012).

Briefly, sickle-cell anemia is an iron deficiency caused by having aberrant hemoglobin, and characterized by sickle-shaped red blood cells (“erythrocytes”). The sickle cell trait is caused by a simple point mutation on the 11th chromosome, at a locus termed the hemoglobin S (or HbS) allele; the ‘normal’ allele is designated A (or HbA). If you have two A alleles you have normal hemoglobin, whereas two S alleles result in sickle cell, which is generally fatal. You don’t want to have two S alleles. The deleterious S allele is nevertheless maintained in the population because heterozygous individuals (AS genotype) have basically normal red blood cells and resistance to malaria, a disease caused by the parasite Plasmodium falciparum. P. falciparum loves red blood cells, and so in populations where malaria is endemic, having normal hemoglobin can actually be a health risk because of stupid smelly P. falciparum. Natural selection therefore maintains both the normal A and sickle S alleles in malarial areas because of a heterozygote advantage.

The outstanding question, however, is how having both an A and an S allele confers resistance to malaria. The textbook explanation (e.g. Larsen, 2010) is that sickle cells are poor in oxygen, and therefore poor hosts for stupid smelly P. falciparum. A recent study, however, points to a much more badass mechanism of resistance.

LaMonte and colleagues (2012) show a role for microRNAs (miRNA) in sickle cell-mediated resistance to malaria. miRNAs are small strands of RNA (21-25 base pairs long) that do not get translated into proteins, but are nevertheless important in regulating gene expression. This mechanism is called RNA interference (RNAi) – check out this sweet slideshow and animation from Nature for more info. What LaMonte and colleagues found was that SS and AS red blood cells had higher concentrations of certain variants of miRNA, which were then transferred into P. falciparum parasitizing these cells. These miRNA-enriched parasites, in turn, showed reduced growth compared to those parasitizing normal cells. It remains to be seen, however, just how these human miRNAs are disrupting development of Plasmodium, since these parasites do not produce the same genetic machinery that utilizes the miRNA used in human RNAi (Feliciano, 2012).

ResearchBlogging.orgNot being a geneticist, I’m really enjoying how complicated the genome is proving to be. The example here illustrates not only our increased appreciation for RNA and especially non-protein-coding elements, but also the dynamic genetic interactions between different species.

Better explanations than I was able to give
Feliciano P (2012). miRNAs and malaria resistance. Nature genetics, 44 (10) PMID: 23011225

Lamonte G, Philip N, Reardon J, Lacsina JR, Majoros W, Chapman L, Thornburg CD, Telen MJ, Ohler U, Nicchitta CV, Haystead T, & Chi JT (2012). Translocation of Sickle Cell Erythrocyte MicroRNAs into Plasmodium falciparum Inhibits Parasite Translation and Contributes to Malaria Resistance. Cell host & microbe, 12 (2), 187-99 PMID: 22901539

As promised, malaria resistance in baboons

Last week I started to mention a recent paper in Nature on the evolution of malaria resistance in baboons, but then went out and partied instead. Not wanting to be a bastard, I’d better make good. While I’ll try to pull a good lesson from this, be warned that I’m about to discuss a topic about which I am no expert.

Malaria sucks, you don’t want to get it. There are anti-malaria medications out there, but I understand that they can make you insane, or at least have crazy dreams. Fortunately for millions of humans, there is a genetic basis for malaria resistance, so they don’t have to buy the anti-malaria crazy pills. Now, the paper tells me that a polymorphism in part of the FY gene turns the gene off in red blood cells, and that individuals with this variant are then strongly protected from malaria. No Lariam for these folks.

Jenny Tung and colleagues analyzed the homologous region of the FY gene in almost 200 yellow baboons (Papio cynocephalus) from Kenya, as well as tested these baboons for Hepatocystis parasites–relatives of Plasmodium vivax, which don’t cause malaria in baboons, but does really suck for them. And wouldn’t you know it–this same region on the baboon FY gene is also associated with Hepatocystis infection, where individuals with certain genetic variants have a lower susceptability to infection!

Now, the underlying genetic architecture and subsequent mechanisms of infection resistance are not exactly the same. But here’s the take home message from the paper:

“These results suggest that the genetic basis of phenotypic variation in different primate species can exhibit a remarkable degree of parallelism. In this case, not only are the similarities present at the molecular level . . . but they also extend to the mechanism that links molecular and phenotypic variation”

In other words, closely related species are equiped with very similar (or often the same) genetic or developmental “hardware,” and so evolution can cause them to come up with similar solutions to the same problem. In this case, there’s a similar genetic basis underlying infection resistance in humans and baboons. But I think this is a lesson that can be extended to, or at least kept in mind when considering, phenotypic evolution generally.

I’ve always (well, for the past three and a half years since I’ve been studying physical anthropology) thought that such a situation might characterize the “robust” australopithecines of East and South Africa. It is possible that these groups are not each others’ closest relatives, but that they evolved many craniodental characters in parallel, in response to selection for a heavy-chewing diet. This becomes even more plausible if it should turn out that many of these cranial and dental features are morphologically integrated–something I’m working on at the moment (if anyone reads this and scoops me, you will pay).

So, interesting paper. Reference

Tung, J. et al. Evolution of a malaria resistance gene in wild primates. Nature, in press.