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

miRNA special reprint in Nature

A while ago I had a small post about RNA interference (RNAi), linking to a really awesome and educational animation and slideshow on the topic. Again, RNAi refers to gene regulation by very small strands of RNA. There are a number of types of RNA in your cells, and a several of these are involved in RNAi: in the last post I cursorily mentioned piwi-interacting RNAs (piRNA), small interfering (siRNA) and long intergenic non-coding (lincRNA).

One type I neglected to mention is “micro” (miRNA), and this is the one about which the journal Nature has a special on-line issue. miRNA, like other types in RNAi, binds to messenger RNA in cells to prevent gene translation. The special issue of Nature focuses on miRNA in various diseases involving tumors and skeletal abnormalities, and so far as I can tell, it’s completely free to all!

What really caught my eye about this issue is its highly interactive medium, produced by some company called zmags. This “zmag” (I guess you’d call it?) has been rendered so that you view and leaf through actual magazine-like pages in your browser. I’ve got a 1+ yr old Macbook and the 2-finger zoom on the trackpad also works within the browser. Want to read and mark up some of it in your preferred program? Well you can save selected pages from the issue as a pdf, giving you flexibility in what content you download (though I did have some issues with this). A while ago I noticed Nature also used a somewhat interactive in-browser, pdf-viewing app called Readcube, though I admit I haven’t really toyed with that program.

It’s a bit challenging but also interesting to follow the possible obsolescence of the (literally) printed word. Amazon’s Kindle and other e-book platforms have all but buried the expensive, clunky hardcover tome. Academic publishers like Springer offer not only articles but also whole book chapters as pdfs available online (though they tend to require some type of university or other affiliation), and major newspapers offer most of their content on their websites.

ResearchBlogging.orgOn this topic, Carl Zimmer had a neat piece in Nature a few weeks ago about the “rise of the e-book.” He raises some excellent points regarding the pros and cons of e-books, some which I think could be extended to digital media more generally. I for one am like millions of others, relying on my handy computer and the internet for nearly all information I need to be a fully-functioning student, teacher and member of society. Still, as Zimmer points out at the end of his article, the permanence of e-books and the like is uncertain. I mean, what to do if we’re hit by another devastating Y2k?

Read on
Nature special issue here

Zimmer, C. (2011). Technology: Rise of the e-book Nature, 480 (7378), 451-452 DOI: 10.1038/480451a

Small-stranded insanity inside your cells

The Nature News Blog posted a fascinating video showing how RNA interference (RNAi) works within a cell. RNAi refers to the regulation of gene expression by short-length RNAs. So far as I understand it, there are a number of types of small stretches of RNA (e.g. siRNApiRNA) that do not code for proteins but rather target other RNAs, and then latch onto them via proteins to ensure the other RNA’s demise.  RNAi is implicated in expression of lots of genes, for instance HOTAIR is a long intergenic noncoding RNA that is itself located in the HOXC cluster but later acts to repress HOXD expression (Woo and Kingston 2007).

The video (there’s also a slideshow) provides a stunning and digestible visual of what exactly is going on during this complex process. It’s online and it’s completely free (see links above), and so could be a valuable resource for teaching about this aspect of gene regulation.

Oh, the humanity. An Argonaute protein is guided by a small interfering RNA to where it will start rending a messenger RNA. From this great slideshow by Nature Reviews Genetics and Arkitek.

Some RNAi reviews
Czech, B., & Hannon, G. (2010). Small RNA sorting: matchmaking for Argonautes Nature Reviews Genetics, 12 (1), 19-31 DOI: 10.1038/nrg2916

Moss, E. (2001). RNA interference: It’s a small RNA world Current Biology, 11 (19) DOI: 10.1016/S0960-9822(01)00467-5

Woo, C., & Kingston, R. (2007). HOTAIR Lifts Noncoding RNAs to New Levels Cell, 129 (7), 1257-1259 DOI: 10.1016/j.cell.2007.06.014

Anton Wutz (2011). RNA-Mediated Silencing Mechanisms in Mammalian Cells Progress in Molecular Biology and Translational Science, 101, 351-376 DOI: 10.1016/B978-0-12-387685-0.00011-1

UPDATE: The Journal of Experimental Zoology B has an entire issue dedicated to “RNA in Developmental Evolution.”