miRNA

The "human" genome?

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The topic this week in my Intro to Bioanthro course is genetics, with the subtheme being the mechanisms getting us from a genotype to “the” human phenotype (next week is variation and population genetics). Of course we talked about things like DNA, simple Mendelian inheritance (even though many traits/diseases probably aren’t really Mendelian), and even epigenetics and genomic imprinting. But I also wanted to point out the many ways that our very existence relies on life extrinsic to that encoded by our personal genomes (this was inspired by the intriguingly titled, “A symbiotic view of life: We have never been individuals,” [Gilbert et al., 2012; free pdf]).

Mitochondria are classic examples. These “powerhouses of the cell” or “cellular powerplants” (thanks, Wikipedia!) seem to have once been, at least a billion years ago, their own unicellular organisms that somehow came under the employ of early enterprising eukaryotes. These little organelles are indispensable players in cell metabolism, implicated also in ageing and certain diseases.

In addition, there’s been a lot of research lately on the human ‘microbiome‘ – the specific set of bacteria living in and on our bodies, which aren’t incorporated into our individual cells like mitochondria, but are nevertheless requisite for us to thrive. Analyses of poop, of all things (a scatological lecture is always a good one), have revealed that the bacterial composition of human digestive tracts varies between geographical regions, but also that age-related changes in the microbiome are similar between regions (Yatsunenko et al., 2012; see the review by Ed Yong). These bacteria are crucial to our ability to digest certain foods, and some variation in gut flora probably underlies some diseases (Smith et al., 2013); this is why you may have read about a rise in poop transplants lately (van Nood et al., 2013).

Finally, and I think perhaps most intriguingly, there is evidence that our own genes may be commandeered by the the RNA produced by the things we eat. Now, the regulation of gene expression is bewilderingly complex, and one important player in this are various types of non-coding RNA, including micro RNA (miRNA), piwi-interacting RNA, etc. (I grew up under the paradigm ‘a gene codes for a protein and our genomes contain all this “junk” DNA,’ so RNA-interference and the like blow my mind). Recently, Lin Zhang and colleagues (2012) have found that some miRNA produced by plants can not only survive cooking and digestion, but that these miRNAs can actually interact with, and alter the expression of, at least one human gene (involved in removing bad cholesterol in this case). WHAT?!

ResearchBlogging.orgOne of the most exciting areas of modern biology is the discovery of the various genetic and developmental mechanisms and processes that literally make us human. Of course the genetics of human uniqueness and variation are, to use a phrase I hate, ‘much more complex than previously thought’ (such a pervasive mantra in any field of research…). Not only that, but being human, arguably the most successful complex organism in recent history, is something we cannot even do on our own.

References
Gilbert, S., Sapp, J., & Tauber, A. (2012). A Symbiotic View of Life: We Have Never Been Individuals The Quarterly Review of Biology, 87 (4), 325-341 DOI: 10.1086/668166

Smith MI, Yatsunenko T, Manary MJ, Trehan I, Mkakosya R, Cheng J, Kau AL, Rich SS, Concannon P, Mychaleckyj JC, Liu J, Houpt E, Li JV, Holmes E, Nicholson J, Knights D, Ursell LK, Knight R, & Gordon JI (2013). Gut Microbiomes of Malawian Twin Pairs Discordant for Kwashiorkor. Science PMID: 23363771

van Nood E, Vrieze A, Nieuwdorp M, Fuentes S, Zoetendal EG, de Vos WM, Visser CE, Kuijper EJ, Bartelsman JF, Tijssen JG, Speelman P, Dijkgraaf MG, & Keller JJ (2013). Duodenal infusion of donor feces for recurrent Clostridium difficile. The New England Journal of Medicine, 368 (5), 407-15 PMID: 23323867

Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, Magris M, Hidalgo G, Baldassano RN, Anokhin AP, Heath AC, Warner B, Reeder J, Kuczynski J, Caporaso JG, Lozupone CA, Lauber C, Clemente JC, Knights D, Knight R, & Gordon JI (2012). Human gut microbiome viewed across age and geography. Nature, 486 (7402), 222-7 PMID: 22699611

Zhang L, Hou D, Chen X, Li D, Zhu L, Zhang Y, Li J, Bian Z, Liang X, Cai X, Yin Y, Wang C, Zhang T, Zhu D, Zhang D, Xu J, Chen Q, Ba Y, Liu J, Wang Q, Chen J, Wang J, Wang M, Zhang Q, Zhang J, Zen K, & Zhang CY (2012). Exogenous plant MIR168a specifically targets mammalian LDLRAP1: evidence of cross-kingdom regulation by microRNA. Cell Research, 22 (1), 107-26 PMID: 21931358

microRNAs punch Plasmodium parasites in the face

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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

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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