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E. coli As Biology's Decoder Ring [adaptivecomplexity's column] Posted: 20 Jul 2008 07:20 PM CDT A review of Microcosm: E. coli and The New Science of Life Carl Zimmer, Pantheon, New York, 2008 If you had to pick one organism with which to tell the story of the modern science of biology, you couldn't do better than to pick the tiny gut bacterium E. coli. In his latest book Microcosm, Carl Zimmer, uses E. coli as a decoder ring to open up the dense and diverse world of biological research, taking us on a panoramic tour of some of the most important conceptual advances and outstanding scientific questions in this important realm of science. Biology, in contrast to a science like physics, is a science of particulars. In physics, if you understand one electron, you understand them all, but in biology every organism is unique. In biology it is more challenging to find universals, to pick an object of study that let's you ask big questions with the hope of finding general answers. With E. coli we can come quite close: this tiny bacterium is the hydrogen atom of biology, a model simple enough to be experimentally tractable, but representative of general principles that apply to all life. As the pioneering molecular biologist Jacques Monod put it, "What is true for E. coli is true for the elephant," and also true for us. In Microcosm, we follow E. coli through a survey of some of the deep foundations and controversies of biology. Read More...

Duffy-HIV association: an odd choice of ancestry markers [Genetic Future] Posted: 20 Jul 2008 06:34 PM CDT p-ter at GNXP does a great job of explaining a complex topic: how ancestry can confound a genetic association study, potentially leading to a false positive result. The subject is a recent study suggesting an association between a loss-of-function (null) variant of the Duffy gene with increased susceptibility to HIV infection. The study examined African-American personnel in the US Air Force, and found that individuals who carried two copies of the null variant had a 40% increase in risk of contracting HIV, but paradoxically also display slower progression of the disease once infected. The study is summarised nicely by Nick Wade in the NY Times. p-ter expands on this paragraph from Wade's article: Dr. Goldstein said that in parts of the United States, African-Americans have a higher infection rate than European-Americans, and that patients with a higher proportion of African genes may be more vulnerable to H.I.V. for reasons unconnected to the SNP. Nonetheless, the SNP would show up in a greater proportion of infected people simply because of their African heritage. If so, the gene's apparent association with H.I.V. infection could be just coincidental, not causal. Basically, the problem is that the Duffy null variant is vastly more common in Africans than Europeans. In fact, the difference is about as large as it's possible to be, with frequencies of close to zero in Europeans and approaching 100% in many African populations; African-Americans, being an admixture of European and African ancestry, have a frequency of around 70%. So here's the danger: because the null variant correlates so well with African ancestry, it will likely also show a correlation with any trait that varies between individuals of European and African ancestry - potentially including HIV susceptibility. p-ter notes: ...it's quite possible that the authors have simply shown a correlation between level of African ancestry and susceptibility to HIV (which could be due to any number of sociological, demographic, or genetic factors), rather than an association between Duffy null and susceptibility to HIV. This sort of false positive is a well-known danger in genetic association studies, and is traditionally guarded against by genotyping a set of ancestry-informative markers (AIMs) that differentiate between African and European ancestry, and using this information to correct for any possible effects of confounding by population structure. This step is routine in genome-wide association studies, where the presence of information for hundreds of thousands of genetic markers make this correction straightforward. In the Duffy study the authors attempt to perform this type of correction using a set of just 11 markers they describe as "differentially distributed between European and African populations". p-ter notes that several of these markers are not particularly ancestry-informative, and indeed on closer inspection it's clear why this is: these genes weren't originally selected on the basis of ancestry informativeness, but rather because they are associated with HIV biology. Every single one of the 11 markers has some association with HIV: three of them have previously been associated with HIV infection, progression, or response to treatment (CCR5 delta32, APOBEC3G H186R, GNB3 C825T); most of the remaining markers are in genes that are known binding targets or modulators of HIV (CCR5, CXCR4, PD1, TRIM5, IL-2, IL-4). I can't find anywhere in the article where the authors mention that all of their "ancestry" markers also just happen to be associated with HIV biology; in the supplementary data they're described as "genetic markers that we found and/or have been reported elsewhere (NCBI SNP data bases) to be more prevalent in an ethnic background compared to others." Yet it's obvious that this wasn't the original motivation for selecting these markers. Actually, it seems most plausible that the authors genotyped all of these markers as candidates for association with HIV infection risk; when only the Duffy gene emerged as significant, they instead re-badged their unsuccessful candidates (or at least those with frequency differences between Europeans and Africans) as "ancestry markers". If that's true - and it's difficult to see any other rationale for using these HIV markers rather than a set of validated AIMs - this is poor form for at least two reasons. Firstly, it's unlikely that using such a weak set of ancestry-informative markers provides an effective correction for a marker with as strong a correlation with ancestry as Duffy (as p-ter notes, all of the supposed ancestry markers are far weaker predictors of ancestry than the Duffy variant). Secondly, testing several different variants for an association with HIV and then only reporting the one that achieved significance creates the perfect conditions for a false positive due to multiple comparisons. I'll be discussing this second point in more detail in a separate post. Anyway, the ultimate test will be independent replication - I'm sure we'll all be watching with interest to see if this association holds up in studies where the effects of ancestry are adequately controlled. HE, W., NEIL, S., KULKARNI, H., WRIGHT, E., AGAN, B., MARCONI, V., DOLAN, M., WEISS, R., AHUJA, S. (2008). Duffy Antigen Receptor for Chemokines Mediates trans-Infection of HIV-1 from Red Blood Cells to Target Cells and Affects HIV-AIDS Susceptibility. Cell Host & Microbe, 4(1), 52-62. DOI: 10.1016/j.chom.2008.06.002 Subscribe to Genetic Future.

Web 2.0: A Movement Within The Health Community [ScienceRoll] Posted: 20 Jul 2008 04:29 PM CDT Dr Iain Doherty (Director, Learning Technology Unit; Faculty Medical and Health Sciences; The University of Auckland) published a fantastic and comprehensive article in Health Care and Informatics Review Online about web 2.0 and health. And Scienceroll was mentioned: Web 2.0: A Movement Within The Health Community Pedagogy 2.0 and Health Education Medical and Health Science students are now utilising Web 2.0 tools. For example, undergraduate students in health, medicine and nursing have used a wiki to develop a guide on available support services for parents of intellectually disabled children.26 The education of nurses27 and psychology students28 has been enhanced by the provision of podcasts of course content and discussions. Vodcasts have been supplied to medical students to learn new procedures and to review core medical procedures before seeing patients.29 A medical student is blogging on Genetics, Web 2.0 and Medicine (http://scienceroll.com). These examples represent the beginnings of what might be achieved in education with Web 2.0 technologies; these technologies have the potential to bring together students, health professionals and health consumers in order to enhance learning and to increase collaboration amongst the three distinct yet related groups.8 The pedagogical model presented below represents one way in which this might be achieved. The table of contents looks great: From 1.0 to 2.0 Web 1.0 Web 2.0 Health 2.0 Web 2.0 and Health 2.0 Summary Health 2.0 and Health Professionals Blogs Wikis Podcasts Social Networks Health 2.0 and Health Consumers Health Advice and Information Health Prosumers Health Communities Pedagogy 2.0 and Health Education Pedagogy 2.0 In With The Old Learning from the Past Concluding Remarks

Gene Genie 34: Summertime [ScienceRoll] Posted: 20 Jul 2008 02:05 PM CDT This is the first time I host Gene Genie since January. Gene Genie is the blog carnival of clinical genetics and personalized medicine. Enjoy the numerous posts and articles focusing on these interesting fields of medicine. Many thanks to Ricardo Vidal for the logo! Gene - Phenotype: Walter Jessen at Highlight HEALTH had a great post, Neurofibromatosis: From Genes to Complications to Treatments. On Science Blog, you can read more about women’s genes and alcoholism. Daniel MacArthur at Genetic Future presented the adventure gene. Steve Murphy, our Gene Sherpa, informed us about a new gene in atrial fibrillation. Rebecca Taylor at Mary Meets Dolly talked about a lesson in genetic testing: the I148T mutation. Matt Mealiffe at DNA and You said Rett Syndrome was on Fox Show. Yann Klimentidis analyzed some skin cancer and pigmentation genetic variants. Chavonne Jones at Human Genetics Disorders posted an article and a video about Marfan Syndrome. Genetic Testing: Aaron Rowe at Wired listed 10 reasons why regulators should not hinder genetic testing. The DNA Testing Blog talked about DNA testing for members of the military. Personalized Medicine: Jason Bobe at The Personal Genome shared the Wired article of Thomas Goetz with us. Andrew Yates at Think Gene reviewed the deCODEme Genome Browser. A Forum for Improving Drug Safety featured genetic influence in antidepressant effectiveness. At Genetic Future, you can read more about the challenges of psychiatric genetics. Yann Klimentidis analyzed structure-informative SNPs among European Americans. Deepak Singh at BBGM said thinks your SNPs are your information. The question at Genomeboy is to sink or to swim. Dr. Eric Topol introduces the Genomic Medicine Resource Center with a discussion of personal genomics. Wikis and Else: Larry Moran at Sandwalk presented a Gene Wiki. Check the comments out as well. According to Wired, Genes Don’t Explain African AIDS Epidemic. Evolgen tried to help us answer the question, how many genes we share with our twentieth cousin. The 35th issue of Gene Genie will be hosted on the 3rd of August. Don't forget to submit your articles via the official page. And also check the Gene Genie official blog out! If you'd like to host an edition, don't hesitate to contact me at berci.mesko [at] gmail.com.

Species-Scape: very cool, but... [Genomicron] Posted: 20 Jul 2008 09:55 AM CDT Larry Moran directs us to have a look at Species-Scape at the Cornell website. It's great. But... 1. It has one group of "prokaryotes", Kingdom Monera, which is pretty old school. (Same goes for "Protists"). You don't like dividing the Archaea and Bacteria? Ok, but how about a note that many people now consider this one of the deepest divisions of life? If they can mention something as esoteric to most readers as the phylogenetic species concept, surely they could include a brief line about, you know, phylogenetic groupings at the highest level. 2. And I quote: This is a taxonomic view of life on earth -- based on systematic classifications -- which challenges our typical "mammal-centric" understanding of the world around us. Today there is increasing awareness of the enormous diversity of life on earth, but few people probably appreciate the fact that the Species-Scape is completely dominated by multilegged (more than 4 legs) and legless animals, fungi and microbes. Mammals, with a mere 4,000 species, are dwarfed by "lower" animals. Do we really have to use a misconception to correct a misconception? This is the feed from the original Genomicron. To visit the new version and access other science-related content, see http://www.scientificblogging.com/genomicron.

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