Geometric constraints dominate the antigenic evolution of influenza hemagglutinin
In this month’s issue of PLOS Pathogens, Wilke-lab postdoc Austin Meyer is publishing an article providing a fresh look at influenza hemagglutinin evolution. The influenza virus is one of the most rapidly evolving human viruses. Every year, it accumulates mutations that allow it to evade the host immune response of previously infected individuals. Which sites in the virus’ genome allow this immune escape is not entirely understood, but conventional wisdom states that specific “immune epitope sites” in the protein hemagglutinin are preferentially attacked by host antibodies and that these sites mutate to directly avoid host recognition; as a result, these sites are commonly targeted by vaccine development efforts. Our analysis has found, however, that the available epitope sites are poor predictors of which sites in influenza hemagglutinin evolve rapidly. Instead, we find that a simple geometrical model works best: Sites that are closest to the location where the virus binds the human receptor and are exposed to solvent are the primary drivers of hemagglutinin evolution. This result suggests that either the available epitope sites do not accurately represent the true influenza antigenic sites or that host immune bias may be less important for influenza evolution than commonly thought.
Humanization of yeast genes
In the May 22 issue of Science Magazine, we are publishing an article on systematic replacement of essential genes in baker’s yeast with corresponding human orthologs. This work, spearheaded by the Marcotte lab at UT Austin, demonstrates that almost 50% of these yeast genes can be replaced by their human counterparts, despite over a billion years of evolutionary divergence between humans and yeast. Wilke-lab postdoc Austin Meyer contributed computational modeling to this study, and showed that continued selection for specific function can maintain replaceability despite substantial sequence divergence.
Other news features on this paper: phys.org – Discovery News – The Scientist – Science daily – MeteoWeb (in Italian) – NBC News – Washington Post – Reddit #1 – Science News – Empire State Tribune – Softpedia – Reddit #2 – Daily Mail – redOrbit – Medical Daily – NYC Today – Genetic Literacy Project – Techie News – Tech Times – American Live Wire – Pioneer News – Yahoo News – IFLScience – yeastgenome.org – Ottawa Citizen – PRI
(News features and podcasts updated as they appear.)
Departures and new arrivals
Several lab members are graduating and moving on, while new members are joining. Graduate student Amir Shahmoradi successfully defended his thesis and can now call himself Dr. Shahmoradi. In the fall, he will join UT’s Institute for Computational Engineering and Sciences (ICES) as a postdoc. Undergraduates Andrew Butler, Eric Dawson, and Keerthana Kumar are all graduating with honors. Andrew will go to graduate school at NYU, and Eric will go to Cambridge as an NIH Cambridge Scholar. Among the new arrivals are graduate students Benjamin Jack and Dariya Sydykova. Both are first-year students in the CMB program, and they are joining the lab after completing their rotations this spring. Dariya is not entirely new to the lab, however, since she also was here as an undergrad from 2012 to 2014.
Wilke Lab launches new web page at wilkelab.org
Today, we’re officially unveiling the new Wilke Lab web page at wilkelab.org. For the last couple of years, we had hosted our web page on the openwetware wiki, at wilke.openwetware.org. However, it was time to move on and develop a stand-alone page, and thus we have done so. The new page is hosted on github, and its source is freely available in a public github repository. Feel free to browse the code and look behind the scenes. The site is developed in Jekyll and makes extensive use of Markdown and of the Liquid templating language.
Two Wilke-Lab students honored by NSF
The NSF has released the results of this year’s GRFP competition. Two students in the Wilke Lab were honored. Eleisha Jackson, a graduate student in the EEB program, received a fellowship award. Eleisha is studying the biophysical mechanisms that allow viruses to switch host. Dariya Sydykova, currently an undergrad in computational biology, received honorable mention. Dariya will join the CMB graduate program at UT Austin in the fall.
Postdoctoral Position in Bacterial Systems Biology
The Wilke Lab at UT Austin has an open position for a postdoc in computational systems biology. This position is part of an ARO-funded project to investigate how bacterial growth conditions shape bacterial physiology. A successful candidate will use statistical approaches and/or mechanistic models of gene-regulation and metabolism to link bacterial growth conditions with measures of cellular physiology such as RNA and protein abundances. The overarching project goals are to develop new approaches for predicting bacterial growth conditions from the observed phenotype. For more information, click here.
The Wilke Lab goes social media
Last week, nearly the entire lab attended the BEACON Congress, where Titus Brown gave a persuasive talk arguing that scientists should get more involved with social media. In response, we decided to be more active with social media as well. First, we made a figshare account for the lab and posted several of the posters and slides we presented at the BEACON Congress. Second, we tweeted about the materials we posted on figshare. Third, Claus decided to start a blog, where he will post his personal opinions on scientific as well as non-scientific topics.
2006 MBE paper designated as Citation Classic
The journal Molecular Biology and Evolution (MBE) released a list of citation classics, past MBE papers that have been highly cited over the years. Among these papers is a paper by the Wilke lab: Drummond et al. (2006); A single determinant dominates the rate of yeast protein evolution; Mol. Biol. Evol. 23:327-337. This paper is the only MBE paper published in 2006 that was awarded this status. As of today, the paper has been cited 179 times, or 26 times per year, according to the ISI Web of Science.
A Structural Perspective on Protein Sequence Evolution
Today, the Wilke lab has published two studies on the selective pressures that protein structure exerts on evolving genetic sequences. The first, published in BMC Evol. Biol., looks at broad evolutionary trends in yeast. This study shows that evolutionary rate varies linearly with relative solvent accessibility of residues (RSA, a measure for how close to the surface or the core of the protein a residue is located). Hence, more exposed residues evolve faster than more buried residues. The second study, published in Mol. Biol. Evol., uses the insight gained from the first to identify individual sites in viral protein that evolve more rapidly or more slowly than expected given their RSA. When applied to two proteins of the influenza virus, hemagglutinin and neuraminidase, this method identified sites involved in cell entry, antibody binding, and drug resistance.
Bringing Molecules Back into Molecular Evolution
In the latest issue of the journal PLoS Computational Biology, Claus Wilke reviews the growing trend in the field of molecular evolution to incorporate molecular structure and function into computational work. This review is part of the popular Editor’s Outlook series of the journal, where PLoS Computational Biology editors take stock of what computational biology has achieved to date and what it can hope to achieve in the near future.
Matthew Tien wins NSF Graduate Research Fellowship
Matthew Tien, an undergraduate researcher currently working in the Wilke lab, has been awarded an NSF Graduate Research Fellowship in this year’s competition. For his graduate work, Matthew will be joining Allan Drummond’s laboratory at the University of Chicago. Matthew plans to use mass spectrometry to investigate the world of mistranslated and misfolded proteins.
Contact networks shape parasite evolutionary trees
The inference of population dynamics (such as the number of infected individuals as a function of time) from molecular sequence data is becoming an important new method for the surveillance of infectious diseases. We have examined how heterogeneity in host contacts shapes the genealogies of parasitic agents. We find that contact heterogeneity can have a strong effect on how the structure of genealogies reflects epidemiologically relevant quantities such as the proportion of a population that is infected. Contact heterogeneity also can increase the number of sequence isolates required to estimate these quantities over the course of an epidemic. Our results suggest that data about contact-network structure will be required in addition to sequence data for accurate estimation of a parasitic agent’s genealogy. This work is published in a special issue of the journal Perspectives on Infectious Diseases focused on network perspectives on infectious disease dynamics.
Universal trend of reduced RNA stability near translation-initiation site
In an analysis of 340 complete genomes from bacteria, archaea, and eukaryotes including fungi, plants, insects, fish, birds, and mammals, we have found a universal trend for reduced RNA stability near the translation-initiation site. With few exceptions, the secondary structure of mRNAs is less stable than expected in the first 30–50 nucleotides downstream from the start codon, but is more stable than expected further downstream. The effect is strongly correlated with genomic GC content—the higher GC the stronger the destabilization effect—and, in prokaryotes, with growth temperature—the lower the optimal growth temperature, the stronger the destabilization effect. These observations are consistent with a thermodynamic hypothesis that stable RNA secondary structure near the start codon can interfere with efficient translation initiation. This work is published in the February issue of PLoS Computational Biology.
NSF funds BEACON, a Science and Technology Center in Evolutionary Biology
The Wilke lab is part of a $25 million, multi-university center that will study evolution in action in natural and artificial settings. The center is called BEACON, “Bio/computational Evolution in Action CONsortium.” It will be headquartered at Michigan State University. Other participating universities are The University of Texas at Austin, the University of Washington, the University of Idaho and North Carolina A&T State University. Read the UT press release here, or go to the BEACON web-site here.
New York Times article on lethal mutagenesis
In today’s issue of the New York Times, Carl Zimmer discusses the prospects and challenges of combating viruses with lethal mutagenesis. The article features some of the work done in the Wilke lab as well as work done by our colleagues and collaborators in the Bull lab.
Novel source of HIV-1 viremia in patients on HAART
Even though highly active antiretroviral therapy (HAART) can reduce HIV-1 virus load to clinically undetectable levels, the virus never completely disappears and ultrasensitive assays can detect small quantities of virus in all patients on HAART. The exact origin of this virus is unknown. Many researchers assume that it is produced by latently infected CD4+ T cells that reactivate. We analyzed HIV-1 sequences isolated from resting CD4+ T cells, activated CD4+ T cells, and blood plasma using a population-genetics approach. Our analysis showed that sequences from resting and activated CD4+ T cells formed a single population, whereas some of the virus in the blood plasma seemed genetically distinct from the virus in CD4+ T cells. This result shows that circulating CD4+ T cells are not the only source of residual viremia, and it suggests that a novel cellular source may contribute significantly to ongoing virus production under HAART. This research was featured by Science Daily.
Translational-accuracy selection protects buried and structurally important sites
In 1994, Akashi proposed that translationally optimal codons, codons that are translated with relatively low error rate, should preferentially be located at important sites in coding sequences. This signal would be the consequence of translational-accuracy selection, i.e., selection to minimize the amount of non-functional or misfolded protein produced by translation errors. Traditionally, the importance of a site under Akashi’s test has been assessed by evolutionary conservation. The July issue of Mol. Biol. Evol. contains a study by Zhou et al. that correlates the location of optimal codons with sites that are important for protein structure. The study finds that there is a tendency of optimal codons to appear at structurally important sites in a wide range of organisms. The study lends further credence to the mistranslation-induced protein-misfolding hypothesis, which argues that much of the selection pressure on coding sequences stems from the toxic effects of mistranslated and misfolded proteins.
HIV viral-load dynamics under Raltegravir
The spectrum of anti-HIV drugs was recently extended by a new class of drugs, the integrase inhibitors. The first drug of this class that received FDA approval is Raltegravir. Clinical data show that when previously untreated patients start treatment on Raltegravir, their viral load declines more rapidly than it does in patients who take instead the reverse-transcriptase inhibitor Efavirenz. This spring, Antiviral Therapy published a modeling study by Sedaghat et al. that discusses the possible mechanisms responsible for this accelerated decline in viral load. The study argues that the accelerated decline is likely not caused by greater antiviral efficiency of Raltegravir compared to Efavirenz. Instead, because Raltegravir acts later in the viral life cycle than Efavirenz, at the beginning of Raltegravir therapy fewer cells have progressed to a state where the drug can not inhibit virus production, and hence the viral load declines faster. The study is a follow-up to a paper published in 2008 in Proc. Natl. Acad. Sci. USA.