Posts in category Genetics

Microbial Warfare and the Ecological Dynamics of Cystic Fibrosis Lung Disease

In a previous EMR post from December 30 of 2014 (see link below), I discussed a study (Science, 2014) that offered evidence for reciprocal selection of host and pathogen iron-binding proteins arising out the competition for their shared ligand, which is critical to the metabolisms of both parties to the conflict. A recent paper (J. Bacteriol., 2015) by Filkins et al. demonstrates another sort of competition focused on the acquisition of iron that can affect human health. This conflict occurs between two species of bacterial pathogen associated with lung disease in cystic fibrosis (CF) patients. READ MORE »

Fighting HIV Evolution with an Evolved Therapeutic Agent: Phase I Dose Escalation Clinical Trial of a Potent Broadly Neutralizing Human Antibody

In previous commentaries (;;, I have discussed the critical role of extensive B-cell and immunoglobulin gene evolution in generating broadly neutralizing antibodies for HIV-1.  Of course, the unprecedented magnitude of antibody evolution necessary to achieve potent neutralization of a high percentage of HIV strains reflects the unprecedented evolutionary plasticity of HIV that originates in both high mutation and recombination rates for the HIV genome (Korber et al., 2001).  A new study by Caskey et al. (Nature, 2015) from the Nussenzweig Laboratory reports results for a first-in-human dose escalation phase I clinical trial of a human monoclonal antibody (mAb) specific for the HIV envelope (env) protein. READ MORE »

Extent of Tumor Evolution as Assessed by Numbers of Nonsynonymous Somatic Mutations Correlates with the Effectiveness of Anti-Checkpoint Therapy

It would be hard to identify an approach to cancer treatment that has received more attention recently than anti-checkpoint therapy (Pollack, 2015).  This strategy for eliminating tumor cells is based on interfering with one or another pathway that inhibits the initial activation or functions of T cells, such as CD8+ cytotoxic T cells (CTL).  Activated tumor-specific CTL can directly kill their targets.  However, if copies of the T-cell surface molecule, PD-1, are bound by their physiological ligands on tumor cells, either PD-L1 or PD-L2, or other cells the ability of the T cell to perform its functions is substantially reduced.  A report published in Science (2015) by Rizvi et al. last month addresses the question of whether tumor mutation burden correlates with response to anti-checkpoint therapy for non-small cell lung cancer (NSCLC).


A Functional Classification of Genomic Elements Informed by the Principles of Evolution

In an EMR commentary ( from March two years ago, I discussed issues related to the functional classification of genomic DNA sequences that arose in the context of claims from the ENCODE (ENCyclopedia Of DNA Elements) consortium.  A particular focus of that piece was an article by Graur and colleagues (2013) that offered an often humorous but rather stinging critique of the definition of “function” applied by the ENCODE authors to genomic DNA sequences.  Graur and two of his associates have now published (2015) an interesting and valuable functional classification of genomic sequences that is critically informed by their understanding of evolution. READ MORE »

Chromosomal Catastrophe (Chromothripsis) Causing Curative Clonal Conquest

Last month, Murphy and colleagues (Cell, 2015) published a fascinating report about a patient with an immunodeficiency syndrome that underwent spontaneous resolution.  The mechanism for this remarkable outcome points to the importance of somatic cell selection and evolution in the origins, pathogenesis, and most dramatically in this case, elimination of disease. READ MORE »

Altered Androgen Receptor Ligand Specificity in Prostate Cancer Cells Treated with an Androgen Biosynthesis Inhibitor

Carcinomas of the prostate are the most common cancers affecting men and a leading cause of male cancer deaths in the United States (CDC web site, Cancer Prevention and Control).  Given the unique association of the prostate with males, it makes sense that prosate carcinoma cells are often dependent for continued growth and proliferation on signaling by the androgen receptor, as andogens are primarily associated with physiological effects critical for male sexual development.  Therefore, therapies aimed at inhibiting either androgen synthesis or androgen receptor function make great sense. In a recent paper by Chen et al. (2014), Steven Balk and colleagues demonstrate that treatment of castration-resistant prostate cancer with a drug (abiraterone) that inhibits the production of androgens can select for mutant androgen receptors (AR) that more effectively recognize and get activated by a non-androgen. READ MORE »

Putting the Kill in “Shock and Kill”: Overcoming Evolutionary Obstacles to HIV Cure

According to estimates by the World Health Organization, in 2013 on the order of 35 million people were infected with HIV worldwide (  Globally, about 1.5 million people are believed to have died from AIDS-related diseases in that year.  Substantial, although perhaps not insurmountable, obstacles to the development of a highly effective vaccine for HIV-1 have increased interest in curative strategies.  A key challenge to cure strategies is that infected people harbor a latent reservoir of infected CD4+ memory T cells that do not express significant amounts of viral proteins.  The paucity of viral proteins in these cells makes it more difficult to identify infected cells and eradicate them.  A new study (Deng et al., 2015) in Nature from Robert Siliciano’s lab at Johns Hopkins identifies an additional difficulty faced by one of the currently popular approaches to curative therapy but also, more optimistically, suggests a way to overcome this challenge. READ MORE »

Cellular ‘Gold’: Competition for Iron as the Cause of Reciprocal Positive Selection of Host and Pathogen Iron-Binding Proteins

Iron is a critical metal for essential cellular processes, such as respiration, in both human and microbial cells.  Thus, in the context of infection, iron is a high-value cellular commodity and an evolutionist might reasonably expect a metallic tug-of-war between host and pathogen iron-binding proteins or other iron-binding molecules (siderophores).  This speculation is impressively supported in a paper published this month (Barber and Elde, 2014).  These authors provide strong evidence for positive selection affecting several sites in host (transferrin, Tf) and pathogen (transferrin binding protein A) iron-binding proteins based on a combination of genetic, structural, and functional experimental methods. READ MORE »

Eukaryotic Exploitation of Bacterial Anti-Microbial Genes via Trans-Kingdom Horizontal Gene Transfer


An article published online at the Nature web site on November 24 (Chou et al., 2014) presents a fascinating study of examples in which bacterial genes have found their way to a number of distinct eukaryotic lineages including ticks and mites, gastropod (e.g., snails and slugs) and bivalve mollusks (e.g. clams and oysters), and choanoflagellates (a subset of ptotozoans).  Type VI secretion amidase effector (Tae) molecules (encoded by tae genes) can kill rival bacteria by degrading their cells walls when delivered into those competing cells.  The eukaryotes cited above all have “domesticated amidase effectors” (dae) genes, all of which are extremely similar to one of the four extant bacterial tae genes.  Of the four tae genes found in bacterial species, three have been transferred to one or another eukaryotic genome. READ MORE »

Evolution and the Ebola Epidemic. II.

After posting my last commentary on the ongoing Ebola outbreak in West Africa, I listened to the netcast, This Week in Virology (, for September 14, 2014.  TWiV sessions, hosted by Vincent Racaniello, a well-known virologist at Columbia University, are generally highly informative, typically offering thoughtful discussions about recently published studies pertaining to viruses or addressing broad areas of virus-related research. READ MORE »

Evolution and the Ebola Epidemic

Over the past several weeks the health news has been dominated by the outbreak of infections by Ebola virus (EBOV) in several West African nations: Guinea, Sierra Leone, Liberia, and Nigeria.  A study (Gire et al., 2014) published online at the end of August and now in print by a large collaborative group based in the U.S., the U.K., or West Africa applied massively parallel sequencing of the genomes of clinical isolates of the Ebola virus primarily from Sierra Leone. The results bear on the origins of the outbreak and the transmission patterns of the responsible virus lineages and may inform future investigations pertaining to diagnostic tests, the development of vaccines, and the design of therapies based on small-molecule drugs or biologics. READ MORE »

Potentially Positive Therapeutic Applications of Mutations Negatively Affecting Gene Product Function

Altshuler and colleagues (Nature Genetics, 2014) recently reported a study of about 150,000 individuals representing five different ancestral groups in which they identified twelve low-frequency variants of the gene SLC30A8 through either genomic sequencing or genotyping.  These variants are all predicted to truncate the gene product (ZnT8), a protein involved in zinc transport in beta cells in the islets of Langerhans.  In beta cells, zinc is involved for insulin packaging and secretion.

Of particular interest, carriers possessing one or another of these loss-of-function mutations appeared to be at lower risk from type 2 diabetes (T2D).  Averaging over the different variants, these alleles provided an approximately 65% lower risk of T2D. READ MORE »

Epistasis in Adaptive versus Stochastic Evolution of the Influenza A Virus Nucleoprotein Gene

Epistasis refers to the influence of one genomic mutation or variant on the phenotypic effects of another mutation or variant.  Based on available evidence and theory, this phenomenon has a major influence on evolutionary trajectories for organisms of all sorts.  The role of epistasis has been studied primarily in the context of adaptive evolutionary change.  In a recent paper (2014), Gong and Bloom attempt to determine the relative frequencies of epistatic interactions in adaptive versus stochastic evolution, i.e. evolution driven by selection as opposed to evolution resulting from random processes without a significant selective ‘pressure.’  Gong and Bloom perform this comparison by analyzing homologous nucleoprotein (NP) genes in human and swine influenza A viruses.  The authors argue that the human viruses are subject to substantially more intense selection than the swine viruses since domestic swine are much shorter lived and their viruses are not as likely to be subjected to immune memory responses. READ MORE »

Prions, Pathology, and the Promotion of Propitious Phenotypes

A prion is a protein that can adopt a conformation other than the ‘standard’ functional conformation and this alternative conformation favors self-association. The aggregation-associated conformation can then be imposed on additional copies of the protein in the original conformation.  This self-templating mechanism for propagation is known primarily for causing neurodegenerative conditions in humans and in animals, such as kuru or Creutzfeldt-Jakob disease in humans or bovine spongiform encephalopathy (i.e., mad cow disease) in cattle.  Since this process of converting protein conformations can be transmitted from one animal to another or one person to another by some routes, such as cannibalism in the case of kuru, the name prion was created to indicate an infectious protein particle.  This concept of an infectious agent that involved no nucleic acid was the basis for the Nobel Prize in Physiology or Medicine awarded to Stanley Prusiner in 1997 ( READ MORE »

The Future of the “Selfish Gene” Metaphor

This past December, science writer David Dobbs published an essay (2013) in the online magazine Aeon ( that purports to explain why the ‘selfish gene’ concept is outmoded and should be retired.  It elicited a good deal of commentary, and in early March, Aeon published responses (Sapolsky et al., 2014) to the original article from four individuals (two scientists, a genetic counselor, and a philosopher) as well as additional comments by Dobbs.  For those who are interested in this controversy, responses to the original Dobbs article were also posted elsewhere by Richard Dawkins (2013) and Jerry Coyne (2013a, b).  Below, I provide a sense of the arguments of Dobbs, the tenor of the criticisms of Dobbs’s piece, and selected other critiques of the gene-centric approach to evolution. READ MORE »

An Evolutionary Link between Cancer and Scleroderma: Somatic Cell Variation and Selection

Geneticists have recognized for some time that many genes exhibit pleiotropy, meaning that one mutation can manifest in two or more distinguishable phenotypic effects. In a fascinating study recently published in Science [2014 Jan 10;343(6167):152-7. doi:10.1126/science.1246886], Joseph et al. offer evidence for an example of pleiotropy in which the distinct phenotypic effects associated with mutation of the POLR3A gene, which encodes a subunit (RPC1) of RNA polymerase III, are associated with two different diseases: one or another form of cancer and an autoimmune disease (scleroderma). READ MORE »

Teaching the Relevance of Evolution to Understanding Immune Recognition

Last month, I completed teaching a graduate course for the tenth time.  After several years (in the early 1990’s) of thinking about launching a new alternate-year seminar course and then planning it, I began teaching PATH 480 in the fall of 1994.  The original name of the course, maintained through the first seven times I taught it, was: “Immunology, Evolution and Logic.”  Beginning in 2009, another faculty member, Derek Abbott, joined me in teaching the course, and the title was revised to: “Logical Dissection of Biomedical Investigations.”  In my portion of the course, I retained an emphasis on the relevance of logic and evolutionary principles to thinking about immune recognition and immune functioning more generally.  I focused class sessions on concepts and underlying assumptions critical to experimental investigations as well as on experimental design and data interpretation in articles reporting studies pertaining to immune recognition. Dr. Abbott has focused his portion of the course on the practical cognitive skills involved in reviewing papers and grant proposals pertaining primarily to innate immune signaling. READ MORE »

Illumination of the Multiple Sources of Selection Affecting Protein Sequences

Biomedical scientists and biologists routinely consider how selection shapes the structure and function of proteins of interest.  Less commonly, I suspect, do we consider how selection for attributes other than protein structure and function can favor or disfavor nucleotide sequences that encode particular amino acid sequences.   A new study (Stergachis et al., 2013) published in the December 13 issue of Science presents strong evidence for one particular source of selection (unrelated to protein function) influencing coding regions, known as exons, of genes.  This form of selection arises from the  fact, as revealed by the authors, that many transcription factors (TF), proteins that bind to specific nucleotide  sequences and regulate the frequency and pace of gene transcription (i.e., gene expression), bind in exonic regions of genes. READ MORE »

Human Phenotypic Differences and the Blurring Boundary Between Genetic and Epigenetic Variation

Three new papers (Kilpinen et al., 2013; McVickers et al., 2013; Kasowski et al., 2013) published earlier this month in Science all address the effects on human patterns of gene expression and other phenotypes of 1) genetic variation in non-protein coding regions of the genome and 2) covalent modifications of chromatin, the complex of DNA and proteins that facilitates the packaging and organization of DNA in the limited volume of the cell nucleus.  Regulation of gene expression is known to involve enzymes that covalently modify the chromatin proteins, known as histones, by attaching such moieties as methyl, acetyl, or phosphate groups to the so-called histone tails.  These post-translational modifications are commonly known as epigenetic marks and different marks, distinguished by both the chemical structure of the added substituent and the particular histone and precise amino acid modified, are associated with consistent and distinct effects on gene expression. READ MORE »

Contributions and suggestions welcome

Please email