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 »
Posts in category Trade-offs
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 »
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 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 »
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 »
A central focus of recent research aimed at developing a vaccine for HIV-1 is the identification of potent broadly-neutralizing antibodies (bNAbs). Due to work from several laboratories, many such antibodies have now been identified, produced in quantity as monoclonal antibodies, and characterized with respect to key properties such as epitope specificity, affinity for the corresponding HIV-1 epitope, and neutralizing activity against many strains of varying susceptibility to antibody-mediated inactivation (important examples of these publications are: Scheid et al., 2009; Walker et al., 2009; Wu et al., 2010; Walker et al., 2011; Huang et al., 2012). These successes notwithstanding, the scale of the challenge facing the vaccine developers is clarified by the following facts: 1) potent bNAbs only develop in 10-30% of infected individuals, 2) it typically takes between two and three or four years after initial infection for these antibodies to appear in the blood of these individuals, and 3) antibodies with the desired attributes often have extraordinary numbers of somatic mutations in the variable domains that mediate binding to the HIV-1 antigen (Klein et al., 2013a). A study (Klein et al., 2013b) published earlier this year from the laboratory of Michel Nussenzweig both illuminates one possible factor accounting for the impressive length of time and number of mutations associated with the generation of potent bNAbs and provides an extraordinary example of the power of intense selection to confound expectations arising from previously observed associations. In this instance, the undermined expectations related to the well-established functional correlates of hypervariable and framework regions within antibody variable domains. READ MORE »
Phenotypic and Genotypic Variation of a Fungal Pathogen Powered by Codon Ambiguity and Degenerate Translation
The term “genetic code” is associated with a measure of ambiguity. For molecular biologists, “genetic code” has historically referred to a table that provides for each messenger RNA ribonucleotide triplet the corresponding amino acid that is incorporated into the growing end of a nascent polypeptide chain, i.e. the translation from RNA sequence to protein sequence. In colloquial parlance, “genetic code” is frequently used to refer to all or part of the deoxribonucleotide sequence of a genome. A recent paper, published online ahead of print in Proceedings of the National Academy of Sciences (Bezerra et al., PNAS, 2013) demonstrates that this semantic ambiguity can have a counterpart in the ribosomal interpretation of the genetic code, using the technical molecular biological meaning of the latter term. READ MORE »
Influenza A viruses continue to be of enormous interest to biomedical researchers and clinicians alike. In addition to the annual influenza epidemics, which have been inferred to cause substantial excess mortality, there is the ever-present threat of a global pandemic due to several features of influenza virus biology. A high mutation rate associated with a segmented negative-sense RNA genome that facilitates recombination confers on these orthomyxoviruses a prodigious ability to evolve in ways that confound and evade the human immune system. The ability of influenza viruses to infect domesticated mammals, such as pigs, as well as birds, both wild and domesticated, provides additional opportunities for the virus to try out new genetic combinations and to disseminate around the globe by means both dependent and independent of human travel.
A recent paper by Jagger et al. (Science 2012) reveals that influenza A viruses are also, not surprisingly, capable of exploiting rather subtle and ingenious genetic “tricks” to maximize the value of every base pair in a total of a mere 13.5 kilobases of genome. These authors have discovered a new influenza gene product, PA-X, that represents a fusion protein incorporating 191 amino-terminal amino acids of the well-known RNA-dependent RNA polymerase (PA) protein and another carboxy-terminal 61 amino acids of a protein from a reading frame shifted by one nucleotide downstream. They present evidence from multiple experiments suggesting that the frameshift is related to a highly conserved codon that is rarely employed in mammalian and avian genomes and therefore interacts with a cognate tRNA of relatively low concentration in the cytosol. The longer-than-average wait for this tRNA to be recruited to the ribosome makes a frameshift mutation more probable. READ MORE »
An interesting hypothesis in the evolutionary genetics of treating infections and cancers is that if the therapeutic agent does not directly target the pathogen or tumor, then the pathogen or tumor will be less likely to evolve resistance to that agent. While early work on inhibitors of angiogenesis as potential cancer therapeutics suggested that such treatment did not elicit resistance by the tumor cells (Boehm et al., 1997), a recent study by Conley et al. (2012) raises doubts about the reliability of this notion in the context of antiangiogenic therapy for human breast cancer. READ MORE »
Both Nature and Science are currently celebrating the 100th anniversary of the birth of an icon of logic, computer science, and mathematical biology: Alan Turing. In reading Andrew Hodges’s spectacular biography of Turing (1983) many years ago I came to appreciate that the subject of the book was both a deeply creative and extraordinarily rigorous thinker. Although Turing is known for seminal achievements in mathematical logic and computer science, his most directly practical and immediately consequential contribution was his facilitation of the Allied cause in World War II through his guidance of the effort to break the Nazi military code. This effort called primarily on his prodigious talents for far-reaching inference and it was in reading about this effort that I was prompted to consider a concept that might be called “maximum deduction.” Turing and his able colleagues needed to make every possible deductive inference (or at least very close to every possible inference) supported by the available data on German military communications in order to solve a problem of immense and immediate impact (the saving of Allied ships from devastating German submarine attacks). READ MORE »
Natural selection depends on heritable phenotypic variation. The most obvious source of phenotypic variation is genotypic variation. A new study, by Casanueva et al. in Science (2012) suggests that in addition to genotypic variation, variation in life history and stochastic variations in gene expression can substantially affect phenotypic variation.
These authors studied mutation penetrance in Caenorhabditis elegans overexpressing a transgenic transcription factor (heat shock factor 1 or HSF-1) that controls the expression of genes encoding proteins that are involved in stress responses. The worms expressing high levels of the HSF-1 transgene (hsf-1) were previously shown to be better able to cope with diverse environmental stresses than otherwise identical worms not expressing the HSF-1 transgene.
Casanueva et al. then crossed HSF-1 transgenic worms with worms that harbored a variety of mutations that affect embryonic or post-embryonic development . In the majority of these crosses, the overexpression of HSF-1 was associated with reduced penetrance of these genetic variants. READ MORE »
As noted in my last post, the selective advantage of heterozygosity for the sickle allele at the beta-globin locus has been known since Allison’s report in 1954 (Lancet). Nevertheless, a plausible and detailed mechanism to account for the protective effect of an allele that is typically highly deleterious when homozygous has not been forthcoming until now. READ MORE »
In an 1858 humorous poem The Deacon’s Masterpiece, or the Wondeful One Hoss Shay, Oliver Wendell Holmes Sr. described a carriage so artfully constructed as to have no weakest link. The carriage ran smoothly for exactly a hundred years, and then one day
it went to pieces all at once, –
All at once, and nothing first, –
Just as bubbles do when they burst,
leaving its driver sitting atop a pile of rubble and dust.
According to both academic lore and history (Paulos, 1985; Ryerson, 2004), the late Sidney Morgenbesser, a professor of philosophy at Columbia and a renowned conversationalist and wit, was once listening to an Oxford colleague, J. L. Austin, lecturing on the philosophy of language. The eminent Professor Austin proceeded to claim that while a double negative can be taken as a positive, a double positive is never interpreted as a negative. Morgenbesser responded with as concise and incisive a rebuttal as one might ever hope to unleash,”Yeah, yeah,” thereby decisively demonstrating the extent to which the meaning of words can be shaped by the linguistic environment in which they are embedded.
Last month, a report in Nature (Netzer et al.) described one mechanism that causes even the genetic code to be read in a somewhat context-dependent manner. READ MORE »
I recently saw the movie, “The Blind Side,” based on a book of almost the same name (“The Blind Side: Evolution of a Game”) by author, Michael Lewis. The reference to “evolution” in the book title refers to the adaptations necessitated in the (American) game of football on the offensive line, especially at the left tackle position, by the appearance of a larger, faster, more aggressive brand of pass rusher (i.e., a defensive player who seeks to tackle the opposing quarterback), exemplified by Lawrence Taylor, formerly of the New York Giants. Of particular concern are defensive players attacking the quarterback from the latter’s back, or “blind,” side as they prepare to throw a pass . Consequently, large, quick, agile left tackles able to fend off such incursions became more valuable than was previously the case.
The non-fiction plot of “The Blind Side” revolves around an unusually large (6’5″ and >300 lbs.) and athletic young man, Michael Oher, who was from a less-advantaged part of Memphis and never had a stable family life. He is taken in by a wealthy white family and is given the opportunity to play football for an elite private high school. In his debut on the defensive line, where one key objective (perhaps counter-intuitively) is to aggressively pursue the opposition quarterback, he fails to impress, but when he is switched to the offensive line, where defending the quarterback on pass plays is a crucial function, he becomes an all-star performer. Although Oher’s size, strength and speed could conceivably have been of exceptional value in either position, Michael Lewis suggests that his preference for protectiveness over uninhibited aggression made his overall profile much better suited to one role than the other.
An important point to consider when reflecting on the tendency of evolution by natural selection to enhance organismal fitness is that such improvement is not generally usefully regarded as approaching perfection. A major reason for thinking of fitness in less than absolute terms is that environments can fluctuate in ways that critically influence survival and reproduction such that a phenotype that appears to be well-adapted to one set of circumstances (Michael Oher on the offensive line) may be much less advantageous in a different set of circumstances (Michael Oher on the defensive line). A recent paper by Hensley et al. beautifully illustrates this point at a molecular level. READ MORE »
The human appendix has long fascinated both biologists and physicians. A recent bout of appendicitis has heightened my interest in this organ and has stimulated me to write about it. Because of its small and variable size, anBollinger et al. 2007). It seems more likely, however, that these properties simply reflect the development of the appendix as part of the colon; there is little reason to believe that the appendix has unique or especially important immunological or microbiological functions. People who have their appendices removed or who are born with congenital absence of the appendix don’t exhibit any physiological deficits. Darwin was almost certainly correct—the appendix is a rudiment. READ MORE »