The resistance of numerous bacterial pathogens of major clinical significance to many or all relevant antibiotics has become a public health threat of such magnitude that the latest U.N. General Assembly decided to hold a one-day meeting to address the issue (1). Recently, there has been substantial coverage of this issue in the general media, including by major news organizations such as the New York Times, National Public Radio, and the Washington Post (2-4). What the stories running in these outlets often fail to adequately emphasize is that the bacterial pathogens develop resistance to antibiotics by an evolutionary process. Furthermore, the solution to the problem of effectively treating these microbial agents of human disease requires not merely producing more antibiotics but also gaining deeper insights into the evolutionary processes by which antibiotic resistance comes into being and is transmitted between bacteria. In this context, a new study (5) from the laboratory of Roy Kishony, who is affiliated with both Technion and Harvard, is a novel and welcome advance in ways to study the evolution of bacterial antibiotic resistance and potentially to communicate about this process to the broader public.
Category: Trade-offs (Page 1 of 3)
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.
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.
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.
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.
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.
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.