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). (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. (more…)

Intelligent Design, the Resurfacing of a Pseudo-Theory

In the past six months, I have encountered a review, by Thomas Nagel in The New York Review of Books (2012), of Alvin Plantinga’s latest book (Where the Conflict Really Lies: Science, Religion, and Naturalism, 2011 ) and a review, by Alvin Plantinga in The New Republic (2012), of Thomas Nagel’s latest book (Mind and Cosmos: Why the Materialist Neo-Darwinian Conception of Nature is Almost Certainly False, 2012).  Both authors are regarded as distinguished philosophers.  In their respective books, they both criticize what may be called the materialist neo-Darwinian approach to explaining life.  Plantinga and Nagel both discuss as a putative alternative to evolutionary explanations, the framework known as intelligent design (ID).  Whereas Plantinga appears to support ID, Nagel does not endorse ID but criticizes proponents of evolution for being overly disparaging of ID theorists. (more…)

Parallel Evolution Guides Identification of Pathogenic Pathogen Mutations

The new tools for determining nucleotide sequences for whole genomes can sometimes present a problem of data analysis: How can mutations that influence important phenotypes be distinguished from mutations that may be of minimal or no impact on fitness, so-called passenger mutations that arise and persist primarily by chance and can greatly outnumber adaptive genetic variants?  Merely finding nucleotide substitutions or larger genomic differences in comparing independent isolates of a microbial pathogen does not automatically reveal which genetic variants are responsible for the medically-relevant differences in pathogen attributes.

Lieberman et al. (2011) have approached this problem by determining the whole genome sequences for 112 isolates of an opportunistic bacterial pathogen, Burkholderia dolosa, obtained from 14 cystic fibrosis (CF) patients, including the initial patient infected, who were all part of an epidemic of small scale in the Boston area.  A total of 39 individuals were infected in the course of the outbreak, and the patient samples were taken over a period of 16 years.  Bacterial samples were obtained primarily from the airways and from blood.  For these genome sequences, the average read depth was 37x, and the genomes were aligned based on a B. dolosa reference genome. (more…)