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…)

The Making of Metazoans: Cooperative Genes that Constrain Cheater Cells

In his 1987 book, “The Evolution of Individuality,” Leo Buss addressed a fundamental biological question: “How could individual multicellular animals (known as metazoans), like sea anemones, insects, frogs, and humans arise?”  Buss focused on a key challenge confronting any multicellular animal with differentiated cell types performing different functions: the potential conflict between selection on the whole organism and selection on the cells that constitute the organism (or on the whole genome and the individual genes that constitute the genome).   A new study (Dejosez et al., Sciencexpress, 2013) explores this issue by using a genome-wide screen to identify genes that favor cell cooperation and discourage so-called “cheater” cells that through genetic or epigenetic variation outcompete wild-type cells in the developing embryo. (more…)

A Possible Evolutionary Explanation for the Frequency of CCR5Δ32

In 1996, Dean et al. (Science), demonstrated that a loss-of-function allele (CCR5Δ32) encoding a version of the chemokine receptor, CCR5, confers very substantial resistance to infection with HIV-1 in the homozygous state and slows progression in the heterozygous state.  Given the relatively recent origin of HIV-1, this finding raised the question of what source of selection could account for the frequency, approximately 0.08 among Caucasians according to Dean et al., of this allele.  A recent paper (Alonzo et al., 2013) offers new information on a relationship between CCR5 and a different pathogen that might offer insight into the evolutionary trajectory of CCR5Δ32.

The new study presents compelling evidence that leukotoxin ED (LukED), one of a family of bi-component exotoxins produced by Staphylococcus aureus, can bind to CCR5 and thereby cause cell death.  LukED consistently produces substantially more cytotoxicity for CCR5+ than CCR5 cell lines of several types.  Ligands for CCR5, including the drug, maraviroc, which is approved for clinical treatment of HIV-1 infection, significantly inhibit both the binding of LukED to cells and the magnitude of associated cytotoxicity.  LukED also binds to and kills CCR5+ primarycells, such as human memory T cells, macrophages, and dendritic cells. (more…)

Cancer Chemotherapy Informed by Evolutionary Considerations

I recently had the opportunity to learn first-hand about the research of Robert Gatenby.  Dr. Gatenby is a radiologist, but he is probably not your typical radiologist.  He has been employing mathematical methods and the principles and concepts of evolutionary biology in an effort improve therapy for cancers that have historically been relatively unresponsive to traditional approaches based on highly toxic chemotherapeutic agents. 

My introduction to his work was an absorbing commentary on this topic in Nature (2009).  In this piece, Gatenby suggested provocatively, that aiming for the maximum extent of tumor cell destruction might result in a sort of pyrrhic victory.  His reasoning is that by exerting maximum selection pressure on the tumor cell population the likely result would be the preferential proliferation of cells that possessed high levels of resistance to the chemotherapeutic agents being used but that were less fit (in the absence of therapeutic agents) than the chemosensitive cells, thereby setting the stage for an extremely difficult-to-treat relapse.  (more…)