Second-order selection in bacterial evolution: selection acting on mutation and recombination rates in the course of adaptation

The increase in genetic variability of a population can be selected during adaptation, as demonstrated by the selection of mutator alleles. The dynamics of this phenomenon, named second-order selection, can result in an improved adaptability of bacteria through regulation of all facets of mutation and recombination processes.     

Positive natural selection in the evolution of human metapneumovirus attachment glycoprotein

Human metapneumovirus (hMPV), a newly discovered virus of the family Paramyxoviridae, has been associated with upper and lower respiratory tract infections in different age groups in many countries. The putative attachment (G) glycoprotein of this virus was previously reported to have shown more extensive nucleotide and deduced amino acid sequence polymorphism than any other genomic regions of this virus, leading to four sub-lineages. Using a maximum likelihood-based codon substitution model of sequence evolution, here we report that sequences of extracellular domain of 8 amino acid sites in lineage 1a, and 3 amino acid sites each in lineage 1b, 2a, and 2b have a higher rate of nonsynonymous substitutions (d(N)) than the synonymous substitutions (d(S)) with a posterior probability above 0.95, thus suggesting the evidence of adaptive evolution driven by Darwinian selection. Although it is unclear whether these amino acid adaptations are driven by differential immune pressure or some other factors, identification of these positively selected amino acid sites would help in better screening using epitope mapping technology to identify and localize the sites that can be recognized by the immune system. We also observed surprisingly higher nucleotide substitution rates per site, per year for each lineage of hMPV than the rates that were previously reported for the human respiratory syncytial virus, suggesting rapid evolutionary dynamics of hMPV.     

Positive difference in ERPs reflects independent processing of visual changes

To elucidate the nature of the processing of visual stimulus changes, ERPs were recorded while 12 participants performed an S1-S2 matching task with multifeature stimuli. Each trial consisted of two sequentially presented stimuli (S1-S2), where S2 was either the same as S1, different from S1 only in color, different only in shape, or different in both color and shape. The four trial types were presented in random order with equal probability, and participants responded to one of these types in separate blocks. Relative to the no-change stimuli, the change stimuli elicited posterior positivity with different topography according to changing features ranging from 100 to 180 ms in all tasks. The amplitude and topography of the positivity in response to the both changes were the respective sums of those to changes in the corresponding single features. These results suggest that a feature-specific change detection system exists in the human visual system.     

Cross-link immunoprecipitation data to detect polymorphisms lying in splicing regulatory motifs: a method to refine single nucleotide polymorphism selection in association studies

In a previous study we showed that prediction tools are useful to select single-nucleotide polymorphisms (SNPs) which potentially affect phenotype and therefore guide genotyping in association studies, thus saving time and money. Here we use the recently available RNA cross-link immunoprecipitation data to analyze several genes involved in psychiatric disorders and show which disease-associated SNPs can affect the splicing process by altering splicing factor binding sites. We point out the importance of using cross-link immunoprecipitation data in psychiatry to refine the SNP selection methods, to explain the association found and to plan molecular investigations.     

The carcinogenicity of human papillomavirus types reflects viral evolution

Persistent infections with carcinogenic human papillomaviruses (HPV) cause virtually all cervical cancers. Cervical HPV types (n > 40) also represent the most common sexually transmitted agents, and most infections clear in 1-2 years. The risks of persistence and neoplastic progression to cancer and its histologic precursor, cervical intraepithelial neoplasia grade 3 (CIN3), differ markedly by HPV type. To study type-specific HPV natural history, we conducted a 10,000-woman, population-based prospective study of HPV infections and CIN3/cancer in Guanacaste, Costa Rica. By studying large numbers of women, we wished to separate viral persistence from neoplastic progression. We observed a strong concordance of newly-revised HPV evolutionary groupings with the separate risks of persistence and progression to CIN3/cancer. HPV16 was uniquely likely both to persist and to cause neoplastic progression when it persisted, making it a remarkably powerful human carcinogen that merits separate clinical consideration. Specifically, 19.9% of HPV16-infected women were diagnosed with CIN3/cancer at enrollment or during the five-year follow-up. Other carcinogenic types, many related to HPV16, were not particularly persistent but could cause neoplastic progression, at lower rates than HPV16, if they did persist. Some low-risk types were persistent but, nevertheless, virtually never caused CIN3. Therefore, carcinogenicity is not strictly a function of persistence. Separately, we noted that the carcinogenic HPV types code for an E5 protein, whereas most low-risk types either lack a definable homologous E5 ORF and/or a translation start codon for E5. These results present several clear clues and research directions in our ongoing efforts to understand HPV carcinogenesis.     

Positive selection of gamma delta T cells

The issue of T-cell repertoire selection has been addressed recently by several laboratories. While evidence has been provided for both negative and positive selection of CD4+ and CD8+ alpha beta T cells, the molecular basis of positive selection remains unclear. In this article Juan Lafaille and colleagues describe molecular features of gamma delta T-cell selection in the fetal thymus. These features were deduced from extensive junctional sequence data of gamma delta T-cell receptor genes in fetal thymocytes. Their data suggest the active participation of a self peptide in the positive selection of gamma delta T cells.     

Somatic hypermutation of VkappaJkappa rearrangements: targeting of RGYW motifs on both DNA strands and preferential selection of mutated codons within RGYW motifs

Productive and nonproductive VkappaJkappa gene rearrangements from individual peripheral blood B cells were analyzed for the pattern and distribution of mutations. The eight RGYW motifs and their inverse repeats, WRCY, were present in germ-line Vkappa genes significantly more often than anticipated by random chance (1.6-fold and 1.4-fold, respectively) and were also mutated in nonproductive rearrangements significantly more often than expected, with a frequency 1.96 fold greater than that of non-RGYW / WRCY motifs. As a result, 50 % of all mutations in nonproductive VkappaJkappa rearrangements occurred in RGYW / WRCY motifs. Each RGYW tetramer and its corresponding WRCY contained mutations at comparable frequencies. Furthermore, mutations of G and C were significantly more frequent in RGYW / WRCY but not in other tetranucleotides. Finally, mutations in codons contained within RGYW / WRCY were significantly more frequent in complementarity-determining regions but not framework regions of productive compared to nonproductive rearrangements and were increased by a factor that was significantly greater than for mutations in other motifs. These results indicate that the mutational machinery targets the overrepresented RGYW motifs in Vkappa genes on both DNA strands and that the resulting replacement mutations are preferentially selected into the productive repertoire.     

Positive selection on mammalian MHC-DQ genes revisited from a multispecies perspective

Major histocompatibility complex class II DQA and DQB genes have been shown to be under positive selection in certain mammalian species but not in others, fuelling a debate about how their polymorphism has evolved. In this study, we have analysed whether polymorphism in the peptide-binding region (PBR) of DQA (190 sequences, 11 species) and DQB (209 sequences, 7 species) molecules is positively selected by using both approximate (Nei-Gojobori, Li-Wu-Luo and Pamilo-Bianchi-Li) and maximum-likelihood methods. The results obtained with approximate methods were rather inconsistent for DQA, probably due to the high inaccuracy with which d(S) (PBR) is estimated, whereas evidence of positive selection was observed for most of the DQB PBR sequences. A parallel analysis with CodeML allowed us to demonstrate, in a very consistent way, the occurrence of positive selection in the PBR-encoding region of both DQA and DQB genes. Moreover, we have identified several DQA (alpha47, alpha55, alpha56, alpha68, alpha69, alpha76 and alpha79) and DQB (beta9, beta26 and beta57) codons that appear to be under positive selection in different, and often unrelated, mammalian species. Non-synonymous polymorphism at these sites has been evolutionarily conserved meaning that it might have functional consequences on peptide binding.     

Positive and negative selection during B lymphocyte development

Our laboratory is interested in a variety of issues related to lymphocyte development. More specifically, we have focused on the processes that regulate the decision to commit to the B lymphocyte (B cell) lineage, then the subsequent signals that are involved in maintaining this commitment to the B cell lineage. These signals result in the positive selection of those B cells that properly execute the complex genetic changes associated with B cell development, then trigger the elimination of B cells that are responsive to self-antigens and, therefore, possess the potential to mediate autoimmune disease. Our general experimental approach has been to address these issues from the perspective of signal transduction. Our goal is to define the biochemical and genetic processes that are integrated in order to accomplish these selection processes. To do so, we employ in vivo animal models as well as more defined in vitro studies, using both primary and transformed cell lines. For the past several years, we have been primarily interested in the precise mechanisms by which the B cell antigen receptor (BCR), and intermediate forms of this receptor, regulate these complex developmental processes. We have used the ongoing studies described below as two representative examples of how we are approaching these issues and some of the insights that we have made. To place both of these studies in context, we will begin with a brief introduction into B cell development.     

Fuel selection during intense shivering in humans: EMG pattern reflects carbohydrate oxidation

The thermogenic response of humans depends critically on the coordination of muscle fibre recruitment and oxidative fuel metabolism. The primary goal of this study was to determine whether the electromyographic (EMG) pattern of muscle recruitment could provide metabolic information on oxidative fuel selection during high-intensity shivering. EMG activity (of 8 large muscles) and fuel metabolism were monitored simultaneously in non-acclimatized adult men during high-intensity shivering. Even though acute cold exposure elicited similar changes in metabolic rate among subjects, lipid and carbohydrate use was very different. Depending on the subject, the cold-induced increase in carbohydrate (CHO) oxidation ranged between 2- and 8-fold, with CHO accounting for 33–78% of total heat production     , and lipids for 14–60%     . This high variability in fuel selection was primarily explained by differences in 'burst shivering' rate, indicating that the recruitment of type II fibres plays a key role in orchestrating fuel selection. This study is the first to show that the pattern of muscle recruitment can provide quantitative information on energy metabolism. Future work should focus on the study of shivering bursts that may provide essential clues on what limits human survival in the cold.     

Evidence for adaptive selection acting on the tRNA and rRNA genes of human mitochondrial DNA

In order to identify putative adaptive human mitochondrial DNA (mtDNA), transfer RNA (tRNA), and ribosomal RNA (rRNA) variants, we assembled a sequential mutational tree from 2,460 human mtDNA coding sequences, thus providing the relative age of all mtDNA sequence variants. Deleterious mutations affect evolutionarily conserved nucleotides and have been eliminated from the older internal branches of the tree by purifying selection, while beneficial mutations also alter conserved nucleotides but have been enriched in the internal branches of the tree by adaptive selection. Neutral polymorphisms alter poorly conserved nucleotides and are distributed throughout the tree. Stem nucleotides are more constrained than loop nucleotides. The functional importance of both types of nucleotide variants was assessed by comparison to the average evolutionary conservation index (CI) of all known pathogenic tRNA mutations, thus permitting discrimination between internal branch neutral and adaptive tRNA variants. This revealed that 19% of the stem and 13% of the loop internal branch tRNA variants were potentially adaptive. Since few pathogenic rRNA mutations are known, evidence for adaptive rRNA variation was revealed by higher stem to loop variant ratios and elevated CIs in the internal branches vs. external branches. Moreover, variants among stem noncanonical apposition bases predominantly created new Watson-Crick (WC) base pairs, thus also suggesting adaptive selection. Among the putative adaptive tRNA and rRNA polymorphisms, a number were found to occur at the base of the branches of the tree, to have recurred multiple times, and to be associated with altered human phenotypes. Therefore, a significant portion of ancient tRNA and rRNA polymorphisms appear to have been adaptive, and these are affecting human health today.     

Adaptation to the deleterious effects of antimicrobial drug resistance mutations by compensatory evolution

Compensatory mutations, due to their ability to mask the deleterious effects of another mutation, are important for the adaptation and evolution of most organisms. Resistance to antibiotics, antivirals, antifungals, herbicides and insecticides is usually associated with a fitness cost. As a result of compensatory evolution, the initial fitness costs conferred by resistance mutations (or other deleterious mutations) can often be rapidly and efficiently reduced. Such compensatory evolution is potentially of importance for (i) the long-term persistence of drug resistance, (ii) reducing the rate of fitness loss associated with the accumulation of deleterious mutations in small asexual populations, and (iii) the evolution of complexity of cellular processes.