Balancing selection is the main force shaping the evolution of innate immunity genes

The evolutionarily recent geographic expansion of humans, and the even more recent development of large, relatively dense human settlements, has exposed our species to new pathogenic environments. Potentially lethal pathogens are likely to have exerted important selective pressures on our genome, so immunity genes can be expected to show molecular signatures of the adaptation of human populations to these recent conditions. While genes related to the acquired immunity system have indeed been reported to show traces of local adaptation, little is known about the response of the innate immunity system. In this study, we analyze the variability patterns in different human populations of fifteen genes related to innate immunity. We have used both single nucleotide polymorphism and sequence data, and through the analysis of interpopulation differentiation, the linkage disequilibrium pattern, and intrapopulation diversity, we have discovered some signatures of positive and especially balancing selection in these genes, thus confirming the importance of the immune system genetic plasticity in the evolutionary adaptive process. Interestingly, the strongest evidence is found in three TLR genes and CD14. These innate immunity genes play a pivotal role, being involved in the primary recognition of pathogens. In general, more evidences of selection appear in the European populations, in some case possibly related to severe population specific pressures. However, we also describe evidence from African populations, which may reflect parallel or long-term selective forces acting in different geographic areas.     

The driving force for molecular evolution of translation

It is widely argued that protein synthesis evolved out of an RNA world, in which catalytic and other biological functions now carried out by proteins were performed by RNAs. However, it is not clear what selective advantage would have provided the driving force for evolution of a primitive translation apparatus, because of the unlikelihood that rudimentary polypeptides would have contributed sufficiently useful biological functions. Here, I suggest that the availability of even simple peptides could have significantly enlarged the otherwise limited structure space of RNA. In other words, translation initially evolved not to create a protein world, but to extend the structural, and therefore the functional, capabilities of the RNA world. Observed examples of substantial structural rearrangements in RNA that are induced by binding of peptides and other small molecules support this possibility.     

Positive selection in the evolution of cancer

We hypothesize that forms of antagonistic coevolution have forged strong links between positive selection at the molecular level and increased cancer risk. By this hypothesis, evolutionary conflict between males and females, mothers and foetuses, hosts and parasites, and other parties with divergent fitness interests has led to rapid evolution of genetic systems involved in control over fertilization and cellular resources. The genes involved in such systems promote cancer risk as a secondary effect of their roles in antagonistic coevolution, which generates evolutionary disequilibrium and maladaptation. Evidence from two sources: (1) studies on specific genes, including SPANX cancer/testis antigen genes, several Y-linked genes, the pem homebox gene, centromeric histone genes, the breast cancer gene BRCA1, the angiogenesis gene ANG, cadherin genes, cytochrome P450 genes, and viral oncogenes; and (2) large-scale database studies of selection on different functional categories of genes, supports our hypothesis. These results have important implications for understanding the evolutionary underpinnings of cancer and the dynamics of antagonistically-coevolving molecular systems.     

Positive selection of the Hrp pilin HrpE of the plant pathogen Xanthomonas

The plant-pathogenic bacterium Xanthomonas campestris pv. vesicatoria possesses a type III secretion (TTS) system which is encoded by the 23-kb hrp (hypersensitive response and pathogenicity) gene cluster. The TTS system is necessary for pathogenicity in susceptible hosts and induction of the hypersensitive response in resistant plants. At the cell surface, the TTS system is associated with an extracellular filamentous structure, the Hrp pilus, which serves as a conduit for the transfer of bacterial proteins into the plant cell cytosol. The major pilus component, the HrpE pilin, is unique to xanthomonads. Previous work showed that HrpE contains two regions: a hypervariable surface-exposed domain, including the N-terminal secretion signal, and a C-terminal polymerization domain. In this study, the evolutionary rate of the hrpE gene was analyzed. Twenty-one alleles were cloned, sequenced, and compared with five known hrpE alleles. The ratio of synonymous (K(s)) and nonsynonymous (K(a)) substitution rates shows that parts of the HrpE N terminus are subjected to positive selection and the C terminus is subjected to purifying selection. The trade-off between positive and purifying selection at the very-N terminus allowed us to ascertain the amphipathic alpha-helical nature of the TTS signal. This is the first report of a surface structure from a plant-pathogenic bacterium that evolved under the constraint of positive selection and hints to the evolutionary adaptation of this extracellular appendage to avoid recognition by the plant defense surveillance system.     

Positive selection is a general phenomenon in the evolution of abalone sperm lysin

Lysin is a 16kDa acrosomal protein used by abalone sperm to create a hole in the egg vitelline envelope (VE). The interaction of lysin with the VE is species-selective and is one step in the multistep fertilization process that restricts heterospecific (cross-species) fertilization. For this reason, the evolution of lysin could play a role in establishing prezygotic reproductive isolation between species. Previously, we sequenced sperm lysin cDNAs from seven California abalone species and showed that positive Darwinian selection promotes their divergence. In this paper an additional 13 lysin sequences are presented representing species from Japan, Taiwan, Australia, New Zealand, South Africa, and Europe. The total of 20 sequences represents the most extensive analysis of a fertilization protein to date. The phylogenetic analysis divides the sequences into two major clades, one composed of species from the northern Pacific (California and Japan) and the other composed of species from other parts of the world. Analysis of nucleotide substitution demonstrates that positive selection is a general process in the evolution of this fertilization protein. Analysis of nucleotide and codon usage bias shows that neither parameter can account for the robust data supporting positive selection. The selection pressure responsible for the positive selection on lysin remains unknown.      

Pro-fibrotic pathway activation in trabecular meshwork and lamina cribrosa is the main driving force of glaucoma

While primary open-angle glaucoma (POAG) is a leading cause of blindness worldwide, it still does not have a clear mechanism that can explain all clinical cases of the disease. Elevated IOP is associated with increased accumulation of extracellular matrix (ECM) proteins in the trabecular meshwork (TM) that prevents normal outflow of aqueous humor (AH) and has damaging effects on the fine mesh-like lamina cribrosa (LC) through which the optic nerve fibers pass. Applying a pathway analysis algorithm, we discovered that an elevated level of TGFβ observed in glaucoma-affected tissues could lead to pro-fibrotic pathway activation in TM and in LC. In turn, activated pro-fibrotic pathways lead to ECM remodeling in TM and LC, making TM less efficient in AH drainage and making LC more susceptible to damage from elevated IOP via ECM transformation in LC. We propose pathway targets for potential therapeutic interventions to delay or avoid fibrosis initiation in TM and LC tissues.     

Positive selection along the evolution of primate mitogenomes

The mitochondrial genomes of four neotropical primates, Aotus infulatus, Chiropotes israelita, Callimico goeldii and Callicebus lugens were sequenced and annotated. Phylogenetic reconstructions with mitochondrial genes of other 66 primates showed a similar arrangement to a topology based on nuclear genes. Screening for positive selection identified 15 codons in 7 genes along 9 independent lineages, three with two or more genes and five in internal nodes, ruling out false positive estimates. Mitochondrial genes of the electron transport chain (ETC.) complexes evolved with high substitution rates. A study of nuclear ETC. genes might elucidate whether they co-evolved with their mitochondrial counterparts.     

Comparative genomics of in vitro and in vivo evolution of probiotics reveals energy restriction not the main evolution driving force in short term

Probiotics have attracted much attention because of their health-promoting effects, but little is known about the in vivo evolution of probiotics. This study analyzed the genome adaptation of the probiotic Lactiplantibacillus plantarum P-8 strain cultivated in ordinary and glucose restrictive growth media. Then, this study re-analyzed genomes of P-8 isolates recovered from the gut contents of subjects in two feeding trials (in rat and human). The sampling time points were similar to that of the in vitro evolution experiment, which might give parallel comparison of the in vitro and in vivo evolution processes. Our results showed that intra-individual specific microbial genomic variants of the original strain were detected in all human and some rat subjects. The divergent patterns of evolution within the host gastrointestinal tract suggested intra-individual-specific environmental adaptation. Based on comprehensive analysis of adapted-isolates recovered from these experiments, our results showed that the energy restriction was not the main driving force for evolution of probiotics. The individual-specific adaptation of probiotics might partially explain the varying extent of health effects seen between different individuals after probiotic consumption. In addition, the results suggest that probiotics should not only adapt to the environment of the birth canal, but also adapt to other species in the gut, revealing the Red Queen hypothesis in the process of intestinal flora.     

Directed actin polymerization is the driving force for epithelial cell-cell adhesion

We have found that epithelial cells engage in a process of cadherin-mediated intercellular adhesion that utilizes calcium and actin polymerization in unexpected ways. Calcium stimulates filopodia, which penetrate and embed into neighboring cells. E-cadherin complexes cluster at filopodia tips, generating a two-rowed zipper of embedded puncta. Opposing cell surfaces are clamped by desmosomes, while vinculin, zyxin, VASP, and Mena are recruited to adhesion zippers by a mechanism that requires alpha-catenin. Actin reorganizes and polymerizes to merge puncta into a single row and seal cell borders. In keratinocytes either null for alpha-catenin or blocked in VASP/Mena function, filopodia embed, but actin reorganization/polymerization is prevented, and membranes cannot seal. Taken together, a dynamic mechanism for intercellular adhesion is unveiled involving calcium-activated filopodia penetration and VASP/Mena-dependent actin reorganization/polymerization.     

Positive selection drives lactoferrin evolution in mammals

Lactoferrin (LF) is a member of the transferrin family that is abundantly expressed and secreted by glandular epithelial cells. The biological functions of LF involve in iron homeostasis regulation of the body and antibacterial activity. Previous studies demonstrated that it had a high cationic N-terminal domain that could interact with glycosaminoglycans, lipopolysaccharides and the bacterial virulence protein. Two anti-microbial peptides, lactoferricin (LFcin) and lactoferrampin (LFampin), were also isolated and identified in N-terminal of LF. Although the antibacterial mechanism was carefully studied, little was known about the molecular evolution of LF. In this study, we estimated the nonsynonymous-to-synonymous substitution ratios ( w = d_N \mathord

May the driving force be with you--whatever it is

Changes in the atomic coordinate fluctuations contribute to the entropy of biomolecular processes such as complex formation. Characterizations of such changes in proteins reveal that the response may be dramatically different between the backbone and the side chains, and further resolve enthalpy-entropy compensation at the molecular level.     

Adaptive immunity is the primary force driving selection of equine infectious anemia virus envelope SU variants during acute infection

Equine infectious anemia virus (EIAV) is a lentivirus that causes persistent infection in horses. The appearance of antigenically distinct viral variants during recurrent viremic episodes is thought to be due to adaptive immune selection pressure. To test this hypothesis, we evaluated envelope SU cloned sequences from five severe combined immunodeficient (SCID) foals infected with EIAV. Within the SU hypervariable V3 region, 8.5% of the clones had amino acid changes, and 6.4% had amino acid changes within the known cytotoxic T lymphocyte (CTL) epitope Env-RW12. Of all the SU clones, only 3.1% had amino acid changes affecting potential N-linked glycosylation sites. In contrast, a much higher degree of variation was evident in SU sequences obtained from four EIAV-infected immunocompetent foals. Within V3, 68.8% of the clones contained amino acid changes, and 50% of the clones had amino acid changes within the Env-RW12 CTL epitope. Notably, 31.9% of the clones had amino acid changes affecting one or more glycosylation sites. Marked amino acid variation occurred in cloned SU sequences from an immune-reconstituted EIAV-infected SCID foal. Of these clones, 100% had amino acid changes within V3, 100% had amino acid changes within Env-RW12, and 97.5% had amino acid changes affecting glycosylation sites. Analysis of synonymous and nonsynonymous nucleotide substitutions revealed statistically significant differences between SCID and immunocompetent foals and between SCID foals and the reconstituted SCID foal. Interestingly, amino acid selection at one site occurred independently of adaptive immune status. Not only do these data indicate that adaptive immunity primarily drives the selection of EIAV SU variants, but also they demonstrate that other selective forces exist during acute infection.     

Post-insemination selection dominates pre-insemination selection in driving rapid evolution of male competitive ability

Sexual reproduction is a complex process that contributes to differences between the sexes and divergence between species. From a male’s perspective, sexual selection can optimize reproductive success by acting on the variance in mating success (pre-insemination selection) as well as the variance in fertilization success (post-insemination selection). The balance between pre- and post-insemination selection has not yet been investigated using a strong hypothesis-testing framework that directly quantifies the effects of post-insemination selection on the evolution of reproductive success. Here we use experimental evolution of a uniquely engineered genetic system that allows sperm production to be turned off and on in obligate male-female populations of Caenorhabditis elegans. We show that enhanced post-insemination competition increases the efficacy of selection and surpasses pre-insemination sexual selection in driving a polygenic response in male reproductive success. We find that after 10 selective events occurring over 30 generations post-insemination selection increased male reproductive success by an average of 5- to 7-fold. Contrary to expectation, enhanced pre-insemination competition hindered selection and slowed the rate of evolution. Furthermore, we found that post-insemination selection resulted in a strong polygenic response at the whole-genome level. Our results demonstrate that post-insemination sexual selection plays a critical role in the rapid optimization of male reproductive fitness. Therefore, explicit consideration should be given to post-insemination dynamics when considering the population effects of sexual selection.     

Prey availability in time and space is a driving force in life history evolution of predatory insects

Environmental constraints can be determinant key factors conditioning predator life history evolution. Prey seems to have conditioned life history evolution in their ladybird predator, with the predators of aphids apparently presenting faster development, greater fecundity and shorter longevity than species preying on coccids. However a rigorous comparison has never been done. We hypothesize that aphids and coccids differ by their developmental rate, abundance, and distribution in the field, which act as ecological constraints promoting life history evolution in ladybird predators. Field data reveal that aphids are ephemeral resources available in the form of large colonies randomly distributed in the habitat whereas coccids form smaller colonies that tend to be aggregated in space and available for longer periods. A comparison in laboratory conditions of two predatory species belonging to the tribe Scymnini (Coleoptera: Coccinellidae) show that the aphidophagous species lives at a faster pace than the coccidophagous: it develops faster, matures earlier, is more fecund, has a shorter reproductive life-span and allocate proportionally more fat in its gonads relative to soma. This indicates that the life histories of aphidophagous and coccidophagous ladybird predators appear to have evolved in response to particular patterns of prey availability in time and space. Under the light of these results, the existence of a slow-fast continuum in ladybirds is briefly addressed.     

Prevention of amyloid-like aggregation as a driving force of protein evolution

Uncontrolled protein aggregation is a constant challenge in all compartments of living organisms. The failure of a peptide or protein to remain soluble often results in pathology. So far, more than 40 human diseases have been associated with the formation of extracellular fibrillar aggregates - known as amyloid fibrils - or structurally related intracellular deposits. It is well known that molecular chaperones and elaborate quality control mechanisms exist in the cell to counteract aggregation. However, an increasing number of reports during the past few years indicate that proteins have also evolved structural and sequence-based strategies to prevent aggregation. This review describes these strategies and the selection pressures that exist on protein sequences to combat their uncontrolled aggregation. We will describe the different types of mechanism evolved by proteins that adopt different conformational states including normally folded proteins, intrinsically disordered polypeptide chains, elastomeric systems and multimodular proteins.     

The membrane potential is the driving force for siderophore iron transport in fungi

Abstract Respiratory inhibitors and uncouplers severely impair [⁵⁵Fe]ferricrocin uptake by Neurospora crassa . parallel measurements of ATP decay and ferricrocin uptake, however, disprove the idea that direct input of metabolic energy in the form of ATP is required for transmembrane movement of siderophores. The role of the membrane potential for siderophore uptake was demonstrated using iron-deficient cells, which were derepressed in the glucose-II uptake system. Addition of high amounts of glucose (1 mM) to glu-II-derepressed cells leads to a membrane depolarization of about 120 mV, followed by a significant inhibition of ferricrocin uptake, which recovered after some minutes. Full transport inhibition occurred after membrane depolarization in the presence of plasma membrane ATP-ase inhibitors (DCCD or DES), indicating that the membrane potential is essential for siderophore transport in fungi.