Epigenome-wide analysis links SMAD3 methylation at birth to asthma in children of asthmatic mothers.

BACKGROUND: The timing and mechanisms of asthma inception remain imprecisely defined. Although epigenetic mechanisms likely contribute to asthma pathogenesis, little is known about their role in asthma inception. OBJECTIVE: We sought to assess whether the trajectory to asthma begins already at birth and whether epigenetic mechanisms, specifically DNA methylation, contribute to asthma inception. METHODS: We used the Methylated CpG Island Recovery Assay chip to survey DNA methylation in cord blood mononuclear cells from 36 children (18 nonasthmatic and 18 asthmatic subjects by age 9 years) from the Infant Immune Study (IIS), an unselected birth cohort closely monitored for asthma for a decade. SMAD3 methylation in IIS (n = 60) and in 2 replication cohorts (the Manchester Asthma and Allergy Study [n = 30] and the Childhood Origins of Asthma Study [n = 28]) was analyzed by using bisulfite sequencing or Illumina 450K arrays. Cord blood mononuclear cell-derived IL-1ß levels were measured by means of ELISA. RESULTS: Neonatal immune cells harbored 589 differentially methylated regions that distinguished IIS children who did and did not have asthma by age 9 years. In all 3 cohorts methylation in SMAD3, the most connected node within the network of asthma-associated, differentially methylated regions, was selectively increased in asthmatic children of asthmatic mothers and was associated with childhood asthma risk. Moreover, SMAD3 methylation in IIS neonates with maternal asthma was strongly and positively associated with neonatal production of IL-1ß, an innate inflammatory mediator. CONCLUSIONS: The trajectory to childhood asthma begins at birth and involves epigenetic modifications in immunoregulatory and proinflammatory pathways. Maternal asthma influences epigenetic mechanisms that contribute to the inception of this trajectory.

Adaptation and constraint at Toll-like receptors in primates.

Frequent positive selection is a hallmark of genes involved in the adaptive immune system of vertebrates, but the incidence of positive selection for genes underlying innate immunity in vertebrates has not been well studied. The toll-like receptors (TLRs) of the innate immune system represent the first line of defense against pathogens. TLRs lie directly at the host-environment interface, and they target microbial molecules. Because of this, they might be subject to frequent positive selection due to coevolutionary dynamics with their microbial counterparts. However, they also recognize conserved molecular motifs, and this might constrain their evolution. Here, we investigate the evolution of the ten human TLRs in the framework of these competing ideas. We studied rates of protein evolution among primate species and we analyzed patterns of polymorphism in humans and chimpanzees. This provides a window into TLR evolution at both long and short timescales. We found a clear signature of positive selection in the rates of substitution across primates in most TLRs. Some of the implicated sites fall in structurally important protein domains, involve radical amino acid changes, or overlap with polymorphisms with known clinical associations in humans. However, within species, patterns of nucleotide variation were generally compatible with purifying selection, and these patterns differed between humans and chimpanzees and between viral and nonviral TLRs. Thus, adaptive evolution at TLRs does not appear to reflect a constant turnover of alleles and instead might be more episodic in nature. This pattern is consistent with more ephemeral pathogen-host associations rather than with long-term coevolution.

A history of recurrent positive selection at the toll-like receptor 5 in primates.

Many genes involved in immunity evolve rapidly. It remains unclear, however, to what extent pattern-recognition receptors (PRRs) of the innate immune system in vertebrates are subject to recurrent positive selection imposed by pathogens, as suggested by studies in Drosophila, or whether they are evolutionarily constrained. Here, we show that Toll-like receptor 5 (TLR5), a member of the Toll-like receptor family of innate immunity genes that responds to bacterial flagellin, has undergone a history of adaptive evolution in primates. We have identified specific residues that have changed multiple times, sometimes in parallel in primates, and are thus likely candidates for selection. Most of these changes map to the extracellular leucine-rich repeats involved in pathogen recognition, and some are likely to have an effect on protein function due to the radical nature of the amino acid substitutions that are involved. These findings suggest that vertebrate PRRs might show similar patterns of evolution to Drosophila PRRs, in spite of the acquisition of the more complex and specific vertebrate adaptive immune system. At shorter timescales, however, we found no evidence of adaptive evolution in either humans or chimpanzees. In fact, we found that one mutation that abolishes TLR5 function is present at high frequencies in many human populations. Patterns of variation indicate that this mutation is not young, and its high frequency suggests some functional redundancy for this PRR in humans.

The emergence of HIV/AIDS in the Americas and beyond.

HIV-1 group M subtype B was the first HIV discovered and is the predominant variant of AIDS virus in most countries outside of sub-Saharan Africa. However, the circumstances of its origin and emergence remain unresolved. Here we propose a geographic sequence and time line for the origin of subtype B and the emergence of pandemic HIV/AIDS out of Africa. Using HIV-1 gene sequences recovered from archival samples from some of the earliest known Haitian AIDS patients, we find that subtype B likely moved from Africa to Haiti in or around 1966 (1962-1970) and then spread there for some years before successfully dispersing elsewhere. A "pandemic" clade, encompassing the vast majority of non-Haitian subtype B infections in the United States and elsewhere around the world, subsequently emerged after a single migration of the virus out of Haiti in or around 1969 (1966-1972). Haiti appears to have the oldest HIV/AIDS epidemic outside sub-Saharan Africa and the most genetically diverse subtype B epidemic, which might present challenges for HIV-1 vaccine design and testing. The emergence of the pandemic variant of subtype B was an important turning point in the history of AIDS, but its spread was likely driven by ecological rather than evolutionary factors. Our results suggest that HIV-1 circulated cryptically in the United States for approximately 12 years before the recognition of AIDS in 1981.

Genetic and geographic differentiation in the Rio Negro tuco-tuco (Ctenomys rionegrensis): inferring the roles of migration and drift from multiple genetic markers.

Among tuco-tucos, Ctenomys rionegrensis is especially amenable to the study of the forces driving population differentiation because of the restricted geographic range it occupies in Uruguay. Within this limited area, the Rio Negro tuco-tuco is limited to sandy soils. It nonetheless exhibits remarkable variation in pelage color, including melanic, agouti, and dark-backed individuals. Two hypotheses have been put forth to explain this pattern: (1) local differentiation and fixation of alternative pelage types by genetic drift under limited gene flow; or (2) fixation by natural selection that may take place even in the presence of gene flow. A previous allozyme study rejected the genetic drift hypothesis on the basis of high inferred levels of migration. New estimates of gene flow from microsatellites and mitochondrial cytochrome b sequences were obtained for C. rionegrensis populations to further test these hypotheses. Much lower levels of gene flow were estimated with these more sensitive markers. Microsatellite-based estimates of gene flow are close to zero and may come closest to estimating current levels of migration. A lack of equilibrium between migration and genetic drift is also strongly suggested by the absence of an isolation-by-distance pattern found in all three genetic datasets. The microsatellite genotype data show that the species is strongly structured geographically, with subpopulations constituting distinct genetic entities. If current levels of gene flow are very low, as indicated by the new data, the local fixation of alternative alleles, including those responsible for pelage color polymorphism, is possible by drift alone. A scenario is thus proposed in which the species expanded in the recent past from a more restricted geographic range and has subsequently differentiated in near isolation, with genetic drift possibly playing a primary role in overall genetic differentiation. The local fixation of pelage color types could also be due to drift, but selection on this trait cannot be ruled out without direct analysis.

The farm effect, or: when, what and how a farming environment protects from asthma and allergic disease.

PURPOSE OF REVIEW: Multiple studies have shown that the prevalence of asthma and atopy is reduced in children raised on traditional dairy farms. This article discusses the temporal constraints for the protective farm effect, the components of a farming environment that are associated with protection, and novel mechanisms that may underlie protection from asthma and atopy in farming populations. RECENT FINDINGS: Protection from asthma and allergy is strongest when exposure occurs in utero or early in life, but the protective effects can persist into adulthood. Just three exposures (contact with cows and straw and consumption of unprocessed cow's milk) account for virtually all the protective farm effect for asthma but not atopy. Whey proteins appear to be critical for the protective effects of farm milk, whereas the high microbial diversity existing in a farm environment is strongly and inversely associated with asthma, but only weakly associated with atopy. Therefore, distinct mechanisms are likely to mediate protection from asthma and atopy. The biological significance of microbial diversity is still unclear, but multiple lines of evidence link the asthma-protective and allergy-protective effects of farming to immune responses and the microbiome. Work in mouse models is revealing novel cellular and molecular mechanisms through which the microbiota may modulate immune responses and allergic inflammation, and thus contribute to the farm effect. The role of the host's genetic makeup, on the contrary, remains poorly understood. SUMMARY: The discovery of the central role played by microbial diversity in the asthma-protective and allergy-protective effects of farming warrants metagenomic studies that concertedly and longitudinally investigate the microbiome, the genome, and the immune system of farmers and the farms they live on.

Promiscuity and the rate of molecular evolution at primate immunity genes.

Recently, a positive correlation between basal leukocyte counts and mating system across primates suggested that sexual promiscuity could be an important determinant of the evolution of the immune system. Motivated by this idea, we examined the patterns of molecular evolution of 15 immune defense genes in primates in relation to promiscuity and other variables expected to affect disease risk. We obtained maximum likelihood estimates of the rate of protein evolution for terminal branches of the primate phylogeny at these genes. Using phylogenetically independent contrasts, we found that immunity genes evolve faster in more promiscuous species, but only for a subset of genes that interact closely with pathogens. We also observed a significantly greater proportion of branches under positive selection in the more promiscuous species. Analyses of independent contrasts also showed a positive effect of group size. However, this effect was not restricted to genes that interact closely with pathogens, and no differences were observed in the proportion of branches under positive selection in species with small and large groups. Together, these results suggest that mating system has influenced the evolution of some immunity genes in primates, possibly due to increased risk of acquiring sexually transmitted diseases in species with higher levels of promiscuity.

The genetics of adaptive coat color in gophers: coding variation at Mc1r is not responsible for dorsal color differences.

The genetics of adaptation is a key problem in evolutionary biology. Pocket gophers of the species Thomomys bottae provide one of the most striking examples of coat color variation in mammals. Dorsal pelage color is strongly correlated with soil color across the range of the species, presumably reflecting the selective pressure exerted by predation. To investigate the genetic basis of coat color variation in T. bottae, we cloned and sequenced the melanocortin-1 receptor locus (Mc1r), a candidate pigmentation gene, in 5 dark and 5 light populations of the species. Our results show that, in contrast to many other species of mammals and other vertebrates, coding variation at Mc1r is not the main determinant of coat color variation in T. bottae. These results demonstrate that similar phenotypic variation may have a different genetic basis among different mammalian species.