Mendelian randomization: can genetic epidemiology help redress the failures of observational epidemiology?

Establishing causal relationships between environmental exposures and common diseases is beset with problems of unresolved confounding, reverse causation and selection bias that may result in spurious inferences. Mendelian randomization, in which a functional genetic variant acts as a proxy for an environmental exposure, provides a means of overcoming these problems as the inheritance of genetic variants is independent of—that is randomized with respect to—the inheritance of other traits, according to Mendel’s law of independent assortment. Examples drawn from exposures and outcomes as diverse as milk and osteoporosis, alcohol and coronary heart disease, sheep dip and farm workers’ compensation neurosis, folate and neural tube defects are used to illustrate the applications of Mendelian randomization approaches in assessing potential environmental causes of disease. As with all genetic epidemiology studies there are problems associated with the need for large sample sizes, the non-replication of findings, and the lack of relevant functional genetic variants. In addition to these problems, Mendelian randomization findings may be confounded by other genetic variants in linkage disequilibrium with the variant under study, or by population stratification. Furthermore, pleiotropy of effect of a genetic variant may result in null associations, as may canalisation of genetic effects. If correctly conducted and carefully interpreted, Mendelian randomization studies can provide useful evidence to support or reject causal hypotheses linking environmental exposures to common diseases.     

Spatially heterogeneous stochasticity and the adaptive diversification of dormancy

Diversified bet‐hedging, a strategy that leads several individuals with the same genotype to express distinct phenotypes in a given generation, is now well established as a common evolutionary response to environmental stochasticity. Life‐history traits defined as diversified bet‐hedging (e.g. germination or diapause strategies) display marked differences between populations in spatial proximity. In order to find out whether such differences can be explained by local adaptations to spatially heterogeneous environmental stochasticity, we explored the evolution of bet‐hedging dormancy strategies in a metapopulation using a two‐patch model with patch differences in stochastic juvenile survival. We found that spatial differences in the level of environmental stochasticity, restricted dispersal, increased fragmentation and intermediate survival during dormancy all favour the adaptive diversification of bet‐hedging dormancy strategies. Density dependency also plays a major role in the diversification of dormancy strategies because: (i) it may interact locally with environmental stochasticity and amplify its effects; however, (ii) it can also generate chaotic population dynamics that may impede diversification. Our work proposes new hypotheses to explain the spatial patterns of bet‐hedging strategies that we hope will encourage new empirical studies of this topic.     

Modifying effects of phenotypic plasticity on interactions among natural selection, adaptation and gene flow

Divergent natural selection, adaptive divergence and gene flow may interact in a number of ways. Recent studies have focused on the balance between selection and gene flow in natural populations, and empirical work has shown that gene flow can constrain adaptive divergence, and that divergent selection can constrain gene flow. A caveat is that phenotypic diversification may be under the direct influence of environmental factors (i.e. it may be due to phenotypic plasticity), in addition to partial genetic influence. In this case, phenotypic divergence may occur between populations despite high gene flow that imposes a constraint on genetic divergence. Plasticity may dampen the effects of natural selection by allowing individuals to rapidly adapt phenotypically to new conditions, thus slowing adaptive genetic divergence. On the other hand, plasticity may promote future adaptive divergence by allowing populations to persist in novel environments. Plasticity may promote gene flow between selective regimes by allowing dispersers to adapt to alternate conditions, or high gene flow may result in the selection for increased plasticity. Here I expand frameworks for understanding relationships among selection, adaptation and gene flow to include the effects of phenotypic plasticity in natural populations, and highlight its importance in evolutionary diversification.     

Clustered environments and randomized genes: a fundamental distinction between conventional and genetic epidemiology

Background

In conventional epidemiology confounding of the exposure of interest with lifestyle or socioeconomic factors, and reverse causation whereby disease status influences exposure rather than vice versa, may invalidate causal interpretations of observed associations. Conversely, genetic variants should not be related to the confounding factors that distort associations in conventional observational epidemiological studies. Furthermore, disease onset will not influence genotype. Therefore, it has been suggested that genetic variants that are known to be associated with a modifiable (nongenetic) risk factor can be used to help determine the causal effect of this modifiable risk factor on disease outcomes. This approach, mendelian randomization, is increasingly being applied within epidemiological studies. However, there is debate about the underlying premise that associations between genotypes and disease outcomes are not confounded by other risk factors. We examined the extent to which genetic variants, on the one hand, and nongenetic environmental exposures or phenotypic characteristics on the other, tend to be associated with each other, to assess the degree of confounding that would exist in conventional epidemiological studies compared with mendelian randomization studies.

Methods and Findings

We estimated pairwise correlations between nongenetic baseline variables and genetic variables in a cross-sectional study comparing the number of correlations that were statistically significant at the 5%, 1%, and 0.01% level (α = 0.05, 0.01, and 0.0001, respectively) with the number expected by chance if all variables were in fact uncorrelated, using a two-sided binomial exact test. We demonstrate that behavioural, socioeconomic, and physiological factors are strongly interrelated, with 45% of all possible pairwise associations between 96 nongenetic characteristics (n = 4,560 correlations) being significant at the p < 0.01 level (the ratio of observed to expected significant associations was 45; p-value for difference between observed and expected < 0.000001). Similar findings were observed for other levels of significance. In contrast, genetic variants showed no greater association with each other, or with the 96 behavioural, socioeconomic, and physiological factors, than would be expected by chance.

Conclusions

These data illustrate why observational studies have produced misleading claims regarding potentially causal factors for disease. The findings demonstrate the potential power of a methodology that utilizes genetic variants as indicators of exposure level when studying environmentally modifiable risk factors.     

The Phylogeny and Biogeographic History of Ashes (Fraxinus,Oleaceae) Highlight the Roles of Migration and Vicariance in the Diversification of Temperate Trees

The cosmopolitan genus Fraxinus, which comprises about 40 species of temperate trees and shrubs occupying various habitats in the Northern Hemisphere, represents a useful model to study speciation in long-lived angiosperms. We used nuclear external transcribed spacers (nETS), phantastica gene sequences, and two chloroplast loci (trnH-psbA and rpl32-trnL) in combination with previously published and newly obtained nITS sequences to produce a time-calibrated multi-locus phylogeny of the genus. We then inferred the biogeographic history and evolution of floral morphology. An early dispersal event could be inferred from North America to Asia during the Oligocene, leading to the diversification of the section Melioides sensus lato. Another intercontinental dispersal originating from the Eurasian section of Fraxinus could be dated from the Miocene and resulted in the speciation of F. nigra in North America. In addition, vicariance was inferred to account for the distribution of the other Old World species (sections Sciadanthus, Fraxinus and Ornus). Geographic speciation likely involving dispersal and vicariance could also be inferred from the phylogenetic grouping of geographically close taxa. Molecular dating suggested that the initial divergence of the taxonomical sections occurred during the middle and late Eocene and Oligocene periods, whereas diversification within sections occurred mostly during the late Oligocene and Miocene, which is consistent with the climate warming and accompanying large distributional changes observed during these periods. These various results underline the importance of dispersal and vicariance in promoting geographic speciation and diversification in Fraxinus. Similarities in life history, reproductive and demographic attributes as well as geographical distribution patterns suggest that many other temperate trees should exhibit similar speciation patterns. On the other hand, the observed parallel evolution and reversions in floral morphology would imply a major influence of environmental pressure. The phylogeny obtained and its biogeographical implications should facilitate future studies on the evolution of complex adaptive characters, such as habitat preference, and their possible roles in promoting divergent evolution in trees.     

Diversity versus disparity and the radiation of modern cetaceans

Modern whales are frequently described as an adaptive radiation spurred by either the evolution of various key innovations (such as baleen or echolocation) or ecological opportunity following the demise of archaic whales. Recent analyses of diversification rate shifts on molecular phylogenies raise doubts about this interpretation since they find no evidence of increased speciation rates during the early evolution of modern taxa. However, one of the central predictions of ecological adaptive radiation is rapid phenotypic diversification, and the tempo of phenotypic evolution has yet to be quantified in cetaceans. Using a time-calibrated molecular phylogeny of extant cetaceans and a morphological dataset on size, we find evidence that cetacean lineages partitioned size niches early in the evolutionary history of neocetes and that changes in cetacean size are consistent with shifts in dietary strategy. We conclude that the signature of adaptive radiations may be retained within morphological traits even after equilibrium diversity has been reached and high extinction or fluctuations in net diversification have erased any signature of an early burst of diversification in the structure of the phylogeny.     

Correlates of diversification in the plant clade Dipsacales: geographic movement and evolutionary innovations

We explore patterns of diversification in the plant clades Adoxaceae and Valerianaceae (within Dipsacales), evaluating correlations between biogeographic change (i.e., movements into new areas), morphological change (e.g., the origin of putative key innovations associated with vegetative and reproductive characters), and shifts in rates of diversification. Our findings indicate that rates of diversification in these plants tend to be less tightly correlated with the evolution of morphological innovations but instead exhibit a pronounced correlation with movement into new geographic areas, particularly the dispersal of lineages into new mountainous regions. The interdependence among apparent novelties (arising from their nested phylogenetic distribution) and the correlation between morphological and biogeographic change suggests a complex history of diversification in Dipsacales. Overall, these findings highlight the importance of incorporating biogeographic history in studies of diversification rates and in the study of geographic gradients in species richness. Furthermore, these results argue against a simple deterministic relationship between dispersal and diversification: like other factors that may influence the probability of speciation and/or extinction, the impact of dispersal on diversification rates depends on being in the right place at the right time.     

Between a rock and a hard place: adaptive sensing and site‐specific dispersal

Environmental variability can lead to dispersal: why stay put if it is better elsewhere? Without clues about local conditions, the optimal strategy is often to disperse a set fraction of offspring. Many habitats contain environmentally differing sub‐habitats. Is it adaptive for individuals to sense in which sub‐habitat they find themselves, using environmental clues, and respond plastically by altering the dispersal rates? This appears to be done by some plants which produce dimorphic seeds with differential dispersal properties in response to ambient temperature. Here we develop a mathematical model to show, that in highly variable environments, not only does sensing promote plasticity of dispersal morph ratio, individuals who can sense their sub‐habitat and respond in this way have an adaptive advantage over those who cannot. With a rise in environmental variability due to climate change, our understanding of how natural populations persist and respond to changes has become crucially important.     

Area and the rapid radiation of Hawaiian Bidens (Asteraceae)

Aim To estimate the rate of adaptive radiation of endemic Hawaiian Bidens and to compare their diversification rates with those of other plants in Hawaii and elsewhere with rapid rates of radiation. Location Hawaii. Methods Fifty‐nine samples representing all 19 Hawaiian species, six Hawaiian subspecies, two Hawaiian hybrids and an additional two Central American and two African Bidens species had their DNA extracted, amplified by polymerase chain reaction and sequenced for four chloroplast and two nuclear loci, resulting in a total of approximately 5400 base pairs per individual. Internal transcribed spacer sequences for additional outgroup taxa, including 13 non‐Hawaiian Bidens, were obtained from GenBank. Phylogenetic relationships were assessed by maximum likelihood and Bayesian inference. The age of the most recent common ancestor and diversification rates of Hawaiian Bidens were estimated using the methods of previously published studies to allow for direct comparison with other studies. Calculations were made on a per‐unit‐area basis. Results We estimate the age of the Hawaiian clade to be 1.3–3.1 million years old, with an estimated diversification rate of 0.3–2.3 species/million years and 4.8 × 10^?5 to 1.3 × 10^?4 species Myr^?1 km^?2. Bidens species are found in Europe, Africa, Asia and North and South America, but the Hawaiian species have greater diversity of growth form, floral morphology, dispersal mode and habitat type than observed in the rest of the genus world‐wide. Despite this diversity, we found little genetic differentiation among the Hawaiian species. This is similar to the results from other molecular studies on Hawaiian plant taxa, including others with great morphological variability (e.g. silverswords, lobeliads and mints). Main conclusions On a per‐unit‐area basis, Hawaiian Bidens have among the highest rates of speciation for plant radiations documented to date. The rapid diversification within such a small area was probably facilitated by the habitat diversity of the Hawaiian Islands and the adaptive loss of dispersal potential. Our findings point to the need to consider the spatial context of diversification – specifically, the relative scale of habitable area, environmental heterogeneity and dispersal ability – to understand the rate and extent of adaptive radiation.     

Epistemic causality and evidence-based medicine

Causal claims in biomedical contexts are ubiquitous albeit they are not always made explicit. This paper addresses the question of what causal claims mean in the context of disease. It is argued that in medical contexts causality ought to be interpreted according to the epistemic theory. The epistemic theory offers an alternative to traditional accounts that cash out causation either in terms of "difference-making" relations or in terms of mechanisms. According to the epistemic approach, causal claims tell us about which inferences (e.g., diagnoses and prognoses) are appropriate, rather than about the presence of some physical causal relation analogous to distance or gravitational attraction. It is shown that the epistemic theory has important consequences for medical practice, in particular with regard to evidence-based causal assessment.     

Male dispersal patterns in white-faced capuchins, Cebus capucinus: Part 1: patterns and causes of natal emigration

This is the first of two papers examining male dispersal patterns in white-faced capuchins. Our study was based on behavioural and demographic data collected on multiple groups of white-faced capuchins in Santa Rosa National Park, Costa Rica since 1985. Here we examine the patterns and proximate causation of male natal dispersal. Natal dispersal in white-faced capuchins occurred at a median age of 4.5 years, with no males remaining in the natal group past 8 years. Initial departure from the natal group appeared to be in response to an attraction to extragroup males and dispersing groupmates. Rates of parallel dispersal (dispersal with co-resident males and/or into groups containing familiar males) were very high for natal males (71-82%), and this pattern of dispersal may have evolved to increase inclusive fitness benefits in male-dispersed species. Additionally, this pattern of dispersal probably increases survivorship among dispersing males who are not yet physically mature, as is common in white-faced capuchins.     

Biogeography of species richness gradients: linking adaptive traits,demography and diversification

Here we review how adaptive traits contribute to the emergence and maintenance of species richness gradients through their influence on demographic and diversification processes. We start by reviewing how demographic dynamics change along species richness gradients. Empirical studies show that geographical clines in population parameters and measures of demographic variability are frequent along latitudinal and altitudinal gradients. Demographic variability often increases at the extremes of regional species richness gradients and contributes to shape these gradients. Available studies suggest that adaptive traits significantly influence demographic dynamics, and set the limits of species distributions. Traits related to thermal tolerance, resource use, phenology and dispersal seem to play a significant role. For many traits affecting demography and/or diversification processes, complex mechanistic approaches linking genotype, phenotype and fitness are becoming progressively available. In several taxa, species can be distributed along adaptive trait continuums, i.e. a main axis accounting for the bulk of inter‐specific variation in some correlated adaptive traits. It is shown that adaptive trait continuums can provide useful mechanistic frameworks to explain demographic dynamics and diversification in species richness gradients. Finally, we review the existence of sequences of adaptive traits in phylogenies, the interactions of adaptive traits and community context, the clinal variation of traits across geographical gradients, and the role of adaptive traits in determining the history of dispersal and diversification of clades. Overall, we show that the study of demographic and evolutionary mechanisms that shape species richness gradients clearly requires the explicit consideration of adaptive traits. To conclude, future research lines and trends in the field are briefly outlined.     

Assessing the impact of school-based mentoring: Common problems and solutions associated with evaluating nonprescriptive youth development programs

ABSTRACT

Like many youth development programs, most youth mentoring programs do not have prescribed practices that target specific outcomes. Because the construct of mentoring represents a broad range of potential activities, researchers face a conundrum when making generalizable causal inferences about the effects of this and similar services. On the one hand, researchers cannot make valid experimental inferences if they do not describe what they manipulate. On the other hand, experiments that include prescribed protocols do not generalize to most mentoring programs. In most cases, researchers conducting school-based mentoring program evaluations err on the side of not sufficiently specifying treatment constructs, which limits the field’s ability to make practically or theoretically useful inferences about this service. We discuss this reality in light of the fundamental logic of the experimental design and suggest several possible solutions to this conundrum. Our goal is to empower researchers to adequately specify treatments while still preserving the treatment construct validity of this and similar interventions.     

Dispersal, Environmental Correlation, and Spatial Synchrony in Population Dynamics

Many species exhibit widespread spatial synchrony in population fluctuations. This pattern is of great ecological interest and can be a source of concern when the species is rare or endangered. Both dispersal and spatial correlations in the environment have been implicated as possible causes of this pattern, but these two factors have rarely been studied in combination. We develop a spatially structured population model, simple enough to obtain analytic solutions for the population correlation, that incorporates both dispersal and environmental correlation. We ask whether these two synchronizing factors contribute additively to the total spatial population covariance. We find that there is always an interaction between these two factors and that this interaction is small only when one or both of the environmental correlation and the dispersal rate are small. The interaction is opposite in sign to the environmental correlation; so, in the normal case of positive environmental correlation across sites, the population synchrony will be lower than predicted by simply adding the effects of dispersal and environmental correlation. We also find that population synchrony declines as the strength of population regulation increases. These results indicate that dispersal and environmental correlation need to be considered in combination as explanations for observed patterns of population synchrony.     

Anorexia nervosa

Anorexia nervosa remains an enigma among Western cultures. Various causal explanations have been offered, encompassing biological, psychological, and sociocultural models. These explanations, however, focus on the immediate or proximal mechanisms of causation. A more thorough understanding of anorexia nervosa can be achieved by understanding the relationship between these factors and ultimate causation, the level of explanation which deals with individual reproductive fitness. This paper reviews the biological, psychological, sociocultural, and evolutionary models and indicates a necessary synthesis between proximate and ultimate levels of causation in examining the anorexia nervosa puzzle.     

Testing for biogeographic mechanisms promoting divergence in Caribbean crickets (genus Amphiacusta)

Aim This work examines whether the history of diversification of Amphiacusta (Orthoptera, Gryllidae) in the Caribbean corresponds to a vicariant or a dispersalist model. Location The Greater Antillean islands of the Caribbean region. Methods The phylogenetic relationships among species were estimated using a procedure that directly estimates the underlying species tree from independent loci (in this case, one mitochondrial and one nuclear locus). This tree was then used to test for topological congruence with a vicariant model, and to estimate divergence times. Results The analyses based on the expected pattern of species divergence (i.e. species‐tree topology) support a vicariant model. With the notable exception of a dispersal event marking the colonization of Jamaica, the timing of the events are generally consistent with a vicariant scenario, given the current taxon sampling and potential errors with dating the divergence events. Main conclusions The tendency of species to co‐segregate by island suggests that intra‐island diversification is common. Despite their flightlessness, species of Amphiacusta are apparently capable of long‐distance dispersal, such as colonization from the Puerto Rican/Virgin Island bank to Jamaica. The topology of the species tree is consistent with a vicariant model of divergence, and the dates of divergence between island groups are generally consistent with an island–island vicariance model. A strict island–island vicariance scenario can, however, be rejected because of inferred dispersal events such as the colonization of Jamaica. Nevertheless, the biogeographic tests suggest that most of the diversity was generated under a combination of intra‐island diversification and island–island vicariance. Additional sampling of taxa will be needed to verify this hypothesized scenario. Our findings indicate that Amphiacusta presents an ideal opportunity for examining the role of sexual selection in promoting diversification, which would complement the large number of studies focused on adaptive divergence of Caribbean taxa.     

Evolution in metacommunities: on the relative importance of species sorting and monopolization in structuring communities

Abstract: Adaptive evolution within species and community assembly involving multiple species are both affected by dispersal and spatiotemporal environmental variation and may thus interact with each other. We examined this interaction in a simple three-patch metacommunity and found that these two processes produce very different associations between species composition and local environment. In most conditions, we find a pattern we call "species sorting," wherein local adaptation by resident species cannot prevent invasions by other preadapted species as environmental conditions change (strong association between local environmental conditions and local community composition). When dispersal rates are very low relative to the other two rates, local adaptation by resident species predominates, leading to strong priority effects that prevent successful colonization by other species that would have been well adapted, a pattern we call "local monopolization." When dispersal and evolutionary rates are both very high, we find that an evolving species outcompetes other species in all patches, a pattern we call "global monopolization." When environmental oscillations are very frequent, local monopolization predominates. Our findings indicate that there can be strong modification of community assembly by local adaptive processes and that these depend strongly on the relative rates of evolution, dispersal, and environmental change.     

Ionizing radiation and hematopoietic malignancies: Altering the adaptive landscape

Somatic evolution, which underlies tumor progression, is driven by two essential components: 1) diversification of phenotypes through heritable mutations and epigenetic changes and 2) selection for mutant clones which possess maximal fitness. Exposure to ionizing radiation (IR) is strongly associated with increased risk of carcinogenesis. This link is traditionally attributed to causation of oncogenic mutations through the mutagenic effects of irradiation. On the other hand, potential effects of irradiation on altering fitness and increasing selection for mutant clones are frequently ignored. Recent studies bring the effects of irradiation on fitness and selection into focus, demonstrating that IR exposure results in stable reductions in the fitness of hematopoietic stem and progenitor cell populations. These reductions of fitness are associated with alteration of the adaptive landscape, increasing the selective advantages conferred by certain oncogenic mutations. Therefore, the link between irradiation and carcinogenesis might be more complex than traditionally appreciated: while mutagenic effects of irradiation should increase the probability of occurrence of oncogenic mutations, IR can also work as a tumor promoter, increasing the selective expansion of clones bearing mutations which become advantageous in the irradiation-altered environment, such as activated mutations in Notch1 or disrupting mutations in p53.     

Dispersal: risk spreading versus local adaptation

I investigate how risk spreading in stochastic environments and adaptation to permanent properties of local habitats interplay in the simultaneous evolution of dispersal and habitat specialization. In a simple two-patch model, I find many types of locally evolutionarily stable attractors of dispersal and of a trait involved in habitat specialization, including a single habitat specialist and a coalition of two specialists with low dispersal, a generalist with high dispersal, and several types of dispersal polymorphisms. In general, only one attractor is a global evolutionarily stable strategy (ESS). In addition to the ESS analysis, I also present some examples of the dynamics of evolution that exhibit adaptive diversification by evolutionary branching.