Epigenetics and phenotypic variation in mammals

What causes phenotypic variation? By now it is clear that phenotype is a result of the interaction between genotype and environment, in addition to variation not readily attributable to either. Epigenetic phenomena associated with phenotypic variation at the biochemical, cellular, tissue, and organism level are now well recognized and are likely to contribute to the “intangible variation” alluded to. While it is clear that epigenetic modifications are mitotically heritable, the fidelity of this process is not well understood. Inheritance through more than one generation of meioses is even less well studied. So it remains unclear to what extent epigenetic changes contribute to phenotypic variation in natural populations. How might such evidence be obtained? What are the features of phenotypes that might suggest an epigenetic component? How much of the epigenetic component is truly independent of genetic changes? The answers to such questions must come from studies designed specifically to detect subtle, stochastically determined phenotypic variation in suitable animal models.     

What is parallelism?

Although parallel and convergent evolution are discussed extensively in technical articles and textbooks, their meaning can be overlapping, imprecise, and contradictory. The meaning of parallel evolution in much of the evolutionary literature grapples with two separate hypotheses in relation to phenotype and genotype, but often these two hypotheses have been inferred from only one hypothesis, and a number of subsidiary but problematic criteria, in relation to the phenotype. However, examples of parallel evolution of genetic traits that underpin or are at least associated with convergent phenotypes are now emerging. Four criteria for distinguishing parallelism from convergence are reviewed. All are found to be incompatible with any single proposition of homoplasy. Therefore, all homoplasy is equivalent to a broad view of convergence. Based on this concept, all phenotypic homoplasy can be described as convergence and all genotypic homoplasy as parallelism, which can be viewed as the equivalent concept of convergence for molecular data. Parallel changes of molecular traits may or may not be associated with convergent phenotypes but if so describe homoplasy at two biological levels-genotype and phenotype. Parallelism is not an alternative to convergence, but rather it entails homoplastic genetics that can be associated with and potentially explain, at the molecular level, how convergent phenotypes evolve.     

A modeling exercise to show why population models should incorporate distinct life histories of dispersers

Dispersal is an important form of movement influencing population dynamics, species distribution and gene flow between populations. In population models, dispersal is often included in a simplified manner by removing a random proportion of the population. Many ecologists now argue that models should be formulated at the level of individuals instead of the population level. To fully understand the effects of dispersal on natural systems, it is therefore necessary to incorporate individual-level differences in dispersal behavior in population models. Here, we parameterized an integral projection model, which allows for studying how individual life histories determine population-level processes, using bulb mites, Rhizoglyphus robini, to assess to what extent dispersal expression (frequency of individuals in the dispersal stage) and dispersal probability affect the proportion of successful dispersers and natal population growth rate. We find that allowing for life-history differences between resident phenotypes and disperser phenotypes shows that multiple combinations of dispersal probability and dispersal expression can produce the same proportion of leaving individuals. Additionally, a given proportion of successful dispersing individuals result in different natal population growth rates. The results highlight that dispersal life histories, and the frequency with which disperser phenotypes occur in the natal population, significantly affect population-level processes. Thus, biological realism of dispersal population models can be increased by incorporating the typically observed life-history differences between resident phenotypes and disperser phenotypes, and we here present a methodology to do so.     

A biological relativity view of the relationships between genomes and phenotypes

This article explores the relativistic principle that there is no privileged scale of causality in biology to clarify the relationships between genomes and phenotypes. The idea that genetic causes are primary views the genome as a program. Initially, that view was vindicated by the discovery of mutations and knockouts that have large and specific effects on the phenotype. But we now know that these form the minority of cases. Many changes at the genome level are buffered by robust networks of interactions in cells, tissues and organs. The ‘differential’ view of genetics therefore fails because it is too restrictive. An ‘integral’ view, using reverse engineering from systems biological models to quantify contributions to function, can solve this problem. The article concludes by showing that far from breaking the supervenience principle, downward causation requires that it should be obeyed.     

Genomic imprinting in fetal growth and development

Each somatic cell of the human body contains 46 chromosomes consisting of two sets of 23; one inherited from each parent. These chromosomes can be categorised as 22 pairs of autosomes and two sex chromosomes; females are XX and males are XY. Similarly, at the molecular level, two copies of each autosomal gene exist; one copy derived from each parent. Until the mid-1980s, it was assumed that each copy of an autosome or gene was functionally equivalent, irrespective of which parent it was derived from. However, it is now clear from classical experiments in mice and from examples of human genetic disease that this is not the case. The functional activity of some genes or chromosomal regions is unequal, and dependent on whether they have been inherited maternally or paternally. This phenomenon is termed 'genomic imprinting' and the activity or silence of an imprinted gene or chromosomal region is set during gametogenesis. Genomic imprinting involving the autosomes appears to be restricted to eutherian mammals, and has most likely evolved as a result of the conflicting concerns of the parental genomes in the growth and development of their offspring. When the normal pattern of imprinting is disrupted, the phenotypes observed in humans and mice are generally associated with abnormal fetal growth, development and behaviour, illustrating its importance for a normal intrauterine environment. The characteristics of imprinted genes, their regulation and the phenotypes associated with altered imprinting are discussed.     

Evolution of neurodegeneration

A number of neurodegenerative diseases principally affect humans as they age and are characterized by the loss of?specific groups of neurons in different brain regions. Although these disorders are generally sporadic, it is now clear that many of them have a substantial genetic component. As genes are the raw material with which evolution works, we might benefit from understanding these genes in an evolutionary framework. Here, I will discuss how we can understand whether evolution has shaped genes involved in neurodegeneration and the implications for practical issues, such as our choice of model systems for studying these diseases, and more theoretical concerns, such as the level of selection against these phenotypes.     

Assessing the repeatability,robustness to disturbance,and parent–offspring colony resemblance of collective behavior

Groups of animals possess phenotypes such as collective behaviour, which may determine the fitness of group members. However, the stability and robustness to perturbations of collective phenotypes in natural conditions is not established. Furthermore, whether group phenotypes are transmitted from parent to offspring groups with fidelity is required for understanding how selection on group phenotypes contributes to evolution, but parent–offspring resemblance at the group level is rarely estimated. We evaluated the repeatability, robustness to perturbation and parent–offspring resemblance of collective foraging aggressiveness in colonies of the social spider Anelosimus eximius. Among‐colony differences in foraging aggressiveness were consistent over time but changed if the colony was perturbed through the removal of individuals or via individuals’ removal and subsequent return. Offspring and parent colony behaviour were correlated at the phenotypic level, but only once the offspring colony had settled after being translocated, and the correlation overlapped with zero at the among‐colony level. The parent–offspring resemblance was not driven by a shared elevation but could be due to other environmental factors. The behaviour of offspring colonies in a common garden laboratory setting was not correlated with the behaviour of the parent colony nor with the same colony's behaviour once it was returned to the field. The phenotypes of groups represent a potentially important tier of biological organization, and assessing the stability and heritability of such phenotypes helps us better understand their role in evolution.     

Diseases of unstable repeat expansion: mechanisms and common principles

The list of developmental and degenerative diseases that are caused by expansion of unstable repeats continues to grow, and is now approaching 20 disorders. The pathogenic mechanisms that underlie these disorders involve either loss of protein function or gain of function at the protein or RNA level. Common themes have emerged within and between these different classes of disease; for example, among disorders that are caused by gain-of-function mechanisms, altered protein conformations are central to pathogenesis, leading to changes in protein activity or abundance. In all these diseases, the context of the expanded repeat and the abundance, subcellular localization and interactions of the proteins and RNAs that are affected have key roles in disease-specific phenotypes.     

Plants, pairing and phenotypes--two's company?

An RNA-based communication network appears to play a crucial role in regulating gene expression and in repressing viral and transposon sequences in plant genomes. In this article, we consider the evidence that gene expression might also be controlled epigenetically at a level other than non-coding RNA species-chromosome pairing. This epigenetic communication between sequences might be based--as it is in other organisms--on the physical pairing between homologues and the transfer of information between corresponding epigenetic landscapes. We suggest that paramutation might represent just one--albeit extreme and obvious--facet of a pairing-based gene expression regulation system in plants. Further exciting evidence for pairing occurring between homologues in plants is now mounting. An appreciation that pairing interactions might be important throughout plant development could assist in understanding phenomena such as endosperm imprinting, hybrid phenotypes and inbreeding depression.     

On the genetics of the Pi serum proteins

Summary The authors report family studies (51 families with 134 children) on the inheritance of the Pi phenotypes. Combining these data with a Norwegian family material (77 families with 323 children) published by Fagerhol and Gedde-Dahl (1969) a total of 128 families with 457 children is now available, which allows the following conclusion: The Pi phenotypes are inherited by a simple codominant mode of heredity and they are determined by a set of (at least nine) alleles. As up to now no exception to the role of inheritance has been observed, the application of the Pi system in cases of disputed paternity seems to be discussible. Some methodological problems in connection with this are shown.Supported by the Deutsche Forschungsgemeinschaft.     

The amoeba enigma

After more than 70 years of intermittent debate over the true relationship between the 'pathogenic' and 'non-pathogenic' forms of Entamoeba histolytica, the application of molecular biology has finally yielded an unambiguous answer: these are not interconvertible phenotypes of the same parasite, a kind of unicellular Jekyll and Hyde, but two quite distinct genetic entities that just happen to look the same. But given the overwhelming evidence now available from gene sequences, pointing to an evolutionary divergence some tens of millions of years ago, why is it that certain eminent workers in the field are still claiming that, at least in vitro, conversion between the two phenotypes can take place? In this article Bill Spice and John Ackers review recent developments in the molecular biology of E. histolytica and assess the continuing controversy over the status of this enigmatic parasite.     

Probing the aggregated effects of purifying selection per individual on 1,380 medical phenotypes in the UK Biobank

Understanding the relationship between natural selection and phenotypic variation has been a long-standing challenge in human population genetics. With the emergence of biobank-scale datasets, along with new statistical metrics to approximate strength of purifying selection at the variant level, it is now possible to correlate a proxy of individual relative fitness with a range of medical phenotypes. We calculated a per-individual deleterious load score by summing the total number of derived alleles per individual after incorporating a weight that approximates strength of purifying selection. We assessed four methods for the weight, including GERP, phyloP, CADD, and fitcons. By quantitatively tracking each of these scores with the site frequency spectrum, we identified phyloP as the most appropriate weight. The phyloP-weighted load score was then calculated across 15,129,142 variants in 335,161 individuals from the UK Biobank and tested for association on 1,380 medical phenotypes. After accounting for multiple test correction, we observed a strong association of the load score amongst coding sites only on 27 traits including body mass, adiposity and metabolic rate. We further observed that the association signals were driven by common variants (derived allele frequency > 5%) with high phyloP score (phyloP > 2). Finally, through permutation analyses, we showed that the load score amongst coding sites had an excess of nominally significant associations on many medical phenotypes. These results suggest a broad impact of deleterious load on medical phenotypes and highlight the deleterious load score as a tool to disentangle the complex relationship between natural selection and medical phenotypes.     

Smooth muscle cell phenotypes in atherosclerotic lesions

Recently, there has been a dramatic change in the way we think about the role of vascular smooth muscle cells in atherosclerosis, and it is now generally accepted that a dearth of vascular smooth muscle cells in an atherosclerotic plaque is a detrimental feature of the disease. Indeed, it is now recognized that the phenotypes of vascular smooth muscle cells within a plaque dictate its features, progression and stability. Therefore an understanding of the processes that generate and regulate vascular smooth muscle cell heterogeneity are of critical importance for future therapeutic advancement in the treatment of atherosclerosis.     

Homology-dependent resistance: transgenic virus resistance in plants related to homology-dependent gene silencing

Tobacco plants transformed with the RNA polymerase (RdRp) gene of potato virus X (PVX) that are extremely resistant to infection by potato virus X have previously been described. The PVX-resistant plants accumulated the RdRp protein at a lower level than fully susceptible plants transformed with the same RdRp construct. In this paper the difference between the PVX-resistant and susceptible transformed plants is investigated and it is demonstrated that there are three associated phenotypes of the RdRp transgene that vary in parallel between transformed lines. These phenotypes are: accumulation of the transgenic RdRp RNA at a low level; strain-specific resistance to PVX; and the ability of the transgene to trans -inactivate homologous transgenes. This gene-silencing potential of the transgenes conferring PVX resistance was illustrated by analysis of progeny from a cross between a transformant that was extremely resistant to PVX and a second PVX-susceptible transformant. In other transformants, in which the resistance was less extreme, the same three phenotypes were associated but in a transgene dosage-dependent manner. The same association of strain-specific resistance and low-level accumulation of the transgenic RdRp RNA was observed with plants that were transformed with mutant or wild-type versions of the RdRp gene. Strain-specific resistance was also produced in plants transformed with untranslatable versions of the RdRp transgene. Based on these data it is proposed that homology-dependent gene silencing and transgenic resistance to PVX may be due to the same RNA-based mechanism. An undefined genomic feature is proposed to account for the variation in the resistance and trans -inactivation phenotypes of different transformants. It is further proposed that this genome feature influences a cytoplasmic mechanism that degrades RNA with sequence homology to the silencing transgene.     

Nitric oxide in blood. The nitrosative-oxidative disequilibrium hypothesis on the pathogenesis of cardiovascular disease

There is growing evidence that altered production and/or spatio-temporal distribution of reactive oxidant species and reactive nitrosative species in blood creates oxidative and/or nitrosative stresses in the failing myocardium and endothelium. This contributes to the abnormal cardiac and vascular phenotypes that characterize cardiovascular disease. These derangements at the system level can now be interpreted at the integrated cellular and molecular levels in terms of effects on signaling elements in the heart and vasculature. The end results of nitric oxide/redox disequilibrium have implications for cardiac and vascular homeostasis and may result in the development of atherosclerosis, myocardial tissue remodelling and hypertrophy. Reactive oxygen species/reactive nitrogen species generation is also attributed to the transit from hypertrophic to apoptotic phenotypes, a possible mechanism of myocardial failure. In this review, we highlight the possible roles of altered production and/or spatio-temporal distribution of reactive oxidant species and reactive nitrosative species in blood on the pathogenesis of the failing cardiovascular system.     

The Plastic Growth Responses of Three Agamospecies of Dandelion to Two Levels of Nutrient

The ability of a genotype to produce different phenotypes inresponse to variable environments is a crucial aspect of lifehistory strategies as it determines the shape of the fitnessset for the population. Apomictic dandelions generate littlegenetic variation between parent and offspring and plasticityis the main strategy in the face of environmental variability.The plastic response of three coexisiting dandelions has beenmeasured over two nutrient regimes. Cyclical growth patternsare species specific and in some cases independent of nutrientlevels. Differences between the agamospecies are greater athigh nutrient levels and the agamospecies appear to produceonly one phenotype at low nutrient levels. Taraxacum, plasticity, phenotypes, nutrient level     

Alternative activation of tumor-associated macrophages by IL-4

Although macrophages were originally recognized as major immune effector cells, it is now appreciated that they also play many important roles in the maintenance of tissue homeostasis, and are involved in a variety of pathological conditions including cancer. Several studies have demonstrated the contributions of tumor-associated macrophages (TAMs) to tumor initiation, progression, and metastasis. However, the detailed mechanisms underlying how TAMs differ molecularly from their normal counterparts and how the conversion to TAMs occurs have only just begun to be understood. TAMs have been proposed to exhibit phenotypes of ‘alternatively activated’ macrophages, though there has been limited evidence directly linking the phenotypes of TAMs to the alternative activation of macrophages. This review will focus on IL-4, the prototypic cytokine that induces the alternative activation of macrophages, and review current knowledge regarding the contributions of IL-4 to the phenotypes of TAMs and its effects on tumorigenesis.     

Towards deciphering glioblastoma intra-tumoral heterogeneity: The importance of integrating multidimensional models

Glioblastoma (GBM) is the most common and severe form of brain cancer among adults. Its aggressiveness is largely attributed to its complex and heterogeneous biology that despite maximal surgery and multimodal chemoradiation treatment, inevitably recurs. Traditional large-scale profiling approaches have contributed substantially to the understanding of patient-to-patient inter-tumoral differences in GBM. However, it is now clear that biological differences within an individual (intra-tumoral heterogeneity) are also a prominent factor in treatment resistance and recurrence of GBM and will likely require integration of data from multiple recently developed omics platforms to fully unravel. Here we dissect the growing geospatial model of GBM, which layers intra-tumoral heterogeneity on a GBM stem cell (GSC) precursor, single cell, and spatial level. We discuss potential unique and inter-dependant aspects of the model including potential discordances between observed genotypes and phenotypes in GBM.