The modern versus extended evolutionary synthesis : sketch of an intra-genomic gene's eye view for the evolutionary-genetic underpinning of epigenetic and developmental evolution

Studying the phenotypic evolution of organisms in terms of populations of genes and genotypes, the Modern Synthesis (MS) conceptualizes biological evolution in terms of 'inter-organismal' interactions among genes sitting in the different individual organisms that constitute a population. It 'black-boxes' the complex 'intra-organismic' molecular and developmental epigenetics mediating between genotypes and phenotypes. To conceptually integrate epigenetics and evo-devo into evolutionary theory, advocates of an Extended Evolutionary Synthesis (EES) argue that the MS's reductive gene-centrism should be abandoned in favor of a more inclusive organism-centered approach. To push the debate to a new level of understanding, we introduce the evolutionary biology of 'intra-genomic conflict' (IGC) to the controversy. This strategy is based on a twofold rationale. First, the field of IGC is both ‘gene-centered’ and 'intra-organismic' and, as such, could build a bridge between the gene-centered MS and the intra-organismic fields of epigenetics and evo-devo. And second, it is increasingly revealed that IGC plays a significant causal role in epigenetic and developmental evolution and even in speciation. Hence, to deal with the ‘discrepancy’ between the ‘gene-centered’ MS and the ‘intra-organismic’ fields of epigenetics and evo-devo, we sketch a conceptual solution in terms of ‘intra-genomic conflict and compromise’ – an ‘intra-genomic gene’s eye view’ that thinks in terms of intra-genomic ‘evolutionarily stable strategies’ (ESSs) among numerous and various DNA regions and elements – to evolutionary-genetically underwrite both epigenetic and developmental evolution, as such questioning the ‘gene-de-centered’ stance put forward by EES-advocates

Epigenetic inheritance. Concepts, mechanisms and perspectives

Parents' stressful experiences can influence an offspring's vulnerability to many pathological conditions, including psychopathologies, and their effects may even endure for several generations. Nevertheless, the cause of this phenomenon has not been determined, and only recently have scientists turned to epigenetics to answer this question. There is extensive literature on epigenetics, but no consensus exists with regard to how and what can (and must) be considered to study and define epigenetics processes and their inheritance. In this work, we aimed to clarify and systematize these concepts. To this end, we analyzed the dynamics of epigenetic changes over time in detail and defined three types of epigenetics: a direct form of epigenetics (DE) and two indirect epigenetic processes-within (WIE) and across (AIE). DE refers to changes that occur in the lifespan of an individual, due to direct experiences with his environment. WIE concerns changes that occur inside of the womb, due to events during gestation. Finally, AIE defines changes that affect the individual's predecessors (parents, grandparents, etc.), due to events that occur even long before conception and that are somehow (e.g., through gametes, the intrauterine environment setting) transmitted across generations. This distinction allows us to organize the main body of epigenetic evidence according to these categories and then focus on the latter (AIE), referring to it as a faster route of informational transmission across generations-compared with genetic inheritance-that guides human evolution in a Lamarckian (i.e., experience-dependent) manner. Of the molecular processes that are implicated in this phenomenon, well-known (methylation) and novel (non-coding RNA, ncRNA) regulatory mechanisms are converging. Our discussion of the chief methods that are used to study epigenetic inheritance highlights the most compelling technical and theoretical problems of this discipline. Experimental suggestions to expand this field are provided, and their practical and ethical implications are discussed extensivel

Non-mammalian model organisms in epigenetic research : an overview

Recent advances in sequencing technology and genome editing tools had an indisputably enormous impact on our understanding of complex biological pathways and their genetic and epigenetic regulation. Unlike genetics, a study of phenotype development as a result of genotypic diversity, epigenetics studies the emergence of (possibly heritable) phenotypic assortment from one DNA sequence. Epigenetic modifications (i.e., DNA methylation, histone tail modifications, noncoding RNA interference, and many others) are diverse and can bring an additional layer of complexity to phenotype development and it's inheritance. Still, today, detailed mechanisms behind the development of epigenetic marks, their interaction, and their role in transgenerational inheritance of phenotypes are not fully understood. Therefore, chromatin biology and epigenetic research have a rich history of chasing discoveries in a variety of model organisms, including yeast, worms, flies, fish, and plants. Use of these models has opened numerous new avenues for investigation in the field. In the coming future, model organisms will continue to serve as an inseparable part of studies related to interpreting complex genomic and epigenomic data, gene–protein functional relationship, various diseases pathways, aging, and many others. Use of the model organism will provide insights not only into novel genetic players but also the profound impact of epigenetics on phenotype development. Here, we present a brief overview of the most commonly used nonmammalian model organism (i.e., fruit fly, nematode worm, zebrafish, and yeast) as potential experimental systems for epigenetic studies

Crossovers between epigenesis and epigenetics. A multicenter approach to the history of epigenetics (1901-1975)

The origin of epigenetics has been traditionally traced back to Conrad Hal Waddington's foundational work in 1940s. The aim of the present paper is to reveal a hidden history of epigenetics, by means of a multicenter approach. Our analysis shows that genetics and embryology in early XX century--far from being non-communicating vessels--shared similar questions, as epitomized by Thomas Hunt Morgan's works. Such questions were rooted in the theory of epigenesis and set the scene for the development of epigenetics. Since the 1950s, the contribution of key scientists (Mary Lyon and Eduardo Scarano), as well as the discussions at the international conference of Gif-sur-Yvette (1957) paved the way for three fundamental shifts of focus: 1. From the whole embryo to the gene; 2. From the gene to the complex extranuclear processes of development; 3. From cytoplasmic inheritance to the epigenetics mechanisms

Epigenetics as a first exit problem

We develop a framework to discuss stability of epigenetic states as first exit problems in dynamical systems with noise. We consider in particular the stability of the lysogenic state of the lambda prophage, which is known to exhibit exceptionally large stability. The formalism defines a quantative measure of robustness of inherited states. In contrast to Kramers' well-known problem of escape from a potential well, the stability of inherited states in our formulation is not a numerically trivial problem. The most likely exit path does not go along a steepest decent of a potential -- there is no potential. Instead, such a path can be described as a zero-energy trajectory between two equilibria in an auxiliary classical mechanical system. Finding it is similar to e.g. computing heteroclinic orbits in celestial mechanics. The overall lesson of this study is that an examination of equilibria and their bifurcations with changing parameter values allow us to quantify both the stability and the robustness of particular states of a genetic control system.Comment: 6 pages, 3 figures, in REVTe

From early stress to 12-month development in very preterm infants: Preliminary findings on epigenetic mechanisms and brain growth

Very preterm (VPT) infants admitted to Neonatal Intensive Care Unit (NICU) are at risk for altered brain growth and less-than-optimal socio-emotional development. Recent research suggests that early NICU-related stress contributes to socio-emotional impairments in VPT infants at 3 months through epigenetic regulation (i.e., DNA methylation) of the serotonin transporter gene (SLC6A4). In the present longitudinal study we assessed: (a) the effects of NICU-related stress and SLC6A4 methylation variations from birth to discharge on brain development at term equivalent age (TEA); (b) the association between brain volume at TEA and socio-emotional development (i.e., Personal-Social scale of Griffith Mental Development Scales, GMDS) at 12 months corrected age (CA). Twenty-four infants had complete data at 12-month-age. SLC6A4 methylation was measured at a specific CpG previously associated with NICU-related stress and socio-emotional stress. Findings confirmed that higher NICU-related stress associated with greater increase of SLC6A4 methylation at NICU discharge. Moreover, higher SLC6A4 discharge methylation was associated with reduced anterior temporal lobe (ATL) volume at TEA, which in turn was significantly associated with less-than-optimal GMDS Personal-Social scale score at 12 months CA. The reduced ATL volume at TEA mediated the pathway linking stress-related increase in SLC6A4 methylation at NICU discharge and socio-emotional development at 12 months CA. These findings suggest that early adversity-related epigenetic changes might contribute to the long-lasting programming of socio-emotional development in VPT infants through epigenetic regulation and structural modifications of the developing brain

Systematic comparison of monoclonal versus polyclonal antibodies for mapping histone modifications by ChIP-seq.

BackgroundThe robustness of ChIP-seq datasets is highly dependent upon the antibodies used. Currently, polyclonal antibodies are the standard despite several limitations: They are non-renewable, vary in performance between lots and need to be validated with each new lot. In contrast, monoclonal antibody lots are renewable and provide consistent performance. To increase ChIP-seq standardization, we investigated whether monoclonal antibodies could replace polyclonal antibodies. We compared monoclonal antibodies that target five key histone modifications (H3K4me1, H3K4me3, H3K9me3, H3K27ac and H3K27me3) to their polyclonal counterparts in both human and mouse cells.ResultsOverall performance was highly similar for four monoclonal/polyclonal pairs, including when we used two distinct lots of the same monoclonal antibody. In contrast, the binding patterns for H3K27ac differed substantially between polyclonal and monoclonal antibodies. However, this was most likely due to the distinct immunogen used rather than the clonality of the antibody.ConclusionsAltogether, we found that monoclonal antibodies as a class perform equivalently to polyclonal antibodies for the detection of histone post-translational modifications in both human and mouse. Accordingly, we recommend the use of monoclonal antibodies in ChIP-seq experiments