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• W2808893480 abstract "C.H. Waddington introduced the term ‘epigenetic’ to describe a conceptual framework for developmental decisions as they were understood by the mid-1900s. Later the term was applied to silencing phenomena that show clonal inheritance, such as the orange and black coat color patches of the calico cat resulting from X-chromosome inactivation. However, in recent years, this term has exploded in popularity, first among researchers interested in mechanisms of development, and then as a fad for describing anything that affects gene expression but is not a mutation. The term has permeated popular culture, often as a marketing gimmick, such as ‘epigenetic dentistry’. Excitement about epigenetics has also fueled wishful thinking about controlling one’s own genes through epigenetics. Perhaps nurture controlling nature is not such a crazy idea: higher levels of maternal grooming in mice were recently reported to increase mobilization of transposable elements specifically in the hippocampi of offspring [1Bedrosian T.A. Quayle C. Novaresi N. Gage F.H. Early life experience drives structural variation of neural genomes in mice.Science. 2018; 359: 1395-1399Crossref PubMed Scopus (82) Google Scholar]. With such surprising findings being reported with increasing frequency, it seems worthwhile to keep an open mind as to what epigenetics is capable of explaining. Although there is little that is remarkable about levels of gene expression changing in response to environmental perturbations, such as maternal grooming, we are especially intrigued when such effects are transmitted through eggs or sperm. There are many examples of genomic imprinting, in which epigenetic modifications, such as DNA methylation, are passed through the gametes and affect post-zygotic development. However, whether or not transgenerational effects are sufficiently persistent that they can be subject to natural selection has long been a contentious question. In their new book, Extended Heredity, Russell Bonduriansky and Troy Day marshal the arguments in favor of epigenetic and other influences not encoded in DNA sequence as profound contributors to evolution. By bringing together the large body of evidence for non-DNA inheritance in a single narrative, the authors make a persuasive case that genes are not the only determinants of Darwinian evolution. DNA methylation is the clearest example of an epigenetic change that can persist over generations, long enough to be subject to forces of selection. For example, the striking radially symmetric ‘peloric’ floral form of toadflax described by Linnaeus (Linaria vulgaris) is caused by a DNA methylation ‘epimutation’, not by mutation of a DNA sequence. The many examples of heritable DNA methylation in flowering plants likely reflect the lack of a global resetting process during gamete and embryo production and the reliance on gene regulation by DNA methylation during the development of endosperm, extraembryonic tissue analogous to the mammalian placenta that provides nutrients to the developing embryo. In contrast, except for imprinted genes, DNA methylation is globally erased in mammalian germ lines, and it remains unclear whether or not mammalian epialleles persist long enough to be subject to Darwinian selection. However, other forms of non-genetic inheritance have been documented, especially small RNAs, which can in principle be transmitted through the germ line and travel through the vasculature to potentially mediate gene regulatory processes. A striking example that illustrates how non-genetic inheritance of behavior may be subject to natural selection comes from the authors’ own studies of the mating behavior of the neriid fly, Telostylinus angusticollis. In nature, males vary remarkably in height, but, when grown in the lab, they are all the same size. By diluting larval food, the size of adult males can be regulated, and the ejaculate of larger males results in the production of larger offspring. A female who first mates with a well-fed male also produces larger offspring after a second mating with a smaller male fed on diluted food, even when the first male was not their father (a form of extra-parental inheritance classically known as telegony). We might imagine that females who are less choosy about a mate after their first clutch will be more reproductively successful than females who wait for a bigger male to stop by, offsetting likely costs associated with larger size. Note that the evolution of female choice driven in part by non-genetic inheritance in this case can fit comfortably within the standard Darwinian paradigm, and is not a case of Lamarckian inheritance of acquired characteristics. Unlike mutations, which are very low-frequency events that are strictly heritable, epigenetic changes are frequent, but with low heritability. A change in the local environment is more likely to select for an adaptive epigenotype than an adaptive mutation because there are more of them, but they are short-lived. Extended heredity might work when an adaptive epigenetic change lasts long enough in a population for acquisition of a genetic adaptation in an individual, in which case the epimutation and the mutation can ratchet together along the adaptive landscape. Detecting whether such a process has occurred is challenging because of the transience of epimutations, and one might be skeptical that this is an important evolutionary process. However, the concept becomes compelling by expanding the extended heredity concept to include cultural inheritance. For example, the authors describe the scenario whereby polymorphic alleles causing continued production of the enzyme lactase after weaning in humans are thought to have co-evolved with dairy farming from our lactose-intolerant ancestors. Over the past several thousand years, Darwinian selection has resulted in the near ubiquity of lactose tolerance in parts of the globe where milk is consumed by adults and lactose intolerance where it is not. By including extrinsic influences, such as parental care and culture, the authors sidestep the nature versus nurture dichotomy. This might seem acceptable from a theoretical perspective, but from a mechanistic perspective extended heredity defined in this way represents a collection of unrelated phenomena grouped together only because they are not directly encoded in DNA sequence. A key mechanistic distinction is between processes intrinsic to the individual, both genetic and epigenetic, and processes attributable to the individual’s external environment, including nurture and culture. Lumping DNA methylation together with processes that do not directly involve DNA, such as cultural and environmental influences, ignores mechanism, insofar as DNA methylation is a physical feature of DNA. Like DNA sequence, DNA methylation is inherited semi-conservatively and is repaired by some of the same base-excision repair proteins that act on unmodified DNA bases. Likewise, chromatin and DNA-binding proteins that remain associated with DNA during replication and are inherited through the germ line are more sensibly grouped with genetic rather than with behavioral or cultural components of inheritance. Referring to DNA methylation and histone modification as non-genetic processes is a semantic distinction that seems to have no other purpose than to fit biological facts into the authors’ evolutionary scenario. Within the epigenetics community, there is a lively debate about mechanisms of transgenerational inheritance, with small RNAs, DNA methylation, histone modifications and DNA-binding proteins having their proponents and critics [2Heard E. Martienssen R.A. Transgenerational epigenetic inheritance: myths and mechanisms.Cell. 2014; 157: 95-109Abstract Full Text Full Text PDF PubMed Scopus (1053) Google Scholar]. The authors provide a comprehensive and up-to-date description of exciting advances in transgenerational epigenetics — a field that continues to be demystified. For example, Waddington’s experiments selecting for stress-induced phenotypes that led to his epigenetic framework are now thought to have been caused by insertions and deletions resulting from stress-induced transposon mobilizations [3Fanti L. Piacentini L. Cappucci U. Casale A.M. Pimpinelli S. Canalization by selection of de novo induced mutations.Genetics. 2017; 206: 1995-2006Crossref PubMed Scopus (26) Google Scholar]. This example emphasizes the importance of first ruling out genetic explanations for transgenerational phenomena before jumping to conclusions about non-genetic inheritance. Unfortunately, when it comes to observational evidence, the authors are all too ready to propose epigenetic explanations that do not bear scrutiny. For example, there is uncritical acceptance of conclusions from the famous Swedish Överkalix cohort of a century ago based on the supposed effects on health and longevity when previous generations were subjected to different boom-or-bust cycles. Even if the weak associations described for the rather arbitrary subdivisions of data are statistically valid, it is impossible to distinguish true epigenetic effects from confounding environmental variables. The authors recognize the distinction between nature and nurture in familial settings, as they acknowledge that the obesity of offspring of men exposed early in gestation to the Dutch Hunger Winter of 1944–1945 might have been influenced by the habits and resources of their overweight fathers. Such was the conclusion of the authors of the original study based on solid evidence and it was sufficient to fully explain the data [4Veenendaal M.V. Painter R.C. de Rooij S.R. Bossuyt P.M. van der Post J.A. Gluckman P.D. Hanson M.A. Roseboom T.J. Transgenerational effects of prenatal exposure to the 1944–1945 Dutch famine.BJOG. 2013; 120: 548-553Crossref PubMed Scopus (293) Google Scholar], but Bonduriansky and Day favor an epigenetic explanation, despite the multiple, unknown steps required for such a mode of inheritance to be at all plausible. By not delving into the details of molecular processes elucidated in controlled experimental studies, the authors inadvertently overstate the likelihood of epigenetic inheritance being responsible for transgenerational effects. For example, the poster child mechanism for transgenerational inheritance of a starvation response akin to the Swedish and Dutch examples is the transmission of small RNAs in the worm Caenorhabditis elegans, which triggers an evolved starvation response in offspring by targeting nutritional genes [5Rechavi O. Houri-Ze’evi L. Anava S. Goh W.S. Kerk S.Y. Hannon G.J. Hobert O. Starvation-induced transgenerational inheritance of small RNAs in C. elegans.Cell. 2014; 158: 277-287Abstract Full Text Full Text PDF PubMed Scopus (313) Google Scholar]. However, a crucial component of this pathway is the enzyme RNA-directed RNA polymerase, which amplifies the transmitted RNAs in the worm, but is missing in vertebrates. This is not to say that abundant small RNAs in sperm cannot provoke an early developmental change in vertebrate embryos — an attractive prospect — but rather that, by not addressing the mechanistic distinctions, the authors overstate the likelihood that epigenetics is responsible. Without a plausible amplification mechanism, the enormous post-zygotic dilution of small RNAs during development makes it an unlikely mediator of behavioral traits. It is unfortunate that the authors use specious examples of supposed transgenerational epigenetic persistence to warn readers of unfounded threats to the welfare of future generations by new technologies, such as gene editing to treat diseases and improve crops. Despite my reservations about the authors’ unlikely mechanistic interpretations and their doomsday speculations that lack a solid foundation, the many fascinating examples of non-genetic adaptations make the book thought-provoking and entertaining. I just hope that the concept of extended heredity will not become the next marketing gimmick." @default.
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• W2808893480 title "Darwin meets Waddington" @default.
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