REVIEWS Beyond DNA: integrating inclusive inheritance into an extended theory of evolution Étienne Danchin*‡, Anne Charmantier§, Frances A. Champagne||, Alex Mesoudi¶, Benoit Pujol*‡ and Simon Blanchet*# Abstract | Many biologists are calling for an ‘extended evolutionary synthesis’ that would ‘modernize the modern synthesis’ of evolution. Biological information is typically considered as being transmitted across generations by the DNA sequence alone, but accumulating evidence indicates that both genetic and non-genetic inheritance, and the interactions between them, have important effects on evolutionary outcomes. We review the evidence for such effects of epigenetic, ecological and cultural inheritance and parental effects, and outline methods that quantify the relative contributions of genetic and non-genetic heritability to the transmission of phenotypic variation across generations. These issues have implications for diverse areas, from the question of missing heritability in human complex-trait genetics to the basis of major evolutionary transitions. Modern synthesis When Charles Darwin was born in 1809, the idea causes, one of which is that heritability estimates are 10 The merging of Darwinism with that species change over time — that is, evolve — had incorrect , or at least misinterpreted, mainly because genetics that occurred from already emerged1. However, it was only half a century non-genetic heritability is often confounded with the 1930s to the 1950s. later, when Darwin published On the Origin of Species2, purely genetic effects. There is increasing awareness that the theory of evolution profoundly transformed that non-genetic information can also be inherited our understanding of life. Darwin understood that across generations (reviewed in REFS 8,11–13). The natural selection can only affect traits in which there is concepts of ‘general heritability’ (REF. 5) or ‘inclusive variation that is transmitted from parents to offspring; heritability’ (REF. 9) were recently proposed to unify namely, traits that are heritable. Since then, the genetic and non-genetic heritability; the two terms merging of Darwinism with genetics into the modern are synonymous and aim at encompassing all synthesis has led to a semantic shift, resulting in the dimensions of inheritance. tendency to assume that only the DNA sequence is Non-genetic inherited information can arise inherited across generations3–8. However, evolution through several interacting mechanisms, including acts on any phenotypic differences that are stable epigenetics, parental effects and ecological and cultural across generations5,9. According to this view, phenotypic inheritance3,7–9,12,15. All forms of genetic and non-genetic variation should be partitioned into its transmitted inheritance contribute to phenotypic resemblance 7 *Centre National de la versus non-transmitted components rather than into between individuals . Distinguishing among these Recherce Scientifique (CNRS); its classical genetic and environmental components9. various components is crucial because their distinct Université Paul Sabatier; Today, the view that biological information is properties affect evolutionary dynamics in different École Nationale de Formation BOX 1 Agronomique (ENFA); transmitted from one generation to the next by the DNA ways. In particular, as described in , accounting 3,5–8 Laboratoire Évolution et sequence alone appears untenable . This became for the distinct properties of non-genetic inheritance Diversité Biologique (EDB), strikingly obvious when genome-wide association studies may resolve some major evolutionary enigmas. UMR5174, 118 route de (GWA studies) showed that most of the high heritabilities Here, we first briefly review the recent evidence for Narbonne, 31062 Toulouse for phenotypic traits, such as height or common human non-genetic inheritance. Understanding the different cedex 9, France. Correspondence to É.D. diseases, could not be explained by common genetic properties of the various modes of inheritance is 10 e‑mail: [email protected] variants (BOX 1). This lack of a link between variation necessary to fully grasp the impact of non-genetic doi:10.1038/nrg3028 in DNA sequence and heritability might have several inheritance on evolution. Second, we consider the NATURE REVIEWS | GENETICS VOLUME 12 | JULY 2011 | 475 © 2011 Macmillan Publishers Limited. All rights reserved REVIEWS Genome-wide association network of interactions occurring between these Transgenerational epigenetic inheritance can take two studies different forms of inheritance. Third, we introduce contrasting forms (FIG. 1). First, in germline epigenetic (GWA studies). These are the rationale of formally decomposing phenotypic inheritance, the epigenetic state of the DNA is present studies in which associations variation between transmitted versus non-transmitted in germline cells and is thus transmitted to the offspring between genetic variation and a phenotype or trait of interest components, while highlighting the variety and over many generations by transgenerational epigenetic are identified by genotyping importance of non-genetic components of inclusive inheritance (FIG. 1a). For example, prenatal exposure cases (for example, diseased heritability. Fourth, we review methods that can be to the pesticide vinclozolin induces changes in DNA individuals) and controls (for used to estimate the relative weight of each non- methylation in the first filial generation (F1) male example, healthy individuals) genetic component of inclusive heritability and their offspring that are observed to persist to the F generation for a set of genetic variants 4 22 that capture variation across interactions with genetic inheritance. Finally, we call for and beyond in male gametes . Conversely, in experience- the entire genome. Tests of an extended modern synthesis that would not reduce dependent epigenetic inheritance, an epigenetic state statistical association with a inheritance to genes and that would incorporate all affects parental behaviour in a way that generates the same phenotype are performed forms of inheritance9,12,13 to constitute a comprehensive epigenetic state in offspring. For example, in laboratory locally along the genome. evolutionary theory. rats there is transgenerational continuity in individual Heritability differences in postnatal maternal pup licking (FIG. 1b). The percentage of variation Epigenetic inheritance This inheritance depends on maternal licking-induced in a trait that is genetically Today, species evolution through neutral divergence or as epigenetic changes in offspring neural circuits, which transmitted to offspring. a response to natural selection is thought to act primarily alter adult maternal behaviour of offspring23. This effect 23 Inclusive heritability on phenotypic variation resulting from variation in the may persist over many generations . In this example, 16 The percentage of variation DNA sequence . However, phenotypic variation may parental effects and epigenetics interact in producing in a trait that is transmitted also result from changes in DNA expression17–19, which inheritance. However, if maternal behaviour is altered between generations, whatever is determined by various epigenetic mechanisms. For by changes in the quality of the environment (for the mechanism of transmission. Inclusive heritability should example, post-translational modifications of histone example, stress or social isolation), there may be an 24,25 be greater than or equal to proteins and methylation of cytosines in DNA can interruption of the transgenerational continuity . heritability. activate, reduce or completely silence gene expression This possibility to lose epigenetic marks and revert to without altering the DNA sequence18,19. Epigenetics the ancestral phenotype when environmental conditions Prions encompasses the study of these modifications change constitutes a major difference between genetic Prion-forming proteins exist in different stable conformational and other gene-regulatory mechanisms involving and epigenetic inheritance that has major implications 20 states. In addition to a ‘native’ small RNAs, which can regulate gene expression . for adaptation. non-prion conformation, In metacellular organisms, epigenetic modifications One process by which epigenetic marks are they occasionally fold into of gene expression levels can be inherited during both transmitted between generations is genomic imprinting, a prion conformation that replicates itself by templating mitosis (that is, during development) and through whereby certain genes are expressed in a parent-of- 18,21 the conformational conversion transgenerational epigenetic inheritance (across origin-specific manner . Imprinted genes are thus of other molecules of the generations18). Mitotic epigenetic inheritance results only expressed from the alleles that are inherited from same protein. from the transmission of epigenetic marks (for example, one parent, which nullifies the benefits of diploidy of involving the methylation pattern of some genes) from those genes21. Forms of genomic imprinting have been parent to descendant cells. It allows cell differentiation demonstrated in insects, mammals and flowering without changes in the DNA sequence18. By contrast, plants21,26. Another process of transgenerational transgenerational epigenetic inheritance leads to the epigenetic inheritance involves an intimate interaction inheritance of epigenetic marks across generations18. between transposable elements and DNA methylation,