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Key Points Technological advances have vastly expanded the amount of omic data currently available. Historically, each type of data was analysed separately, although approaches to integrate omic data sets to predict complex phenotypic traits are now emerging. Such systems genomics approaches to combine multiple data types provide a more comprehensive understanding of complex genotype–phenotype associations than analysis of one data set. Data from multiple sources that point to the association of the same gene or pathway are less likely to result in false positives. There are various strengths and weaknesses of the available strategies. The approach used needs to be selected according to specific types of data, different types of scientific questions or different types of underlying genomic models. Integrating multiple data types can be substantially more informative than analysing data sets separately, and methods to combine data sets are now emerging. This Review outlines the current approaches for data integration and the various strengths and weaknesses of these strategies. The analytical challenges that emerge with data sets of this magnitude are also described, and the authors provide their perspective on how such systems genomic analyses might develop in the future. Recent technological advances have expanded the breadth of available omic data, from whole-genome sequencing data, to extensive transcriptomic, methylomic and metabolomic data. A key goal of analyses of these data is the identification of effective models that predict phenotypic traits and outcomes, elucidating important biomarkers and generating important insights into the genetic underpinnings of the heritability of complex traits. There is still a need for powerful and advanced analysis strategies to fully harness the utility of these comprehensive high-throughput data, identifying true associations and reducing the number of false associations. In this Review, we explore the emerging approaches for data integration — including meta-dimensional and multi-staged analyses — which aim to deepen our understanding of the role of genetics and genomics in complex outcomes. With the use and further development of these approaches, an improved understanding of the relationship between genomic variation and human phenotypes may be revealed.

Estimating the polygenicity (proportion of causally associated single nucleotide polymorphisms (SNPs)) and discoverability (effect size variance) of causal SNPs for human traits is currently of considerable interest. SNP-heritability is proportional to the product of these quantities. We present a basic model, using detailed linkage disequilibrium structure from a reference panel of 11 million SNPs, to estimate these quantities from genome-wide association studies (GWAS) summary statistics. We apply the model to diverse phenotypes and validate the implementation with simulations. We find model polygenicities (as a fraction of the reference panel) ranging from ≃ 2 × 10-5 to ≃ 4 × 10-3, with discoverabilities similarly ranging over two orders of magnitude. A power analysis allows us to estimate the proportions of phenotypic variance explained additively by causal SNPs reaching genome-wide significance at current sample sizes, and map out sample sizes required to explain larger portions of additive SNP heritability. The model also allows for estimating residual inflation (or deflation from over-correcting of z-scores), and assessing compatibility of replication and discovery GWAS summary statistics.

Ancestral environmental exposures have previously been shown to promote epigenetic transgenerational inheritance and influence all aspects of an individual's life history. In addition, proximate life events such as chronic stress have documented effects on the development of physiological, neural, and behavioral phenotypes in adulthood. We used a systems biology approach to investigate in male rats the interaction of the ancestral modifications carried transgenerationally in the germ line and the proximate modifications involving chronic restraint stress during adolescence. We find that a single exposure to a common-use fungicide (vinclozolin) three generations removed alters the physiology, behavior, metabolic activity, and transcriptome in discrete brain nuclei in descendant males, causing them to respond differently to chronic restraint stress. This alteration of baseline brain development promotes a change in neural genomic activity that correlates with changes in physiology and behavior, revealing the interaction of genetics, environment, and epigenetic transgenerational inheritance in the shaping of the adult phenotype. This is an important demonstration in an animal that ancestral exposure to an environmental compound modifies how descendants of these progenitor individuals perceive and respond to a stress challenge experienced during their own life history.

Key Points An emerging idea in evolutionary biology is that inheritance implies more than the sole transmission of the DNA sequence across generations. Non-genetic inheritance of information across generations results from various processes that contribute to parent–offspring resemblance, a property that is called heritability. The concept of heritability has been generalized into that of inclusive heritability, which is the heredity of differences, including all forms of inheritance. It unifies genetic and non-genetic heritability into a single framework encompassing the multiple dimensions of inheritance. We briefly provide evidence for the four identified processes of non-genetic inheritance. Epigenetic changes in DNA expression result in epigenetic inheritance when they are transmitted across generations, thus contributing to the transgenerational transmission of phenotypic variation. Epigenetic changes are usually mediated by changes in environmental conditions. Examples include the inheritance of maternal behaviour in rodents or the inheritance of flower symmetry. Parental non-genetic effects can result in the inheritance of non-genetic information across generations, thus contributing to the non-genetic component of inclusive heritability. Examples include the inheritance of immunocompetence against given parasites in birds or flexible adaptation to the maternal light environment in plants. Ecological inheritance occurs when offspring inherit the habitat of their parents. This indicates that any modification of the environment that results from ancestral activity and that affects fitness will change subsequent selective pressures. Examples include the webs, nests, dams and burrows that numerous animal species create, but also the changes in atmospheric gases and soil nutrients brought about by bacteria and plant species. Culture is the part of phenotypic variance that is transmitted through social learning. Recent evidence suggests that cultural transmission is widespread among animals. Examples concern mate choice and species recognition. Cultural selection constitutes another engine of evolution when it interacts with natural selection in both animals and humans. Non-genetic inheritance can easily be confounded with genetic inheritance. It is the intricate network of genetic and non-genetic inheritance systems that produce parent–offspring resemblance, which constitutes the whole evolutionary potential of a trait quantified by inclusive heritability. We formally partition inclusive heritability and propose methods to disentangle its components in order to better integrate them into a comprehensive view of inheritance. We propose specific designs coupling field or experimental longitudinal data with animal model types of statistical tools. Such methods should help to unravel fascinating enigmas in evolution and medicine, such as major evolutionary transitions or the 'missing heritability' in the human genome. The time is ripe to broaden concepts of inheritance and heritability in order to fully grasp the richness of evolutionary processes, and we call for a multidimensional modern synthesis that would merge the current modern synthesis with an inclusive view of inheritance. Increasing evidence indicates that non-genetic information, as well as DNA sequence, is transmitted across generations to influence evolution. The authors review the evidence for different modes of non-genetic inheritance and discuss how they can be accounted for in evolutionary studies. 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.

Genetic factors do not fully account for the relatively high heritability of neurodevelopmental conditions, suggesting that non-genetic heritable factors contribute to their etiology. To evaluate the potential contribution of aberrant thyroid hormone status to the epigenetic inheritance of neurological phenotypes, we examined genetically normal F2 generation descendants of mice that were developmentally overexposed to thyroid hormone due to a Dio3 mutation. Hypothalamic gene expression profiling in postnatal day 15 F2 descendants on the paternal lineage of ancestral male and female T3-overexposed mice revealed, respectively, 1089 and 1549 differentially expressed genes. A large number of them, 675 genes, were common to both sets, suggesting comparable epigenetic effects of thyroid hormone on both the male and female ancestral germ lines. Oligodendrocyte- and neuron-specific genes were strongly overrepresented among genes showing, respectively, increased and decreased expression. Altered gene expression extended to other brain regions and was associated in adulthood with decreased anxiety-like behavior, increased marble burying and reduced physical activity. The sperm of T3-overexposed male ancestors revealed significant hypomethylation of CpG islands associated with the promoters of genes involved in the early development of the central nervous system. Some of them were candidates for neurodevelopmental disorders in humans including Nrg3, Nrxn1, Gabrb3, Gabra5, Apba2, Grik3, Reln, Nsd1, Pcdh8, En1, and Elavl2. Thus, developmental levels of thyroid hormone influence the epigenetic information of the germ line, disproportionately affecting genes with critical roles in early brain development, and leading in future generations to disease-relevant alterations in postnatal brain gene expression and adult behavior.

Indirect genetic effects from relatives may result in misleading quantifications of heritability, but can also be of interest in their own right. In this paper we propose Trio-GCTA, a model for separating direct and indirect genetic effects when genome-wide single nucleotide polymorphism data have been collected from parent-offspring trios. The model is applicable to phenotypes obtained from any of the family members. We discuss appropriate parameter interpretations and apply the method to three exemplar phenotypes: offspring birth weight, maternal relationship satisfaction, and paternal body-mass index, using real data from the Norwegian Mother, Father and Child Cohort Study (MoBa).

Patterning of body parts in multicellular organisms relies on the interpretation of transcription factor (TF) concentrations by genetic networks. To determine the extent by which absolute TF concentration dictates gene expression and morphogenesis programs that ultimately lead to patterns in Drosophila embryos, we manipulate maternally supplied patterning determinants and measure readout concentration at the position of various developmental markers. When we increase the overall amount of the maternal TF Bicoid (Bcd) fivefold, Bcd concentrations in cells at positions of the cephalic furrow, an early morphological marker, differ by a factor of 2. This finding apparently contradicts the traditional threshold-dependent readout model, which predicts that the Bcd concentrations at these positions should be identical. In contrast, Bcd concentration at target gene expression boundaries is nearly unchanged early in development but adjusts dynamically toward the same twofold change as development progresses. Thus, the Drosophila segmentation gene network responds faithfully to Bcd concentration during early development, in agreement with the threshold model, but subsequently partially adapts in response to altered Bcd dosage, driving segmentation patterns toward their WT positions. This dynamic response requires other maternal regulators, such as Torso and Nanos, suggesting that integration of maternal input information is not achieved through molecular interactions at the time of readout but through the subsequent collective interplay of the network.

Inheritance of gene expression states is fundamental for cells to ‘remember’ past events, such as environmental or developmental cues. The conserved Polycomb Repressive Complex 2 (PRC2) maintains epigenetic repression of many genes in animals and plants and modifies chromatin at its targets. Histones modified by PRC2 can be inherited through cell division. However, it remains unclear whether this inheritance can direct long-term memory of individual gene expression states (cis memory) or instead if local chromatin states are dictated by the concentrations of diffusible factors (trans memory). By monitoring the expression of two copies of the Arabidopsis Polycomb target gene FLOWERING LOCUS C (FLC) in the same plants, we show that one copy can be repressed while the other is active. Furthermore, this ‘mixed’ expression state is inherited through many cell divisions as plants develop. These data demonstrate that epigenetic memory of FLC expression is stored not in trans but in cis. Genetic material is contained within molecules of DNA. In plants and many other organisms, these DNA molecules are packaged around proteins called histones to make a structure known as chromatin. Altering how the DNA is packaged in chromatin can control the activity of genes. For example, a group of proteins called the Polycomb Repressive Complex 2 (PRC2) adds methyl tags to histones, which can alter the packaging of chromatin to lower the activity of particular genes. When a cell divides, it is sometimes important that genes in the daughter cells have similar levels of activity as the parent cell. This allows individual cells to ‘remember’ past events, such as exposure to cold temperatures or other environmental conditions. The pattern of methyl tags on histones can be passed onto the daughter cells, but it is not clear if this is actually responsible for providing the memory. One gene that PRC2 regulates is called FLC, which influences when a plant called Arabidopsis produces flowers. If the plants are exposed to cold temperatures, the activity of FLC is repressed. FLC activity remains low after the period of cold has ended to ensure that the plants produce flowers at an appropriate time. If this 'memory of cold' is held locally in the chromatin of the FLC gene, then it should be possible for two copies of the FLC gene in the same cell to show different gene activities. However, if the memory is stored more globally inside each cell by other proteins, then the two copies should have identical gene activities. To distinguish between these two possibilities, Berry et al. added different fluorescent tags to two copies of the FLC gene in Arabidopsis plants, which allowed the activity of each gene copy to be tracked in individual cells under a microscope. The experiments show that one copy of FLC may be switched off, while the other remains switched on inside the same cell. Furthermore, it was found that this pattern of gene activity is passed onto the daughter cells when the original cell divides. Berry et al.'s findings show that the memory of FLC gene activity is stored locally in the chromatin of the FLC gene itself. The alteration of histones by PRC2 is one important aspect of the packaging of chromatin. The next challenge is to identify what other features of chromatin are required for a gene to be able to store this memory locally.

The past decade has seen an explosion of articles in scientific journals involving non-genetic influences on phenotype through modulation of gene function without changes in gene sequence. The excitement in modern molecular biology surrounding the impact exerted by the environment on development of the phenotype is focused largely on mechanism and has not incorporated questions asked (and answers provided) by early philosophers, biologists, and psychologists. As such, this emergence of epigenetic studies is somewhat “old wine in new bottles” and represents a reformulation of the old debate of preformationism versus epigenesis—one resolved in the 1800s. Indeed, this tendency to always look forward, with minimal concern or regard of what has gone before, has led to the present situation in which “true” epigenetic studies are believed to consist of one of two schools. The first is primarily medically based and views epigenetic mechanisms as pathways for disease (e.g., “the epigenetics of cancer”). The second is primarily from the basic sciences, particularly molecular genetics, and regards epigenetics as a potentially important mechanism for organisms exposed to variable environments across multiple generations. There is, however, a third, and separate, school based on the historical literature and debates and regards epigenetics as more of a perspective than a phenomenon. Against this backdrop, comparative integrative biologists are particularly well-suited to understand epigenetic phenomena as a way for organisms to respond rapidly with modified phenotypes (relative to natural selection) to changes in the environment. Using evolutionary principles, it is also possible to interpret “sunsetting” of modified phenotypes when environmental conditions result in a disappearance of the epigenetic modification of gene regulation. Comparative integrative biologists also recognize epigenetics as a potentially confounding source of variation in their data. Epigenetic modification of phenotype (molecular, cellular, morphological, physiological, and behavioral) can be highly variable depending upon ancestral environmental exposure and can contribute to apparent “random” noise in collected datasets. Thus, future research should go beyond the study of epigenetic mechanisms at the level of the gene and devote additional investigation of epigenetic outcomes at the level of both the individual organism and how it affects the evolution of populations. This review is the first of seven in this special issue of Integrative and Comparative Biology that addresses in detail these and other key topics in the study of epigenetics.

It is notable that the occurrence of multiple sex chromosomes differs significantly between major lineages of amniote vertebrates. In this respect, birds are especially conspicuous, as multiple sex chromosomes have not been observed in this lineage so far. On the other hand, in mammals, multiple sex chromosomes have evolved many times independently. We hypothesize that this contrast can be related to the different involvement of sex-specific sex chromosomes in female meiosis subjected to the female meiotic drive under male versus female heterogamety. Essentially, the male-specific Y chromosome is not involved in female meiosis and is therefore sheltered against the effects of the female meiotic drive affecting the X chromosome and autosomes. Conversely, the Z and W sex chromosomes are both present in female meiosis. Nonrandom segregation of these sex chromosomes as a consequence of their rearrangements connected with the emergence of multiple sex chromosomes would result in a biased sex ratio, which should be penalized by selection. Therefore, the emergence of multiple sex chromosomes should be less constrained in the lineages with male rather than female heterogamety. Our broader phylogenetic comparison across amniotes supports this prediction. We suggest that our results are consistent with the widespread occurrence of female meiotic drive in amniotes.