BEHAVIORAL AND BRAIN SCIENCES (2012), Page 1 of 80 doi:10.1017/S0140525X11002226 Behavior genetics and postgenomics Q1 Evan Charney Department of Public Policy and Political Science, Duke Institute for Brain Sciences, Duke Institute for Genome Sciences and Policy, Duke University, Durham NC 90239 http://fds.duke.edu/db/Sanford/faculty/echar Abstract: The science of genetics is undergoing a paradigm shift. Recent discoveries, including the activity of retrotransposons, the extent of copy number variations, somatic and chromosomal mosaicism, and the nature of the epigenome as a regulator of DNA expressivity, are challenging a series of dogmas concerning the nature of the genome and the relationship between genotype and phenotype. According to three widely held dogmas, DNA is the unchanging template of heredity, is identical in all the cells and tissues of the body, and is the sole agent of inheritance. Rather than being an unchanging template, DNA appears subject to a good deal of environmentally induced change. Instead of identical DNA in all the cells of the body, somatic mosaicism appears to be the normal human condition. And DNA can no longer be considered the sole agent of inheritance. We now know that the epigenome, which regulates gene expressivity, can be inherited via the germline. These developments are particularly significant for behavior genetics for at least three reasons: First, epigenetic regulation, DNA variability, and somatic mosaicism appear to be particularly prevalent in the human brain and probably are involved in much of human behavior; second, they have important implications for the validity of heritability and gene association studies, the methodologies that largely define the discipline of behavior genetics; and third, they appear to play a critical role in development during the perinatal period and, in particular, in enabling phenotypic plasticity in offspring. I examine one of the central claims to emerge from the use of heritability studies in the behavioral sciences, the principle of minimal shared maternal effects, in light of the growing awareness that the maternal perinatal environment is a critical venue for the exercise of adaptive phenotypic plasticity. This consideration has important implications for both developmental and evolutionary biology. Keywords: behavior genetics; developmental biology; evolutionary developmental biology; epigenetics; evo-devo; gene association studies; genetics; heritability; maternal effects; phenotypic plasticity; stochasticity; twin studies 1. A paradigm shift the exception of the occasional point mutation or mutations associated with, for example, cancer, does not change It is one of the aims of any scientific discipline to construct throughout life. It has become increasingly clear that models that will account for as many observations as possible DNA is dynamic rather than static, being subject to a within a coherent framework. These models, and the frame- wide array of rearrangements, insertions, and deletions. work of which they are a part, constitute a scientific paradigm. During embryogenesis, the genome is altered by such A paradigm commonly includes a set of dogmas, or key phenomena as retrotransposons, or “jumping genes,” assumptions concerning both the nature of certain phenom- which are mobile DNA elements that “copy and paste” ena and the methodologies employed to study them that are themselves at various positions in an individual’s DNA never doubted as long as the paradigm appears to work well. sequence; de novo copy number variations – deletions, The history of science, as it turns out, is a history of over- insertions, and duplications in segments of DNA; and aneu- turned dogmas and supplanted paradigms (Kuhn 1970). ploidy, alterations in the number of copies of chromosomes The discovery of new phenomena – anomalies – that appear per cell. Some of these phenomena, such as retrotransposi- to violate a central dogma or dogmas – perhaps, according tion, likely continue throughout the course of life and may to the paradigm, they have been deemed incapable of exist- be environmentally responsive. ing – can constitute a serious challenge to a paradigm. Some- 2. These same phenomena challenge another long- times, these phenomena can successfully be accounted for by standing dogma – that persons have identical DNA in all the current paradigm and incorporated into it. But when they cannot, a new paradigm will emerge from new models con- structed to better explain the phenomena. This is the process that Thomas Kuhn (1970) famously called a “para- EVAN CHARNEY is an associate professor of the practice digm shift” or a scientific revolution. of public policy and political science at the Sanford The science of genetics is undergoing a paradigm shift School of Public Policy at Duke University, a faculty (Dear 2009; Gressler & Haslberger 2010; McClellan & fellow at the Duke Institute for Brain Sciences, and a King 2010; Ooi & Wood 2008; Petronis 2010; Sgaramella faculty researcher at the Duke Institute for Genome & Astolfi 2010; Whitelaw & Whitelaw 2006). Consider Sciences and Policy. He received his Ph.D. in political science from Harvard University in 2000 with a focus in the following developments: political theory. His research focuses on genetic, bio- 1. It has been a long-standing dogma in molecular gen- logical, and evolutionary explanations of human behav- etics that an individual’s genome, his or her entire DNA ior, ranging from personality to political orientation. sequence, is fixed at the moment of conception and, with © Cambridge University Press 2012 0140-525X/12 $40.00 1 Charney: Behavior genetics and postgenomics the cells and tissues of their bodies (with the exception of represents a new frontier in the study of mammalian behav- germ cells, red blood cells, and certain cells in the ior. Second, heritability and gene association studies are the immune system). It is appearing more and more likely two methodologies in genetics that are most dependent that the normal human condition is one of somatic and upon the genetic paradigm. Because these methodologies chromosomal mosaicism, that is, different genomes in in large measure define the discipline of behavior genetics, different cells and tissues of the same individual. the impact of these developments upon this discipline is 3. Since DNA’s discovery in 1953, it has been a key likely to be most profound. Third, these developments dogma of molecular genetics that DNA is the sole biologi- have important implications for one of the most influential cal agent of heritability, and it is still commonly treated as generalizations in behavior genetics concerning human be- such. We now know, however, that it is not. The epigen- havior to emerge from the use of heritability studies. This ome, that is, the complex biochemical system that regulates can be referred to as the principle of minimal shared DNA expression, turning genes on and off and modulating maternal effects, according to which the early (primarily their “transcribability,” has been found to be heritable, both maternal) rearing environment, prenatal and postnatal, is somatically and intergenerationally via the germline, not a cause of phenotypic concordance among offspring enabling the biological inheritance of traits with no but, if anything, a cause of phenotypic discordance. changes to the DNA sequence. Furthermore, the epigen- As it turns out, the phenomena we shall consider have a ome is highly environmentally responsive. Environmentally significant bearing upon the validity of this principle, and induced changes in gene transcribability can have long- for reasons independent of the soundness of the method- term – sometimes lifelong – phenotypic consequences. ology used to derive it. This is because these same pheno- 4. The idea that environmentally induced phenotypic mena appear to play a number of critical roles in changes can be inherited transgenerationally violates a embryogenesis, fetal development, and the early postnatal central dogma of neo-Darwinism, which insists that this is period. One of these roles is in enabling what is termed an impossibility. It bespeaks (to neo-Darwinists) a resurrec- “adaptive phenotypic plasticity.” As we shall see, the prin- tion of the “Lamarckian heresy”–Lamarck, a predecessor ciple of adaptive phenotypic plasticity is fundamentally at of Darwin, having proposed just such a possibility. It is odds with the principle of minimal shared maternal effects, not uncommon nowadays to encounter in respected sci- with implications not only for the sources of behavioral vari- entific journals defenses of “neo-Lamarckianism”–minus ation but for developmental and evolutionary biology as well. Lamarck’s quasi-teleological ideas (Gissis & Jablonka 2011; Finally, although my focus is on behavior genetics Champagne 2008; Ho & Burggren 2010; Lemke et al. 2004). throughout, the phenomena I shall consider have profound What are the implications of these recent paradigm- implications for all of genetics and for the ongoing search for shifting developments in genetics for behavior genetics? the role of genes in any number of human diseases. Herit- This article is an attempt to answer this question. As we ability and gene association studies have been employed, shall see, the cumulative evidence of recent discoveries in and continue to be employed, in the search for the causes genetics and epigenetics calls into question the validity of of cancer, heart disease, and diabetes, among others. two classes of methodologies