Beyond Title: Nature and Nurture. By: Robinson, Gene E., Science, 00368075, 4/16/2004, Vol. 304, Issue 5669 Database: Academic Search Complete
The horns of a dilemma are usually on the same bull (1).
When it comes to behavior, the nature-nurture controversy has not disappeared. The public is leery of attributing behavioral influence to DNA rather than to the environment and free will; worries abound over the ethical implications of biological determinism. Many social and behavioral scientists are skeptical as well, either because the concept of "DNA as destiny" does not jibe with their understanding of the dynamic nature of behavior or because they consider human behavior to be much more complex than that of animals studied from a genetic perspective. By contrast, biologists have long accepted that genes, the environment, and interactions between them affect behavioral variation. Traditionally, behavioral variation has been partitioned using statistical analysis into genetic (G), environmental (E), and G x E components, an approach that began long before the advent of molecular biology. This retains the flavor of the nature-nurture dichotomy, which influences how research in this field is interpreted. Fortunately, we can now study genes in enough detail to move beyond the nature-nurture debate. It is now clear that DNA is both inherited and environmentally responsive. Behavior is orchestrated by an interplay between inherited and environmental influences acting on the same substrate, the genome (see the figure). For behavior, gene expression in the brain is the initial readout of the interaction between hereditary and environmental information. Inherited influences ("nature") include variations (polymorphisms) in DNA sequence transmitted from generation to generation over an evolutionary time scale. DNA polymorphisms can affect protein activity (sometimes via posttranslational mechanisms) and gene expression in the brain: when, where, and how much of each protein is produced. The environment ("nurture") also influences gene expression in the brain during the lifetime of an individual ( 2, 3). Environmental effects occur over developmental and physiological time scales. Gene expression in the brain constitutes the first measurable indicator of the interaction between the genome and the environment. Until recently, this "first phenotype" was not easy to study. However, it is now possible to investigate the relationship between gene expression and behavior in the brains of animal models, thanks to new genomic techniques that make gene expression analysis more sensitive, efficient, and comprehensive. As the following three examples illustrate, we can finally begin to understand the interplay of hereditary and environmental influences on genomic activity and individual behavior. Each example deals with just one gene, but don't be misled. All behaviors are influenced by the actions of many genes; the three highlighted here exert their effects as part of gene networks that give rise to diverse pathways of physiological activity.
The gene encoding the vasopressin V1a receptor plays a prominent part in the social behavior of voles ( 4). The vasopressin system is dynamic in mammals, and surges of this neuropeptide hormone occur in the brains of males after mating. Inherited differences in the brain distribution of V1a receptors underlie striking species differences in vole mating habits. The prairie vole (Microtus ochrogaster) is monogamous, whereas most other species of mammal are polygamous. Differences in receptor distribution and behavior are associated with a microsatellite length polymorphism in the promoter of the V1a receptor gene. Transgenic male mice with a prairie vole version of this promoter respond to vasopressin by bonding with females as if they were prairie voles. The V1a receptor gene demonstrates how behavioral variation can be generated by inherited influences on gene expression. The foraging gene (for), which encodes a guanosine 3',5'-monophosphate-dependent protein kinase (PKG), causes inherited differences in behavior in natural populations of the fruit fly Drosophila melanogaster ( 5). Allelic differences in for expression result in two foraging variants: "Rover" flies have higher levels of for mRNA and PKG activity and are more active food gatherers than "sitter" flies. An ortholog of Drosophila for is involved in regulating food gathering in the honey bee Apis mellifera. In this case, the effect occurs over a developmental, rather than an evolutionary, time scale ( 6). The agerelated transition by bees from hive work to foraging is associated with an increase in for expression in the brain. Expression of for in the bee brain also responds to the dynamic aspects of life in a bee colony, such as when the need arises for some individuals to begin foraging earlier in life than usual. For example, a spike in birthrate that results from favorable environmental conditions in the spring yields a colony deficient in foragers; precocious show foragers a premature increase in for brain expression. Likewise, treatment that elevates PKG activity also causes precocious foraging. The for gene demonstrates how behavioral variation can be generated by both inherited and social (environmental) influences on the same gene, albeit in different species. The steroid glucocorticoid hormone is an important component of the system that coordinates behavioral responses to stress in vertebrates. Rats (Rattus norvegicus) with a more active glucocorticoid receptor-encoding gene in their brains are more tolerant of stress than individuals producing fewer receptors. These differences explain variation in maternal care exhibited by different mother rats ( 7). Variation in maternal care in rats is inherited; pups that receive the minimum care from their mothers grow up to return the favor when they have their own offspring. Apparently, pups experiencing indifferent care show profound changes in brain gene activity, including decreased expression of the glucocorticoid receptor gene. But these inherited differences in gene expression and behavior occur even in the absence of DNA polymorphisms. In the case of the glucocorticoid receptor gene of neglected rat pups, it is epigenetic modification of the DNA sequence through methylation that is involved in their altered adult behavior ( 8). Hence, environmental influences on behavior can cause epigenetic changes in the genome that are inherited. Any modern reformulation of nature-nurture questions concerning behavior requires knowing which genes vary as a result of heredity and which genes respond to
environmental factors. A broad search for genes sensitive to both influences might provide breakthroughs in the study of genes and behavior. These genes might be pacemakers -- evolutionarily labile and mechanistically important -- and their identification may lead to molecular pathways that are critical to the brain machinery that modulates behavior. Identification and analysis of the promoters and enhancers that regulate these genes should also provide important insights into how inherited and environmental factors affect brain and behavior. Emphasizing the dynamic responsiveness of the genome over different time scales not only provides a framework that includes both mechanistic and evolutionary explanations of behavior at the molecular level, but may also attract more social and behavioral scientists to the quest to understand the relationship between genes and behavior. In the past, social and behavioral scientists might have dismissed molecular studies of behavior in animal models by pointing to the greater complexity of human behavior. Yet the examples offered here -- pair bonding, foraging, and care of offspring, each involving molecules known to also be present in humans -- illustrate complex behaviors performed over days and weeks or even a lifetime. These behaviors have learned components and are performed in a social context. The value of animal models can be further enhanced by applying genomics to generate large-scale expression profiles of individuals with different genotypes tested in different environments ( 9). In addition, the application of informatics should enable new literature-based comparative analyses of behaviors across different species ( 10). Development of new tools marrying the vast literature on behavior with genomics could also spark increasing involvement by social and behavioral scientists in molecular genetic studies of behavior. This would be a welcome development indeed. A complete explication will require the integration of diverse perspectives in molecular biology, neuroscience, evolutionary biology, and the social sciences. Such a collaboration, grounded in our rapidly increasing knowledge of the dynamic genome, should help everyone get past the dilemma of nature versus nurture. Then we can all focus on both the tremendous opportunities and the challenging ethical concerns related to the study of genes and behavior. DIAGRAM References and Notes 1. Spanish proverb, cited in J. R. C. Turner, Biol. J. Linn. Soc. 29, 277 (1983). 2. A. Chakravarti, P. Little, Nature 421, 412 (2003). 3. D. Ferster, Science 303, 1619 (2004). 4. T. R. Insel, L. J. Young, Nature Rev. Neurosci. 2, 129 (2001). 5. K. A. Osborne et al., Science 277, 834 (1997).
6. Y. Ben-Shahar, A. Robichon, M. B. Sokolowski, G. E. Robinson, Science 296, 741 (2002). 7. D. Francis, J. Diorio, D. Liu, M. J. Meaney, Science 286, 1155 (1999). 8. I. C. Weaver, M. Szyf, M. J. Meaney, Endocr. Res. 28, 699 (2002). 9. C. W. Whitfield, A.-M. Cziko, C. E. Robinson, Science 302, 296 (2003). 10. B. Schatz, Computer 35, 56 (2002). 11. I thank M. R. Berenbaum for the reference to the proverb, and Y. Ben-Shahar, S. N. Beshers, N. E. Cantor, I. H. Carmen, D. F. Clayton, S. E. Fahrbach, T. R. Insel, H. A. Lewin, M. Sen Sarma, M. B. Sokolowski, A. L. Toth, B. Schatz, and L. Wraight for helpful discussions. Research from my laboratory cited here was supported by NSF, NIH, and the Burroughs Wellcome Fund. ~~~~~~~~ By Gene E. Robinson