From Trait To Gene And Back A General Outline

The fundamental goal in behavior neurogenetics is to understand the genetic basis of the neuronal processes underlying individual differences in behavior. At the outset, the relative contribution of genetic factors to a trait needs to be established. In humans, the similarities in a trait are examined in subjects of different degrees of genetic relatedness. Comparison of monozygotic and dizygotic twins in the classical twin method, for instance, allows a reasonable estimate of the heritability of a trait. In animals, for instance, the ability to selectively breed lines that score either extremely low or extremely high on a trait is a good indication of the amount of genetic influence on that trait. If substantial heritability has been demonstrated for a trait, it becomes feasible to search for the building stones, i.e., the differences in coding DNA sequences underlying the genetic part of the individual differences in that trait.

Finding the actual genes is a formidable task for several reasons. Many of the targeted behaviors (aggression, cognitive ability, and depression) are very complex and can usually be quantified on more than one aspect (often with more than one measure per aspect). As a first step the trait under study is refined by using a combination of multiple measures of the trait that best capture a common underlying genetic factor. A subsequent problem is the vast amount of genes involved. Candidate gene studies can be used when previous studies have identified a specific gene that codes for a protein involved in a pathway known to be relevant to the variation of the trait under study. This applies only to genes with known location and function and to pathways that are already partially understood. All other situations need a different approach. Whole genomic searches are used to establish the most likely location on the entire DNA of genes that influence the trait under study. These may be genes that were identified but had not been suspected to be linked to the trait, or they may be new genes. Because there is a large degree of homology between animal DNA and human DNA, animal studies can be very helpful to focus genomic searches on only a part of the human DNA (a single chromosome or even a part thereof). Also, after a putative location has been found, animal studies may help to fine map that region to find the actual gene. Gene finding in animals is generally easier because various types of controlled crosses, such as repeatedly backcrossing or intercrossing, can be made at will.

Once the gene has been found, many studies can be performed to elucidate the exact biological pathway by which the allelic variation in the gene influences variation in the neurophysiological or behavioral trait. In animals, genes can be deleted (knockout models) or inserted (transgenic animals) to investigate the scope of the gene's effects and how it operates. By selecting either animals with a known genetic background or humans with known allelic variants for the gene under study, it is possible to do gene-by-environment studies in which the differential effects of manipulations of the environment on different genotypes can be directly tested. Most important, once animals/humans can be characterized by their genetic predisposition for a trait, structural (e.g., size of hippocampal cell population) and functional aspects of the brain (e.g., electrophysiolo-gical response to a stimulus) can be compared to lay bare the actual biological pathways connecting gene and behavior.

In the following sections, the most commonly applied research paradigms in behavioral neuroge-netics will be discussed and illustrated on the basis of a specific trait. The methods to determine the actual presence of genetic factors—selective breeding and/ or comparing inbred strains in animal studies and the classical twin method in human studies— are discussed in Sections III and IV, respectively. The search for genes is discussed in Sections V (linkage, association studies in humans) and VI (intercrosses and backcrosses in animals). Recently developed techniques, such as knockout and transgenic methods in animals, are discussed in Section VII, while interactions between genes and the environment are discussed in Section VIII. Finally, in

Section IX we focus on the intermediate brain structures.

In our discussion of the various research paradigms, we use aggression as the main example of a behavioral trait. Aggression is exemplary for complex traits such as depression or cognition, with their multiple aspects and multiple levels of measurement. One of the first problems encountered is the definition and the consequent way of measuring the trait under investigation. In humans, we can use the outcomes of questionnaires as a measure of aggression, but we can also use registered criminal acts or convictions for violence. All three variables might very well yield different results. Aggressive behavior in animals appears to be easier to measure than in humans: We can stage an actual fight between two animals. However, there are many different ways to influence the results of a test—for example, by varying the opponent to be attacked, the environment in which the encounter takes place, or the duration of the test. Also, many different aggression parameters are used, ranging from simple ones such as attack latency, which is the time it takes for the animal under investigation to attack its opponent, to more complex measures that combine different aspects of offensive behavior over time and calculate an overall aggression score. This has created an abundance of aggression tests and measures that are sometimes difficult to compare.

Different measures of aggression may be under distinct genetic control mechanisms. Thus, the way aggression is measured will strongly influence results of behavioral neurogenetic testing. This is not only true for aggression but also for all other complex traits. This cautionary note must be kept in mind.

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