(Taken from Behavioural Genetics in the Post Genomic Era, Edited by Robert Plomin, John C Defries, Ian W Craig and Peter McGuffin, American Psychological Association 2002.ISBN 1-55798-926-5)

   Introduction
   General Strategy & Outline of the Genes to Cognition Program
   Connecting the Molecular Mechanisms of Learning Between Mouse & Human    (Page 2)
   A Multilayer Organisation   (Page 2)

   Structural Issues for a Large Multidisciplinary Program   (Page 4)
   Conclusions   (Page 4)

Introduction

The year 2001 marked the arrival of almost complete genome sequence for four organisms with nervous systems, which are also the subject of intense genetic studies: humans, mice, flies, and worms. In the same way that the advent of molecular biology or electrophysiology opened grand new insights into the function of the nervous system, the genome era offers yet another exciting platform for discovery. As with any new set of tools, we want to see them result in improved forms of health care and in the discovery of new biological processes. This chapter does not aim to predict either the future of this "postgenomic revolution" or all of the ways genome information can be applied to understanding behaviour Here I outline a structure for a program of study, referred to as the Genes to Cognition program (G2C), which takes advantage of genomic information and combines it with a diverse set of methodologies. The G2C is driven by studies in basic genetic organisms with the aim of using this information to understand mechanisms of behaviour and diseases of the human nervous system.

The potential of the G2C is illustrated using the biology of learning and memory. Learning is a fundamental cognitive process that has been at the center of mechanistic studies of neural function for more than a century. In the past decade, studies in rodents have led to the identification of a large number of genes involved with learning, which far outstrips those known in any other area of cognitive science. This knowledge can now be applied to humans, where it is likely to be relevant to the pathologies of learning impairment in children, dementias, schizophrenia, and brain injury.

By the very nature of the quest to link genes with behaviour, it is necessary to construct a broadly integrative program that encompasses many distinct methods apart from genetics and psychology. These other areas include cell biology, electrophysiology, biochemistry, proteomics, microarrays, brain imaging, and more. This raises a new and fascinating problem of how to construct information networks that facilitate linking of these areas within a framework that not only provides rapid and simple access to information but also leads to the generation of new hypotheses and insights.

Despite the logic of constructing a framework linking large datasets ranging from molecular biology to psychology, and the inevitability of information accumulating and being organized in this manner, there needs to be a more purposeful drive to this goal. A potentially powerful focus of organization is based on the general recognition that biological functions are performed by sets of proteins (or genes) working together in pathways or as macromolecular machines (Alberts, 1998; Brent, 2000; Tjian, 1995). This logic can be adapted and applied to the study of behaviour Below are some guiding principles that underpin the G2C strategy:
1. Basic aspects of behaviour and brain function are evolutionarily conserved.
2. Core biochemical processes (e.g., signaling pathways and protein complexes) conduct these functions.
3. Sets of genes encoding the core processes can be defined.
4. Core processes are disrupted by mutations and produce phenotypes in humans.
5. Multiple mutations or alleles cooperate to disrupt the core processes.
6. Behaviors and some psychiatric diseases are polygenic; this nature may reflect multiple genes encoding core processes.

The following sections outline aspects of a general strategy for the assembly of a knowledge base that encompasses a biological spectrum from gene to behaviour

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General Strategy and Outline of the G2C

A key feature of this strategy is the linking of mouse and human genetics. Genes involved with learning can be discovered in mice (Grant et al., 1992; Grant & Silva, 1994; Silva, Paylor, Wehner, & Tonegawa, 1992). Because of the homology between mice and humans at the levels of the gene, the protein, the synapse, the brain region, and the behaviour, there is a high probability that a gene involved with learning in a mouse will also be important in humans. This notion has been substantially supported by many studies.

An alternative approach to finding the genes involved with learning, or other behaviors, is to score for variation in the phenotype between individuals and then seek the genetic differences that correlate with these changes. This approach has been widely used and particularly successfully for finding large-effect genes underpinning some disorders (e.g., Huntington's disease).

Gene-targeting technology and the use of embryonic stem (ES) cells allow the experimentalist to modify the structure of any given gene or chromosome in the mouse in a controlled manner (Bradley, Zheng, & Liu, 1998). The widespread use of this technology has led to many hundreds of mouse genes being disrupted or modified. These mutant mice are routinely examined in a wide variety of assays, many of which are aimed at exploring the dysfunction of the nervous system. In this way, lists of genes are being developed in which the named genes are known to be required for the normal physiological function in question. These lists can be used to design experiments in humans, in which one asks, Does the behavioral abnormality in humans correspond to an altered structure of the corresponding human gene? To illustrate how this might work, let us consider the molecular mechanisms of learning as revealed by studies in the mouse and ask if this is informative for studies in humans. First, I provide a brief overview of the history of the molecular biology of learning.

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