Genes, genomes and neurological disease

‘Grasping the genetic roots…has the potential to reveal basic mechanisms of pathology, and this knowledge will undoubtedly lead to new and more effective treatments…’

The recent completion of the Human Genome Project inspires reflection on how to build on recent gains and confront immediate challenges in the field of neurogenetics. Mendelian or monogenic disease traits have commanded our attention during the previous two decades. This is not surprising when we consider that approximately a third of the recognizable monogenic disease traits show dramatic phenotypic expression in the nervous system. In 1983, Gusella and colleagues reported the chromosomal location of the Huntington's disease locus, quickly leading to the development of presymptomatic testing in families afflicted with this disease [1]. This pioneering discovery was followed by the mapping of the genes for Duchenne muscular dystrophy, neurofibromatosis and many other neurological and neuromuscular diseases. The identification of these disease genes, discovered mainly through linkage and positional cloning methods, profoundly influenced clinical practice. Prognoses and differential diagnoses were refashioned; presymptomatic and prenatal diagnosis became a reality, and triplet repeat, dynamic mutation, anticipation and polyglutamine disorders were introduced into the daily clinical neurology lexicon. Although we did not recognize it at the time, the genes responsible for monogenic traits were the low-lying fruit. The pathogenesis of most neurological diseases is not monogenic, but rather complex and multifactorial with a genetic component that is not Mendelian (dominant, recessive or sex linked) resulting from the action of allelic variants in several genes. Incomplete penetrance and moderate individual allelic effect probably reflect epistatic interactions and postgenomic events. These include genes that rearrange somatically, post-transcriptional regulatory mechanisms and the incorporation of retroviral sequences. In addition, genetic vulnerability is strongly influenced by infection as well as nutritional, climatic and/or other environmental influences. Grasping the genetic roots of these diseases, however complex, has the potential to reveal basic mechanisms of pathology, and this knowledge will undoubtedly lead to new and more effective treatments, and perhaps to prevention and cure. The discovery of sig-nificant gene–disease associations, such as apolipoprotein E (ApoE) in late-onset Alzheimer's disease, neuroregulin (NRG) in schizophrenia and human leukocyte antigen (HLA) in multiple sclerosis, represent the first steps towards this goal.

Although genetic components in many complex neurological diseases are clearly present, the lack of obvious and homogeneous modes of transmission has slowed progress by preventing the full exploitation of classical genetic epidemiological techniques. However, several recent discoveries have dramatically changed our ability to examine genetic variation as it relates to human disease. In 1980, Botstein and colleagues documented the occurrence of restriction fragment length polymorphisms in the human genome, providing, for the first time, a practical experimental approach to link nucleotide diversity with a specific trait [2]. Shortly thereafter, the variable number tandem repeat (VNTR), (also referred to as mini- or micro-satellites) loci, (consisting of sets of consecutively repeated short DNA core sequences), were indexed with sufficient resolution to allow the development of comprehensive genetic maps covering the entire genome. Finally, on February 15^th 2001, the International Human Genome Sequencing Consortium and the private company Celera simultaneously reported the completion of the first draft of the human genome sequence [3,4]. Recently, attention has focused on the goal to register most of the DNA sequence variations in the human genome across different ancestry groups.

These landmark efforts have resulted in an extraordinary amount of fundamental information that promises to advance our comprehension of the genetic basis of complex multifactorial diseases. In addition to the development of large-scale laboratory methods and tools to efficiently recognize and catalog DNA diversity, over the past few years there has been noteable progress in the application of new analytical and data-management approaches. Furthermore, improvements in data mining are leading to the identification of coregulated genes and to the characterization of vast genetic networks underlying specific cellular processes. This complex organization ultimately defines function and, therefore, phenotype. With the aid of novel analytical algorithms, the combined study of genomic, transcriptional, proteomic and phenotypic information in well-controlled and adequately powered data sets will refine conceptual models of pathogenesis and provide a framework for understanding therapeutic mechanisms of action, as well as the rationale for novel curative strategies.

‘The pathogenesis of most neurological diseases is not monogenic, but rather complex and multifactorial…’

Thus, the challenge over the next few years is to persist relentlessly (in the face of dwindling NIH resources) in the discovery of disease genes and to clarify function and downstream mechanisms. The focus should be on the development of more accurate diagnostic tools, the identification of individuals at risk or in the early stages of disease and the monitoring of disease evolution and response to therapy. Genomic progress of this type is crucial in the setting of an aging population and increasing costs of neurological disease. The ultimate goal is to personalize neurological care to maximize each patient's standard of care and quality of life. Even the US FDA recognizes the importance of pharmacogenomics and encourages its use in drug development (see FDA white paper ‘Stagnation or Innovation? Challenge and Opportunity on the Critical Path to New Medical Products’ [101], which identifies pharmacogenomics as a key opportunity for the critical path strategy). The role of genomics in promoting global health and closing the gap between industrialized and developing countries has also drawn the attention of the WHO [102]. There are, however, important ethical issues to consider when embarking on large-scale attempts to characterize the genetics of human disease and response to drugs. These include the potential for gaining information that could harm the study participants or their close relatives, stigmatization of ethnic groups and the risk of providing an incentive for pharmaceutical companies to focus drug development on the easy-to-treat or easy-to-predict individuals. It is our responsibility to remain aware of these ethical concerns whilst pursuing a greater understanding of the origins of neurological diseases. Although the final impact of genetic research and profiling on the practice of neurology is unclear, enthusiasm for this type of research is great, propelled by the potential payoff in concrete healthcare benefits.