New genetic and genomic technologies for dissecting complex diseases

The success of modern genetics, aided by the Human Genome Project, has led to the positional cloning and identification of several genes underlying mendelian phenotypes. Genetic and functional analysis of these genes have shown that the basis of the phenotypes lies in mutations which are necessary and sufficient for the trait in question. Invariably, these mutations are rare in most human populations and are of recent origin. In contrast, the genetic basis of most human diseases has a complex pattern of inheritance and is not understood. In the few rare cases where genes underlying complex phenotypes have been identified they have, more often than not, been pinpointed by association studies of candidate genes. Genetic and functional analysis of these genes have shown that the basis of the complex phenotype lies in mutations which are neither necessary nor sufficient for the trait in question. Moreover, these variants are common in most human populations and can have great antiquity. Whether this apparent dichotomy in the nature of genetic variation which underlies Mendelian versus complex phenotypes is true or not remains to be elucidated. However, it is clear that identification of genes for complex traits is difficult by classical family-based linkage studies and can greatly benefit from population-based and family-based association studies. The completion of a reference human genome sequence by 2005 will provide geneticists with a complete ordered catalog of all human genes and their regulatory sequences. Although we will not understand the function of human genes from the sequence per se , we, in theory, can perform association studies of any measurable phenotype and all common human sequence variation. The current interest in a catalog of common human single nucleotide polymorphisms (SNPs) is based on this reasoning. The current preoccupation with statistical power will likely be replaced with issues of phenotype measures, experimental design of population samples, and resolution of false positives. There is no clearly stated hypothesis regarding the genetic nature of complex human traits (diseases). One plausible scenario is that complex diseases arise from multiple mutations in genes which encode members participating in a common biochemical pathway or network. These mutations may arise de novo but are more likely common variants segregating in the population. Each of these variants, either in homozygous or heterozygous form, imparts a small genetic effect so that phenotypic expression occurs whenever the biochemical output of the pathway or network is compromised by the cumulative effect of all members. It is also likely that environmental or stochastic influences on a phenotype represent those aspects that can regulate the expression of the genes in this pathway or network. Mendelian varieties of the phenotype can occur whenever a mutation with a large phenotypic effect occurs at a rate-limiting step of the pathway. Consequently, the search for complex trait genes can involve members of known or suspected biochemical pathways or lead to the identification of such pathways based on association studies of genomic variation with phenotypes.