Substitutions in evolutionarily well-conserved amino acids among homologous proteins in different species are excellent candidates for pathogenic
mutations. Mutations that are predicted to alter the function of the protein or have been experimentally demonstrated to do so are excellent candidates. Certain mutations need to be tested in model organisms Inhibitors,research,lifescience,medical in order to study their effect. Other mutations require long-term epidemiological studies to prove their involvement with a disease phenotype. The study of the molecular basis of the disease phenotype in unrelated pedigrees and the demonstration of mutations in the same gene often confirm the involvement of this gene in the disease. The description of studies to elucidate the function of the disease-related protein and the pathogenetic mechanism of the disease is beyond the scope of this article. It is, however, important to emphasize that the evolutionary conservation of genes makes model organisms (yeast, worm, fruitfly, zebrafish, or mouse) indispensable tools for the functional Inhibitors,research,lifescience,medical analysis of human genes. The methodology described above for gene cloning responsible for monogenic disorders
has been repeatedly successful.2 A considerable number of diseaserelated genes and alleles Inhibitors,research,lifescience,medical have been identified in the last 15 years. The OMIM contains 1168 genes with mutant alleles associated with disease phenotypes. Most of these have been identified using positional cloning efforts without any previous knowledge Inhibitors,research,lifescience,medical of the biochemistry or pathophysiology of the disease phenotype. Functional gene variants for predisposition to common, complex, phenotypes One of the greatest challenges of this decade for biomedicine is to identify the mutant/polymorphic alleles that cause or predispose to common human disorders with a strong genetic component. It is not far from the truth if we state that the entire effort for the mapping, sequencing, and Inhibitors,research,lifescience,medical determination of the mTOR inhibitor normal variability of our genome has been done in order to be able to find the mutant alleles of the common, complex phenotypes. These phenotypes include
disorders such as Calpain schizophrenia and bipolar disease, diabetes, asthma, atherosclerosis, multiple sclerosis, obesity, hypertension, Alzheimer’s disease, aging, and susceptibility to infectious diseases. The tasks appear enormous, but the expected benefits for medicine could be so profound that are certainly worth the effort and expenses from both academia and industry. The discovery of predisposing mutant alleles for common disorders is nevertheless very difficult. Although we do not understand all the reasons for this difficulty, we could certainly mention the following points. First, the inheritance of the common complex phenotypes is not clearly mendelian. It is true that there is an aggregation of affected individuals in certain families, but the mode of inheritance is not compatible with the usual recognizable patterns.