The millions of mutations and polymorphisms that occur in human populations are potential predictors of disease, of our reactions to drugs, of predisposition to microbial infections, and of age-related conditions such as impaired brain and cardiovascular functions. However, predicting the phenotypic consequences and eventual clinical significance of a sequence variant is not an easy task. Computational approaches have found perturbation of conserved amino acids to be a useful criterion for identifying variants likely to have phenotypic consequences. To our knowledge, however, no study to date has explored the potential of variants that occur at homologous positions within paralogous human proteins as a means of identifying polymorphisms with likely phenotypic consequences. In order to investigate the potential of this approach, we have assembled a unique collection of known disease-causing variants from OMIM and the Human Genome Mutation Database (HGMD) and used them to identify and characterize pairs of sequence variants that occur at homologous positions within paralogous human proteins. Our analyses demonstrate that the locations of variants are correlated in paralogous proteins. Moreover, if one member of a variant-pair is disease-causing, its partner is likely to be disease-causing as well. Thus, information about variant-pairs can be used to identify potentially disease-causing variants, extend existing procedures for polymorphism prioritization, and provide a suite of candidates for further diagnostic and therapeutic purposes.

The Cadlab Work Station Design Environment is an integrated CAD environment. Like other integrated CAD environments, it consists of a single design management sub-environment and a set of application sub-environments integrated into a CAD framework. Unlike other integrated CAD environments, all of the components which combine to form the Cadlab Design Environment and the methodologies which are used to work with it are defined using a single object-oriented approach. By using an object-oriented approach, rapid integration, extension, and modification of the component sub-environments is possible. In this paper, the object-oriented Cadlab Design Environment is presented and the integration methodology is explained.