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The PharmacoGenetic Knowledge Base (PharmGKB), an integrated data resource, is being created by Stanford Medical Informatics (Russ B. Altman (PI); Teri E. Klein (Project Director)) as part of a nationwide collaborative research effort funded by NIH's National Institute of General Medical Sciences. The purpose of this project is to aid researchers in understanding how genetic variation among individuals contributes to their differences in responses to drugs. PharmGKB will provide a repository of pharmacogenetic data, and will be publicly available on the Internet. The knowledge base interlinks genomic, molecular, cellular and clinical information about gene systems important for modulating drug responses. A hierarchical data representation system allows the data model to change as new knowledge is learned, while a relational database foundation ensures the security and stability of the data.

One of the goals of the PharmGKB is to include three-dimensional modeling of structures that have mutations and polymorphisms. SNPs are typically displayed in the context of DNA sequences. In the case where SNPs occur in genes that encode for proteins whose structures have been solved, it is possible to display the SNPs within a structural context. We are developing an extension to Chimera, an extensible molecular modeling system, that enables end users to view SNPs in both sequence and structural contexts in an integrated manner by providing the following user interface:

Sequence View

The protein sequence (translated from DNA sequence if necessary) is displayed in a scrollable text window, with all SNPs underlined. The part of the sequence that actually codes for the solved structure is highlighted using user-selectable colors.

Selection Panel

A number of properties may be associated with a SNP. For example, androgen receptor gene mutations have been collected in the Androgen Receptor Gene Mutations Database at at McGill University where each SNP is annotated with mutation type, substitution frequency and related disease. The selection panel displays the range of properties associated with all SNPs and enables the end user to select, based on properties, the SNPs of interest, which are then highlighted in the Sequence View.

Sequence Action Panel

Once SNPs of interest are selected, they may be displayed differently in the Sequence View using color and font selectors in the Sequence Action Panel. For example, one might color-code mutations by their related diseases.

Structure Action Panel

Analogous to the Sequence Action Panel, the Structure Action Panel provides the interface to control the display of selected SNPs in the Chimera graphics window. A simple highlighting method is to select the SNPs in the 3D view, which displays green outlines around selected amino acids. Observations of interest include whether the SNPs are spatially clustered or located near active sites. Alternative highlighting methods include changing the display color and adding annotation labels, such as substitution type or related disease name.

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