Are there analogous sequence positions in families of related proteins where disease-linked mutations occur with unusually high frequency? We attempt to answer this question by examining sequence alignments for G-protein coupled receptors (GPCRs) and voltage-gated potassium channels that have a significant number of missense mutations linked to some form of human disease. When the disease-linked mutations are mapped onto the sequences for each family, there are a large number of aligned sites at which disease-linked mutations occur in more than one protein. The statistical significance of the aligned sites is judged by analysis of artificially-generated random datasets. There are a modest number of aligned sites that are statistically significant-we refer to these as "phenotologous" sequence positions. Phenotologous sites represent aligned positions at which mutations linked to disease phenotypes occur with high frequency within a family of proteins. The most interesting of these sites are those which are not conserved-such sites are apparently critical in defining structural or functional differences between related proteins. Phenotology may be used to make experimentally testable predictions regarding medical genetics, the molecular basis of disease, and protein structure-function relationships.

The mechanism of the Cr(VI) oxidation of an alkene C@C is not known for certain. A particularly useful and novel example of this process is the intramolecular oxidative cyclization of bishomoallylic tertiary alcohols by pyridinium chlorochromate (PCC) to yield substituted tetrahydrofuran products via the tethered chromate ester. Several such tertiary alcohols were prepared in this study which varied in the number and position of alkyl groups attached to the C@C. The relative reactivity of these substrates toward PCC under standard conditions is dependent only on the number of R groups on the C@C, not on the degree of substitution on the most highly substituted alkene carbon. This observation suggests a symmetrical transition state in this intramolecular Cr(VI) alkene oxidation.