To achieve the full potential of pharmacogenomics, one must accurately predict the functional outcomes that arise from amino acid substitutions in proteins. Classically, researchers have focused on understanding the consequences of individual substitutions. However, literature surveys have shown that most substitutions were created at evolutionarily conserved positions. Awareness of this bias leads to a shift in perspective, from considering the outcomes of individual substitutions to understanding the roles of individual protein positions. Conserved positions tend to act as "toggle" switches, with most substitutions abolishing function. However, nonconserved positions have been found equally capable of affecting protein function. Indeed, many nonconserved positions act like functional dimmer switches ("rheostat" positions): this is revealed when multiple substitutions are made at a single position. Each substitution has a different functional outcome; the set of substitutions spans a range of outcomes. Finally, some nonconserved positions appear neutral, capable of accommodating all amino acid types without modifying function. This paper reviews the currently-known properties of rheostat positions, with examples shown for pyruvate kinase, organic anion transporting polypeptide 1B1, the beta-lactamase inhibitory protein, and angiotensin-converting enzyme 2. Outcomes observed for rheostat positions have implications for the rational design of drug analogs and allosteric drugs. Furthermore, this new framework-comprising three types of protein positions-provides a new approach to interpreting disease and population-based databases of amino acid changes. In conclusion, although a full understanding of substitution outcomes at rheostat positions poses a challenge, utilization of this new frame of reference will further advance the application of pharmacogenomics.

Viruses are trailblazers in hijacking host systems for their own needs. Plant viruses have been shown to exploit alternative avenues of translocation within a host, including a challenging route through the xylem, to expand their niche and establish systemic spread, despite apparent host-imposed obstacles. Recent findings indicate that plant viruses from many families could successfully hack xylem cells in a broad range of plant hosts, including herbaceous and perennial woody plants. Similar to virus-related structures present in the phloem, virus particles and membrane-containing viral replication complexes are often observed in the xylem. Except for a few single-stranded DNA viruses in the family Geminiviridae and a negative-sense single-stranded RNA rhabdovirus, Lettuce necrotic yellows virus, the majority of the viruses that were detected in the xylem belong to the group of positive-sense RNA viruses. The diversity of the genome organization and virion morphology of those viruses indicates that xylem exploitation appears to be a widely adapted strategy for plant viruses. This review outlines the examples of the xylem-associated viruses and discusses factors that regulate virus inhabitation of the xylem as well as possible strategies of virus introduction into the xylem. In some cases, plant disease symptoms have been shown to be closely related to virus colonization of the xylem. Inhibiting viral xylem invasion could raise potential attractive approaches to manage virus diseases. Therefore, the identification of the host genes mediating virus interaction with the plant xylem tissue and understanding the underlying mechanisms call for more attention.