Pharmacophylogenomics: genes, evolution and drug targets

Key Points

  • Orthologues (genes in different species arising from a common ancestral gene during speciation) are important in drug discovery for establishing assays and animal models, but a wider-ranging phylogenomic view can lend further insight into function. This can be accomplished not only through the detection of conserved functional elements, but also of functional shifts that could shed light on species differences that often adversely affect drug discovery projects.

  • Establishing orthology is best accomplished through full phylogenetic reconstructions, which then also provide a framework for assessing selective pressures that could signal functional shifts. The nature and extent of selection can be estimated, for example, on the basis of ratios of non-synonymous-to-synonymous nucleotide substitutions and evidence of selective sweeps in patterns of polymorphism.

  • Paralogues (homologous genes in the same species arising by duplication) are also important in drug discovery, not only for compiling classes of tractable targets and outlining selectivity issues, but also for the evolutionary relationship of paralogues to pleiotropy (multifunctionality) and functional redundancy of targets, phenomena that are critical to assessing druggability.

  • Pleiotropy and redundancy are in turn related to crosstalk and heteromery, increasingly prominent themes in drug discovery and (along with alternative transcription) sources of combinatoric diversity of function arising from the genome. Such phenomena also indicate the relevance of an evolutionary view of pathways and networks, whose elements can co-evolve in a way that can also be detected by phylogenomic means and further contribute to functional characterization.

  • Putative drug targets may be profitably viewed through a variety of phylogenomic 'property filters' related to evolutionary rates, selective pressures, degree and nature of paralogy, and factors reflecting pleiotropy such as size, breadth of expression and interaction potential.

Abstract

Phylogenomics, which advocates an evolutionary view of genomic data, has been useful in the prediction of protein function, of significant sequence and structural elements, and of protein interactions and other relationships. Although such information is important in characterizing individual pharmacological targets, evolutionary analyses also indicate new ways to view the overall space of gene products in terms of their suitability for therapeutic intervention. This view places increased emphasis on the comprehensive analysis of the evolutionary history of targets, in particular their orthology and paralogy relationships, the rate and nature of evolutionary change they have undergone, and their involvement in evolving pathways and networks.

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Figure 1: Relationship of orthology and paralogy to the rate and nature of evolutionary change.
Figure 2: Phylogenetic reconstruction of the CYP2 family of cytochrome P450s.
Figure 3: Schematic representations of various mappings of genes to functions.
Figure 4: Phylogenomics and expression patterns.
Figure 5: Phylogenomics and interaction patterns.

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Acknowledgements

The author thanks J. R. Brown, K. Rice, and N. Odendahl for many helpful comments on the manuscript.

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DATABASE

LocusLink

DCOHM

BRCA1

CFTR

Cyp2a1

Cyp2a3

Cyp2a4

CYP2A6

dopamine D2

EGFR

ERBB2

FOXP2

GPI

PPAR-γ

SRD5A1

SRD5A2

FURTHER INFORMATION

PHYLogeny Inference Package (PHYLIP)

Phylogenetic Analysis Using Parsimony (PAUP)

Resampled Inference of Orthologs (RIO)

Phylogenetic Analysis by Maximum Likelihood (PAML)

Glossary

PHYLOGENOMICS

The application to genomics of principles and techniques from evolutionary biology, to achieve a better understanding of gene function. 'Pharmacophylogenomics' is the use of phylogenomics in aid of drug discovery, through improved target selection and validation.

HOMOLOGUES

Genes that are similar by virtue of having derived from the same ancestral gene. The similarity might be evident in the DNA sequences of the genes, or in the sequence and/or structure of the gene products. Similarity does not guarantee homology, as unrelated sequences can undergo convergent evolution.

ORTHOLOGUES

Homologous genes in different species arising from a common ancestral gene at the time of speciation (Box 2). Orthology does not guarantee common function, as function can change over time and vary in different evolutionary lineages.

PARALOGUES

Homologous genes in the same species arising by duplication (Box 2).

PHYLOGENETIC RECONSTRUCTION

The attempt to recreate the evolutionary history of a set of orthologues and/or paralogues (or, more generally, any set of measurable characters) and portray it in tree form. A number of different methods and algorithms are used for this purpose, and are the subject of much technical debate, but in the final analysis certainty as to ancestral forms is not possible.

PLEIOTROPY

The property of a gene or gene product by which it exhibits multiple phenotypic effects or possesses multiple functions.

REDUNDANCY

The property by which more than one gene or gene product is able to produce a given phenotype or function.

BLAST

Basic Local Alignment Search Tool, the most widely used bioinformatics algorithm130. It efficiently searches sequence databases for the entries most similar to a query sequence. Recent, more advanced, versions and related tools are specially adapted to finding distant homologues, for which sequence similarity is not obvious but typically some structural similarity is retained.

INCONGRUENT EVOLUTION

Apparent topological differences in the phylogenetic trees of individual genes relative to that of the species, or of individual domains or regions within genes relative to each other. This can arise from phenomena such as domain shuffling or horizontal transmission of genes between species.

CONCERTED EVOLUTION

Greater-than-expected similarity seen in members of gene families within a species relative to that seen between species. This can arise from phenomena related to physical mechanisms of replication and recombination that tend to maintain uniformity between (often tandem) copies.

SYNTENY

The property of genes of being found on the same chromosome. The ordering of orthologues on chromosomes is often conserved between related species over extended segments, indicating a common ancestry of those segments; this phenomenon is referred to as conservation of synteny. (To describe the orthologues or regions of the different species as being syntenic to each other is a common misuse of the term.)

MOLECULAR CLOCK

The hypothesis that, except for the effects of functional constraints on gene products, sequence substitutions occur at a constant rate on an evolutionary timescale. It is closely tied to the 'neutral theory' of evolution, which asserts that most such mutations are selectively neutral and driven only by random drift. Although subject to certain caveats and continuing debate, the notion of the molecular clock has proven to be an important and useful tool in many contexts131.

NON-SYNONYMOUS SUBSTITUTION

A nucleotide substitution that results in an amino acid change.

SYNONYMOUS SUBSTITUTION

A 'silent' nucleotide substitution, often in the third codon position, that does not result in an amino acid change.

GENE SHARING (RECRUITMENT)

An adaptation of a gene to serve an additional unrelated function, generally in a different tissue and presumably by the incorporation of alternative regulatory elements at the same locus. It is one proposed mechanism for establishing pleiotropy.

CROSSTALK

The interaction of elements of distinct signalling or regulatory pathways such that an input to one pathway has some effect on the output of the other.

HETEROMERY

The physical association of distinct but often similar macromolecules, as when a pair of protein subunits combine to form a heterodimer. A combination of identical subunits is called homomery.

DOMAIN SWAPPING

The symmetric exchange of portions of polypeptides (ranging up to entire domains), by partial unfolding, between subunits of a multimeric (usually dimeric) assemblage, such that the exchanged portions occupy positions in their counterpart subunits analogous to those they would assume in the monomers.

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Searls, D. Pharmacophylogenomics: genes, evolution and drug targets. Nat Rev Drug Discov 2, 613–623 (2003). https://doi.org/10.1038/nrd1152

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