Comparative Genomics

The comparative approach in biology is probably as old as this science itself. Systematic comparative analysis of organisms can be traced at least to the eighteenth century naturalist Carl Linnaeus, who developed the hierarchical classification of plant and animal species on the basis of detailed observations of comparative morphology. The first half of the nineteenth century was marked by outstanding achievements of comparative anatomy, as exemplified by the work of George Cuvier and Richard Owen. Owen coined the term ‘homology’ to describe similar, albeit modified, ‘organs’ with common underlying structures that are shared between different species. These scientists lacked the evolutionary perspective, however. It was left to Darwin and his followers to emphasize that homologous structures result from descent with modification from a common ancestor. For more than a century after the publication of Darwin’s Origin of Species, comparative morphology flourished as the preeminent method of discerning evolutionary relationships among species and ordering the vast organismic diversity of the natural world. The last 40 years of the twentieth century witnessed the burgeoning of molecular evolutionary studies pioneered by Emile Zuckerkandl and Linus Pauling in 1962. Molecular evolution can be considered to consist mainly of two subdisciplines: (1) the use of molecules as markers to reconstruct the evolutionary histories of organisms and (2) the study of the nature of evolutionary change of the molecules (genes and proteins) themselves. Molecular evolutionary studies have resulted in previously unimaginable advances in our understanding of fundamental evolutionary events and processes. For example, phylogenetic analysis, primarily by Carl Woese and colleagues, of ribosomal ribonucleic acid (RNA) sequences resulted in the abandonment of the established five-kingdom taxonomic system. Their discovery of a completely phylogenetically distinct form of life, the archaea, precipitated the reorganization of the biosphere into primary domains: bacteria, archaea and eukarya. The theoretical foundation of molecular evolution, the neutral theory, developed primarily by Motoo Kimura, provided a new understanding of the mode of genome evolution – that is, that the vast majority of changes at the molecular level were neutral, or nonadaptive, with respect to organismic fitness. The neutral theory of molecular evolution is at present widely used as a null hypothesis against which to test results bearing on the molecular basis of adaptation. A corollary of the neutral theory that is critical for functional inferences from comparisons of molecular sequences is that certain portions of these sequences are conserved because they are subject to strong purifying selection and, accordingly, are functionally important. Molecular evolution studies flourished in the pregenomics era. However, the rules of the game were forever altered in 1995, with the availability of multiple complete genome sequences. At that time, it became possible to employ whole-genome comparisons to address functional and evolutionary questions. Comparative genomics, in the modern sense, was born. Once the complete genome sequence of an organism is available, it becomes possible, at least in principle, to deduce the entire sets of genes and proteins and to obtain comprehensive information on the linear order of genes on chromosomes. Thus, it became possible to confidently (with some limitations, owing to imperfect methods of gene identification and comparison, but, on the whole, with a high reliability) infer the presence or absence of a given gene, gene family or functional class of gene from a genome. It was also possible to address higher-order global questions about the evolution of gene order, through the comparison of complete genomes. Comparative analysis of complete genomes has facilitated the development of a robust natural classification system for genes (or proteins). Such a Introductory article