Molecular Evolution in the Genomic Era

Molecular Evolution. A Phylogenetic Approach By Roderic D. M. Page, Edward C. Holmes. Oxford: Blackwell Science Ltd (1998). 352 pp. $40.00In the era of complete genome sequencing, molecular evolution is finally coming of age. What has in the past been an esoteric and perhaps even suspect field is rapidly becoming a part of the everyday business of several brands of biologists. Indeed, meaningful comparative analysis of genomes is impossible without using some basic concepts of molecular evolution. However, many modern biologists, both accomplished professionals and students, are ill prepared for this changing role of evolutionary studies because of the understandable bias in their background toward experimental techniques and results. Therefore introductory-level texts that strive to blend comparative genomics with theory and methods of molecular evolution are certainly timely and welcome. In the first chapter of their textbook Molecular Evolution. A Phylogenetic Approach, Page and Holmes give the reader some hope that they attempt such a synthesis. In this respect, the book is a disappointment. Comparative genomics is not explicitly dealt with at all. It is surprising that the authors do not even mention the biggest piece of news brought about by comparative genomics, even in its infancy—the recent realization that horizontal gene transfer and lineage-specific gene loss are dominant forces in evolution, at least in the prokaryotic part of the world (see, for example, Aravind et al., Trends Genet. 14, 442–444, 1998; Doolittle, Science 284, 2124–2129, 1999). This seems to be a major challenge for both the theory and the practical methods of molecular phylogenetics, but we do not find even a one-sentence discussion of the issue in the book by Page and Holmes. Thus this book is not, in any sense, a reinterpretation of molecular evolution in light of the genomic data.What this book is, in reality, is a basic introduction to some of the traditional concepts and methods of phylogenetic analysis. In that capacity, it can be useful to many readers, and indeed, we mostly enjoyed reading it since the text is lucid and easy. Still, beyond the general disappointment mentioned above, the book suffers from some serious, specific flaws.First, it is not clear who the book is written for. After reading chapter 2, which deals with cladograms and phylogenetic trees and introduces concepts important in molecular evolution such as additive and ultrametric trees, autapomorphy and synapomorphy, and orthology and paralogy, one could agree that “the book is intended for senior undergraduate and graduate students taking courses in molecular evolution/phylogenetic reconstruction,” as indicated on the back of its cover. This, however, is unexpectedly followed by chapter 3, which takes up about 15% of the entire book and presents a picture of the DNA double-helix, the list of 20 amino acids, and explanations of what mitochondria, promoters, and exons are. Anyone who took Intro. Bio. (or, for that matter, Honors Biology in high school) is supposed to know all this.Chapter 4 presents the very basics of population genetics. Only a fraction of its material is used later, and treatment of many concepts, such as heritability, sympatric speciation, or Haldane's rule, is too superficial to be useful. The concept of effective population size, Ne, is plainly misrepresented—it is not enough that in an equivalent “perfect” population, “every individual has the same probability of contributing genes to the next generation” (p. 109). Such a population, if reproduction is asexual and everyone contributes exactly 1 offspring, has Ne = 0. The distribution of the number of offspring per parent is crucial, and there is no way to treat this issue without explicitly dealing with the Fisher-Wright sampling. This oversimplification is inexcusable since Ne is indeed central to population genetics and is extensively used later in the book.The book returns to its track with chapter 5, “Measuring Evolutionary Change,” which treats sequence alignments, genetic distance, distribution of evolutionary rates among sites in a gene, and the use of known phylogenetic trees to estimate distances between genes. This chapter includes much useful information, although it begins with a rather misleading discussion of the nature of homology (pp. 135–141). The authors define homology as identity (similarity) inherited from the common ancestor, after which they proceed with the section on “Homology among Sequences” (already a strange title) where they seem to imply that homology can be proved by aligning sequences. At face value, this is just wrong—alignment procedures delineate similarity between sequences but tell us nothing about their common ancestors, if such ever existed. To give an absurd but relevant example, poly-A tails of any two processed pseudogenes are perfectly alignable, but it would be a stretch to consider them homologous. The real—and rather subtle—issue of why and when homology can be legitimately inferred from statistically significant similarity is not even mentioned. The notorious sin of equating homology and similarity (Reeck et al., Cell 50, 667, 1977) is not actually committed, but the authors come dangerously close.Chapter 6 on “Inferring Molecular Phylogenies” is, more or less, the core of the book. It offers concise and coherent explanations of the strengths and caveats of different phylogenetic analysis methods. The presentation here is quite appropriate, neither too technical nor superficial. There is one regrettable slip where the authors discuss NP-completeness (p. 175)—problems are NP-complete not if “no efficient algorithms for their solution are known to exist,” but if it is known (proved) that such algorithms do not exist! Looking for polynomial algorithms to solve an NP-complete problem is akin to attempting to square the circle. On a different note, it is worthwhile to emphasize that the methods described in this chapter are actually more general than it could seem from the description in the book. Most of these approaches are just as applicable to other types of data as they are to sequences. This should be kept in mind not only to appreciate the continuity between classical and molecular phylogenetics, but also to extend phylogenetic methods to new types of data that become available thanks to genome sequencing (e.g., gene adjacency).Chapter 7 treats patterns and factors of molecular evolution. This chapter is disappointing in that it does not take into account crucial theoretical advances published in the last three decades. Over 20 years ago, Maynard Smith realized that, instead of substitutional load (p. 232), which penalizes the population for trying to incorporate a good allele, it is more appropriate to think in terms of lag load, which penalizes the population for not doing this fast enough (Maynard Smith, The Evolution of Sex, Cambridge Univ. Press, 1978). In any case, we know now that selection alone, in principle, can be responsible for all observed rates of evolution, which, of course, does not mean that neutral evolution does not occur. In fact, casting the discussion in terms of selectionist–neutralist debate now appears to be misleading since almost everybody would agree that the issue is quantitative, rather than qualitative; neither of the alternatives shown in Figure 7.3 of Page and Holmes is likely to be correct.The final chapter 8 deals with applications of phylogenetic methods to real-life problems of biological evolution. This would be the opportunity for the authors to place phylogenetic analysis into the more general context of molecular biology and genomics and to critically discuss such major issues as discrepancies between tree topologies for different gene families, and between any of them and the so-called organismal tree. This discussion is indeed present, but so brief that the reader hardly has a chance to assess the scale of the problem.Coming back to where we started, the problem with this book (setting aside regrettable but perhaps minor errors) seems to be that it is surprisingly oriented toward the past (however glorious), rather than the future of molecular evolutionary studies. In addition to the lack of any discussion of horizontal gene transfer and its implications, molecular evolution of form and function with respect to either protein structure or organ development is all but ignored. How new proteins evolve is a central question of molecular evolution, and it should be tackled with growing persistence given the advances of genomics. In this book, such a problem does not exist.Comparing this book to other available texts in molecular evolution, it appears that the book by Wen-Hsiung Li (Molecular Evolution, Sinauer Associates Inc., 1997) seems to be a better, more balanced introduction to molecular evolution, although the book by Page and Holmes may be preferred by some beginners for the greater simplicity of certain explanations. The compendium of phylogenetic methods edited by Hillis and colleagues (Hillis et al., eds., Molecular Systematics, 1996) certainly is the source of choice for someone who is actually starting working with phylogenetic methods. In fairness, however, we must note that none of these books explore the new and sometimes unforeseen opportunities created by massive genome sequencing in any detail. It seems that the real book of Molecular Evolution for the New Age of biology remains to be written.