Toward a selection theory of molecular evolution.

The Neutral Theory Models describing the dynamics of genetic variants with no effect on fitness—so-called neutral models—have been around almost as long as the field of population genetics (Fisher 1922; Wright 1931). Decades after the first models were introduced Motoo Kimura gave a complete description of the dynamics of neutral mutations in finite populations, using mathematical tools borrowed from particle physics (Kimura 1955). Although the elegance of this and other results from Kimura and colleagues were uncontested, their applicability to data seemed remote until experiments revealed enormous amounts of molecular genetic variation, both within and between species (Zuckerkandl and Pauling 1965; Harris 1966; Lewontin and Hubby 1966). The observed levels of variation appeared inconsistent with models that proposed selective effects for all or most mutations, and what has become known as the Neutral Theory of Molecular Evolution was born (Kimura 1968; King and Jukes 1969; Kimura and Ohta 1971). Despite contentious argument over the validity of the Neutral Theory (Kimura 1983; Gillespie 1991), it has become the predominant framework for research in population genetics and molecular evolution for almost 40 years. Increasingly complex models describing the expected patterns of variation within and between species allow researchers to ask about the evolutionary processes acting in nature, both at single loci and in increasingly large datasets encompassing all or most genes in a genome. The Neutral Theory provides a theoretical basis for understanding DNA variation with clear, testable hypotheses and an array of statistical tools that distinguish natural selection from random genetic drift (Kreitman 2000; Nielsen 2001; Hahn 2007). However, the recent paper by Begun and colleagues (Begun et al. 2007) should finally begin to change people’s view of this scientific paradigm. Although results inconsistent with the Neutral Theory have been mounting for some time (see below), the field has continued to use it as a foundation for understanding the molecular world. As the first true “population genomic” dataset, the results of Begun et al. force us to see that the central predictions of the Neutral Theory do not hold in natural populations. Far from just the half-caught glimpses of nonneutral evolution afforded by studies of limited numbers of loci, by sequencing the whole genomes of multiple lines of Drosophila simulans this work should cause a major shift in how we interpret DNA variation within populations and among species. As the conclusions of this article are appropriately cautious with respect to the implications of the work, I will use this essay to provide a wider view of the importance of these results and a synthesis with previous results. To do this I will address the two major tenets of the Neutral Theory, and how increasing amounts of data are showing that these claims and their attendant predictions do not hold for the vast majority of genes and species. I also argue that the implications of our continued use of neutral models are dire—at