Recent studies suggest that the mutations contributing to phenotypic variation [evolutionarily relevant mutations (2
)] are not distributed randomly across all genetic regions. The most compelling evidence comes from cases of parallel genetic evolution: the independent evolution of similar phenotypic changes in different species due to changes in homologous genes or sometimes in the same amino acid position of homologous genes.
Many cases of parallel evolution have been discovered across all of the kingdoms. At least 20 separate populations of the plant Arabidopsis thaliana
have evolved null coding mutations (mutations that completely eliminate protein func tion) in the Frigida
gene that cause early flowering (3
). Resistance to DDT and pyrethroids has evolved in 11 insect species by mutations in either amino acid Leu1014
of the voltage-gated sodium channel gene para
). Two virus populations independently subjected to experimental evolution in a novel host accumulated many of the same amino acid mutations (5
). In total, about 350 evolutionarily relevant mutations have been found in plants and animals, and more than half of these represent cases of parallel genetic evolution (1
One explanation for parallel genetic evolution is that most genes play specialized roles during development, and only some genes can evolve to generate particular phenotypic variants. For example, mutations in rhodopsin
can alter light-wavelength sensitivity (6
), and mutations in lysozyme
may enhance enzyme activity at the particular pH of a fermenting gut (7
). But the reverse would not be true. Mutations in rhodopsin
are unlikely to enhance fermentation, and mutations in a digestive enzyme will not aid detection of a particular wavelength of light, even if each protein was expressed in the reciprocal organ.
Gene function explains part but not all of the observed pattern of parallel genetic evolution. In several cases, parallelism has been observed even though mutations in a large number of genes can produce similar phenotypic changes. For example, although more than 80 genes regulate flowering time (8
), changes in only a subset of these genes have produced evolutionary changes in flowering time (3
). Hundreds of genes regulate the pattern of fine epidermal projections, called trichomes, on Drosophila melanogaster
larvae. But only one gene, called shavenbaby
, has evolved to alter larval trichome patterns between Drosophila
species, and this gene has accumulated multiple evolutionarily relevant mutations (9
). What is special about these hotspot genes?
Developmental biology illuminates why hot-spot genes such as shavenbaby exist. During development, multiple cell-signaling pathways and transcription factors act together to progressively divide the embryo into a virtual map that specifies when and where organs will form. The interactions between the genes encoding these signaling molecules and transcription factors can be represented as a genetic network. Gene interactions are modulated in large part by the cis-regulatory regions of patterning genes. (All genes are composed of two fundamentally different regions: a region encoding the gene product—a protein or an RNA—and adjacent cis-regulatory DNA that encodes the instructions governing when and where the gene product will be produced.) Transcription factors bind to cis-regulatory regions of target genes, and the summed effect of many such interactions at a target gene determines whether the gene is expressed or not. Patterning genes act within complex genetic net-works, and usually each patterning gene contributes to the development of multiple cell types. For example, most patterning genes that are active during embryonic development of the epidermis contribute to the development of muscle-attachment sites, sensory organs, tracheal pits, trichomes, or other cell types.
The importance of regulatory networks in determining which genes may be evolutionary hotspots can be illustrated with the genetic network that governs larval trichome development in D. melanogaster
(). In this network, developmental patterning genes first collaborate to divide the embryonic epidermis into domains expressing distinct transcription factors. These patterning genes then regulate the expression of the shavenbaby
gene, a so-called input-output gene (10
). Input-output genes integrate complex spatiotemporal information (the input) and trigger development of an entire program of cell differentiation (the output). The Shavenbaby protein activates expression of a battery of target genes that transform an epidermal cell into a trichome cell. Each target gene triggers a specific aspect of cell differentiation, and production of a differentiated trichome requires coordinated expression of all target genes. The pattern of trichomes over the body is thus determined by the distribution of Shavenbaby protein in the epidermis, which is controlled by the cis
-regulatory region of the shavenbaby
gene. The shavenbaby
gene serves as a nexus for patterning information flowing in and for cell-fate information flowing out.
Fig. 1 Morphological divergence between species has been caused by repeated evolution at an input-output gene. (A) D. melanogaster and D. sechellia differ in the pattern of fine trichomes decorating the dorsal and lateral surfaces of the larvae. This difference (more ...)
In the entire regulatory network governing development of the Drosophila
embryo, only shavenbaby
, with its specialized function to rally the entire module of trichome morphogenesis, can accumulate mutations that alter trichome patterns without disrupting other developmental processes. Genetic changes in upstream developmental genes will alter trichome production, but these mutations also disrupt other organs. Changes in any one of the downstream genes are not sufficient to create or eliminate a trichome; concerted changes in multiple downstream genes are required to build a trichome (11
). Furthermore, all of the evolutionarily relevant mutations in shavenbaby
that have been identified so far alter the cis
-regulatory region and not the protein-coding region. Mutations in the protein-coding region would alter shavenbaby
function in every cell that accumulates Shavenbaby protein, and this would alter every trichome produced in larvae and adults. Thus, a developmental perspective clarifies why shavenbaby
is a hotspot for evolutionarily relevant mutations and why these mutations occur in the cis
-regulatory region of the gene. We predict that the cis
-regulatory regions of other input-output genes may be hot-spots for other phenotypic characteristics.
The shavenbaby gene provides one example of a more general principle: that mutations affecting multiple phenotypic traits, so-called pleiotropic mutations, are unlikely to contribute to adaptive evolution. As we discuss next, pleiotropy and other genetic and population-genetic parameters seem to influence the distribution of evolutionarily relevant mutations.