Modules and the promise of the evo-devo research program

Since Evolgen recognizes the importance of evo-devo, I'll return the favor: bioinformatics is going to be critical to the evo-devo research program, which to date has emphasized the "devo" part with much work on model systems, but is going to put increasing demands on comparative molecular information from genomics and bioinformatics to fulfill the promise of the "evo" part. I'm sitting on a plane flying east, and to pass the time I've been reading a very nice review of the concept of modularity in evo-devo by Paula Mabee (also a fish developmental biologist, and also working in a small college in a small town in the midwest…but rather deservedly better known than yours truly). In addition to summarizing the importance of the concept of modularity to evolution and development, the paper also does something I always appreciate: it summarizes the key questions that the modern evo-devo research program is working to answer.

What is a module? That's a difficult question, for a couple of reasons. One is that while we can conceptually break up an organism into smaller, simpler units, modules aren't strictly atomic: organisms form integrated wholes, and modules are of necessity always going to be a bit fuzzy around the edges, where they link up to form interoperable assemblies of multiple modules. Another is that different disciplines view modules in different ways. Geneticists are going to see it as an outcome of gene structure, and will describe a module in terms of the different regulatory regions associated with a set of genes. Developmental biologists think of regulatory networks, build maps of how genes talk to one another, and see modules as recognizable, largely self-contained domains of gene interaction. Mabee makes the interesting point that to an evolutionary biologist, developmental modules align well with what they would call phenotypic characters, the features of an organism that are used to construct phylogenetic trees.

We can see the developmental biologists perspective in this complicated diagram of the genetic circuits that specify one tissue in an echinoderm. Each of the cryptically abbreviated names is a different gene, and the different colored arrows from each gene indicate what other genes it regulates. The central green box represents a kind of island of interacting genes, with specific inputs and outputs that affect other tissues.

(click for larger image)
Regulatory gene network for endomesoderm specification (from Eric Davidson ). Forty genes are currently known to be involved in specifying this single cell type. Each short horizontal line from which a bent arrow extends to indicate transcription represents the cis-regulatory element that is responsible for expression of the gene named in the domain shown. The architecture ofthe
network is based on perturbation and expression data, on data from cis-regulatory analyses for several genes, and on other experiments.

That diagram represents a collection of genes from a sea urchin, and maybe those names look strange to you, but as a developmental biologist who has worked with fish and frogs and insects, they all look so familiar. Notch, Delta, frizzled, Krox, Wnt8, Bra, and VEGF…these are all old friends, good buddies that turn up over and over again in papers we all read about the development of any animal. Developmental biologists are getting used to seeing the same tools turn up in every toolbox, and what this kind of diagram is telling us is the next step up: how those tools are used to construct a tissue. What we'd like to know next is how well conserved this module is in other organisms—can we find some echo of this module in vertebrates and arthropods? Can we examine the differences and get a clearer picture of how evolution transforms this circuitry?

That's where Mabee makes the case for more comparative molecular biology. Some of the great successes in developmental biology have come from working out in great detail the network of genes involved in specifying distinct modules or characters in model systems. We're going to be able to make great strides in answering some of the biggest questions in evolution with a comparative approach—and not just between whole phyla, but within smaller clades.

From that perspective, Mabee offers up a list of questions. What's cool about these, and what sets them apart from the tiresome and ignorant questions that creationists like to raise as objections, is the intent. These are not questions that evolutionary biology can't answer; these are the questions that biology promises to answer with much hard work and the expected cross-fertilization of biological disciplines.

The pattern of phylogenetic history is critical for tests, predictions, and investigations in evolutionary developmental biology,
or evo-devo. Patterns of character evolution must be synthesized across the full spectrum of biological levels to answer the
major questions below and those subsumed within them. Because of the complexity and volume of these data, new methods
of visualization and analysis will be required to fully grasp the patterns of such evolutionary changes.

Developmental network-level questions:

• What is the pattern of evolution of gene regulatory network modules?
• What are the specific changes that have occurred in a particular gene network as it is transformed in evolution, and exactly
  where have these have occurred?
• Where exactly does the remodeling of developmental pathways occur? (cis-acting elements? Protein function?)
• What is the frequency and nature of parallel co-option of genetic networks? (Co-option appears to occur frequently in
  evolution, as evidenced by the parallel independent co-option of Pax-6, Dll, and tinman to pattern eyes, limbs, and hearts,
  respectively, in insects and vertebrates)
• Developmental pathways may be redeployed in other tissues (heterotopy) or at other developmental times (heterochrony),
  or both. How often and under what circumstances does this happen?
• What are the specific bases for constraint in gene networks?
• What are the network properties that promote resilience or enhance evolvability? (The interactivity among genes indicates
  that there might be considerable flexibility in the capacity of the genome to respond to diverse conditions; Greenspan 2001.)
• How is constraint at the morphological level related to that at the network level?
• Which sites in a gene network are most conserved or constrained, and which are most labile?
• What types of changes are most common? (Cork and Purugganan [2004] predict that genes functioning early in a genetic
  pathway are subject to stronger stabilizing selection than downstream loci, since mutations in these genes are likely to have
  greater pleiotropic effects and affect all downstream phenotypes. )

Phenotype-level questions:

• What is the developmental basis for the phenotypic characters (modules) of evolution?
• Is there a "signature" modular composition to the morphological characters (modules) of systematics?
• What are the probabilities of different types of changes within modules?
• Are new linkages between submodules made to produce modular characters?
• Are sets of modules (at different or similar biological levels) correlated evolutionarily? (By mapping multiple modules
  simultaneously, the patterns of character association can tested for correlation. Levels of correlation can be quantified.)

Systems-level questions (requiring information from ecology and environment as well):

• What accounts for major novelties?
• Generally, what accounts for homology?
• Can we generalize about homoplasy? Why are some characters susceptible to parallel evolution?
• Why are there trends or "metapatterns" in evolution?

Now that's an interesting list. One of the signs of a healthy science is the range of questions expected to be answered.

Mabee, P (2006) Integrating evolution and development: the need for bioinformatics in evo-devo. Bioscience 56(4):301-309.