Gene Regulation and Morphology

There is an essay in the July issue of PLoS Biology by Sean Carroll discussing evolution of morphology by changes in gene regulation, as opposed to changes to the gene sequence itself. (Dr. Carroll has written a book, Endless Forms Most Beautiful: The New Science of Evo Devo, which I plan to read.)

Although changes in genes get a lot of attention, some scientists think that the changes are not great enough to explain major morphological differences. Instead, Carroll argues that it is they way the genes are used that makes the difference. This may especially be true for genes that are used in a variety of tissues. It is one thing to mutate a gene that will be used in different ways in a number of tissues, and it is another to simply turn the gene on or off in a subset of those tissues.

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I think the main point of the essay is captured in this paragraph:

While we are often able to infer coding sequence function from primary sequences, we are generally unable to decipher functional properties from mere inspection of non-coding sequences. This has led to a bias in comparative genomics and evolutionary genetics toward the analysis and reporting of readily detectable events in coding regions, such as gene duplications and protein sequence evolution, while non-coding, regulatory sequences are often ignored. However, approximately two-thirds of all sequences under purifying selection in our genome are non-coding. One consequence of the underconsideration of non-coding, regulatory sequences is unrealistic expectations about what can currently be learned about the genetic basis of morphological diversity from comparisons of genome sequences alone. The visible diversity of any group is not reflected by the most visible components of gene diversity—that is, the diversity of gene number or of coding sequences. In order to understand the evolution of anatomy, we have to study and understand regulatory sequences, as well as the proteins that connect them into the regulatory circuits that govern development. (Emphasis added.)

The essay cites several examples in support of his argument, and those examples are captured in several figures. We'll look at two of them here.

Figure 1


The top line in this figure is a generic schematic of a stretch of DNA containing a gene. The black boxes represent portions of a gene. Our genes are usually broken up into several segments ("exons"). When the DNA is copied into RNA, the extra junk in between ("introns") is spliced out. The arrow indicates where the gene starts, and the red circle represents a section of DNA that helps regulate whether the gene is expressed or not. (A) shows what can happen when a gene is duplicated--the normal gene and regulation are retained while either the duplicated gene or its regulation can change due to mutaitons. This is thought to preserve the normal function of the gene while allowing nature to experiment with the duplicate. (B) shows only the regulatory region being duplicated and changed so that the original function is maintained, but with additional regulatory potential. Finally, (C) shows the development of a new exon which allows the gene to be spliced in different ways, thus increasing the functional capability of the gene.

Figure 2


(A) shows that differences in regulation of the gene, yellow, are responsible for differences in pigment pattern between two species of Drosophila (fruit fly). (B) shows that "the expression of the Pitx1 gene of vertebrates is inferred to be controlled by multiple elements (red circles). In pelvic-reduced stickleback fish, Pitx1 expression is absent from the pelvic region. This is proposed to occur through a selective loss of activity of the hindlimb regulatory element (cross through the red circle)."

The same gene, Pitx1, also plays a role in mouse hindlimb development (and presumably all vertebrates) as well as other critical aspects of development. (Deletion of the gene is lethal.) The scenario represented by Figure 2B makes it easier to imagine how snakes and whales lost (or mostly lost) their legs and pelvis. It wasn't (just) mutation of genes--it was a change in they way the genes were deployed. (Note: I don't think that it is yet known whether Pitx1 was involved in snakes or whales losing their legs, but that is beside the point.) I hope the book has more of these kinds of examples.

For more learned commentary, see here and here.