Sunday, October 15, 2006

Why the regulatory changes vs. coding sequence changes debate is inane   posted by JP @ 10/15/2006 08:59:00 PM

According to the latest estimates, the common ancestor of humans and chimpanzees lived sometime around 5 million years ago. Since then, a lot has happened. Presumably, there has been plenty of change along the lineage leading to chimpanzees, but let's be honest-- from our point of view, a lot more has happened along our lineage. We have Shakespeare, Klimt, and the International Space Station; they jab sticks into anthills. The biological basis for this disparity is certainly a worthy line of inquiry. As a first step down this path, I assume most readers here will agree with me that invoking the hand of God, while awfully tempting, would be laughable. So let's turn our focus to a more profitable enterprise: genetics.

In the 1970s, the technology was a such a state that the proteins in the blood of both humans and chimps could be compared at some rough level. And as it turns out, we aren't that different after all. Or rather, we're less different than people expected to find, given that, as humans, we consider ourselves the Greatest. Species. Ever. So if our blood proteins aren't that different, what makes us human?

One possible answer was provided in 1975, in an influential paper by Mary-Claire King and Allan Wilson. In their own words:
We suggest that evolutionary changes in anatomy and way of life are more often based on changes in the mechanisms controlling the expression of genes than on sequence changes in proteins. We therefore propose that regulatory mutations account for the major biological differences between humans and chimpanzees
Of course, this hypothesis was based on very little data (as Bruce Lahn pointed out in his interview) -- the fact that human red blood cells and chimp red blood cells are almost the same doesn't really tell us that much. But at the time, people were apparently expecting radical differences between human and chimp proteins across the board, so this paper shifted some paradigms[1].

Now, 30 years later, it's possible to compare the genome sequences of the two species, and microarray technology makes it possible to compare gene expression levels as well. So are we close to settling this issue? My answer: hell no. And here's why:

Here's the question we're supposed to answer: which are more important-- protein-coding changes or regulatory changes? And here's the problem with that question: how do you define important? Let's make a list of the ways humans differ from chimpanzees-- we walk on two feet, we have bigger brains, we have less hair, etc. etc. You can add your own if you like. If a protein-coding change gives us the bigger brain, but a regulatory change the lack of hair, who wins? Sure, you could argue about which trait contributes more to some notion of "human-ness", but frankly, who gives a shit? Both are pretty important.

And in reality, any of those traits is likely to be influenced by a number of factors. In the developmental networks that have evolved seperately in the last 5 million years, the components of the networks (protin-coding changes) as well as the relationships between those components (regulatory changes) are both likely to have changed. So no single mutation is going to be the mutation. I feel like many people are under the impression there's going the equivalent of an SRY gene [2] that easily discriminates between chimps and humans. Ain't gonna happen.

So let's say someone is a true partisan on one side of this debate and wants to settle it once and for all. What would be necessary? Here's my list:
1. A catalogue of all the phenotypic difference between humans and chimps.
2. A list of all the genetic changes underlying these difference (classified as coding and regulatory, of course), and a weight assigned to each change accoring to its relative importance in the generation of the phenotype.
3. An objective measure of "human-ness" that assigns relative importance to each of the phenotypic differences.

And there you go. For the person that does this, I will buy a cold beer.

[1] King and Wilson also propose that point mutations may be less important than rearrangements like tranlocations and inversions in human evolution, but they present no data on this and no one really remembers this hypothesis anymore.

[2] In sex determination in humans, there's a single gene, SRY, that pretty much determines who's a male and who's a female (with, of course, the necessary caveats). In this case, it's clear-- take a female, add this gene, and you pretty much get a male. This protein-coding difference is arguably the most important difference between males and females.