Wednesday, April 25, 2007

Breaking: People are different   posted by p-ter @ 4/25/2007 10:10:00 AM

Heredity has a summary of a study on the genetics of gene expression differences between European and Asian populations (which I summarized here). The opening lines are a striking glimpse into the academic world:
It has often been observed that people are different. Indeed, some observers have gone further to suggest that this diversity exists between people from different parts of the world, or of different ethnic groups, and it is hereditary. This latter observation has led to a certain amount of contention over time. As a result, many geneticists have been wary about asserting that such differences exist.
That's right, it's contentious to say that the "diversity" we are all so fond of might have some relation to genetic diversity, something that is patently obvious given a basic knowledge of evolutionary processes and a pair of eyes.

But whatever, it's a good summary of the research, though I must take issue with the argument that gene expression variation between individuals may have no effect on phenotype:
[W]hile the exact numbers of differences could be debated, the data at least suggest that there should be considerable variation in actual humans. But, does this matter? One problem with establishing the importance of microarray results is that they only tell about gene expression, not about the physiological effects of the gene. Earlier studies on the dynamics of metabolic pathways have shown that fluxes through the pathways may be relatively insensitive to changes in the concentration of many of the enzymes in a pathway
Overall, it is not clear how the variation in gene expression relates to phenotype, and fitness
This shows a striking lack of familiarity with studies on the evolution of gene expression. Where it has been well-studied, it's clear that gene expression levels are under strict control-- they are under strong negative selection and do not vary neutrally[1]. This implies, of course, that changes in gene expression have an effect on fitness (though it's true the precise effects of individual genes are mainly unknown). Changes in gene expression levels are very likely to have some sort of phenotypic consequence.

[1] Citations: For a meta-analysis of gene expression evolution in a number of organisms, see this paper, which concludes "Our analyses used a number of metrics to show that most mRNA levels are evolutionary stable, changing little across the range of taxonomic distances compared. This implies that, overall, widespread stabilizing selection on transcription levels has prevented greater evolutionary changes in mRNA levels."

A more rigorous look at changes in gene expression in Drosophila concludes, "Although spontaneous mutations have the potential to generate abundant variation in gene expression, natural variation is relatively constrained". In C. elegans, as well, a similar study to that done in Drosophila concludes, "We directly compared observed transcriptional variation patterns in the mutation-accumulation and natural isolate lines to a neutral model of transcriptome evolution to show that strong stabilizing selection dominates the evolution of transcriptional change for thousands of C. elegans expressed sequences."

These studies have all looked at broad evolutionary patterns; some researchers are now able to look at the evolution of gene expression globally while making inferences about individual genes. For example, this study in humans identifies a number of genes whose expression has evolved rapidly in humans, as well as a number whose expression levels appear to be stable.

Overall, to imply that genetic differences between populations, which then translate into gene expression differences between populations, have no effect on phenotype or fitness is naive at best.