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When "Broken" Is Better

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Anna DiRenzo

Geneticist

University of Chicago

Do genetic diseases come from defective genes? Not always, as Anna Di Rienzo and her colleagues found in a study published last year in the American Journal of Human Genetics: sometimes it's just that circumstances change faster than our genes can adapt. Di Rienzo, along with her research assistant, Emma Thompson, has been looking at particular genes involved in metabolizing everything from salt to hormones to modern drugs. Her findings turned out to support a hypothesis linking salt retention to the climates in which different peoples evolved.

Harold Henderson: Why choose these genes to study?

Anna DiRenzo: They're very important in pharmacogenetics, where the hope is ultimately to allow individualized drug treatment based on each person's genetic makeup.

HH: I gather from your article that these genes evolved long before human beings did.

AD: Animals needed these genes to deal with toxic chemicals in plants and the environment and to metabolize hormones. These genes also produce an enzyme involved in metabolizing cortisol, which plays a role in maintaining the salt and water balance in the body.

HH: Many people have a "broken" or nonfunctional variant of the gene known as CYP3A5 [which acts to retain salt in the kidney]. Why?

AD: Before we started our study we knew that African-Americans have a high frequency of the functional gene CYP3A5, while European-Americans have a high frequency of the "broken" CYP3A5*3. It was suggested that this might be consistent with the salt-retention hypothesis proposed in 1973 by Lillian Gleibermann: that ancient human populations who lived in hot, humid areas where salt was hard to find might adapt to their environment by retaining more salt, and those who lived in more temperate climates might find some advantage in retaining less.

HH: And now you have more tools to test this hypothesis than were available in 1973.

AD: We genotyped over 1,000 people from 52 different populations worldwide to see which groups had more of the "broken" variant CYP3A5*3. Then we ranked the 52 populations in two lists: one in order by distance from the equator, the other in order by percentage of the population having the broken gene. We used a statistical test to determine just how similar the two lists were, and they were very similar. There was less than one chance in 10,000 that they would appear so similar just by chance.

HH: That must have been an exciting moment.

AD: Other biologists get interested in a picture of a gel or a particular color in a result. We get a good P value [a probability value showing a statistically significant result] and we're excited.

HH: And then you were able to go through the same process with a different gene that showed the same pattern.

AD: The angiotensinogen (AGT) gene isn't associated with CYP3A5, but it also has a variant that's associated with hypertension and complications of pregnancy--and that variant too varies clearly with distance from the equator. Having two different pathways both affected this way suggests even more strongly that this was not a chance variation.

HH: You were able to check your result in other ways as well.

AD: We checked a large public data set of more than 300 other variants. Very few of them show a pattern like this. And when we looked at subgroups within east Asia they too varied with distance from the equator. So the effect appears both between groups and within groups. It looks very much like the signature of natural selection.

HH: So this tends to confirm the salt-retention hypothesis: when humans left Africa for different, cooler environments, the functional CYP3A5 gene--for retaining salt--no longer contributed to survival. Did it just not matter, or was it an actual hazard to life?

AD: If it just didn't matter, I don't think we would see as much variation or the same strong pattern of variation as we do. What exactly the selective pressure was we don't know. It may not be hypertension, because that's a late-onset condition. It might be pregnancy complications such as preeclampsia, which would be a severe selective pressure in favor of the nonfunctional variant.

HH: The big picture here is kind of surprising.

AD: Yes. As human geneticists, we're used to thinking of human genetic diseases as cases where something went wrong. Here it's kind of the opposite. Humans evolved in certain environments and gained a very ancient adaptation to maintain the proper salt water balance. But once humans change their own environment by moving away from the equator--or by eating at fast-food restaurants--they create for themselves new selective pressures. In this new environment the functional version of the gene may no longer promote the ideal salt balance in the body, and the "broken" version may actually promote that balance. This could change the way we look for disease genes in other areas. Now we're starting to look for common genes that may have been beneficial in an environment of scarcity but have become harmful in a world of plenty.

HH: How about the medium-sized picture? Supposing, as some studies suggest, there's a link between salt retention and hypertension. Could we then say that African-Americans suffer disproportionately from hypertension in part because they left Africa more recently than did European-Americans?

AD: It makes sense, but there is a lot of variability among native Africans. African-Americans themselves are drawn from many different African gene pools and have mixed with other ethnic groups in this country. So generalizations about this have to be taken with a large grain of salt.

Art accompanying story in printed newspaper (not available in this archive): photo/Lloyd DeGrane.

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