When fighting leukemia, evolutionary history matters
Where's the evolution?
These HLA genes are all located close together on Chromosome 6. This means that they are rarely mixed up as a result of recombination and are inherited almost as a single gene would be. Each person carries two versions of their HLA genes, one on the copy of Chromosome 6 inherited from his or her mother and one on the copy inherited from his or her father. A person in need of a marrow transplant might get lucky and have a perfectly matched sibling, who inherited the same gene versions from their parents. However, 70% of people in need of such a transplant don't have a matching sibling and have to look for an unrelated donor.
Finding a match can be a challenge because hundreds of versions of each of the key HLA genes exist and a donor needs to carry just the right combination. In fact, HLA genes vary more from person to person than most other parts of the genome. Why are HLA genes so diverse? The answer lies in the evolutionary forces that shaped these genes in the first place. From one generation to the next, HLA genes are stable and transmitted with a high degree of fidelity from parent to offspring. But over hundreds of generations, HLA genes accumulate mutations and evolve ...
HLA genes are key players in the evolutionary arms race between humans and pathogens. They code for proteins that present foreign proteins to the immune system, alerting it to danger. Different versions of HLA genes are better at helping the immune system detect different pathogens, and natural selection strongly favors individuals who can fight off whatever pathogen is currently making the rounds (e.g., bubonic plague in the 14th century). However, pathogens evolve quickly, sometimes evolving right out from under our bodies' defenses. This means that natural selection on human HLA genes is strong and variable, favoring different gene versions whenever a new pathogen becomes common. Furthermore, individuals who have inherited two different versions of each of their HLA genes from their parents (i.e., are heterozygous) likely have a survival advantage because their bodies can detect more different kinds of pathogens. Having diverse HLA genes is a boon for individuals and populations. Because of all this, HLA genes evolve quickly relative to many other human genes (though this process still involves multiple generations), and much of this genetic variation is present in human populations today. The overwhelming diversity of HLA genes means that perfect matches can be hard to come by. The Be The Match Registry® provides access to more than nine million potential donors, offering the hope that at least one of them will carry the same (or nearly the same) HLA gene versions as the patient in need.
What are the odds of finding a match in the registry? The answer depends on one's evolutionary history. That's because, as with the rest of the human genome, HLA genes have diverged over the past 60,000 years as human populations migrated out of Africa and spread over the globe. In that process, different populations faced different pathogens and experienced natural selection favoring different gene versions. Because of this, particular HLA gene versions are much more common in some populations than in others. This means that a patient's best chance of finding a match is in someone with a similar evolutionary history. There are more Caucasians in the registry than any other ethnic group, and hence, Caucasians have the best chance of finding a close match (93%). For comparison, African American patients have a much smaller chance (66%) of finding a close match. This is largely because most African Americans are of mixed descent. They are likely to carry combinations of gene versions from different parts of the world African, European, Hispanic, and Native American. This means that there are many more possible combinations of gene versions and so it is more difficult to find a match. Similarly if a patient is of mixed ethnicity and his or her parents hail from different, far flung parts of the world (say, Thailand and Central America), the patient is likely to carry a particularly unusual combination of HLA gene versions and his or her odds of finding a match may be considerably lower. This means that marrow donor registries are particularly in need of potential donors that are non-Caucasian or of mixed ethnicity.
To further complicate matters, some ethnic groups have more diversity at their HLA genes than others, and more diverse genes mean that it's harder to find a match, even within one's own ethnic group. In general, east African populations have the highest levels of genetic variation at their HLA genes, and populations further from Africa have lower levels. So, for example, people from the Middle East (which is a short jaunt from East Africa) tend to have higher levels of HLA diversity than Pacific Islander populations.
While there is no biological basis for the traditional concept of race no genetic markers or discrete biological characteristics that neatly distinguish one "racial" group from another evolutionary history (messy as it might be) is real. HLA genes are a case in point. HLA gene versions don't fall out neatly along "racial" lines, and some HLA gene versions can be found in people of many different ethnic backgrounds so there is clearly genetic continuity across traditional "racial" divides. Nevertheless, some HLA genetic markers are more common in people of particular ethnicities, a clear mark of our sometimes divergent, sometimes concordant evolutionary histories. Understanding how evolution has shaped these genes helps explain several medical issues the surprising diversity of HLA genes, the differences in diversity levels between different ethnic groups and geographic regions, and why a leukemia patient's best chance for a match has little to do with where he or she grew up and much to do with the parts of the globe to which his or her ancestral lineages trace.
Discussion and extension questions
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