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When fighting leukemia, evolutionary history matters
December 2011

Cheek swab
Cheek swabbing
In the next few months, college students across the country will be offered the chance to save a life by swabbing cells from the insides of their cheeks and registering as a potential marrow donor with Be The Match®. The Give A Spit About Cancer campaign, which launched in October, helps college students organize marrow donor registry drives. The cells collected in these drives are used to figure out who might be able to donate marrow or blood stem cells to a patient with a life-threatening disease like leukemia. While ethnicity is irrelevant to most medical procedures, marrow and blood stem cell transplants are an exception to this rule. Registering potential donors of non-Caucasian descent and mixed ethnicity is particularly important in these drives. Evolutionary theory helps us understand why ...

Where's the evolution?
To understand how evolution factors into such transplants, you first need to know a bit about the genes that determine the success of these procedures. One of the jobs of bone marrow and blood stem cells is to produce the cells of the immune system, which are responsible for recognizing the difference between invading pathogens and the cells of your own body. Because of this, the genetic match between donor and recipient in a marrow or blood stem cell transplant must be very close. Otherwise, the transplanted donor cells may start making cells that attack the recipient's body. There is a group of genes that matter most in terms of whether the transplanted cells will thrive in their new body or whether they will cause major problems for the patient. These genes are called Human Leukocyte Antigens — HLA genes for short. The closer the genetic match between the donor's and recipient's versions of the HLA genes, the more likely the transplant will go smoothly and be successful.

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.

HLA genes

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.

migration routes out of Africa
Migration routes out of Africa.
These observations also make sense when viewed in the light of human evolution. East Africa is where humans first evolved. This is the original population from which other human populations arose. When small groups of humans left Africa and founded populations in other regions, they took only small samples of African genetic diversity with them. Hence, these derivative populations (e.g., Asians, Europeans, Pacific Islanders, etc.) generally have low diversity in comparison with Africans. In addition, populations that live in places with many different types of pathogens (like Uganda) are likely to have more diverse HLA gene versions than populations that live in places with fewer pathogens (e.g., American Samoa). This is because, in places with diverse pathogens, natural selection favoring diverse HLA genes has been stronger.

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.


If you are a college student interested in hosting a marrow registry drive on your campus, contact the Give A Spit About Cancer campaign.



Read more about it

Primary literature:

  • Prugnolle, F., Manica, A., Charpentier, M., Guégan, J. F., Guernier, V., and Balloux, F. (2005). Pathogen-driven selection and worldwide HLA Class I diversity. Current Biology. 15: 1022-1027.
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News articles:

Understanding Evolution resources:

Discussion and extension questions

  1. Why do HLA genes evolve quickly in comparison to the rate at which other parts of the genome evolve?

  2. In your own words, explain what an evolutionary arms race is. How does this concept relate to the evolution of HLA genes?

  3. Use evolutionary concepts to explain why it might be particularly hard for people of mixed ethnicity to find an HLA match.

  4. Imagine that an isolated population has recently experienced a deadly viral epidemic. How is this epidemic likely to affect genetic variation at the HLA genes in this population? Would surviving members of the population be more or less likely to match one another's HLA gene versions? Explain your reasoning.

  5. Advanced: When it comes to HLA loci, heterozygotes have an advantage over homozygotes. What effect does this form of selection have on genetic variation in a population? Explain why. Research and describe another gene that is undergoing this form of selection.

  6. Advanced: If you are not familiar with it already, research the concept of frequency-based selection. What effect does this form of selection have on genetic variation in a population? Is it plausible or implausible that frequency-based selection could help explain the diversity of the HLA genes? Explain why or why not.

  7. Advanced: Based on Mendelian genetics, what are the chances that an individual's full sibling will be a perfect match for his or her HLA genes?


Related lessons and teaching resources

  • Teach about variation: In this activity for grades 9-12, students conduct a classwide inventory of human traits, construct histograms of the data they collect, and play a brief game that introduces students to major concepts related to human genetic variation and the notion of each individual's uniqueness.

  • Teach about human molecular variation: In this activity for grades 9-12, students investigate variation in the beta globin gene by identifying base changes that do and do not alter function, and by using several internet-based resources to consider the significance in different environments of the base change associated with sickle cell disease.

  • Teach about another example of human microevolution: This article for grades 9-16 describes how evolution has allowed different human populations to take advantage of the nutritional possibilities of dairying.



References

  • Hertz, T., Nolan, D., James, I., John, M., Gaudieri, S., Phillips, E., ... Jojic, N. (2011). Mapping the landscape of host-pathogen coevolution: HLA Class I binding and its relationship with evolutionary conservation in human viral proteins. Journal of Virology. 85: 1310-1321.

  • Prugnolle, F., Manica, A., Charpentier, M., Guégan, J. F., Guernier, V., and Balloux, F. (2005). Pathogen-driven selection and worldwide HLA Class I diversity. Current Biology. 15: 1022-1027.


Cheek swabbing photo is by Canadian Blood Services and licensed by Creative Commons.



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