Simplifying genetics with sickle-cell anemia


Last year I described how overhearing one fifth-grade teacher’s laments about teaching her class genetics inspired me to initiate genetics conversations with my own kids—one of whom was a fifth grader at the time. This teacher was describing how her discussions of eye-color inheritance were leading to mass confusion in her classroom. Although it was clear that vocabulary was part of the problem (she didn’t seem to truly understand the difference between recessive and dominant traits), I had a broader concern. I wondered why standard classroom procedure was to explain Mendelian inheritance patterns by talking about a characteristic, eye color, that does not follow single-gene Mendelian patterns but is actually determined by complex interactions between multiple genes. Wouldn’t it be better to tell the kids about one of the many single-gene traits before getting into the complexities of multi-gene characteristics?

I thought polydactyly (having an extra finger or toe) would be a good example, and it probably would be. But the March issue of AJHG gave me a better idea: sickle-cell anemia.

In this potentially fatal disease, misshapen red blood cells get stuck as they move through the body, and the blockage can cause painful swelling, vision problems, and heart complications. The sickle-shaped blood cells also don’t live as long as healthy cells, and they aren’t as good at transporting oxygen, which means affected individuals can have delayed growth. Sometimes organs become damaged, and the person might have trouble fighting infections.

The first official documentation of sickle-cell disease was in 1910. With the publication of the third documented case in 1915, a genetic link seemed likely. Fast forward to 2018, and the genetic link and inheritance patterns are well documented: the disease is caused by a single recessive mutation, usually passed down by healthy, unaffected parents who each carry one copy of the mutated gene. What has not been understood is whether the sickle-cell mutation arose just once in human history or on up to five separate occasions.

Researchers have debated this point because there are five variations of the disease, and these variations range in severity as well as where the affected individuals generally are located. Could such a deadly disease—which happens to protect individuals against an even deadlier disease called malaria—have arisen independently multiple times?

In the March issue of AJHG, Daniel Shriner and Charles Rotimi of the National Human Genome Research Institute concluded that, in fact, the sickle-cell gene can be traced back to the birth of a single child roughly 7,300 years ago in West Africa. Their work clarifies the sub-classification of the different sickle-cell variations and could help clinicians to better understand and predict disease severity. The original article is freely available here.

I shared the more digestible NY Times coverage of the research with my 8-, 10-, and 12-year-old sons. We had a fascinating conversation about what genetic pressures would be acting on the sickle-cell gene in different environments—those with and without high populations of malaria-carrying mosquitos—and what other kinds of traits would or would not be subject to genetic pressures. For example, my kids pointed out that many traits, such as poor eyesight, that would have been highly detrimental before modern medicine are much less likely to affect one’s ability to pass on one’s genes today.

Then I drew a quick chart (which my kids had learned last year is called a Punnett square) to illustrate the chances that a child born to parents who each carried one copy of the sickle-cell gene would be born with sickle-cell disease.

Punnett square

Now that we had reinforced the concept of a single-gene inheritance pattern, I figured it was time to introduce multi-gene effects. This is one reason sickle-cell anemia makes such a great example; it is a classic single-gene disorder, but if someone with the sickle-cell gene also happens to have the gene for beta-thalassemia, which reduces the production of normal hemoglobin, they might end up with disease symptoms as severe as if they had inherited two copies of the sickle-cell gene. So it gets complicated, but we can build the complications on top of a solid understanding of the way a single gene is inherited.

Brigham and Women’s Hospital has an informative web page, complete with clear diagrams outlining the inheritance patterns of sickle-cell disease coupled with beta-thalassemia, that helped us think through these scenarios.

Finally, we watched a half-hour documentary from the Howard Hughes Medical Institute. The documentary recreated the story of how Tony Allison, working in the 1950s, figured out that carriers of the sickle-cell gene are resistant to malaria (Dr. Allison also discussed his work in 2006 as part of a mini-series on the most significant discoveries in biological chemistry over the past 125 years). Not only was this an interesting story detailing how significant discoveries can come from unexpected directions, but it explicitly discussed the scientific method and thus made a great teaching tool.

If I were writing curricula for fifth-grade genetics units, I’d definitely include sickle-cell anemia. It’s got the human interest factor, it affects kids, it’s a perfect example of a single-cell trait that follows classic Mendelian inheritance patterns but also lends itself to discussions of multi-gene interactions, and the story behind the discovery of the malaria-sickle-cell connection provides the perfect context for illustrating the scientific method at work. Alas, I’m not writing curricula for fifth-grade genetics units, but I can at least share these sorts of interesting stories with my own kids, and perhaps you’ll do the same with a child in your life.

If you also happen to write curricula for fifth-grade genetics units, so much the better.


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