Sickle Cell Trait in Raw DNA: rs334 and the Malaria Trade-Off
One T-to-A change at rs334 in the HBB gene separates typical haemoglobin from sickle cell trait and sickle cell disease. How to read it on the forward strand, why the variant persists, and where a raw file falls short.
In 1949 Linus Pauling and his colleagues showed that the red cells of people with sickle cell anaemia contained a haemoglobin that behaved differently in an electric field. It was the first time any disease had been traced to a specific altered protein, and the title of their paper - “Sickle Cell Anemia, a Molecular Disease” - gave the field a phrase it still uses. Seven years later Vernon Ingram narrowed the difference to a single amino acid. Today the same difference is one letter in your raw file, at rs334, and it is one of the few positions a consumer chip reads that carries real medical weight.
What the variant does
HBB, on chromosome 11, encodes beta-globin, one of the two protein chains in adult haemoglobin. The sickle variant, HbS, swaps glutamic acid for valine at the sixth position of that chain (the seventh in current numbering, which counts the starting methionine). The substitution makes haemoglobin molecules stick together into long fibres when they give up their oxygen, pulling red cells into the crescent shape James Herrick first described in 1910 in a dental student from Grenada. Sickled cells are stiff and short-lived. They block small vessels and are destroyed early, producing the pain crises, anaemia, organ damage and stroke risk of sickle cell disease.
Reading rs334 in your file
HBB is transcribed from the reverse strand, so genetics papers describe the mutation from the gene’s point of view as A to T (GAG becomes GTG). Raw files report the forward strand, where the same change reads T to A:
| rs334 | Meaning |
|---|---|
| TT | Two typical beta-globin genes |
| AT | One sickle allele - sickle cell trait |
| AA | Two sickle alleles - sickle cell anaemia |
The strand matters more here than for most markers, because some popular reference sites orient rs334 the other way and list A as the typical allele. If a source tells you AA is normal, it is describing the gene strand, not your file. Our explainer on forward and reverse strand covers why this happens. Genespiral keys rs334 to the forward strand, so AT in the health analysis means sickle cell trait.
The marker is on current 23andMe chips, where it feeds the sickle cell carrier status report, and on many other consumer arrays. A plain text search of your file for rs334 will tell you whether yours includes it.
Why one copy is common
A variant that causes serious disease in people who carry two copies ought to be rare. HbS is not. In parts of sub-Saharan Africa one person in five or more carries a single copy, and the allele is also found around the Mediterranean, in the Arabian Peninsula and across India. In the United States about one in thirteen Black or African American babies is born with the trait, and worldwide roughly 300,000 babies a year are born with sickle cell disease.
The reason was worked out in 1954 by Anthony Allison, who noticed that the map of sickle cell trait in East Africa matched the map of malaria. Carriers infected with Plasmodium falciparum are far less likely to develop severe disease - about 90 percent less in the 2012 meta-analysis by Taylor and colleagues, with a smaller reduction in uncomplicated malaria - while remaining healthy for almost every other purpose. Where malaria killed many children, carriers survived at higher rates than non-carriers, and the homozygous children who died of sickle cell disease were the price the population paid. The allele settled at a frequency set by the balance between two kinds of death. It is the textbook case of heterozygote advantage, and in 2010 Piel and colleagues confirmed the fit between the two maps at global scale.
Trait is not disease
Sickle cell trait is a carrier state, not a mild form of the disease. Most carriers never notice it. A few risks are real and worth knowing:
- Extreme exertion, dehydration and altitude can trigger exertional collapse and muscle breakdown. A 2016 study of nearly 48,000 Black US Army soldiers found carriers had about 50 percent higher risk of exertional rhabdomyolysis but no higher mortality once precautions were in place. The NCAA has screened Division I athletes since 2010 after the exertional death of a college football player.
- Carriers have a reduced ability to concentrate urine, occasional blood in the urine, and a modestly raised risk of chronic kidney disease and blood clots in later life.
- A rare kidney cancer, renal medullary carcinoma, occurs almost exclusively in carriers.
None of this changes what a carrier should do day to day beyond hydrating and pacing sensibly in extreme heat. The main significance of trait is reproductive: two carriers have a one-in-four chance in each pregnancy of a child with sickle cell disease.
What the file cannot tell you
Three gaps matter.
- Other beta-globin variants. Sickle cell disease also arises when HbS is paired with a different HBB variant - haemoglobin C (rs33930165, at the neighbouring base), haemoglobin E, or one of hundreds of beta-thalassaemia mutations. A file showing AT rules out two sickle alleles. It does not rule out disease if the other chromosome carries a variant the chip never reads.
- Newborn screening already knows. Every US state, the UK and many other countries test all newborns for haemoglobin disorders. If you were born under such a programme, a result exists that is more reliable than a chip, even if nobody told you what it said.
- Confirmation. A chip call at one clinically important position should be confirmed by haemoglobin electrophoresis or a clinical genetic test before anyone acts on it. Chips are accurate, but not perfectly so, and the cost of a wrong answer here is high.
If you carry AT and did not know, that is worth a conversation with a doctor, particularly before having children with a partner who may also carry a haemoglobin variant. It is not an emergency, and it is not a diagnosis.
This article is educational only and is not medical advice.
References
- Pauling L, Itano HA, Singer SJ, Wells IC. Sickle cell anemia, a molecular disease. Science. 1949. PubMed 15395398
- Ingram VM. A specific chemical difference between the globins of normal human and sickle-cell anaemia haemoglobin. Nature. 1956. PubMed 13369537
- Allison AC. Protection afforded by sickle-cell trait against subtertian malarial infection. BMJ. 1954. PubMed 13115700
- Piel FB, et al. Global distribution of the sickle cell gene and geographical confirmation of the malaria hypothesis. Nature Communications. 2010. PubMed 21045822
- Piel FB, et al. Global epidemiology of sickle haemoglobin in neonates. The Lancet. 2013. PubMed 23103089
- Taylor SM, Parobek CM, Fairhurst RM. Haemoglobinopathies and the clinical epidemiology of malaria: a systematic review and meta-analysis. Lancet Infectious Diseases. 2012. PubMed 22445352
- Nelson DA, et al. Sickle cell trait, rhabdomyolysis, and mortality among U.S. Army soldiers. NEJM. 2016. PubMed 27518662
- Centers for Disease Control and Prevention. Data and statistics on sickle cell disease.
- dbSNP entry for rs334, NCBI.