A new study in Science Magazine by Simonti et al has linked this SNP to a rare condition known as protein-calorie malnutrition (PCM). The study compared electronic health records (EHR) for 28,000 people with SNPs that are now known to derive from Neandertal DNA.
SNP rs12049593 is in an intron of SLC35F3, which means it does not change the actual structure of the protein, but instead alters the amount of protein produced. SLC35F3 codes for a protein that helps transport vitamin B1 (thiamine) through the body to the mitochondria, where it can be used to generate and store energy from sugar. The linkage to PCM makes sense, because PCM is characterized by fatigue, malnutrition, and wasting even in the presence of adequate caloric intake.
"Humans depend on diet for their thiamine needs. Very little thiamine is stored in the body and depletion can occur within 14 days. Severe thiamine deficiency may lead to serious complications involving the nervous system, brain, muscles, heart, and stomach and intestines." (Mayoclinic)
"Thiamine is required for the assembly and proper functioning of several enzymes that are important for the breakdown, or metabolism, of sugar molecules into other types of molecules (i.e., in carbohydrate catabolism). Proper functioning of these thiamine–using enzymes is required for numerous critical biochemical reactions in the body, including the synthesis of certain brain chemicals (i.e., neurotransmitters); production of the molecules making up the cells’ genetic material (i.e., nucleic acids); and production of fatty acids, steroids, and certain complex sugar molecules.
Thiamine deficiency can lead to cell damage in the central nervous system through several mechanisms. First, the changes in carbohydrate metabolism, particularly the reduction in a–KGDH activity, can lead to damage to the mitochondria. Because the mitochondria produce by far the most energy required for cellular function, mitochondrial damage can result in cell death through a mechanism called necrosis. Altered carbohydrate metabolism can lead to oxidative stress, characterized by excess levels of highly reactive molecules such as free radicals and/or the presence of insufficient levels of compounds to eliminate those free radicals (i.e., antioxidants, such as glutathione). Oxidative stress can lead to various types of cell damage and even cell death." (from Role of Thiamine Deficiency in Alcoholic Brain Disease)
Simonti et al state:
"Decreased expression of this transporter in the brain or GI tract could exacerbate malnutrition or its symptoms. It is possible that new dietary pressures may have caused changes in carbohydrate metabolism to be beneficial in early human migrants out of Africa; indeed, there is evidence suggesting that Neandertal-derived genes increase the efficiency of fat digestion. More recently, the reduction of thiamine present in foods from the grain-refining process, as well as an increased intake of simple carbohydrates, make this a potentially harmful allele, because it could reduce thiamine availability although modern diets increase demand."
I am homozygous for the recessive allele of SNP rs12049593. I have a C where 95% of people have a G or T, courtesy of my Neandertal ancestry. According to the Simnoti study, I may have some malnutrition symptoms if I do not express the B1 transporter gene. According to my research, B1 can also passively diffuse if it is ingested at high enough concentrations.
I tested oral administration of 100mg/day of B1, which is more than 6000% of the US RDA but is the only size pill commercially available; apparently, this is a standard doze for supplementing B vitamins. I weighed myself morning and night for 1 week and did not notice any change in weight. Subjectively, I noticed some tiredness the first two times I took B1, then I noticed some energy, and after four or five days I do not notice any effect from supplementation.
UPDATE: Figuring out what allele is variant and which is most common is difficult. My information above was from 23andme raw data viewer, but when I loaded my data into the excellent Enlis Genome Personal software, I see that I actually have the reference allele, not the rare allele. So that may explain why I don't respond to supplemental B1.