When our early Homo sapiens ancestors intermingled with their Neanderthal cousins, little did they know that this inter-hominin rendezvous would one day influence the health of an entire species. However, as reported in a new study in The Pharmacogenomics Journal, the presence of Neanderthal genes within the modern human genome may actually compromise the ability of certain individuals to safely metabolize common medications.
The elimination of drugs from the body is largely entrusted to a family of catalysts known as cytochrome P450 enzymes. However, the activity of these enzymes can differ between individuals, which means that a safe dose of medication for one person could be harmful for another.
For example, the enzyme CYP2C9 is encoded by a gene found on chromosome 10, which comes in dozens of different forms. The most common of these is known as CYP2C9*1, and is carried by around 88 percent of modern Europeans.
The remaining 12 percent carry an allele called CYP2C9*2, which differs rom CYP2C9*1 by a single nucleotide, but is around 70 percent less efficient at breaking down drugs such as the blood-thinner warfarin or the antiepileptic medication phenytoin.
According to the study authors, carriers of the CYP2C9*2 are classed as “slow metabolizers” and may therefore require lower doses of certain pharmaceuticals than non-carriers. Intriguingly, people with this genetic variant also tend to carry a particular form of the gene for an enzyme called CYP2C8, which plays a key role in the metabolism of anti-inflammatory drugs like Ibuprofen, as well as chemotherapy agents and cholesterol-lowering statins.
Known as CYP2C8*3, this allele is also found on chromosome 10 but is located some 96.7 kilobases away from the CYP2C9*2 allele. The fact that the two variants tend to co-occur means they can be classed as a haplotype, although it is rather unusual for paired genes to be separated by such a long stretch of DNA.
However, because similarly long haplotypes within the human genome have previously been traced back to Neanderthals, the study authors suspected that these genetic variants may also be inherited from our ancient relatives. To investigate, they obtained genetic sequences taken from people from 146 different families and cross-referenced these against a database of modern and ancient hominin genomes.
Results indicated that both of these genetic variants are indeed derived from Neanderthal DNA, and ended up in our genome as a result of those early interbreeding events. According to the study authors, this exchange of genetics between the two lineages began around 60,000 years ago, yet it is only thanks to the recent advent of modern pharmaceuticals that the consequences of this process have become apparent.
"This is one case where the admixture with Neandertals has a direct impact in the clinic,” said study author Hugo Zeberg in a statement. Regarding the potential impact of these ancient alleles on our health, he explained that “otherwise therapeutic doses can be toxic for carriers of the Neandertal gene variant.”