Covid and Cavemen

Recent research is showing that what's past really is prologue when it comes to our biological heritage. Buried amidst the 3 billion nucleotide bases that comprise the text of our genome, a tiny fraction of our DNA inherited from our Neanderthal cousins tens of thousands of years ago, suddenly became front and center in our efforts to understand and manage the Covid-19 pandemic.

Once considered a separate species from modern humans, Neanderthal humans (Homo neanderthalensis) proliferated in Europe and the Levant from about 500,000 years ago (give or take a couple of hundred, thousand years) before being finally driven to extinction about 30,000 years ago, probably as the result of competition with modern humans. Thanks to the Human Genome Project and the more recent assembly of a high quality Neanderthal genome, we now know that humans and Neanderthals actually interbred, contrary to the previous scientific consensus that Homo sapiens and Neanderthals are genetically distinct species whose gene pools were never mixed.

One consequence of this newly discovered chapter in our biological history, is that about 2% of the individual genome in most modern humans, is Neanderthal in origin. In some people, this Neanderthal DNA content can be as high as 4%. By contrast, people who can trace their more recent lineage directly to Africa, have zero (or close to zero) Neanderthal DNA content in their genomes. This finding accords with the current paleontological consensus that modern humans emerged from Africa within the last 100,000 years or so, encountering and interbreeding with Neanderthals who had already established themselves in Europe and other places. Trace amounts of Neanderthal DNA may have filtered back into the African population via some small groups of migrants returning to Africa, but by and large, the genomes of the modern human population of African descent, remain pretty much pure Homo sapiens.

Until the advent of the current Covid-19 pandemic, the presence of Neanderthal DNA in our genomes was for most of us, largely a curiosity - an interesting story to share with friends after getting the results of one of the many, commercially available genetic tests. It was fun to have a humorous, tongue-in-cheek explanation for your partner's brutish behavior, based upon the popular but now widely-discredited image of the Neanderthal as some kind of dull-witted and unresourceful proto-human cousin. It now seems however, that these vestiges of our biological past that we carry in our genomes may be far more consequential for us than we ever realized.

As the SARS-CoV-2 virus spread around the world and people started falling ill and dying, scientists launched a number of genetic association studies in which the DNA from patients infected with the virus was collected and sequenced. The hope was that a comparison between the genomes of patients with really severe Covid-19, and the genomes of patients who weathered the disease more easily, might yield some correlated genomic variants that scientists could identify as potential risk factors for severe disease. Such an exercise holds the promise of yielding valuable insights into the nature of the viral disease - and while it might have little or no immediate impact on any therapeutic intervention for a Covid-19 patient, it could potentially offer a way to identify high risk patient groups for whom additional quarantine precautions or early vaccination might be recommended in future pandemics.

One of the most obvious genetic markers to look at is blood type, especially since tests for this are already widely available and routinely used in hospitals around the world. Furthermore, the identification of blood type does not require the comparatively intensive and time-consuming effort of whole genome sequencing that was being undertaken in the genetic association studies. I think it is fair to say that to date, studies of blood type as a risk factor for severe Covid-19 have been intriguing but somewhat inconclusive. There does appear to be a marginally higher risk of severe disease for those with type A blood, while those with type O blood seem to enjoy some degree of "protection". The statistical significance of these studies is persuasive but not totally compelling. If the impact of a patient's blood type on the severity of their Covid-19 disease is real, it may prove to be only marginal at best. Work on blood type as a risk factor for severe Covid-19 disease is ongoing however, so watch this space!

A recent genetic association study of 3,199 hospitalized Covid patients whose genomes were compared with control data, has now identified what the study's authors describe as "the major genetic risk factor for severe SARS-CoV-2 infection and hospitalization". It turns out that this genetic risk factor is associated with a ~50 kilobase segment of the genome on chromosome 3 that is inherited from Neanderthals. This segment of the genome contains about 8 or 9 genes, all of which are in high linkage disequilibrium (as shown in the plot below) - which is a geneticist's way of saying that these genes all tend to be inherited together as part of a single genomic chunk. This is usually (though not always) the case when genes are located very close together on the chromosome as these genes are. Although the genes in this segment are distinct, they can be considered as a unit of inheritance since they are almost always inherited as a group.

This somewhat complicates the answer to the next obvious question - what is the nature of the risk factor? How are the genetic variations in one or more of these genes actually affecting a patient's ability to fight Covid? The answer to this question will require more research.

The needle has been found in the haystack, but now we need to better understand the needle!

This 50 kilobase Neanderthal variant region of our genome is not equally distributed across all populations of modern humans. In South Asia for example, this variant segment of the genome is found in almost 50% of people, whereas its prevalence is only about 16% amongst Europeans. The highest prevalence of this Neanderthal variant is observed in Bangladesh, where about 63% of the population carry it and about 13% are homozygous for this variant - meaning that they carry the variant genes on both copies of chromosome 3. If both copies of a gene carry the genetic alterations, any effects of this variant on the development and health of the individual will be more pronounced since there is no "normal" copy of the gene to offset them. In haemophilia for example which is carried on the X chromosome, women with only one copy of the haemophilia gene carry the disease but do not suffer from it because the healthy gene on the other X chromosome is able to compensate for the defective gene. A woman with two copies of the gene will not only be a carrier of the disease, but also a sufferer of it. With only one X chromosome, men who carry the haemophilia gene on their X chromosome are always sufferers since they lack the extra X chromosome on which a healthy copy of the gene could substitute for the defective gene.

It is tempting to try to correlate the genetic prevalence data for the Neanderthal variant of chromosome 3, with healthcare outcomes in these different regions of the world. This is complicated by the fact that the outcomes for populations of Covid patients are the product of many different factors that include (but are not limited to) age, general population health, nutrition, environmental factors, access to healthcare, quality of healthcare etc. etc. - any or all of which may be more determinative in a patient's medical trajectory than the genetic risk factor itself. That said however, it is interesting to note that individuals of Bangladeshi origin in the UK are observed to have approximately twice the risk of dying from COVID-19 than the rest of the UK population.

The subtle differences between the Neanderthal and modern human variants in this 50 kilobase region of the genome may belie the potential magnitude of their impact on the resulting phenotype (the composite observable characteristics or traits of the organism).

As different as Neanderthals and modern humans superficially appear to be (exemplified in the image of the human and Neanderthal skulls shown at the top of this article), the genetic differences between modern humans and Neanderthals are astoundingly small. The Neanderthal genome is 99.7% identical with the genome of modern humans. Even the drastically different physical appearance of chimpanzees obscures the fact that their genomes are 98.8% identical to those of humans.

Only a tiny fraction of the human genome (about 1%) actually contains genes that are translated into proteins, of which there are ~25,000 in total by the most recent estimates. In a recent examination of a set of about 14,000 of the best characterized genes that encode proteins whose differences between humans and chimpanzees are known, it was discovered that there are only about 90 amino acid positions across all of these proteins, that differ between modern humans and Neanderthals, when the natural, genomic diversity amongst modern humans is taken into account. By contrast, the overwhelming majority (> 75%) of this set of proteins were different between chimpanzees and humans.

Aside from the wealth of invaluable data that the human genome project has generated, one of its greatest benefits is that it has showed us how much we still have to learn about this incredibly complex database of biological instructions that largely define our growth and development as living organisms. For all of the striking and apparent differences between ourselves, our cousins in the hominid family, and even other animals, we are much closer to them genetically than outward appearances might lead us to believe. Consider for example, that it only takes the alteration of a letter or two in our 3 billion-letter library, to create the dramatic physiological changes associated with diseases like cystic fibrosis, Tay-Sachs disease, or sickle-cell anemia.

Revealed to us by a global viral pandemic, the surprising significance of this ancient genetic variant of chromosome 3 inherited from our Neanderthal cousins, is further testimony to the subtlety of the genetic code, and the extent to which our biological past still asserts itself in our modern lives.

© Gordon Webster - Gordon is a partner at the digital biology research firm Amber Biology, a Ronin Scholar, and co-author of Python For The Life Sciences.