When it comes to the use of genomics in modern healthcare, the vast majority of studies focus on individuals alive in the present day. In this feature, we take a look at a lesser discussed aspect of health research – the study of ancient DNA from both Homo sapiens and extinct archaic species, known as paleogenomics. From bodies in peat bogs to fossilized fingers, we explore some examples of the use of ancient DNA in the healthcare field and the implications for our understanding of human evolution.
You may remember early high school history lessons detailing the discovery of Ötzi the Iceman, whose mummified remains were found in the early 1990s on the Austria-Italy border. The shockingly well-preserved remains were initially thought to be much younger than they were, but analysis revealed that Ötzi was in fact around 5,000 years old. His body had remained in such good condition due to the chilly conditions of the Ötztal Alps, for which he was named.
Figure 1. Image of Otzi, ‘The Iceman’. His remains are now held in the South Tyrol Museum of Archaeology. Credit: South Tyrol Museum of Archaeology.
Analysis of the body revealed his cause of death, his age and some aspects of his appearance. His personal belongings revealed information about his life and his likely role within ancient society. The archaeological and anthropological gains of his discovery were second to none.
But what did his genes tell us?
In 2012, Ötzi’s whole genome sequence was published. He belonged to a previously unknown mitochondrial DNA clade and analysis of his Y-chromosome haplogroup revealed new insights into human migration and evolution. Further analysis revealed that he was likely lactose intolerant – a significant finding given that lactose intolerance is more commonly found in Asian populations – and an analysis of bacteria in his microbiome revealed he could have suffered from Lyme disease. Studies into Ötzi’s DNA are still ongoing, and just last month researchers published a more high-coverage genome than the 2012 version, which revealed that the 45-year-old Iceman was likely suffering from male pattern baldness!
Ötzi is not the only example of a well-preserved, ancient human corpse, but his discovery has contributed to a wealth of knowledge of how ancient humans lived, their interactions with microbes in the environment and the disease-causing mutations that may have arisen thousands of years ago. But DNA from ancient Homo sapiens like Ötzi is not the only source of genetic information that can help to inform our understanding of human history.
A complicated history
It may be hard to imagine the world without humans, but we really haven’t been around for all that long. The modern human, Homo sapiens, arose around 300,000 years ago – meaning we have only existed in our current form for 0.007% of Earth’s history!
Some of Homo sapiens’ closest relatives were the Neanderthals and the recently discovered Denisovans. Hailing from Europe and Western Asia, and Eastern Asia, respectively, much of what we know about these archaic human species comes from the study of what is left of their genomes – not an easy task when both species went extinct thousands of years ago.
Figure 2: Reconstructed image of a Neanderthal face. Numerous studies have explored what our ancient cousins may have looked like. Source: Associated Press.
But why did they disappear? We will never have a comprehensive answer to this question, but it is thought that, perhaps, competition between Homo sapiens and their ancient counterparts following the former’s migration out of Africa, alongside factors such as climate change, led to their demise. That said, some Neanderthal and Denisovan genes have persisted throughout human history, owing to interbreeding during the brief time period when the species had the opportunity to interact.
This has been backed up by studies that show modern humans, typically from non-African populations, do in fact harbour a small percentage of Neanderthal or Denisovan DNA. Unfortunately, without better and more complete fossil records, we will never fully understand the complexities of their history or their interactions with Homo sapiens. But by combining these sources of DNA with data from specimens like Ötzi, we can gain insights into not only how ancient humans lived and evolved, but also understand why the human health landscape is the way it is today.
The 2022 Nobel Prize
The above was the subject of the 2022 Nobel Prize in Medicine. Swedish geneticist Svante Pääbo is a big name in the study of ancient DNA, and is one of the founders of ‘paleogenomics’, the study of ancient genetic material. He and his team were the first to assess DNA from Denisovans, and he was the first to classify them as a new species in 2010. Pääbo was also responsible for the earliest efforts to construct a Neanderthal genome. He concluded that there was likely interbreeding between archaic and modern humans, leading to the persistence of these genes in the population today. His findings were fundamental in our understanding of human evolution.
Pääbo earned his Nobel prize for his significant contributions to paleogenomics, but you may have noted that he was awarded the prize in the Medicine category. So, what benefit did these findings have on the modern human health landscape?
The impact of ancient genes on your health varies depending on where you live; those residing in, for example, Tibet have the Denisovans to thank for their tolerance to high-altitudes. But the small percentage of DNA that we share with our extinct relatives has also been seen to shape our immune responses and even our mental health. And by allowing us to see where modern humans differ to ancient specimens, we can gain insights into the evolutionary pressures that allowed us to survive this long when our ancient cousins did not. Below, we dive into some specific examples of how paleogenomics and ancient DNA has contributed to the healthcare field.
Ancient genes, modern virus
Despite having worked in the paleogenomics field for decades, one of Pääbo’s most famous works is his relatively recent discovery that severe COVID-19 infection is associated with genes derived from Neanderthals. A GWAS examining the response to infection revealed that those who suffered most with COVID-19 were more likely to harbour genetic risk variants in a section of chromosome 3 that is inherited from Neanderthals. The locus is found in a significant number of people; nearly half of those of South Asian ancestry and around 16% of Europeans harbour this Neanderthal-derived locus.
A second study by another group revealed that four of these Neanderthal-derived variants were likely to regulate the expression of the chemokine receptor genes CCR1 and CCR5. The researchers concluded that the altered regulation of these genes could lead to cytokine storms, a marker of severe COVID-19 infection.
These works highlighted the differences in the innate response to pathogens in different populations, owing not only to environmental factors but also the evolutionary patterns that emerged thousands of years ago. By highlighting this diversity in response, we can be better prepared for future pandemics by potentially employing tailored responses in the populations that need them most.
Ancient pathogen selection
Much like how Ötzi’s microbiome revealed a potential Lyme disease infection, ancient DNA can be used to track responses to pathogens and pandemics. And it is not just human DNA that plays a role in these discoveries. Archaic bacterial or viral DNA is just as valuable, allowing us to see how these pathogens have evolved over time and their responses to the evolution of protective traits in humans.
One of the most famous examples of utilising ancient bacterial DNA, extracted from centuries old specimens, was the identification of Yersinia pestis as the causative agent of the Black Death. While this plague may have occurred centuries ago, understanding how it arose can better prepare us for the emergence of dangerous pathogens in the modern day.
Figure 3. Scanning electron micrograph of Yersinia pestis. This bacterium was responsible for the Black Death, a finding confirmed via the use of ancient DNA studies.
And speaking of the Black death, studies of humans living before and after the plague revealed the selection of a protective variant that emerged in response to the ancient pandemic that persists today. Once again, these findings could contribute to our modern understanding of how both pathogens and humans respond to each other’s evolutionary behaviours, providing a historical take on the Red Queen Hypothesis.
Many studies have shown that there was adaptive introgression between Homo sapiens and Neanderthals and Denisovans; that is, the introduction of a foreign variant that increased the fitness of the former population. The most widely studied example of this is in the innate human immune system, where a number of haplotypes are seen to have originated in Neanderthals and persist in certain populations of modern humans, but do not appear in populations where the archaic humans did not live.
Additionally, it is believed that Neanderthal DNA could influence human fertility in the present day. Almost a third of European women carry a gene inherited from the archaic humans that controls the progesterone receptor. This gene can subsequently impact fertility rates and the chance of miscarriages and other complications arising in pregnancy. Once again, the findings taken from our knowledge of the past could help to shape our future with regards to personalised medicine for those hailing from populations where interbreeding was high.
Another significant finding came from a 2017 study. Researchers from the National Institute of Mental Health discovered that persistent ancient genes were associated with having a Neanderthal-like brain and skull structure. This evidence, derived from MRI scanning, was implicated in mental and psychiatric health conditions such as schizophrenia.
And the health impacts do not stop there, ancient DNA has even provided us with insights into dental health, hair loss and skin colour – the latter of which can have implications in the development of skin cancers.
Not a substitute
Whilst it may seem that we have gained a significant amount of knowledge from studies of ancient specimens, it is certainly not a substitute for effective analysis of modern-day populations. The analysis of remains from a certain area may tell you more about that location and its residents, but there is relatively little that can be ascertained from one sample alone. There must, therefore, be a push to increase genomic diversity in modern research, with ancient DNA remaining a supplement to our evolutionary knowledge.
This is particularly true for African populations; although Homo sapiens may have originated in Africa, the modern human genome has been altered by variations over thousands of years and interbreeding with archaic species massively influenced our genes. The diversity that we now see in modern human populations as a result of this means tailored research is necessary, something that has been historically overlooked. Similarly, some Asian populations remain understudied, and with such little knowledge to date on Denisovans, we cannot say for sure where certain genes arose from. In that light, we must strive to understand the modern population to ensure appropriate health care for all.
Whilst most genomic research will continue to focus on modern man, it is clear that the field of paleogenomics is only growing and the use of ancient DNA will persist in health research. With the field garnering significant attention in the wake of Pääbo’s Nobel Prize, the potential of using ancient specimens to inform modern healthcare remains largely untapped. As proven by the fact that Ötzi is still receiving the sequencing treatment today, there is much left to be done. As genomic technologies exponentially increase in potential, we should be excited about what the future can tell us about the past, and what the past can subsequently tell us about the future.