nature medicine https://doi.org/10.1038/s41591-023-02244-4 Comment Ancient DNA as a tool for medical research Gaspard Kerner, Jeremy Choin & Lluis Quintana-Murci Paleogenomics can help elucidate the genetic basis of modern diseases, including inborn errors of immunity that impair the response to infections, providing a tool for drug development. The advent of new technologies and analytical approaches in genomics, such as high-throughput sequencing and CRISPR–Cas gene editing, has opened new avenues of medical research. Polygenic risk scores are being assessed for routine use by the UK National Health Service, and the use of gene editing should improve outcomes for many patients. Similarly, improvements in techniques for obtaining and sequencing DNA from fossil remains have been a major breakthrough in the field of evolutionary genetics. These discoveries have shed new light on the origins of human populations, their migratory history, and the extent of admixture between humans and ancient, now-extinct hominins, such as Neanderthals, and between modern human populations 1–3 . However, ancient genomics is also of value for medical research, making it pos- sible to reconstruct the history of human health over time, including past epidemics. This research allows increased understanding of the present-day links between genomic diversity and disease. A golden age of paleogenomics The study of ancient DNA (aDNA) has developed into a field in its own right: paleogenomics. The oldest nuclear genome sequences from the genus Homo obtained thus far were from a 430,000-year-old Neander- thal 4 , but most available ancient human genomes date back no more than 10,000 years (Table 1). aDNA has been extracted from samples from around the world, but particularly from the high latitudes of the northern hemisphere, reflecting an archeological bias intrinsic to the preservation of samples but also a more general bias toward the inves- tigation of people of European ancestry in genomic studies 5 . Paleogenomics can contribute to studies of human physiology in obvious ways, through the identification of regions of the human genome affected by the introgression of Neanderthal material, for example, which has revealed genes of major physiological relevance 2,3 . However, the potential contributions of paleogenomics to medical research are less self-evident. The increasing availability of aDNA samples is making it possible to address key questions related to human health and disease. For exam- ple, humans are an extremely successful species, but little is known about how they survived life-threatening environmental pressures, such as exposure to pathogens, in the past. Research on modern-day humans has shown that specific DNA mutations that alter host defense mechanisms can largely explain differential outcomes after infection. Thus, studying fluctuations in the frequency of genetic variants associ- ated with infectious-disease risks in fossil remains, which represent a continuous and uncontrolled natural experiment, provides an obvious example of the potential value of paleogenomics in medicine. Immune disorders The simplest model used to study human susceptibility to infection is genetic predisposition to infectious diseases through inborn errors of immunity — mutations that increase the risk of severe infections 6 . The most successful approach has been to study people who are extremely susceptible to infections, as they have the highest odds of carrying highly penetrant genetic lesions. The main advantage of this approach is that causality between genotype and phenotype follows naturally from the study of an in vivo (human) model, although its implementa- tion requires the extensive genetic screening of severely ill patients. An alternative approach is to study the effects of natural selection from pathogenic pressure on human genome variability 7 . These two Check for updates CREDIT: PCH.VECTOR / ALAMY STOCK VECTOR