January 21, 202512 min readHow Neandertal DNA May Affect the Way We ThinkDNA inherited from Neandertals may influence modern human cognitionBy Emily L. Casanova & F. Alex Feltus edited by Kate Wong Sam FalconerWhen Neandertals were first discovered nearly 170 years ago, the conceptual gap between their lineage and thatof modern humans seemed vast. Initially scientists prejudicially believed that the Neandertals were primitive brutes hardly more intelligent than apes and that their lack of advanced thinking had doomed them to extinction. Since that time, researchers have amassed evidence that they shared many of the cognitive abilities once considered unique to our species, Homo sapiens. They made complex tools, produced staples such as flour, treated their ailments with plant-based medicines, used symbols to communicate and engaged in ritual treatment of their dead.The divide between their lineage and ours narrowed even further in 2010, when researchers published the first Neandertal genome sequence. Comparison of that ancient DNA with modern human DNA showed that the two species had interbred and that people today still carry the genetic fingerprint of that intermixing. Since then, numerous studies have explored the ways in which Neandertal DNA affects our modern physiology, revolutionizing our understanding not only of our extinct cousins but of ourselves as a hybrid species.This area of research, clinical paleogenomics, is still in its infancy, and there are many complexities to unravel as we explore this new frontier. We therefore must take the findings from these studies with a grain of salt. Nevertheless, the research conducted to date raises the fascinating possibility that Neandertal DNA has wide-reaching effects on our speciesnot only on general health but on brain development, including our propensity for conditions such as autism. In other words, DNA from our extinct relatives may, to some extent, shape the cognition of people today.On supporting science journalismIf you're enjoying this article, consider supporting our award-winning journalism by subscribing. By purchasing a subscription you are helping to ensure the future of impactful stories about the discoveries and ideas shaping our world today.It seems that every few weeks a new study expands our understanding of how Neandertal DNA affects modern human health and physiology. Researchers have found that some Neandertal DNA makes carriers more vulnerable to various immune disorders, such as systemic lupus erythematosus and Crohns disease, and some gene variants affect an immune molecule known as interleukin-18, which plays a role in predisposition to autoimmune disorders. Some Neandertal DNA variants are implicated in increased risk for severe COVID, whereas others appear to be protective factors. Still other Neandertal-derived variants may be instrumental in determining whether we develop allergies. And there is some evidence to suggest that our ancient cousins DNA may even be implicated in asthmaa subject of ongoing research.Scientists have also documented a number of effects of Neandertal DNA beyond the immune system. Neandertal DNA may affect the color of our skin and hair, how readily our blood clots, our propensity for heart disease, and how our cells respond to various environmental stressors such as radiation. It can also help determine how prone we are to certain skin cancers, thiamine (vitamin B1) deficiency, obesity and diabetes.The notion that Neandertal DNA might significantly influence our brains and behavior, however, is actually a bit counterintuitive. Previous research has shown that this ancient DNA tends to be underrepresented in the brain-related genes of modern humans, primarily because these types of genes are very sensitive to change, and anything new gets weeded out fairly quickly. These regions of the genome are known as Neandertal DNA deserts. Yet studies published over the past decade have shown that some Neandertal DNA has in fact persisted in and around some brain-related genes in modern humans.The effects of Neandertal DNA are apparent throughout the brain and associated structures in people today.The effects of this DNA are apparent throughout the brain and associated structures. Philipp Gunz of the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany, and his colleagues found that people with higher percentages of Neandertal DNA are more likely to have skull shapes that are modestly elongated and reminiscent of the Neandertal skull, particularly around the parietal and occipital regions toward the back of the cranium. This skull elongation is sometimes associated with Neandertal variants that are located near the genes UBR4 and PHLPP1, which are involved in neuron production and the formation of myelin, the fatty sheath that insulates the axons of larger neurons, allowing them to communicate more reliably over longer distances. The skull elongation is also associated with Neandertal variants located near GPR26. This gene is still poorly understood, but it appears to have antitumor effects and is therefore probably also involved in regulating the production of neurons and other nervous systems cells called glia.In another study, Michael D. Gregory of the National Institutes of Health and his colleagues observed differences in the structure of the brain in regions related to visual processing and socialization. Specifically, people with more Neandertal DNA tend to have increased connectivity in visual-processing tracts but reduced connectivity in nearby tracts that are implicated in social cognition. This intriguing finding suggests there could be trade-offs between visual processing and social skills in the Homo lineage.Of particular importance, Neandertal DNA also seems to influence the structure and function of the cerebellum. Although most neuroscientists have tended to think of this brain region as functionally dedicated to motor memory and coordination, it is also involved in attention, emotional regulation, sensory processing and social cognition. The cerebellum seems to be vital for systems involved in mentalizing, which underlies many aspects of our ability to infer the mental states of other people. In 2018 Takanori Kochiyama of Advanced Telecommunications Research Institute International in Kyoto and his colleagues published a study in which they reconstructed the crania of Neandertals and those of early modern humans and compared them. Their research showed that the cerebellum was significantly smaller in our extinct cousins than in members of our own lineage. These data suggest that there could be significant variability in the structure and function of the cerebellum (and therefore in social cognition) in modern humans as a result of the DNA we have inherited from Neandertals.When it comes to the inheritance of genetic variations, the overall size of a population has a dramatic effect on whether a particular DNA mutation is passed on, especially if its somewhat deleterious or harmful. In a large population, a modestly deleterious mutation is likely to get weeded out relatively quickly just by sheer probability. But in a small, isolated population, such a mutation is far more likely to spread as if it were neutral, and it may even become permanently retained in the population. Small groups tend to accumulate more mutations over time than larger populations do, which may reduce the number of children that individuals in those populations can raise, putting the groups at risk of dying out. Its for this reason that most modern human cultures consider it taboo to marry a close relation such as a first cousin. Cultures that still allow this practice often have unusually high rates of so-called recessive diseases, which arise when an individual inherits the same genetic susceptibility factor from both parents.Research into the Neandertal genome has indicated that our extinct relatives underwent a significant and somewhat protracted reduction in their population size, an event known as a genetic bottleneck. Between 50,000 and 40,000 years ago, their population dwindled to perhaps as few as 5,000 individuals. Because of that genetic bottleneck, the Neandertal genome contains an overabundance of potentially harmful mutations, which most likely led to reduced reproductive fitness and high rates of recessive disease in their population. There is evidence of this bottleneck event and its consequences in Neandertal fossils from the site of El Sidrn in Spain, where 13 closely related individuals exhibit evidence of 17 different skeletal birth defects.Neandertals had a braincase that was long and low in shape (left), in contrast to the globular braincase of Homo sapiens (right). People today with higher percentages of Neandertal DNA are more likely to have an elongate skull reminiscent of Neandertals.Philipp Gunz/MPI EVA LeipzigOur species probably inherited some of these unfavorable genetic variants when our ancestors interbred with Neandertals tens of millennia ago. Is it possible that some of the harmful Neandertal-derived variants that have stuck around in our genomes now influence not only the sizes and shapes of some of our brain structures but also our propensity for neurodevelopmental and psychiatric conditions?The accumulation of evidence to date suggests that this may well be happening. For instance, some Neandertal variants have been linked with the presence of major depression. Perhaps not coincidentally, these variants have also been implicated in determining chronotypethat is, whether someone is a morning or night person. Some scientists posit that the effects of Neandertal DNA on our chronotype, which is determined by our circadian rhythms, might predispose us toward depression because many mood disorders have a significant seasonal component (to wit: seasonal affective disorder, a type of mood disorder in which symptoms come and go with the changing of the seasons).Neandertal DNA has also been associated with substance use such as drinking and smoking. Other genetic variants seem to increase pain sensitivity and prompt people to consume more pain medications. And a subset of Neandertal DNA variants may increase some peoples likelihood of developing attention deficit hyperactivity disorder (ADHD), although these variants are slowly disappearing from the modern human genome.One particularly intriguing connection that the two of us have been investigating is the possible link between Neandertal ancestry and autism. We first became interested in this link when we learned of the parallels between some of the brain connectivity patterns in visual- and social-processing pathways in nonautistic people who have more Neandertal DNA and people on the autism spectrum. People with autism often have enhanced visuospatial abilitiesfor instance, they tend to excel at picking out a target shape from a sea of distracting shapes in cognitive tests. At the same time, challenges with social cognition are typically central to the autistic experience and call to mind the reduced connectivity in those same neural pathways in nonautistic people with more Neandertal DNA. We also knew that just as Neandertals had smaller cerebellums than early modern humans did, which may have influenced their social cognitive abilities, people with autism consistently exhibit reduced volume in subregions of the cerebellum.This wealth of data from genetics, neuroimaging and brain reconstruction prompted the two of us to question whether Neandertal DNA could be influencing autism susceptibility in modern human populations. Our laboratories set out to address this important question together, accessing genetic data on both autistic and nonautistic people from several large, well-established databases. We were also interested in looking at Neandertal DNA according to ethnic background because there is a lot of variability across modern populations. For instance, people of African ancestry tend to have less Neandertal DNA than Asian and European people. Thus, it was important to match our groups of autistic and nonautistic people according to ethnicity.When studying Neandertal DNA in the modern human genome, scientists typically investigate single points in the DNA that vary across populations. These points of variation are known as single nucleotide polymorphisms (SNPs, pronounced snips). We were very interested in studying common and rare Neandertal SNPs separately because the rarer a DNA variant is, the more likely it is to be harmful and the less likely it is to be passed down to offspring. What we found was that autistic people tend to have more rare Neandertal SNPs than ethnically matched nonautistic people have. Its important to note that autistic people dont necessarily have more Neandertal DNA in generaltheyre not more Neandertal than the next person. Its just that the Neandertal DNA they carry includes more of the rare variants than nonautistic people tend to have.Neandertal DNA variants appear to be influencing development of autism in measurable ways across ethnicities.We also investigated SNPs that specifically influence gene activity in the brain. We were able to identify 25 of these Neandertal-derived expression quantitative trait loci (eQTLs), as they are known, that were overrepresented in our autism groups. For example, about 80 percent of white Hispanic autistic males with epilepsy carried a particular Neandertal SNP in the USP47 gene, compared with 15 percent of those in the nonautistic control group. Although the function of USP47 is poorly understood, this gene has tentative links with epilepsy, which often co-occurs with autism.In addition, we found a mutation in the COX10 gene that occurred more frequently in Black people with autism than in Black people without autism. Animals genetically engineered so that their COX10 is inactive tend to have a functional imbalance between the activity of excitatory neurons and inhibitory ones in the brain that is very characteristic of conditions like autism.We dont yet have a clear idea of what all these Neandertal SNPs are doing in people with autism. They appear to be influencing development of the condition in measurable ways across all ethnicities studied. And our research suggests that many of the rare Neandertal-derived SNPs, which are associated with autism, help to orchestrate neural connectivity, which in turn may affect how neurons communicate with one another. But precisely how these variants are affecting brain development remains to be determined. In all likelihood, there is no single answer.Genetics is an extremely complicated field of study. Although the human genome was sequenced more than 20 years ago, our understanding of molecular networks and how they influence organ development and function is still relatively rudimentary. As we dig deeper into how Neandertal DNA is influencing our genes, it is important to accept the complexity of the problem. There are more than 78,000 modern human genes that have mixed with nearly the same number of Neandertal genes. Humans can wrap their minds around a three-dimensional problem, but a 78,000D problem is rather more difficult! Fortunately, modern computers executing artificial-intelligence code can handle the analytical burden that our brains cannot.Our initial study tagged Neandertal DNA in partial genome sequences that constitute just 1 percent or so of the entire human genome. In the next phase of our research we will scan recently available complete genome sequences from modern human families with a propensity for autism. By expanding our search area for ancient DNA from genes to regions between genes, we will be able to investigate millions of additional eQTLs, which regulate the intensity of gene expression much as a dimmer switch controls the amount of light coming from a bulb. Once we map these eQTLs to Neandertal-derived DNA variations in a modern human genome, we will be able to infer whether some Neandertal DNA is measurably altering gene expression.A complete genome search will allow us to identify eQTLs from the Neandertal lineage that are involved in the function and development of not only the brain as a whole but also specific brain tissues and regions, such as the cerebellum. We may find that H. sapiens inherited entirely new neurodevelopmental traits from Neandertals that did not exist in our lineage until the two groups interbred. A more likely scenario, however, is that the introduction of Neandertal DNA into H. sapiens modified, but did not override or replace, genetic control mechanisms for extraordinarily complex brain conditions such as autism, ADHD and depression.If we can identify the exact neurodevelopmental pathways controlled by mixed Neandertal/H. sapiens gene regulatory networks, we may be able to figure out how ancient DNA reconfigured gene expression in the brain at the point of hybridization. This type of knowledge would have a variety of potential therapeutic applications within the burgeoning field of personalized medicine.We arent interested only in Neandertal DNA. It may be that hybridization in general, not just DNA inherited from Neandertals specifically, contributes to autism susceptibilitythe result of a type of genetic mismatch, if you will. If thats the case, we might also expect to see DNA from other cousins, the Denisovans, who also interbred with early H. sapiens, playing roles in autism and other neurological conditions in ethnic groups of people today who carry Denisovan DNA (primarily people of Asian and Native American ancestry). We will be looking for signs of Denisovan influence in the next phase of our research.Like the ADHD-related Neandertal variants that are gradually getting winnowed out of the modern human genome, the rare Neandertal variants that autistic people have may be getting weeded out of the gene pool, too. Some rare Neandertal DNA is probably fading away simply as a result of what population geneticists call the law of large numbers, which predicts that uncommon and rare DNA, regardless of its effects on the organism, will tend to slowly disappear from a large breeding population over time. But other Neandertal DNA may be rare because it is modestly harmful, affecting an individuals ability to have children and pass down their DNA.We know from research that, on average, people with autism are significantly less likely than the general population to have children, although there are certainly some who do have kids. But we dont know whether their reproductive rates are lower because people on the autism spectrum face challenges with romantic relationships or because they are more likely to have certain health-related disorders such as polycystic ovary syndrome that affect fertility. The answer is probably multifactorial. But regardless of the reasons, fewer offspring means fewer genetic variants associated with autism get passed down over time. So, if these variants arent getting passed down as often, why are they still sticking around in the human genome, albeit in low numbers?When it comes to autism, the medical community has traditionally focused on the deficits and challenges that people with the condition may experience. This approach is rooted in the medical model of disability, which in the case of neurodevelopmental differences holds that they should be treated medically with a focus on fixing or managing the condition and a goal of normalizing the persons behavior. But the autism spectrum is also associated with traits that may have been adaptive during more recent human brain evolutionenhanced visuospatial processing, high intelligence, exceptional memory and creativity, among others. Multiple genetics studies have found that many of the common genetic variants associated with autism are also associated with high intelligence, enhanced cognitive ability and educational attainment.In addition, family members of people on the spectrum are more likely to have careers in fields related to science and technology and, according to our recent study, are also likely to carry some of these same rare Neandertal variants. Therefore, although autistic people have lower reproductive rates on average, their nonautistic (though potentially still neurodivergent) family members may also be helping to keep this DNA in the gene pool. In other words, even as some evolutionary factors are working to push these autism-related Neandertal-derived genetic variants out of the human genome, other factors are working to retain them.Although we dont yet know whether the Neandertal DNA associated with autism is also linked to intelligence, savantism or general creativity, we are slowly connecting the dots. If such a relation exists, it suggests that intermixing with Neandertals has affected multiple aspects of brain evolution in our species. In this way, Neandertal DNA is not only a part of the story of autism and other neurodevelopmental and psychological conditions; its central to the story of all of us.