.png)
4 hours ago
2
The Indigenous peoples of the Bolivian highlands are survivors. For thousands of years they have lived at altitudes of more than two miles, where oxygen is about 35 percent lower than at sea level. This type of setting is among the harshest environments humans have ever inhabited. Scientists have recognized for some time that these residents of the Andes Mountains have evolved genetic adaptations to the thin air of their lofty home. Now researchers are learning that they have also evolved another remarkable genetic adaptation since their ancestors first settled the highlands of South America around 10,000 years ago.
In the volcanic bedrock of the Andes, arsenic is naturally abundant and leaches into the drinking water. The dangers it poses are well known: inorganic arsenic is associated with cancers, skin lesions, heart disease, diabetes and infant mortality in other populations. But the biochemistry of Andeans has evolved to efficiently metabolize this notoriously toxic substance. Populations in Bolivia—along with groups in Argentina and Chile—have evolved variants around the gene AS3MT, which makes enzymes that break down arsenic in the liver. It is a prime example of natural selection, the evolutionary process by which organisms adapt to their environments to survive longer and produce more offspring. Apparently natural selection among the Uru, Aymara and Quechua peoples of the Bolivian Altiplano took DNA sequences that are present but rare in other populations around the world and increased their frequency to the point where the normally uncommon sequences are predominant in these groups. The case is one of many discoveries of relatively recent biological adaptation that could upend a long-standing idea about the evolution of our species.
For most of the 21st century many evolutionary biologists have assumed that humans evolved at a leisurely pace in recent millennia, in contrast to the dramatic transformations that occurred earlier in our prehistory. The oldest known members of the human family evolved in Africa around six million to seven million years ago and looked apelike in many ways. Our own species, Homo sapiens, arose in Africa a few hundred thousand years ago and began venturing into other parts of the world in significant numbers around 60,000 years ago. By that point our physical appearance seems to have settled into an evolutionary plateau, with only minor differences among human populations around the globe. After natural selection had worked its wonders for millions of years, transforming small-brained quadrupeds into large-brained bipeds, it appeared that biological evolution had slowed to a crawl in our lineage as H. sapiens developed agriculture, founded civilizations and transformed the planet.
On supporting science journalism
If 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.
Early studies of the DNA of modern people turned up few fixed differences—genetic variants possessed exclusively by one population—which seemed to confirm this apparent stasis. Consequently, many scholars believed that the latest chapter of the human saga revolved around cultural changes rather than biological ones—figuring out more reliable means of obtaining food instead of changing our digestive or metabolic systems, for instance.
But advances in the sequencing of ancient and modern DNA have allowed scientists to look more closely at how our genetic code has evolved over time—and the results are startling. Genetic studies suggest that H. sapiens experienced many major episodes of natural selection in the past few thousand years as our ancestors fanned across the globe and entered new environments containing foods, diseases and toxic substances they had never before encountered. “It shows the plasticity of the human genome,” says Karin Broberg of the Karolinska Institute in Sweden, who studies the genetics of susceptibility to environmental toxic substances. “We’ve spread throughout the world, and we live in very extreme environments, and we’re able to make them our homes. We are like rats or cockroaches—extremely adaptable.” This research offers fresh insights into how our species conquered every corner of the planet. We didn’t manage this feat through cultural adaptation alone, as some scientists previously supposed. Rather humans continued to evolve biologically to keep pace with the radical changes they were making in their ways of life as they pushed into terra incognita.
To appreciate how these evolutionary changes came about, it helps to know the basics of how DNA is structured and how it can vary among individuals and populations. The human genome contains about three billion nucleotide base pairs, the matched sets of two complementary nucleic acids that form the basic unit of our genetic code. The DNA sequences of people today are extremely similar; we differ on only about one tenth of a percent of the genome, or about one out of 1,000 positions. A difference between two people at any position on the genome is called a single nucleotide polymorphism, or SNP (pronounced “snip”). A variant of genetic code—which may be a single position or thousands—that differs between individuals is called an allele. In general, human populations share most of the same genetic variation and evolutionary history.
New research raises the possibility that recent human history involved far more dynamic evolution than previously thought.
In Darwinian biology, the classic conception of natural selection is a “hard sweep,” in which a beneficial mutation allows some individuals to survive longer or produce more offspring such that eventually that variant becomes fixed in the population. In the early 2000s, when researchers were starting to look for signs of hard sweeps in the genomes of contemporary peoples, the clearest examples came from populations that had adapted to unique circumstances. For instance, around 42,000 years ago a selective sweep changed a protein on the surface of red blood cells in Africans to boost their resistance to malaria. People in the Tibetan Highlands underwent selective sweeps for genes that helped them tolerate low oxygen (intriguingly, populations of the Himalayas, Andes and Ethiopian highlands adapted to high altitude with different assortments of genes, taking different evolutionary paths to solve similar problems).
Some of the best-known selective sweeps happened in western Eurasia and involved alleles associated with diet, skin pigmentation and immunity. Many of these sweeps are linked to the profound shifts wrought by the transition to agriculture. Around 8,500 years ago early farmers spread an allele that helped them synthesize long-chain polyunsaturated fatty acids from plant-based foods. These fatty acids are essential for cell membranes, particularly in the brain, and hunter-gatherers obtained them easily from meat and seafood. The new genetic variant allowed agricultural populations to synthesize them from short-chain fatty acids found in plants. This variant was rare at first, but now it is present in about 60 percent of Europeans.
The Uru people of the Bolivian Altiplano have a gene variant that helps them metabolize the toxic arsenic found in their drinking water.
Gaston Zilberman
Likewise, as dairy farming rose, so, too, did a gene variant that helped people consume milk products into adulthood. When Stonehenge was built around 5,000 years ago, virtually no Europeans possessed the genes people need to digest milk as adults. In most mammals—and most human populations—the body ceases producing the milk-digesting enzyme lactase after weaning. Yet around 4,500 years ago a gene that kept the lactase turned on in adulthood began to spread through Europe and South Asia. Another series of sweeps beginning around 8,000 years ago gave Eurasians their distinctive pale complexion. These changes reduced their production of the dark skin pigment known as melanin, which is believed to have allowed more sunlight to penetrate their skin and help them synthesize vitamin D, a nutrient in short supply among early agriculturalists.
These examples of hard sweeps became well known among geneticists, mostly because they seemed so uncommon. In the past two decades studies have found that contemporary human populations have relatively few fixed differences. Many researchers thus concluded that selective sweeps accounted for only a little of the genetic change our species has undergone over the past several thousand years. Most of the change, they proposed, stemmed not from natural selection but from gene flow (when populations interbreed as a consequence of migration) and genetic drift (when a genetic variant becomes more or less prevalent through random chance).
Yet reconstructing the past from genomes of modern-day people is tricky business because evolution often brushes over its own footprints. Early studies relied on the DNA of modern people to make inferences about evolution, but these methods could detect only events that had lasting effects. Episodes of natural selection are sometimes ephemeral, and evidence of them vanishes from our genomes when the selective pressures subside or when populations mix. Now ancient DNA is allowing investigators to find episodes of long-ago selection that have since been overwritten.
The first ancient human genome was sequenced in 2010. Since then, the number of ancient genomes has expanded steadily to more than 10,000 today. With this growing dataset, researchers can conduct more precise analyses of how the three billion positions in the genome have changed in recent millennia in populations around the world. One 2024 study of ancient DNA tracked the genetic changes in Europe amid major migrations and the transition to farming and pastoralism. Researchers analyzed more than 1,600 ancient genomes spanning the time from 11,000 years ago through the Middle Ages, comparing them with more than 400,000 modern genomes from the U.K. Biobank. When they looked at the modern data alone, they found no instances of selection. But when they examined ancient genomes, they found 11 sweeps. And when they divided those ancient genomes into ancestral lineages, they found 21. The lesson: to fully appreciate the extent of natural selection in history, one must look at local populations in narrow windows of time.
Modern Europeans descend from three main ancestral populations: hunter-gatherers who colonized the continent by around 40,000 years ago, early farmers from Anatolia who came into Europe about 8,500 years ago, and pastoralists from the Pontic-Caspian steppe who arrived around 5,000 years ago. In 2022 a research team led by Yassine Souilmi of the University of Adelaide’s Australian Center for Ancient DNA examined 1,162 ancient DNA samples from these ancestral lineages and captured snapshots of their genetics before and after they mixed. They scanned the genomes for any regions with unusually low- or high-frequency alleles, signs of ancient sweeps. They found 57 hard sweeps over the past 50,000 years linked to fat storage, metabolism, skin physiology, immunity and neural function—changes collectively believed to represent adaptations to colder climates. None were shared with a comparative population of sub-Saharan Africans, suggesting they originated after our species began spreading beyond its African birthplace into other parts of the world.
One striking finding was a hard sweep on a region of chromosome 6 called major histocompatibility complex class III, or MHC III, in ancient Anatolians. This ensemble of genes encodes proteins involved in immunity, and natural selection usually promotes genetic diversity in that region to defend against an array of potential threats. In this case, however, the researchers were surprised to find just the opposite—what they called a “distinctive trough of genetic diversity”—in that part of the genome, suggesting that these early farmers were ravaged by disease. “The population had been exposed to something so severe that it wiped out all the diversity that is generally favored in that region,” Souilmi says. “It was one of the strongest, if not the strongest, adaptation signals we have ever seen in humans.”
Pathogens such as the bacterium Yersinia pestis, which caused the bubonic plague pandemic known as the Black Death, have been major drivers of human evolution.
Niday Picture Library/Alamy Stock Photo
When the Anatolians later mixed with other populations, however, the MHC III adaptation signal disappeared. The researchers found similar patterns in dozens of other cases from the past 50,000 years. Again and again the selection pressures relaxed, and the traces of adaptations that had been widespread were “almost entirely erased from descendant populations” through interbreeding with other groups or genetic drift, Souilmi and his co-authors write in their study. “Such strong positive selection events have been much more common in recent human history than previously recognized,” they conclude.
This finding contradicts the notion that technological innovation and intelligence exempted later H. sapiens from biological adaptation. “It tells us our social fabric and technologies do not necessarily shield us from everything nature has to throw at us,” Souilmi says.
One thing nature regularly throws at us is deadly disease. Human populations have long been locked in an evolutionary arms race with pathogens. In a never-ending cycle, disease-causing microorganisms evolve to exploit vulnerabilities in our immune systems, and we adapt to resist these attacks. Even as ancient humans vanquished dangerous predators, they remained vulnerable to these microscopic enemies. For example, the bubonic plague pandemic known as the Black Death, which was caused by the bacterium Yersinia pestis, wiped out 30 to 50 percent of the population of Europe in the 14th century.
In this way pathogens helped shape who we are today. “Where there is mortality, there is selection: individuals who die before reaching reproductive age do not pass on their genes,” says Lluis Quintana-Murci, a population geneticist at the Institut Pasteur in Paris. “Indeed, infectious diseases and pathogens have been major drivers of natural selection throughout human history.”
Those battles became inscribed in our genomes. In a 2023 study, Quintana-Murci and his colleagues analyzed 2,879 ancient and modern genomes to see how the DNA of Europeans changed over the past 10,000 years. They found 139 positions on the genome that had been targeted by strong natural selection—either “positive selection” to promote advantageous genetic variants or “negative selection” to purge harmful ones. These changes largely involved the response to infections. More than 80 percent of the positive selection events began in the past 4,500 years—a time of swelling urban communities, growing dependence on agriculture, proximity to domesticated animals and a rise in epidemics. “Natural selection has been pervasive throughout this period,” Quintana-Murci says.
Some adaptations to infectious pathogens came at a cost, however: strengthening resistance to ancient diseases might have elevated the likelihood of immune overreaction. In other words, a hypervigilant defense system could go haywire and attack one’s own body. As the risk of infectious disease dropped, the probability of inflammatory and autoimmune disorders appears to have risen. For example, there was a sharp increase in several genetic variants that protect against infectious illnesses but also raise the risk of inflammatory bowel conditions such as Crohn’s disease.
Several variants in the MHC (also known as the human leukocyte antigen, or HLA, region in humans) also appear to have undergone selection to resist pathogens. These same variants increased the risk of autoimmune disorders such as ankylosing spondylitis, an inflammatory disease that can cause the vertebrae to fuse, and type 1 diabetes, in which the immune system attacks the cells in the pancreas that make the hormone insulin. Some parts of the genome showed evidence of negative selection as nature weeded out harmful variants. There was a drop in variants that increase the risk of COVID-19, for instance, suggesting that ancient people battled coronaviruses centuries before the recent pandemic.
Taken together, the results suggest that our immune system has been repeatedly tweaked by recent selection like a software system that requires constant updates. Despite the plethora of new discoveries, Quintana-Murci believes researchers have uncovered only the most obvious examples of ancient selection, and he suspects many more cases will come to light as analytical methods become more powerful and researchers obtain more ancient DNA from other regions of the world. “Many surprises are likely to emerge,” he says.
One big surprise is just how pervasive these adaptations have been. A team led by scientists at Harvard Medical School analyzed more than 8,400 DNA samples from people who lived in western Eurasia during the past 14,000 years. They compared these ancient genomes with genetic data from 6,510 modern people and examined nearly 10 million genetic variants. For each SNP, they computed selection coefficients to measure how much natural selection acted to promote or suppress that variant in the next generation.
In a pre-peer-review draft of the paper released publicly last year, David Reich and his colleagues report that they found evidence for natural selection at 347 places on the genome—an order of magnitude more than previously known. The changes were related to immunity, inflammatory responses and cardio-metabolic traits and most likely reflect adaptations to new diets, more crowded living conditions, diseases and domestic livestock.
Native Tibetans have a genetic adaptation to the low oxygen levels of their high-altitude home.
hadynyah/Getty Images
Reich declined to discuss the results for this story because the paper is currently under review for publication in a journal, but he disclosed that the team expects to expand the number of samples and strengthen the methodology in the final version of the study. In an interview with podcaster Dwarkesh Patel, Reich previewed the findings and described striking shifts in genetic variants over the past 10 millennia: “We think we have many, many hundreds of places where there [have] been very strong changes in frequency over time,” he said. “We think there are many thousands that we can see traces of. The whole genome is seething with these changes in this period.”
The preprint of the paper offers examples. Early farming populations underwent strong selection to abandon the “thrifty genes” that promote body-fat storage. These gene variants had been advantageous for hunter-gatherers who endured times of scarcity, but they became liabilities in the more abundant age of agriculture. Other sweeps forged dramatic genetic changes affecting skin pigmentation; blood type; and susceptibility to diseases such as tuberculosis, multiple sclerosis, diabetes, celiac disease, bipolar disorder and schizophrenia.
Like the earlier studies, the Harvard study found a hotspot of activity at the MHC/HLA region of the genome (about 20 percent of the signals came from this area). One allele that increases the risk of celiac disease went from being virtually nonexistent to occurring in 20 percent of the population over the course of just 4,000 years. Presumably this allele offered some as yet unknown protective effect that outweighed its attendant risk of celiac disease.
In many cases, the selection was so strong that the variants would have become universal in the population had the selection continued, but then the pressure waned, and the variants lost their evolutionary cachet. In other cases, the populations interbred with other lineages, and the evidence of past selection was masked.
With new analytical techniques, researchers can read these erasures like an ancient palimpsest. “That’s the holy grail—having a really powerful method to detect locations in the genome that are very likely to be under selection,” says Ray Tobler, a population geneticist and ancient DNA specialist at Australian National University. “Now the tools we have are very powerful, so we will find a lot more,” he predicts.
One promising area of discovery concerns so-called polygenic traits, which are controlled by multiple genes. Most traits and diseases of interest are polygenic. Traditionally they have proved very difficult to study because they can involve the interplay of hundreds or thousands of positions scattered around the genome, each exerting only a minuscule effect on the trait. Human height, for instance, is estimated to be influenced by more than 100,000 positions. Each individual gene involved in a polygenic trait may exert only a small influence on that trait. This distributed influence can make it hard to identify genetic targets of natural selection. “Human adaptation is a polygenic process, usually with small effect sizes of individual genes,” says Bing Su, a professor at the Kunming Institute of Zoology at the Chinese Academy of Sciences. But with technological advances that have made it faster and cheaper than ever to sequence high volumes of DNA, he says, scientists now can spot polygenic adaptations that previously were invisible.
These latest genetic studies have opened a new frontier in research into traits that are far more complex than the single-gene-mediated ability to digest milk in adulthood. But not everyone agrees that these traits are necessarily products of natural selection. Perhaps, skeptics have suggested, the observed fluctuations in allele frequencies are just routine oscillations of variants in the gene pool rather than proof positive of natural selection acting to adapt the human body to environmental challenges. Some of the papers have drawn criticism about their statistical methods. Some findings of ancient selection have not been replicated by other studies. The numerous papers reporting more natural selection differ on where in the genome it is occurring.
Iain Mathieson, a geneticist at the University of Pennsylvania, is circumspect. He thinks new studies such as the Harvard paper are indeed detecting real shifts in gene frequencies, but he notes that quite a few of them appear to be transient. Mathieson suspects that many genetic variants have been subject to only weak or fleeting selection without much lasting effect. “I mean, that’s still selection, but I’m not sure I’d call it directional selection,” he says, referring to the type of natural selection responsible for selective sweeps.
Sasha Gusev, a statistical geneticist and associate professor at the Dana-Farber Cancer Institute and Harvard Medical School, takes a different view. The new research raises the possibility that recent human history involved far more dynamic evolution than previously recognized, with repeated episodes of selection followed by reversals. “It’s a super interesting question that ancient DNA is opening back up,” he says, even if there isn’t yet consensus in the field about the extent to which this kind of evolution has occurred.
That consensus may emerge as scientists obtain additional ancient DNA samples and further refine the tools they use to analyze them. The discovery of more hitherto unknown examples of adaptation, meanwhile, seems all but inevitable. Most of the detailed studies of ancient selection have focused on populations in western Eurasia. Much remains to be learned about people in Asia, the Americas, and especially Africa, the birthplace of our species, which holds more human genetic diversity than the rest of the world combined. “While it might seem that we’re currently detecting huge amounts of selection, in my opinion we’re not detecting enough,” Souilmi says. “I think there is a lot more out there.”
