Starvation

A new study explores 'balancing selection' by analyzing thousands of modern human genomes alongside ancient hominin groups, such as Neanderthal and Denisovan genomes. The research has 'implications for understanding human diversity, the origin of diseases, and biological trade-offs that may have shaped our evolution,' says evolutionary biologists. Like a merchant of old, balancing the weights of two different commodities on a scale, nature can keep different genetic traits in balance as a species evolves over millions of years. These traits can be beneficial (for example, fending off disease) or harmful (making humans more susceptible to illness), depending on the environment. The theory behind these evolutionary trade-offs is called balancing selection. A University at Buffalo-led study accepted on Jan. 10 and published on Feb. 21 in eLife explores this phenomenon by analyzing thousands of modern human genomes alongside ancient hominin groups, such as Neanderthal and Denisovan genomes. The research has "implications for understanding human diversity, the origin of diseases, and biological trade-offs that may have shaped our evolution," says evolutionary biologist Omer Gokcumen, the study's corresponding author. Gokcumen, PhD, associate professor of biological sciences in the UB College of Arts and Sciences, adds that the study shows that many biologically relevant variants "have been segregating among our ancestors for hundreds of thousands, or even millions, of years. These ancient variations are our shared legacy as a species." Ties with Neanderthals stronger than previously thought The work builds upon genetic discoveries in the past decade, including when scientists uncovered that modern humans and Neanderthals interbred as early humans moved out of Africa. It also coincides with the growth of personalized genetic testing, with many people now claiming that a small percentage of their genome comes from Neanderthals. But, as the eLife study show, humans share much more in common with Neanderthals than those small percentages indicate. This additional sharing can be traced back to a common ancestor of Neanderthals and humans that lived about 700,000 years ago. This common ancestor bequeathed to the Neanderthals and modern humans a shared legacy in the form of genetic variation. The research team explored this ancient genetic legacy, focusing on a particular type of genetic variation: deletions. Gokcumen says that the "deletions are strange because they affect large segments. Some of us are missing large chunks of our genome. These deletions should have negative effects and, as a result, be eliminated from the population by natural selection. However, we observed that some deletions are older than modern humans, dating back millions of years ago." Gene variations passed down over millions of years The researchers used computational models to show an excess of these ancient deletions, some of which have persisted since our ancestors first learned to make tools, some 2.6 million years ago. Furthermore, the models found that balancing selection can explain this surplus of ancient deletions. "Our study contributes to the growing body of evidence suggesting that balancing selection may be an important force in the evolution of genomic variation among humans," says first author Alber Aqil, a PhD candidate in biological sciences in Gokcumen's lab. The investigators found that deletions dating back millions of years are more likely to play an outsized role in metabolic and autoimmune conditions. Indeed, the persistence of versions of genes that cause severe disease in human populations has long baffled scientists since they expect natural selection to get rid of these versions of genes. It is, after all, very unusual for potentially disease-causing variation to persist for such long periods. The authors argue that balancing selection can solve this riddle. Aqil says that these variations may "protect against infectious diseases, outbreaks, and starvation, which have occurred periodically throughout human history. Thus, the findings represent a considerable leap in our understanding of how genetic variations evolve in humans. A variant may be protective against a pathogen or starvation while also underlying certain metabolic or autoimmune disorders, like Crohn's disease." Additional co-authors include Leo Speidel, PhD, Sir Henry Wellcome Postdoctoral Fellow at the Genetics Institute of University College London and the Francis Crick Institute; and Pavlos Pavlidis of the Institute of Computer Science, one of eight institutes of the Foundation of Research and Technology-Hellas in Greece. The research was supported by the National Science Foundation, the Sir Henry Wellcome Fellowship, and the Wellcome Trust.

An ancient human foraging instinct, fueled by fructose production in the brain, may hold clues to the development and possible treatment of Alzheimer's disease (AD). An ancient human foraging instinct, fueled by fructose production in the brain, may hold clues to the development and possible treatment of Alzheimer's disease (AD), according to researchers at the University of Colorado Anschutz Medical Campus. The study, published recently in The American Journal of Clinical Nutrition, offers a new way of looking at a fatal disease characterized by abnormal accumulations of proteins in the brain that slowly erode memory and cognition. "We make the case that Alzheimer's disease is driven by diet," said the study's lead author Richard Johnson, MD, professor at the University of Colorado School of Medicine specializing in renal disease and hypertension. The study co-authors include Maria Nagel, MD, research professor of neurology at the CU School of Medicine. Johnson and his team suggest that AD is a harmful adaptation of an evolutionary survival pathway used in animals and our distant ancestors during times of scarcity. "A basic tenet of life is to assure enough food, water and oxygen for survival," the study said. "Much attention has focused on the acute survival responses to hypoxia and starvation. However, nature has developed a clever way to protect animals before the crisis actually occurs." When threatened with the possibility of starvation, early humans developed a survival response which sent them foraging for food. Yet foraging is only effective if metabolism is inhibited in various parts of the brain. Foraging requires focus, rapid assessment, impulsivity, exploratory behavior and risk taking. It is enhanced by blocking whatever gets in the way, like recent memories and attention to time. Fructose, a kind of sugar, helps damp down these centers, allowing more focus on food gathering. In fact, the researchers found the entire foraging response was set in motion by the metabolism of fructose whether it was eaten or produced in the body. Metabolizing fructose and its byproduct, intracellular uric acid, was critical to the survival of both humans and animals. The researchers noted that fructose reduces blood flow to the brain's cerebral cortex involved in self-control, as well as the hippocampus and thalamus. Meanwhile, blood flow increased around the visual cortex associated with food reward. All of this stimulated the foraging response. "We believe that initially the fructose-dependent reduction in cerebral metabolism in these regions was reversible and meant to be beneficial," Johnson said. "But chronic and persistent reduction in cerebral metabolism driven by recurrent fructose metabolism leads to progressive brain atrophy and neuron loss with all of the features of AD." Johnson suspects the survival response, what he calls the `survival switch,' that helped ancient humans get through periods of scarcity, is now stuck in the `on' position in a time of relative abundance. This leads to the overeating of high fat, sugary and salty food prompting excess fructose production. Fructose produced in the brain can lead to inflammation and ultimately Alzheimer's disease, the study said. Animals given fructose show memory lapses, a loss in the ability to navigate a maze and inflammation of the neurons. "A study found that if you keep laboratory rats on fructose long enough they get tau and amyloid beta proteins in the brain, the same proteins seen in Alzheimer's disease," Johnson said. "You can find high fructose levels in the brains of people with Alzheimer's as well." Johnson suspects that the tendency of some AD patients to wander off might be a vestige of the ancient foraging response. The study said more research is needed on the role of fructose and uric acid metabolism in AD. "We suggest that both dietary and pharmacologic trials to reduce fructose exposure or block fructose metabolism should be performed to determine if there is potential benefit in the prevention, management or treatment of this disease," Johnson said. The study's co-authors include Dean R. Tolan, Dale Bredesen, Laura G. Sanchez-Lozada, Mehdi Fini, Scott Burtis, Miguel A. Lanaspa and David Pearlmutter.

The World Health Organization (WHO) has launched a funding appeal for $2.54bn to provide assistance to those facing health emergencies around the world. The emergency health appeal comes as the number of people in need of humanitarian relief has increased to a record 339 million – up by almost a quarter from 2022 figures – with WHO saying that it is currently responding to an ‘unprecedented’ number of intersecting health emergencies. Included in this are climate change-related disasters such as flooding in Pakistan and food insecurity across the Sahel and in the greater Horn of Africa, the war in Ukraine and the health impact of conflict in Yemen, Afghanistan, Syria and northern Ethiopia. These emergencies are also coinciding with the health system disruptions caused by the COVID-19 pandemic, as well as outbreaks of illnesses such as measles and cholera. “This unprecedented convergence of crises demands an unprecedented response,” said WHO director-general, Dr Tedros Adhanom Ghebreyesus. “More people than ever before face the imminent risk of disease and starvation and need help now. The world cannot look away and hope these crises resolve themselves. I urge donors to be generous and help WHO to save lives, prevent the spread of disease within and across borders, and support communities as they rebuild," Ghebreyesus added. WHO is currently responding to 54 health crises across the world, eleven of which are classified as grade 3 – the organisation’s highest level of response – and require a major response. Speaking at the event from WHO’s headquarters in Geneva, when the launch of the appeal was announced, Ghebreyesus referenced the organisation’s “first consolidated” health emergency appeal last year. To help protect those around the world from urgent emergency and humanitarian health needs, including the COVID-19 response, WHO asked for $2.7bn in 2022. “Thanks to the generous support of donors, we were able to respond to many health emergencies,” Ghebreyesus said, citing outbreaks of ebola in Uganda, cholera in 31 countries and m-pox around the world. In a statement, WHO outlined that in 2022 it ‘provided medicines, other supplies, training for doctors and other health workers, vaccines, enhanced disease surveillance, mobile clinics, mental health support, maternal health consultations and much more’.