Human evolution wasn't just the sheet music, but how it was played

A team of Duke researchers has identified a group of human DNA sequences driving changes in brain development, digestion and immunity that seem to have evolved rapidly after our family line split from that of the chimpanzees, but before we split with the Neanderthals.

Our brains are bigger, and are guts are shorter than our ape peers.

"A lot of the traits that we think of as uniquely human, and human-specific, probably appear during that time period," in the 7.5 million years since the split with the common ancestor we share with the chimpanzee, said Craig Lowe, Ph.D., an assistant professor of molecular genetics and microbiology in the Duke School of Medicine.

Specifically, the DNA sequences in question, which the researchers have dubbed Human Ancestor Quickly Evolved Regions (HAQERS), pronounced like hackers, regulate genes. They are the switches that tell nearby genes when to turn on and off. The findings appear Nov.23 in the journal Cell.

The rapid evolution of these regions of the genome seems to have served as a fine-tuning of regulatory control, Lowe said. More switches were added to the human operating system as sequences developed into regulatory regions, and they were more finely tuned to adapt to environmental or developmental cues. By and large, those changes were advantageous to our species.

"They seem especially specific in causing genes to turn on, we think just in certain cell types at certain times of development, or even genes that turn on when the environment changes in some way," Lowe said.

A lot of this genomic innovation was found in brain development and the GI tract. "We see lots of regulatory elements that are turning on in these tissues," Lowe said. "These are the tissues where humans are refining which genes are expressed and at what level."

Today, our brains are larger than other apes, and our guts are shorter. "People have hypothesized that those two are even linked, because they are two really expensive metabolic tissues to have around," Lowe said. "I think what we're seeing is that there wasn't really one mutation that gave you a large brain and one mutation that really struck the gut, it was probably many of these small changes over time."

To produce the new findings, Lowe's lab collaborated with Duke colleagues Tim Reddy, an associate professor of biostatistics and bioinformatics, and Debra Silver, an associate professor of molecular genetics and microbiology to tap their expertise. Reddy's lab is capable of looking at millions of genetic switches at once and Silver is watching switches in action in developing mouse brains.

"Our contribution was, if we could bring both of those technologies together, then we could look at hundreds of switches in this sort of complex developing tissue, which you can't really get from a cell line," Lowe said.

"We wanted to identify switches that were totally new in humans," Lowe said. Computationally, they were able to infer what the human-chimp ancestor's DNA would have been like, as well as the extinct Neanderthal and Denisovan lineages. The researchers were able to compare the genome sequences of these other post-chimpanzee relatives thanks to databases created from the pioneering work of 2022 Nobel laureate Svante Pääbo.

"So, we know the Neanderthal sequence, but let's test that Neanderthal sequence and see if it can really turn on genes or not," which they did dozens of times.

"And we showed that, whoa, this really is a switch that turns on and off genes," Lowe said. "It was really fun to see that new gene regulation came from totally new switches, rather than just sort of rewiring switches that already existed."

Along with the positive traits that HAQERs gave humans, they can also be implicated in some diseases.

Most of us have remarkably similar HAQER sequences, but there are some variances, "and we were able to show that those variants tend to correlate with certain diseases," Lowe said, namely hypertension, neuroblastoma, unipolar depression, bipolar depression and schizophrenia. The mechanisms of action aren't known yet, and more research will have to be done in these areas, Lowe said.

"Maybe human-specific diseases or human-specific susceptibilities to these diseases are going to be preferentially mapped back to these new genetic switches that only exist in humans," Lowe said.

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The Black Death shaped the evolution of immunity genes, setting the course for how we respond to disease today

An international team of scientists who analyzed centuries-old DNA from victims and survivors of the Black Death pandemic has identified key genetic differences that determined who lived and who died, and how those aspects of our immune systems have continued to evolve since that time.

Researchers from McMaster University, the University of Chicago, the Pasteur Institute and other organizations analyzed and identified genes that protected some against the devastating bubonic plague pandemic that swept through Europe, Asia and Africa nearly 700 years ago. Their study has been published today in the journal Nature.

The same genes that once conferred protection against the Black Death are today associated with an increased susceptibility to autoimmune diseases such as Crohn's and rheumatoid arthritis, the researchers report.

The team focused on a 100-year window before, during and after the Black Death, which reached London in the mid-1300s. It remains the single greatest human mortality event in recorded history, killing upwards of 50 per cent of the people in what were then some of the most densely populated parts of the world.

More than 500 ancient DNA samples were extracted and screened from the remains of individuals who had died before the plague, died from it or survived the Black Death in London, including individuals buried in the East Smithfield plague pits used for mass burials in 1348-9. Additional samples were taken from remains buried in five other locations across Denmark.

Scientists searched for signs of genetic adaptation related to the plague, which is caused by the bacterium Yersinia pestis.

They identified four genes that were under selection, all of which are involved in the production of proteins that defend our systems from invading pathogens and found that versions of those genes, called alleles, either protected or rendered one susceptible to plague.

Individuals with two identical copies of a particular gene, known as ERAP2, survived the pandemic at a much higher rates than those with the opposing set of copies, because the 'good' copies allowed for more efficient neutralization of Y. pestis by immune cells.

"When a pandemic of this nature -- killing 30 to 50 per cent of the population -- occurs, there is bound to be selection for protective alleles in humans, which is to say people susceptible to the circulating pathogen will succumb. Even a slight advantage means the difference between surviving or passing. Of course, those survivors who are of breeding age will pass on their genes," explains evolutionary geneticist Hendrik Poinar, an author of the Nature paper, director of McMaster's Ancient DNA Centre, and a principal investigator with the Michael G. DeGroote Institute for Infectious Disease Research and McMaster's Global Nexus for Pandemics & Biological Threats.

Europeans living at the time of the Black Death were initially very vulnerable because they had had no recent exposure to Yersinia pestis. As waves of the pandemic occurred again and again over the following centuries, mortality rates decreased.

Researchers estimate that people with the ERAP2 protective allele (the good copy of the gene, or trait), were 40 to 50 per cent more likely to survive than those who did not.

"The selective advantage associated with the selected loci are among the strongest ever reported in humans showing how a single pathogen can have such a strong impact to the evolution of the immune system," says human geneticist Luis Barreiro, an author on the paper, and professor in Genetic Medicine at the University of Chicago.

The team reports that over time our immune systems have evolved to respond in different ways to pathogens, to the point that what had once been a protective gene against plague in the Middle Ages is today associated with increased susceptibility to autoimmune diseases. This is the balancing act upon which evolution plays with our genome.

"This highly original work has been possible only through a successful collaboration between very complementary teams working on ancient DNA, on human population genetics and the interaction between live virulent Yersinia pestis and immune cells," says Javier Pizarro-Cerda, head of the Yersinia Research Unit and director of the World Health Organization Collaborating Centre for Plague at the Pasteur Institute.

"Understanding the dynamics that have shaped the human immune system is key to understanding how past pandemics, like the plague, contribute to our susceptibility to disease in modern times," says Poinar.

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Decoding a direct dialog between the gut microbiota and the brain

Gut microbiota by-products circulate in the bloodstream, regulating host physiological processes including immunity, metabolism and brain functions. Scientists from the Institut Pasteur (a partner research organization of Université Paris Cité), Inserm and the CNRS have discovered that hypothalamic neurons in an animal model directly detect variations in bacterial activity and adapt appetite and body temperature accordingly. These findings demonstrate that a direct dialog occurs between the gut microbiota and the brain, a discovery that could lead to new therapeutic approaches for tackling metabolic disorders such as diabetes and obesity. The findings are due to be published in Science on April 15, 2022.

The gut is the body's largest reservoir of bacteria. A growing body of evidence reveals the degree of interdependence between hosts and their gut microbiota, and emphasizes the importance of the gut-brain axis. At the Institut Pasteur, neurobiologists from the Perception and Memory Unit (Institut Pasteur/CNRS), immunobiologists from the Microenvironment and Immunity Unit (Institut Pasteur/Inserm), and microbiologists from the Biology and Genetics of the Bacterial Cell Wall Unit (Institut Pasteur/CNRS/Inserm) have shared their expertise to investigate how bacteria in the gut directly control the activity of particular neurons in the brain.

The scientists focused on the NOD2 (nucleotide oligomerization domain) receptor which is found inside of mostly immune cells. This receptor detects the presence of muropeptides, which are the building blocks of the bacterial cell wall. Moreover, it has previously been established that variants of the gene coding for the NOD2 receptor are associated with digestive disorders, including Crohn's disease, as well as neurological diseases and mood disorders. However, these data were insufficient to demonstrate a direct relationship between neuronal activity in the brain and bacterial activity in the gut. This was revealed by the consortium of scientists in the new study.

Using brain imaging techniques, the scientists initially observed that the NOD2 receptor in mice is expressed by neurons in different regions of the brain, and in particular, in a region known as the hypothalamus. They subsequently discovered that these neurons' electrical activity is suppressed when they come into contact with bacterial muropeptides from the gut. "Muropeptides in the gut, blood and brain are considered to be markers of bacterial proliferation," explains Ivo G. Boneca, Head of the Biology and Genetics of the Bacterial Cell Wall Unit at the Institut Pasteur (CNRS/Inserm). Conversely, if the NOD2 receptor is absent, these neurons are no longer suppressed by muropeptides. Consequently, the brain loses control of food intake and body temperature. The mice gain weight and are more susceptible to developing type 2 diabetes, particularly in older females.

In this study, the scientists have demonstrated the astonishing fact that neurons perceive bacterial muropeptides directly, while this task was thought to be primarily assigned to immune cells. "It is extraordinary to discover that bacterial fragments act directly on a brain center as strategic as the hypothalamus, which is known to manage vital functions such as body temperature, reproduction, hunger and thirst," comments Pierre-Marie Lledo, CNRS scientist and Head of the Institut Pasteur's Perception and Memory Unit.

The neurons thus appear to detect bacterial activity (proliferation and death) as a direct gauge of the impact of food intake on the intestinal ecosystem. "Excessive intake of a specific food may stimulate the disproportionate growth of certain bacteria or pathogens, thus jeopardizing intestinal balance," says Gérard Eberl, Head of the Microenvironment and Immunity Unit at the Institut Pasteur (Inserm).

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Study with healthcare workers supports that immunity to SARS-CoV-2 is long-lasting

One year after infection by SARS-CoV-2, most people maintain anti-Spike antibodies regardless of the severity of their symptoms, according to a study with healthcare workers co-led by the Barcelona Institute for Global Health (ISGlobal), the Catalan Health Institute (ICS) and the Jordi Gol Institute (IDIAP JG), with the collaboration of the Daniel Bravo Andreu Private Foundation. The results suggest that vaccine-generated immunity will also be long-lasting.

One of the key questions to better predict the pandemic's evolution is the duration of natural immunity. A growing number of studies suggest that most people generate a humoral (antibody) and cellular (T cells) response that is maintained during several months, maybe years.

During the first wave of the pandemic, the team at ICS/IDIAP JG in collaboration with Carlota Dobaño's team at ISGlobal started a follow-up study of a cohort of healthcare workers with COVID-19 -- a total of 173 people working in healthcare centers of central Catalonia. Most infections were mild to moderate, although some cases required hospitalization.

The research team took regular blood samples from September 2020 onwards to measure the level and type of SARS-CoV-2-specific antibodies in these patients. This work was possible thanks to the support of the Daniel Bravo Foundation, which equipped ISGlobal with the latest technology and necessary resources to perform the study and rapidly reach conclusions during the subsequent waves.

"The results obtained until now lead us to believe that immunity to SARS-CoV-2 will last longer than we originally thought. Being a new virus, it is very important to understand how it behaves and affects different people," says Anna Ruiz Comellas, researcher at the Catalan Institute of Health and co-author of the study.

No significant decay in antibody levels was observed over the first five months, and at 9 months, 92.4% of peoples remained seropositive -- 90% of them had IgG, 76% had IgA and 61% had IgM recognising the Spike protein or the receptor binding domain (RBD). The results were similar among healthcare workers who had not been vaccinated in April (95% had IgG, 83% IgA and 25% IgM).

"These data confirm that IgG have a longer duration, but IgM levels, which are supposed to last less, were unexpectedly quite sustained over time," says Gemma Moncunill, ISGlobal researcher and senior co-author of the study, together with Ruíz-Comellas. Hospitalization, fever, and loss of smell and taste were associated with higher antibody levels at five or nine months.

Four reinfections were observed among the participants. Two of them were symptomatic and occurred in seronegative individuals. Another asymptomatic reinfection occurred in a subject with very low antibody levels. These results indicate that anti-Spike antibodies protect against symptomatic infections. "They also indicate that people who have not been previously infected should be prioritised for vaccination, since those who have already been infected may be protected for at least one year," says Anna Ramírez-Morros, first co-author of the study.

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New method could reveal what genes we might have inherited from Neanderthals

Thousands of years ago, archaic humans such as Neanderthals and Denisovans went extinct. But before that, they interbred with the ancestors of present-day humans, who still to this day carry genetic mutations from the extinct species.

Over 40 percent of the Neanderthal genome is thought to have survived in different present-day humans of non-African descent, but spread out so that any individual genome is only composed of up to two percent Neanderthal material. Some human populations also carry genetic material from Denisovans -- a mysterious group of archaic humans that may have lived in Eastern Eurasia and Oceania thousands of years ago.

The introduction of beneficial genetic material into our gene pool, a process known as adaptive introgression, often happened because it was advantageous to humans after they expanded across the globe. To name a few examples, scientists believe some of the mutations affected skin development and metabolism. But many mutations are yet still undiscovered.

Now, researchers from GLOBE Institute at the University of Copenhagen have developed a new method using deep learning techniques to search the human genome for undiscovered mutations.

"We developed a deep learning method called 'genomatnn' that jointly models introgression, which is the transfer of genetic information between species, and natural selection. The model was developed in order to identify regions in the human genome where this introgression could have happened," says Associate Professor Fernando Racimo, GLOBE Institute, corresponding author of the new study.

"Our method is highly accurate and outcompetes previous approaches in power. We applied it to various human genomic datasets and found several candidate beneficial gene variants that were introduced into the human gene pool," he says.

The new method is based on a so-called convolutional neural network (CNN), which is a type of deep learning framework commonly used in image and video recognition.

Using hundreds of thousands of simulations, the researchers at the University of Copenhagen trained the CNN to identify patterns in images of the genome that would be produced by adaptive introgression with archaic humans.

Besides confirming already suggested genetic mutations from adaptive introgression, the researchers also discovered possible mutations that were not known to be introgressed.

"We recovered previously identified candidates for adaptive introgression in modern humans, as well as several candidates which have not previously been described," says postdoc Graham Gower, first author of the new study.

Some of the previously undescribed mutations are involved in core pathways in human metabolism and immunity.

"In European genomes, we found two strong candidates for adaptive introgression from Neanderthals in regions of the genome that affect phenotypes related to blood, including blood cell counts. In Melanesian genomes, we found candidate variants introgressed from Denisovans that potentially affected a wide range of traits, such as blood-related diseases, tumor suppression, skin development, metabolism, and various neurological diseases. It's not clear how such traits are affected in present-day carriers of the archaic variants, e.g. neutrally, positively or negatively, although historically the introgressed genetic material is assumed to have had a positive effect on those individuals carrying them," he explains.

The next stage for the research team is to adapt the method to more complex demographic and selection scenarios to understand the overall fate of Neanderthal genetic material. Graham Gower points out that the team aims to follow up on the function of the candidate variants in the genome that they found in this study.

Looking forward, it remains a challenge to search the human genome for genetic material from as yet unsampled populations, so-called ghost populations. However, the researchers are hopeful that they can further train the neural network to recognize mutations from these unsampled populations.

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Natural immunity to malaria provides clues to potential therapies

WEHI researchers have identified how natural human antibodies can block malaria parasites from entering red blood cells, potentially indicating how new protective therapies could be developed against this globally significant disease.

The research provides greater insight into how antibodies block the entry of Plasmodium vivax malaria parasites into young red blood cells called reticulocytes. It builds on an earlier discovery that the P. vivax latches onto the transferrin receptor 1 (TfR1) to enter cells.

The research, led by Associate Professor Wai-Hong Tham and PhD student Li-Jin Chan from WEHI, alongside Professor Christopher King from Case Western University, US, was published in Nature Communications.

At a glance
 

• By examining antibodies from people with a history of malaria infection, researchers observed that naturally occurring antibodies can block Plasmodium vivax from latching onto transferrin receptor 1 on reticulocytes.
• One way the antibodies work is by preventing parasite proteins from getting close enough to the cell to allow parasite entry.
• The discovery opens up new avenues for developing antibody-based therapies for malaria.
   
• Shedding light on pathogen-blocking antibodies
   
• Plasmodium vivax is the most widespread malaria parasite in the world, and the predominant cause of malaria in the vast majority of countries outside Africa. It is also the main parasite responsible for recurrent malaria infections.

The malaria parasite is a complex single-celled organism, with diverse proteins that help it to invade red blood cells, reproduce and spread. Adhesins on the surface of the parasite are key-like proteins that 'unlock' cells, allowing the parasite to enter.

Previous research studies in Papua New Guinea, Thailand and Brazil showed antibodies against P. vivax adhesins were correlated with protection against infection and disease, Associate Professor Tham said.

"We wanted to understand how these human antibodies in natural infection block the parasite from getting in. By extracting and examining antibodies from people who have had P. vivax infections, we identified the different ways human antibodies against P. vivax work. One of these ways, is by stopping the parasite adhesins from getting too close to the reticulocyte membrane, denying the parasite entry," she said.

This discovery opens the door to potentially preventing not only P. vivax malaria, but also P. falciparum malaria, another significant cause of deaths globally.

"Although this was a vivax study, we believe the implications are that a broadly neutralising antibody could be created to target both P. vivax and P. falciparum malaria infections," Associate Professor Tham said.

Improving detection of relapsing malaria

WEHI Professor Ivo Mueller said beyond understanding how antibodies can block infection, there was also a crucial need to understand the development of immunity and how this could be used to detect P. vivax infections in endemic populations.

"We are currently using this information to develop diagnostic tests that will be used in the field to identify and treat people with hidden vivax infection in their livers and spleens. This is a key step towards eliminating malaria, by preventing silently infected people reinfecting their communities," he said.

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