New insights on how bird flu crosses the species barrier

In recent years, public health measures, surveillance, and vaccination have helped bring about significant progress in reducing the impact of seasonal flu epidemics, caused by human influenza viruses A and B. However, a possible outbreak of avian influenza A (commonly known as 'bird flu') in mammals, including humans, poses a significant threat to public health.

The Cusack group at EMBL Grenoble studies the replication process of influenza viruses. A new study from this group sheds light on the different mutations that the avian influenza virus can undergo to be able to replicate in mammalian cells.

Some avian influenza strains can cause severe disease and mortality. Fortunately, significant biological differences between birds and mammals normally prevent avian influenza from spreading from birds to other species. To infect mammals, the avian influenza virus must mutate to overcome two main barriers: the ability to enter the cell and to replicate within that cell. To cause an epidemic or pandemic, it must also acquire the ability to be transmitted between humans.

However, sporadic contamination of wild and domestic mammals by bird flu is becoming increasingly common. Of particular concern is the recent unexpected infection of dairy cows in the USA by an avian H5N1 strain, which risks becoming endemic in cattle. This might facilitate adaptation to humans, and indeed, a few cases of transmission to humans have been reported, so far resulting in only mild symptoms.

At the heart of this process is the polymerase, an enzyme that orchestrates the virus's replication inside host cells. This flexible protein can rearrange itself according to the different functions it performs during infection. These include transcription -- copying the viral RNA into messenger RNA to make viral proteins -- and replication -- making copies of the viral RNA to package into new viruses.

Viral replication is a complex process to study because it involves two viral polymerases and a host cell protein -- ANP32. Together, these three proteins form the replication complex, a molecular machine that carries out replication. ANP32 is known as a 'chaperone', meaning that it acts as a stabiliser for certain cellular proteins. It can do this thanks to a key structure -- its long acidic tail. In 2015, it was discovered that ANP32 is critical for influenza virus replication, but its function was not fully understood.

The results of the new study, published in the journal Nature Communications, show that ANP32 acts as a bridge between the two viral polymerases -- called replicase and encapsidase. The names reflect the two distinct conformations taken up by the polymerases to perform two different functions -- creating copies of the viral RNA (replicase) and packaging the copy inside a protective coating with ANP32's help (encapsidase).

Through its tail, ANP32 acts as a stabiliser for the replication complex, allowing it to form within the host cell. Interestingly, the ANP32 tail differs between birds and mammals, although the core of the protein remains very similar. This biological difference explains why the avian influenza virus does not replicate easily in mammals and humans.

"The key difference between avian and human ANP32 is a 33-amino-acid insertion in the avian tail, and the polymerase has to adapt to this difference," explained Benoît Arragain, a postdoctoral fellow in the Cusack group and first author of the publication. "For the avian-adapted polymerase to replicate in human cells, it must acquire certain mutations to be able to use human ANP32."

To better understand this process, Arragain and his collaborators obtained the structure of the replicase and encapsidase conformations of a human-adapted avian influenza polymerase (from strain H7N9) while they were interacting with human ANP32. This structure gives detailed information about which amino acids are important in forming the replication complex and which mutations could allow the avian influenza polymerase to adapt to mammalian cells.

To obtain these results, Arragain carried out in vitro experiments at EMBL Grenoble, using the Eukaryotic Expression Facility, the ISBG biophysical platform, and the cryo-electron microscopy platform available through the Partnership for Structural Biology. "We also collaborated with the Naffakh group at the Institut Pasteur, who carried out cellularexperiments," added Arragain. "In addition, we obtained the structure of the human type B influenza replication complex, which is similar to that of influenza A. The cellular experiments confirmed our structural data."

These new insights into the influenza replication complex can be used to study polymerase mutations in other similar strains of the avian influenza virus. It is therefore possible to use the structure obtained from the H7N9 strain and adapt it to other strains such as H5N1.

"The threat of a new pandemic caused by highly pathogenic, human-adapted avian influenza strains with a high mortality rate needs to be taken seriously," said Stephen Cusack, EMBL Grenoble Senior Scientist who led the study and has been studying influenza viruses for 30 years. "One of the key responses to this threat includes monitoring mutations in the virus in the field. Knowing this structure allows us to interpret these mutations and assess if a strain is on the path of adaptation to infect and transmit between mammals."

Read more at Science Daily

Modeling the origins of life: New evidence for an 'RNA World'

Charles Darwin described evolution as "descent with modification." Genetic information in the form of DNA sequences is copied and passed down from one generation to the next. But this process must also be somewhat flexible, allowing slight variations of genes to arise over time and introduce new traits into the population.

But how did all of this begin? In the origins of life, long before cells and proteins and DNA, could a similar sort of evolution have taken place on a simpler scale? Scientists in the 1960s, including Salk Fellow Leslie Orgel, proposed that life began with the "RNA World," a hypothetical era in which small, stringy RNA molecules ruled the early Earth and established the dynamics of Darwinian evolution.

New research at the Salk Institute now provides fresh insights on the origins of life, presenting compelling evidence supporting the RNA World hypothesis. The study, published in Proceedings of the National Academy of Sciences (PNAS) on March 4, 2024, unveils an RNA enzyme that can make accurate copies of other functional RNA strands, while also allowing new variants of the molecule to emerge over time. These remarkable capabilities suggest the earliest forms of evolution may have occurred on a molecular scale in RNA.

The findings also bring scientists one step closer to re-creating RNA-based life in the laboratory. By modeling these primitive environments in the lab, scientists can directly test hypotheses about how life may have started on Earth, or even other planets.

"We're chasing the dawn of evolution," says senior author and Salk President Gerald Joyce. "By revealing these novel capabilities of RNA, we're uncovering the potential origins of life itself, and how simple molecules could have paved the way for the complexity and diversity of life we see today."

Scientists can use DNA to trace the history of evolution from modern plants and animals all the way back to the earliest single-celled organisms. But what came before that remains unclear. Double-stranded DNA helices are great for storing genetic information. Many of those genes ultimately code for proteins -- complex molecular machines that carry out all sorts of functions to keep cells alive. What makes RNA unique is that these molecules can do a bit of both. They're made of extended nucleotide sequences, similar to DNA, but they can also act as enzymes to facilitate reactions, much like proteins. So, is it possible that RNA served as the precursor to life as we know it?

Scientists like Joyce have been exploring this idea for years, with a particular focus on RNA polymerase ribozymes -- RNA molecules that can make copies of other RNA strands. Over the last decade, Joyce and his team have been developing RNA polymerase ribozymes in the lab, using a form of directed evolution to produce new versions capable of replicating larger molecules. But most have come with a fatal flaw: they aren't able to copy the sequences with a high enough accuracy. Over many generations, so many errors are introduced into the sequence that the resulting RNA strands no longer resemble the original sequence and have lost their function entirely.

Until now. The latest RNA polymerase ribozyme developed in the lab includes a number of crucial mutations that allow it to copy a strand of RNA with much higher accuracy.

In these experiments, the RNA strand being copied is a "hammerhead," a small molecule that cleaves other RNA molecules into pieces. The researchers were surprised to find that not only did the RNA polymerase ribozyme accurately replicate functional hammerheads, but over time, new variations of the hammerheads began to emerge. These new variants performed similarly, but their mutations made them easier to replicate, which increased their evolutionary fitness and led them to eventually dominate the lab's hammerhead population.

"We've long wondered how simple life was at its beginning and when it gained the ability to start improving itself," says first author Nikolaos Papastavrou, a research associate in Joyce's lab. "This study suggests the dawn of evolution could have been very early and very simple. Something at the level of individual molecules could sustain Darwinian evolution, and that might have been the spark that allowed life to become more complex, going from molecules to cells to multicellular organisms."

The findings highlight the critical importance of replication fidelity in making evolution possible. The RNA polymerase's copying accuracy must exceed a critical threshold to maintain heritable information over multiple generations, and this threshold would have risen as the evolving RNAs increased in size and complexity.

Joyce's team is re-creating this processin laboratory test tubes, applying increasing selective pressure on the system to produce better-performing polymerases, with the goal of one day producing an RNA polymerase that can replicate itself. This would mark the beginnings of autonomous RNA life in the laboratory, which the researchers say could be accomplished within the next decade.

The scientists are also interested in what else might occur once this mini "RNA World" has gained more autonomy.

"We've seen that selection pressure can improve RNAs with an existing function, but if we let the system evolve for longer with larger populations of RNA molecules, can new functions be invented?" says co-author David Horning, a staff scientist in Joyce's lab. "We're excited to answer how early life could ratchet up its own complexity, using the tools developed here at Salk."

Read more at Science Daily

Using cancer's strength to fight against it

Scientists at the UC San Francisco (UCSF) and Northwestern Medicine may have found a way around the limitations of engineered T cells by borrowing a few tricks from cancer itself.

By studying mutations in malignant T cells that cause lymphoma, they zeroed in on one that imparted exceptional potency to engineered T cells.

Inserting a gene encoding this unique mutation into normal human T cells made them more than 100 times more potent at killing cancer cells without any signs of becoming toxic.

While current immunotherapies work only against cancers of the blood and bone marrow, the T cells engineered by Northwestern and UCSF were able to kill tumors derived from skin, lung and stomach in mice.

The team has already begun working toward testing this new approach in people.

"We used nature's roadmap to make better T cell therapies," said Dr. Jaehyuk Choi, an associate professor of dermatology and of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

"The superpower that makes cancer cells so strong can be transferred into T cell therapies to make them powerful enough to eliminate what were once incurable cancers."

"Mutations underlying the resilience and adaptability of cancer cells can super-charge T cells to survive and thrive in the harsh conditions that tumors create," said Kole Roybal, associate professor of microbiology and immunology at UCSF, center director for the Parker Institute for Cancer Immunotherapy Center at UCSF, and a member of the Gladstone Institute of Genomic Immunology.

The study will appear in Nature Feb. 7.

A solution hiding in plain sight

Creating effective immunotherapies has proven difficult against most cancers because the tumor creates an environment focused on sustaining itself, redirecting resources like oxygen and nutrients for its own benefit.

Often, tumors hijack the body's immune system, causing it to defend the cancer, instead of attacking it.

Not only does this impair the ability of regular T cells to target cancer cells, it undermines the effectiveness of the engineered T cells that are used in immunotherapies, which quickly tire against the tumor's defenses.

"For cell-based treatments to work under these conditions," Roybal said, "we need to give healthy T cells abilities that are beyond what they can naturally achieve."

The Northwestern and UCSF teams screened 71 mutations found in patients with T cell lymphoma and identified which ones could enhance engineered T cell therapies in mouse tumor models.

Eventually, they isolated one that proved both potent and non-toxic, subjecting it to a rigorous set of safety tests.

"Our discoveries empower T cells to kill multiple cancer types," said Choi, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University.

"This approach performs better than anything we've seen before." Their discoveries can be incorporated into treatments for many types of cancer, the scientists said.

"T cells have the potential to offer cures to people who are heavily pretreated and have a poor prognosis," Choi said.

"Cell therapies are living drugs, because they live and grow inside the patient and can provide long-term immunity against cancer."

In collaboration with the Parker Institute for Cancer Immunotherapy and Venrock, Roybal and Choi are building a new company, Moonlight Bio, to realize the potential of their groundbreaking approach.

They are currently developing a cancer therapy that they hope to begin testing in people within the next few years.

"We see this as the starting point," Roybal said. "There's so much to learn from nature about how we can enhance these cells and tailor them to different types of diseases."

Read more at Science Daily

Unraveling the long history of breast cancer formation

From the early stages of cell mutations starting in puberty to their manifestations as breast cancer in later years, the entire process has remained shrouded in mystery.

Now, a team of researchers at Kyoto University has revealed the mechanism by which breast cancer is formed in the cells of the mammalian epithelium, whose main function is to secrete milk.

According to the team's first analysis, approximately 20 mutations accumulate annually in each epithelial cell until menopause. After menopause, however, the mutation rate significantlydecreases.

"Additionally, our results suggest that estrogen influences mutation accumulation in mammary epithelium, which correlates with our discovery of decreased accumulation after childbirth," says corresponding author Seishi Ogawa of KyotoU's Graduate School of Medicine.

As 70% of breast cancers are understood to be estrogen-sensitive, Ogawa's team may shed light on estrogen's role in the initiation of breast cancer.

Further investigation of the genetic relationship between breast cancer, its surrounding lesions, and normal epithelial cells led to mapping breast cancer's translocation-positive expansion. During this expansion process, cells of multiple origins that would subsequently develop breast cancer manifested themselves at the average age of 30. Previous studies have focused on driver mutations -- the genetic changes in cells that are already cancerous -- leading to abnormal growth. But these findings only paint a partial picture of the process and do not reveal the timing and order of driver mutations or cancer formation.

"Normal-looking tissues may already contain numerous populations of non-cancer cells -- or clones -- that have acquired mutations in cancer-related genes," says co-author author Tomomi Nishimuraof KyotoU's Graduate School of Medicine.

After examining the similarities and differences in the mutations of both cancer and non-cancer lesions originating from the clones, the team reconstructed an evolutionary tree to visualize the unique pattern of cancer evolution.

Read more at Science Daily

Novel molecules fight viruses by bursting their bubble-like membranes

Antiviral therapies are notoriously difficult to develop, as viruses can quickly mutate to become resistant to drugs. But what if a new generation of antivirals ignores the fast-mutating proteins on the surface of viruses and instead disrupts their protective layers?

"We found an Achilles heel of many viruses: their bubble-like membranes. Exploiting this vulnerability and disrupting the membrane is a promising mechanism of action for developing new antivirals," said Kent Kirshenbaum, professor of chemistry at NYU and the study's senior author.

In a new study published Aug. 2 in the journal ACS Infectious Diseases, the researchers show how a group of novel molecules inspired by our own immune system inactivates several viruses, including Zika and chikungunya. Their approach may not only lead to drugs that can be used against many viruses, but could also help overcome antiviral resistance.

The urgent need for new antivirals

Viruses have different proteins on their surfaces that are often the targets of therapeutics like monoclonal antibodies and vaccines. But targeting these proteins has limitations, as viruses can quickly evolve, changing the properties of the proteins and making treatments less effective. These limitations were on display when new SARS-CoV-2 variants emerged that evaded both the drugs and the vaccines developed against the original virus.

"There is an urgent need for antiviral agents that act in new ways to inactivate viruses," said Kirshenbaum. "Ideally, new antivirals won't be specific to one virus or protein, so they will be ready to treat new viruses that emerge without delay and will be able to overcome the development of resistance."

"We need to develop this next generation of drugs now and have them on the shelves in order to be ready for the next pandemic threat -- and there will be another one, for sure," added Kirshenbaum.

Drawing inspiration from our immune systems

Our innate immune system combats pathogens by producing antimicrobial peptides, the body's first line of defense against bacteria, fungi, and viruses. Most viruses that cause disease are encapsulated in membranes made of lipids, and antimicrobial peptides work by disrupting or even bursting these membranes.

While antimicrobial peptides can be synthesized in the lab, they are rarely used to treat infectious diseases in humans because they break down easily and can be toxic to healthy cells. Instead, scientists have developed synthetic materials called peptoids, which have similar chemical backbones to peptides but are better able to break through virus membranes and are less likely to degrade.

"We began to think about how to mimic natural peptides and create molecules with many of the same structural and functional features as peptides, but are composed of something that our bodies won't be able to rapidly degrade," said Kirshenbaum.

The researchers investigated seven peptoids, many originally discovered in the lab of Annelise Barron at Stanford, a co-author of the study. The NYU team studied the antiviral effects of the peptoids against four viruses: three enveloped in membranes (Zika, Rift Valley fever, and chikungunya) and one without (coxsackievirus B3).

"We were particularly interested in studying these viruses as they have no available treatment options," said Patrick Tate, a chemistry PhD student at NYU and the study's first author.

How peptoids disrupt viral membranes and avoid other cells

The membranes surrounding viruses are made of different molecules than the virus itself, as lipids are acquired from the host to form membranes. One such lipid, phosphatidylserine, is present in the membrane on the outside of viruses, but is sequestered towards the interior of human cells under normal conditions.

"Because phosphatidylserine is found on the exterior of viruses, it can be a specific target for peptoids to recognize viruses, but not recognize -- and therefore spare -- our own cells," said Tate. "Moreover, because viruses acquire lipids from the host rather than encoding from their own genomes, they have better potential to avoid antiviral resistance."

The researchers tested seven peptoids against the four viruses. They found that the peptoids inactivated all three enveloped viruses -- Zika, Rift Valley fever, and chikungunya -- by disrupting the virus membrane, but did not disrupt coxsackievirus B3, the only virus without a membrane.

Moreover, chikungunya virus containing higher levels of phosphatidylserine in its membrane was more susceptible to the peptoids. In contrast, a membrane formed exclusively with a different lipid named phosphatidylcholine was not disrupted by the peptoids, suggesting that phosphatidylserine is crucial in order for peptoids to reduce viral activity.

"We're now starting to understand how peptoids actually exert their antiviral effect -- specifically, through the recognition of phosphatidylserine," said Tate.

The researchers are continuing pre-clinical studies to evaluate the potential of these molecules in fighting viruses and to understand if they can overcome the development of resistance. Their peptoid-focused approach may hold promise for treating a wide range of viruses with membranes that can be difficult to treat, including Ebola, SARS-CoV-2, and herpes.

Read more at Science Daily

Using paleogenomics to elucidate 10,000 years of immune system evolution

Scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France have used paleogenomics to trace 10,000 years of human immune system evolution. They analyzed the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia. They were able to date the increase in frequency of most of the mutations that are advantageous in defending against pathogens to after the Bronze Age, 4,500 years ago. The scientists also observed that mutations conferring a higher risk of developing inflammatory disorders have become more frequent over the past 10,000 years. These enlightening results on the effects of natural selection on immunity genes were published in the journal Cell Genomics on January 13, 2023.

In the 1950s, the geneticist J.B.S. Haldane attributed the maintenance or persistence of the mutation responsible for anomalies in red blood cells commonly observed in Africa to the protection these anomalies provided against malaria, an endemic infection that claims millions of lives. This theory suggested that pathogens are among the strongest selective pressures faced by humans. Several population genetics studies subsequently confirmed the theory. But major questions remained, especially regarding the specific epochs during which the selective pressures exerted by pathogens on human populations were strongest and their impact on the present-day risk of developing inflammatory or autoimmune disorders.

To address these questions, scientists from the Institut Pasteur, Université Paris Cité, the CNRS and the Collège de France, in collaboration with the Imagine Institute and The Rockefeller University (United States), adopted an approach based on paleogenomics. This discipline, which studies the DNA from fossil remains, has led to major discoveries about the history and evolution of humans and human diseases, as illustrated by the decision to award the 2022 Nobel Prize in Physiology or Medicine to the paleogeneticist Svante Pääbo. In the study led by the Institut Pasteur, published on January 13 in the journal Cell Genomics, the scientists analyzed the variability of the genomes of more than 2,800 individuals who lived in Europe over the past ten millennia -- a period covering the Neolithic, the Bronze Age, the Iron Age, the Middle Ages and the present.

By reconstituting the evolution over time of hundreds of thousands of genetic mutations, the scientists initially identified mutations that rapidly increased in frequency in Europe, indicating that they were advantageous. These mutations that evolved under "positive" natural selection are mainly located in 89 genes enriched in functions relating to the innate immune response, including especially the OAS genes -- which are responsible for antiviral activity -- and the gene responsible for the ABO blood group system. Surprisingly, most of these positive selection events, which demonstrate a genetic adaptation to the pathogenic environment, began recently, from the start of the Bronze Age, around 4,500 years ago. The scientists explain this "acceleration" in adaptation by the growth in the human population during this period and/or by strong selective pressures exerted by pathogens in the Bronze Age, probably linked to the spread of severe infectious diseases such as plague.

At the same time, the scientists also looked at the opposite situation, in other words, mutations whose frequency fell significantly over the past ten millennia. These mutations are probably subject to "negative" selection because they increase the risk of disease. They noted that once again, these selection events mainly began in the Bronze Age. Many of these disadvantageous mutations were also located in genes associated with the innate immune response, such as TYK2, LPB, TLR3 and IL23R, and have been confirmed in experimental research to have a deleterious effect in terms of infectious disease risk. The results emphasize the value of adopting an evolutionary approach in research on genetic susceptibility to infectious diseases.

Finally, the scientists explored the theory that the selection exerted by pathogens in the past gave an advantage to alleles conferring resistance to infectious diseases, but that in turn these alleles have increased the present-day risk of autoimmune or inflammatory disorders. They investigated the few thousand mutations known to increase susceptibility firstly to tuberculosis, hepatitis, HIV or COVID-19, and secondly to rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease. By looking at the evolution of these mutations over time, they observed that those associated with an increased risk of inflammatory disorders -- including Crohn's disease -- became more frequent over the past 10,000 years, while the frequency of those associated with a risk of developing infectious diseases decreased. "These results suggest that the risk of inflammatory disorders has increased in Europeans since the Neolithic period because of a positive selection of mutations improving resistance to infectious diseases," explains Lluis Quintana-Murci, director of the study and Head of the Human Evolutionary Genetics Unit (Institut Pasteur/CNRS Evolutionary Genomics, Modeling and Health Unit/Université Paris Cité).

The results of the study, which harnessed the huge potential of paleogenomics, show that natural selection has targeted human immunity genes over the past ten millennia in Europe, especially since the start of the Bronze Age, and contributed to present-day disparities in terms of the risk of infectious and inflammatory diseases.

Read more at Science Daily

Eye-opening discovery about adult brain's ability to recover vision

A discovery about how some visually impaired adults could start to see offers a new vision of the brain's possibilities. The finding that the adult brain has the potential to partially recover from inherited blindness comes from a collaboration between researchers in the University of California, Irvine School of Biological Sciences and the School of Medicine. Their paper appears in Current Biology.

The team was examining treatment for Leber congenital amaurosis, known as LCA. The term refers to a group of inherited retinal diseases distinguished by severe visual impairment at birth. The condition, which stems from mutations in any of over two dozen genes, causes degeneration or dysfunction in the retina's photoreceptors.

Administering chemical compounds that target the retina, called synthetic retinoids, can restore a notable amount of vision in children with LCA. The UCI team wanted to find out if the treatment could make a difference for adults who have the condition.

"Frankly, we were blown away by how much the treatment rescued brain circuits involved in vision," said Sunil Gandhi, professor of neurobiology and behavior and the corresponding author. Gandhi is a fellow of UCI's Center for the Neurobiology of Learning and Memory and a member of the Center for Translational Vision Research. "Seeing involves more than intact and functioning retinae. It starts in the eye, which sends signals throughout the brain. It's in the central circuits of the brain where visual perception actually arises." Until now, scientists believed that the brain must receive those signals in childhood so that central circuits could wire themselves correctly.

Working with rodent models of LCA, the collaborators were surprised by what they found. "The central visual pathway signaling was significantly restored in adults, especially the circuits that deal with information coming from both eyes," Gandhi said. "Immediately after the treatment, the signals coming from the opposite-side eye, which is the dominant pathway in the mouse, activated two times more neurons in the brain. What was even more mind-blowing was that the signals coming from the same-side eye pathway activated five-fold more neurons in the brain after the treatment and this impressive effect was long-lasting. The restoration of visual function at the level of the brain was much greater than expected from the improvements we saw at the level of the retinae. The fact that this treatment works so well in the central visual pathway in adulthood supports a new concept, which is that there is latent potential for vision that is just waiting to be triggered."

The finding opens exciting research possibilities. "Whenever you have a discovery that breaks with your expectations about the possibility for the brain to adapt and rewire, it teaches you a broader concept," Gandhi said. "This new paradigm could aid in the development of retinoid therapies to more completely rescue the central visual pathway of adults with this condition."

Read more at Science Daily

Corals pass mutations acquired during their lifetimes to offspring

In a discovery that challenges over a century of evolutionary conventional wisdom, corals have been shown to pass somatic mutations -- changes to the DNA sequence that occur in non-reproductive cells -- to their offspring. The finding, by an international team of scientists led by Penn State biologists, demonstrates a potential new route for the generation of genetic diversity, which is the raw material for evolutionary adaptation, and could be vital for allowing endangered corals to adapt to rapidly changing environmental conditions.

"For a trait, such as growth rate, to evolve, the genetic basis of that trait must be passed from generation to generation," said Iliana Baums, professor of biology at Penn State and leader of the research team. "For most animals, a new genetic mutation can only contribute to evolutionary change if it occurs in a germline or reproductive cell, for example in an egg or sperm cell. Mutations that occur in the rest of the body, in the somatic cells, were thought to be evolutionarily irrelevant because they do not get passed on to offspring. However, corals appear to have a way around this barrier that seems to allow them to break this evolutionary rule."

Since the time of Darwin, our understanding of evolution has become ever more detailed. We now know that an organism's traits are heavily determined by the sequence of their DNA. Individuals in a population vary in their DNA sequence, and this genetic variation can lead to the variation in traits, such as body size, that could give an individual a reproductive advantage. Only rarely does a new genetic mutation occur that gives an individual such a reproductive advantage and evolution can only proceed further if -- and this is the key -- the individual can pass the change to its offspring.

"In most animals, reproductive cells are segregated from body cells early in development," said Kate Vasquez Kuntz, a graduate student at Penn State and the co-lead author of the study. "So only genetic mutations that occur in the reproductive cells have the potential to contribute to the evolution of the species. This slow process of waiting for rare mutations in a particular set of cells can be particularly problematic given the rapid nature of climate change. However, for some organisms, like corals, the segregation of reproductive cells from all other cells may occur later in development or may never occur at all, allowing a path for genetic mutations to travel from a parent's body to its offspring. This would increase genetic variation and potentially even serve as a 'pre-screening' system for advantageous mutations."

Corals can reproduce both asexually (through budding and colony fragmentation) and sexually, by producing egg and sperm cells. For the Elkhorn corals studied here, which broadcast their egg and sperm cells into the water in spawning events, eggs from one coral colony are usually fertilized by sperm from a neighboring colony. However, the research team found that some Elkhorn coral eggs developed into viable offspring without a second coral being involved, a kind of single-parent sexual reproduction.

"This single-parent reproduction allowed us to more easily search for potential somatic mutations from the parent coral and track them into the offspring by simplifying the total number of genetic possibilities that could occur in the offspring," said Sheila Kitchen, co-lead author of the study, a postdoctoral researcher at Penn State and the California Institute of Technology co-lead author of the study.

The research team genotyped samples -- using a high-resolution molecular tool called a microarray to investigate DNA differences between the samples -- from ten different locations on a large Elkhorn coral colony that had produced single-parent offspring, and samples from five neighboring colonies at nearly 20,000 genetic locations. The results showed that all six of the separate coral colonies belonged to the same original coral genotype (known as a "genet"), meaning essentially that they were clones derived from a single original colony through asexual reproduction and colony fragmentation. Thus, any genetic variation found in these corals would have been the result of somatic mutation. The team found a total of 268 somatic mutations in the samples, with each coral sample harboring between 2 and 149 somatic mutations.

The team then looked at the single-parent offspring from the parent Elkhorn coral colony and found that 50% of the somatic mutations had been inherited. The exact mechanism of how the somatic mutations make their way into germline cells in the corals is still unknown, but the researchers suspect that the segregation between body and germline cells in corals may be incomplete and some body cells may retain the capacity to form germ cells, allowing somatic mutations to make their way into offspring. They also found evidence for the inheritance of somatic mutations in some offspring from the mating of two separate coral parents but will need additional studies to confirm this.

Read more at Science Daily

Gene mutation linked to learning deficits in 'Clueless' mice

A single mutation in a gene, Kcnc3, which encodes a potassium channel in neurons, causes learning deficits in mice, UT Southwestern researchers report in a new study in PNAS. The novel mutation decreases the activity of neurons in the hippocampus, the area of the brain important for learning and memory, and highlights a new role for potassium channels.

"Learning and memory are very complex at the genetic level. Unbiased searches for genes underlying learning and memory have not been successfully conducted in mice before," said Joseph Takahashi, Ph.D., Professor and Chair of Neuroscience at UT Southwestern and a Howard Hughes Medical Institute Investigator.

The discovery of the Kcnc3 mutation came out of an extraordinary effort by Dr. Takahashi and colleagues to conduct a large-scale mutagenesis screen in mice. Using a highly potent mutagen called ENU, the researchers induced random mutations in the mouse genome. The progeny of ENU-treated mice were then screened for neural and behavioral traits that could be mapped to specific genes to identify the causal mutation. This approach to unbiased gene discovery is called forward genetics.

From the mutagenesis screen, Dr. Takahashi and his team isolated a mutant mouse with spatial learning defects, which they named Clueless. In fear-conditioning tests, the mutants exhibited reduced freezing (a natural fear response in mice) as well as defects in long-term and short-term memory. The defects in Clueless mice mapped to a mutation in the Kcnc3 gene, which encodes a subunit of a special type of potassium channel called a voltage-gated potassium channel.

This is the first study to implicate Kcnc3 in learning, explained Dr. Takahashi, an investigator in UTSW's Peter O'Donnell Jr. Brain Institute. The full Kcnc3 knockout mouse model shows only mild gait issues with no defects in learning and memory, which could be due to developmental compensation or functional redundancy with other voltage-gated potassium channel subunits. Future research will help to answer some of these outstanding questions.

Dr. Takahashi said the findings underscore the power of applying forward genetics to gene discovery and could lead to potential new targets for therapy in learning and memory as well as other disease areas.

Read more at Science Daily

Plant study hints evolution may be predictable

Evolution has long been viewed as a rather random process, with the traits of species shaped by chance mutations and environmental events -- and therefore largely unpredictable.

But an international team of scientists led by researchers from Yale University and Columbia University has found that a particular plant lineage independently evolved three similar leaf types over and over again in mountainous regions scattered throughout the neotropics.

The findings provided the first examples in plants of a phenomenon known as "replicated radiation," in which similar forms evolve repeatedly within different regions, suggesting that evolution is not always such a random process but can be predicted.

The study is published July 18 in the journal Nature Ecology & Evolution.

"The findings demonstrate how predictable evolution can actually be, with organismal development and natural selection combining to produce the same forms again and again under certain circumstances," said Yale's Michael Donoghue, Sterling Professor Emeritus of Ecology & Evolutionary Biology and co-corresponding author. "Maybe evolutionary biology can become much more of a predictive science than we ever imagined in the past."

For the study, the research team studied the genetics and morphology of the plant lineage Viburnum, a genus of flowering plants that began to spread south from Mexico into Central and South America some 10 million years ago. Donoghue studied this same plant group for his Ph.D. dissertation at Harvard 40 years ago. At the time, he argued in favor of an alternative theory in which large, hair-covered leaves and small smooth leaves evolved early in the evolution of the group and then both forms migrated separately, being dispersed by birds, through the various mountain ranges.

The new genetic analyses reported in the paper, however, show that the two different leaf types evolved independently, in parallel, in each of a number of mountain regions.

"I came to the wrong conclusion because I lacked the relevant genomic data back in the 1970s," Donoghue said.

The team found that a very similar set of leaf types evolved in nine of 11 regions studied. However, the full array of leaf types may have yet to evolve in places where Viburnum has only more recently migrated. For instance, the mountains of Bolivia lack the large hairy leaf types found in other wetter areas with little sunshine in the cloud forest in Mexico, Central America, and northern South America.

"These plants arrived in Bolivia less than a million years ago, so we predict that the large, hairy leaf form will eventually evolve in Bolivia as well," Donoghue said.

Several examples of replicated radiation have been found in animals, such as Anolis lizards in the Caribbean. In that case, the same set of body forms, or "ectomorphs," evolved independently on several different islands. With a plant example now in hand, evolutionary biologists will try to discover the general circumstances under which solid predictions can be made about evolutionary trajectories.

"This collaborative work, spanning decades, has revealed a wonderful new system to study evolutionary adaptation," said Ericka Edwards, professor of ecology and evolutionary biology at Yale and co-corresponding author of the paper. "Now that we have established the pattern, our next challenges are to better understand the functional significance of these leaf types and the underlying genetic architecture that enables their repeated emergence."

Read more at Science Daily

When did the genetic variations that make us human emerge?

The study of the genomes of our closest relatives, the Neanderthals and Denisovans, has opened up new research paths that can broaden our understanding of the evolutionary history of Homo sapiens. A study led by the University of Barcelona has made an estimation of the time when some of the genetic variants that characterise our species emerged. It does so by analysing mutations that are very frequent in modern human populations, but not in these other species of archaic humans.

The results, published in the journal Scientific Reports, show two moments in which mutations accumulated: one around 40,000 years ago, associated with the growth of the Homo sapiens population and its departure from Africa, and an older one, more than 100,000 years ago, related to the time of the greatest diversity of types of Homo sapiens in Africa.

"The understanding of the deep history of our species is expanding rapidly. However, it is difficult to determine when the genetic variants that distinguish us from other human species emerged. In this study, we have placed species-specific variants on a timeline. We have discovered how these variants accumulate over time, reflecting events such as the point of divergence between Homo sapiens and other human species around 100,000 years ago," says Alejandro Andirkó, first author of this article, which was part of his doctoral thesis at the UB.

The study, led by Cedric Boeckx, ICREA research professor in the section of General Linguistics and member of the Institute of Complex Systems of the UB (UBICS), included the participation of Juan Moriano, UB researcher, Alessandro Vitriolo and Giuseppe Testa, experts from the University of Milan and the European Institute of Oncology, and Martin Kuhlwilm, researcher at the University of Vienna.

Predominance of behavioural and facial-related variations

The results of the research study also show differences between evolutionary periods. Specifically, they highlight the predominance of genetic variants related to behaviour and facial structure -- key characteristics in the differentiation of our species from other human species -- more than 300,000 years ago, a date that coincides with the available fossil and archaeological evidence. "We have discovered sets of genetic variants which affect the evolution of the face and which we have dated between 300,000 and 500,000 years ago, the period just prior to the dating of the earliest fossils of our species, such as the ones discovered at the Jebel Irhoud archaeological site in Morocco," notes Andirkó.

The researchers also analysed variants related to the brain, the organ that can best help explain key features of the rich repertoire of behaviours associated with Homo sapiens. Specifically, they dated variants which medical studies conducted in present-day humans have linked to the volume of the cerebellum, corpus callosum and other structures. "We found that brain tissues have a particular genomic expression profile at different times in our history; that is, certain genes related to neural development were more highly expressed at certain times," says the researcher.

Supporting the mosaic nature of the evolution of Homo sapiens

These results complement an idea that is dominant in evolutionary anthropology: that there is no linear history of human species, but that different branches of our evolutionary tree coexisted and often intersected. "The breadth of the range of human diversity in the past has surprised anthropologists. Even within Homo sapiens there are fossils, such as the ones I mentioned earlier from Jebel Irhoud, which, because of their features, were thought to belong to another species. That's why we say that human beings have lived a mosaic evolution," he notes.

"Our results," the researcher continues, "offer a picture of how our genetics changed, which fits this idea, as we found no evidence of evolutionary changes that depended on one or a several key mutations," he says.

Application of machine learning techniques

The methodology used in the study was based on a Genealogical Estimation of Variant Age method, developed by researchers at the University of Oxford. Once they had this estimation, they applied a machine learning tool to predict which genes have changed the most in certain time windows and which tissues these genes may have impacted. Specifically, they used ExPecto, a deep learning tool that uses a convolutional network -- a type of computational model -- to predict gene expression levels and function from a DNA sequence.

"Since there are no data on the genomic expression of variants in the past, this tool is an approach to a problem that has not been addressed until now. Although the use of machine learning prediction is increasingly common in the clinical world, as far as we know, nobody has tried to predict the consequences of genomic changes over time," notes Andirkó.

The importance of the perinatal phase in the brain development of our species

In a previous study, the same UB team, together with the researcher Raül Gómez Buisán, used genomic information from archaic humans. In that study they analysed genomic deserts, regions of the genome of our species where there are no genetic fragments of Neanderthals or Denisovans, and which, moreover, have been subjected to positive pressure in our species: that is, they have accumulated more mutations than would have been expected by neutral evolution. The researchers studied the expression of genes -- i.e., which proteins code for different functions -- found in desert regions throughout brain development, from prenatal to adult stages, covering sixteen brain structures. The results showed differences in gene expression in the cerebellum, striatum and thalamus. "These results bring into focus the relevance of brain structures beyond the neocortex, which has traditionally dominated research on the evolution of the human brain," says Juan Moriano.

Read more at Science Daily

'Junk' DNA could lead to cancer by stopping copying of DNA

Scientists have found that non-coding 'junk' DNA, far from being harmless and inert, could potentially contribute to the development of cancer.

Their study has shown how non-coding DNA can get in the way of the replication and repair of our genome, potentially allowing mutations to accumulate.

It has been previously found that non-coding or repetitive patterns of DNA -- which make up around half of our genome -- could disrupt the replication of the genome.

But until now scientists have not understood the underlying mechanism, or how it could contribute to cancer's development. In the new study, scientists at The Institute of Cancer Research, London, reconstituted the entire process of DNA replication in a test tube in order to understand it more completely.

The researchers were able to describe how repetitive patterns of DNA are copied during replication and how they are able to stall replication entirely -- increasing the risk of errors that can be an early driver of cancer. This vital knowledge may eventually lead to better drugs and treatments.

The researchers believe the work could also help to improve the diagnosis and monitoring of some cancers, such as bowel cancer, where common errors in copying the repetitive sequences of DNA indicate whether cancer is progressing.

The study, published in Nature Communications, was funded by Wellcome and the Royal Society, with additional support from The Institute of Cancer Research (ICR) itself.

Scientists at the ICR -- a charity and research institute -- found that when the DNA replication machinery encountered repetitive DNA, it was able to unwind the DNA strands, but it sometimes failed to copy the opposite DNA strand. This error could cause replication to stall, resulting in collapse of the replication machinery in a manner similar to that induced by DNA damage.

The findings lead scientists to believe that repetitive DNA sequences could trigger a damage response signal indicating that errors in DNA replication have occurred and require repair.

DNA damage and ensuing genome instability are known to promote cancer formation and progression, so the research strengthens the link between junk DNA and cancer.

It was scientists at the ICR who, in the 1960s, provided the first conclusive evidence that DNA damage is the fundamental cause of cancer. In the early 2000s, ICR researchers then showed that drugs called PARP inhibitors could be genetically targeted against cancers with DNA repair mutations.

Our researchers now hope that improved understanding of DNA replication, and how it can go wrong, might lead to new ways of treating the disease.

Study leader Dr Gideon Coster, Team Leader in Genome Replication at The Institute of Cancer Research, London, said:

"We wanted to understand why it seems more difficult for cells to copy repetitive DNA sequences than other parts of the genome. Our study suggests that so-called junk DNA is actually playing an important and potentially damaging role in cells, by blocking DNA replication and potentially opening the door to cancerous mutations.

"We now believe that repetitive DNA sequences trigger a response that is very similar to the one induced by DNA damage, which we know can lead to cancer. Our study therefore fundamentally advances our understanding of cancer, and I'm hopeful it will help us come up with new treatments in the future."

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:

"This study helps to unravel the puzzle of junk DNA -- showing how these repetitive sequences can block DNA replication and repair. It's possible that this mechanism could play a role in the development of cancer as a cause of genetic instability -- especially as cancer cells start dividing more quickly and so place the process of DNA replication under more stress.

Read more at Science Daily

The importance of elders

According to long-standing canon in evolutionary biology, natural selection is cruelly selfish, favoring traits that help promote reproductive success. This usually means that the so-called "force" of selection is well equipped to remove harmful mutations that appear during early life and throughout the reproductive years. However, by the age fertility ceases, the story goes that selection becomes blind to what happens to our bodies. After the age of menopause, our cells are more vulnerable to harmful mutations. In the vast majority of animals, this usually means that death follows shortly after fertility ends.

Which puts humans (and some species of whale) in a unique club: animals that continue to live long after their reproductive lives end. How is it that we can live decades in selection's shadow?

"From the perspective of natural selection, long post-menopausal life is a puzzle," said UC Santa Barbara anthropology professor Michael Gurven. In most animals, including chimpanzees -- our closest primate brethren -- this link between fertility and longevity is very pronounced, where survival drops in sync with the ability to reproduce. Meanwhile in humans, women can live for decades after their ability to have children ends. "We don't just gain a few extra years -- we have a true post-reproductive life stage," Gurven said.

In a paper published in the Proceedings of the National Academy of Sciences, senior author Gurven, with former UCSB postdoctoral fellow and population ecologist Raziel Davison, challenge the longstanding view that the force of natural selection in humans must decline to zero once reproduction is complete.

They assert that a long post-reproductive lifespan is not just due to recent advancements in health and medicine. "The potential for long life is part of who we are as humans, an evolved feature of the life course," Gurven said.

The secret to our success? Our grandparents.

"Ideas about the potential value of older adults have been floating around for awhile," Gurven said. "Our paper formalizes those ideas, and asks what the force of selection might be once you take into account the contributions of older adults."

For example, one of the leading ideas for human longevity is called the Grandmother Hypothesis -- the idea that, through their efforts, maternal grandmothers can increase their fitness by helping improve the survival of their grandchildren, thereby enabling their daughters to have more children. Such fitness effects help ensure that the grandmother's DNA is passed down.

"And so that's not reproduction, but it's sort of an indirect reproduction. The ability to pool resources, and not just rely on your own efforts, is a game changer for highly social animals like humans," Davison said.

In their paper, the researchers take the kernel of that idea -- intergenerational transfers, or resource sharing between old and young -- and show that it, too, has played a fundamental role in the force of selection at different ages. Food sharing in non-industrial societies is perhaps the most obvious example.

"It takes up to two decades from birth before people produce more food than they're consuming," said Gurven, who has studied the economy and demography of the Tsimané and other indigenous groups of South America. A lot of food has to be procured and shared to get kids to the point where they can fend for themselves and be productive group members. Adults fill most of this need with their ability to obtain more food than they need for themselves, a provisioning strategy that has sustained pre-industrial societies for ages and also carries over into industrialized societies.

"In our model, the large surplus that adults produce helps improve the survival and fertility of close kin, and of other group members who reliably share their food, too," Davison said. "Viewed through the lens of food production and its effects, it turns out that the indirect fitness value of adults is also highest among reproductive-aged adults. But using demographic and economic data from multiple hunter-gatherers and horticulturalists, we find that the surplus provided by older adults also generates positive selection for their survival. We calculate all this extra fitness in late adulthood to be worth up to a few extra kids!"

"We show that elders are valuable, but only up to a point," contends Gurven. "Not all grandmothers are worth their weight. By about their mid-seventies, hunter-gatherers and farmers end up soaking up more resources than they provide. Plus, by their mid-seventies, most of their grandkids won't be dependents anymore, and so the circle of close kin who stand to benefit from their help is small."

But food isn't everything. Beyond getting fed, children are also taught and socialized, trained in relevant skills and worldviews. This is where older adults can make their biggest contributions: While they don't contribute as much to the food surplus, they have the accumulation of a lifetime of skills they can deploy to ease the burden of childcare on parents, as well as knowledge and training that they can pass on to their grandchildren.

"Once you take into account that elders are also actively involved in helping others forage, then it adds even more fitness value to their activity and to them being alive," Gurven said. "Not only do elders contribute to the group, but their usefulness helps ensure that they also receive from the surpluses, protections and care from their group. In other words, interdependence runs both ways, from old to young, and young to old."

"If you're part of my social world, there might be some kickback," Davison explained. "So to the extent that we're interdependent, I'm vested in your interest, beyond just simple kinship. I'm interested in getting you to be as skilled as possible because some of your productivity could help me down the road."

Gurven and Davison found that rather than our long lifespans opening up opportunities that led to a human-like foraging economy and social behavior, the reverse is more likely -- our skills-intensive strategies and long-term investments in the health of the group preceded and evolved with our shift to our particular human life history, with its extended childhood and unusually long post-reproductive stage.

In contrast, chimpanzees -- who represent our best guess as to what humans' last common ancestor may have been like -- are able to forage for themselves by age 5. However, their foraging activities require less skill, and they produce minimal surplus. Even so, the authors show that if a chimpanzee-like ancestor would share their food more widely, they could still generate enough indirect fitness contributions to increase the force of selection in later adulthood.

"What this suggests is that human longevity is really a story about cooperation," said Gurven. "Chimpanzee grandmothers are rarely observed doing anything for their grandkids."

Though the authors say their work is more about how the capacity for long life came to first exist in the Homo lineage, the implication that we owe it to elders everywhere is an important reminder looking forward.

"Despite elders being far more numerous today than ever before in the past, there's still much ageism and underappreciation of older adults," Gurven said. "When COVID seemed to be most deadly just for older adults, many shrugged their shoulders about the urgency of lockdown or other major precautions.

Read more at Science Daily

New model helps identify mutations that drive cancer

Cancer cells can have thousands of mutations in their DNA. However, only a handful of those actually drive the progression of cancer; the rest are just along for the ride.

Distinguishing these harmful driver mutations from the neutral passengers could help researchers identify better drug targets. To boost those efforts, an MIT-led team has built a new computer model that can rapidly scan the entire genome of cancer cells and identify mutations that occur more frequently than expected, suggesting that they are driving tumor growth. This type of prediction has been challenging because some genomic regions have an extremely high frequency of passenger mutations, drowning out the signal of actual drivers

"We created a probabilistic, deep-learning method that allowed us to get a really accurate model of the number of passenger mutations that should exist anywhere in the genome," says Maxwell Sherman, an MIT graduate student. "Then we can look all across the genome for regions where you have an unexpected accumulation of mutations, which suggests that those are driver mutations."

In their new study, the researchers found additional mutations across the genome that appear to contribute to tumor growth in 5 to 10 percent of cancer patients. The findings could help doctors to identify drugs that would have greater chance of successfully treating those patients, the researchers say. Currently, at least 30 percent of cancer patients have no detectable driver mutation that can be used to guide treatment.

Sherman, MIT graduate student Adam Yaari, and former MIT research assistant Oliver Priebe are the lead authors of the study, which appears today in Nature Biotechnology. Bonnie Berger, the Simons Professor of Mathematics at MIT and head of the Computation and Biology group at the Computer Science and Artificial Intelligence Laboratory (CSAIL), is a senior author of the study, along with Po-Ru Loh, an assistant professor at Harvard Medical School and associate member of the Broad Institute of MIT and Harvard. Felix Dietlein, an associate professor at Harvard Medical School and Boston Children's Hospital, is also an author of the paper.

A new tool

Since the human genome was sequenced two decades ago, researchers have been scouring the genome to try to find mutations that contribute to cancer by causing cells to grow uncontrollably or evade the immune system. This has successfully yielded targets such as epidermal growth factor receptor (EGFR), which is commonly mutated in lung tumors, and BRAF, a common driver of melanoma. Both of these mutations can now be targeted by specific drugs.

While those targets have proven useful, protein-coding genes make up only about 2 percent of the genome. The other 98 percent also contains mutations that can occur in cancer cells, but it has been much more difficult to figure out if any of those mutations contribute to cancer development.

"There has really been a lack of computational tools that allow us to search for these driver mutations outside of protein-coding regions," Berger says. "That's what we were trying to do here: design a computational method to let us look at not only the 2 percent of the genome that codes for proteins, but 100 percent of it."

To do that, the researchers trained a type of computational model known as a deep neural network to search cancer genomes for mutations that occur more frequently than expected. As a first step, they trained the model on genomic data from 37 different types of cancer, which allowed the model to determine the background mutation rates for each of those types.

"The really nice thing about our model is that you train it once for a given cancer type, and it learns the mutation rate everywhere across the genome simultaneously for that particular type of cancer," Sherman says. "Then you can query the mutations that you see in a patient cohort against the number of mutations you should expect to see."

The data used to train the models came from the Roadmap Epigenomics Project and an international collection of data called the Pan-Cancer Analysis of Whole Genomes (PCAWG). The model's analysis of this data gave the researchers a map of the expected passenger mutation rate across the genome, such that the expected rate in any set of regions (down to the single base pair) can be compared to the observed mutation count anywhere across the genome.

Changing the landscape

Using this model, the MIT team was able to add to the known landscape of mutations that can drive cancer. Currently, when cancer patients' tumors are screened for cancer-causing mutations, a known driver will turn up about two-thirds of the time. The new results of the MIT study offer possible driver mutations for an additional 5 to 10 percent of the pool of patients.

One type of noncoding mutation the researchers focused on is called "cryptic splice mutations." Most genes consist of sequences of exons, which encode protein-building instructions, and introns, which are spacer elements that usually get trimmed out of messenger RNA before it is translated into protein. Cryptic splice mutations are found in introns, where they can confuse the cellular machinery that splices them out. This results in introns being included when they shouldn't be.

Using their model, the researchers found that many cryptic splice mutations appear to disrupt tumor suppressor genes. When these mutations are present, the tumor suppressors are spliced incorrectly and stop working, and the cell loses one of its defenses against cancer. The number of cryptic splice sites that the researchers found in this study accounts for about 5 percent of the driver mutations found in tumor suppressor genes.

Targeting these mutations could offer a new way to potentially treat those patients, the researchers say. One possible approach that is still in development uses short strands of RNA called antisense oligonucleotides (ASOs) to patch over a mutated piece of DNA with the correct sequence.

"If you could make the mutation disappear in a way, then you solve the problem. Those tumor suppressor genes could keep operating and perhaps combat the cancer," Yaari says. "The ASO technology is actively being developed, and this could be a very good application for it."

Another region where the researchers found a high concentration of noncoding driver mutations is in the untranslated regions of some tumor suppressor genes. The tumor suppressor gene TP53, which is defective in many types of cancer, was already known to accumulate many deletions in these sequences, known as 5' untranslated regions. The MIT team found the same pattern in a tumor suppressor called ELF3.

The researchers also used their model to investigate whether common mutations that were already known might also be driving different types of cancers. As one example, the researchers found that BRAF, previously linked to melanoma, also contributes to cancer progression in smaller percentages of other types of cancers, including pancreatic, liver, and gastroesophageal.

Read more at Science Daily

Most 'silent' genetic mutations are harmful, not neutral -- a finding with broad implications

In the early 1960s, University of Michigan alumnus Marshall Nirenberg and a few other scientists deciphered the genetic code of life, determining the rules by which information in DNA molecules is translated into proteins, the working parts of living cells.

They identified three-letter units in DNA sequences, known as codons, that specify each of the 20 amino acids that make up proteins, work for which Nirenberg later shared a Nobel Prize with two others.

Occasionally, single-letter misspellings in the genetic code, known as point mutations, occur. Point mutations that alter the resulting protein sequences are called nonsynonymous mutations, while those that do not alter protein sequences are called silent or synonymous mutations.

Between one-quarter and one-third of point mutations in protein-coding DNA sequences are synonymous. Ever since the genetic code was cracked, those mutations have generally been assumed to be neutral, or nearly so.

But in a study scheduled for online publication June 8 in the journal Nature that involved the genetic manipulation of yeast cells in the laboratory, University of Michigan biologists show that most synonymous mutations are strongly harmful.

The strong nonneutrality of most synonymous mutations -- if found to be true for other genes and in other organisms -- would have major implications for the study of human disease mechanisms, population and conservation biology, and evolutionary biology, according to the study authors.

"Since the genetic code was solved in the 1960s, synonymous mutations have been generally thought to be benign. We now show that this belief is false," said study senior author Jianzhi "George" Zhang, the Marshall W. Nirenberg Collegiate Professor in the U-M Department of Ecology and Evolutionary Biology.

"Because many biological conclusions rely on the presumption that synonymous mutations are neutral, its invalidation has broad implications. For example, synonymous mutations are generally ignored in the study of disease-causing mutations, but they might be an underappreciated and common mechanism."

In the past decade, anecdotal evidence has suggested that some synonymous mutations are nonneutral. Zhang and his colleagues wanted to know if such cases are the exception or the rule.

They chose to address this question in budding yeast (Saccharomyces cerevisiae) because the organism's short generation time (about 80 minutes) and small size allowed them to measure the effects of a large number of synonymous mutations relatively quickly, precisely and conveniently.

They used CRISPR/Cas9 genome editing to construct more than 8,000 mutant yeast strains, each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 genes the researchers targeted.

Then they quantified the "fitness" of each mutant strain by measuring how quickly it reproduced relative to the nonmutant strain. Darwinian fitness, simply put, refers to the number of offspring an individual has. In this case, measuring the reproductive rates of the yeast strains showed whether the mutations were beneficial, harmful or neutral.

To their surprise, the researchers found that 75.9% of synonymous mutations were significantly deleterious, while 1.3% were significantly beneficial.

"The previous anecdotes of nonneutral synonymous mutations turned out to be the tip of the iceberg," said study lead author Xukang Shen, a graduate student research assistant in Zhang's lab.

"We also studied the mechanisms through which synonymous mutations affect fitness and found that at least one reason is that both synonymous and nonsynonymous mutations alter the gene-expression level, and the extent of this expression effect predicts the fitness effect."

Zhang said the researchers knew beforehand, based on the anecdotal reports, that some synonymous mutations would likely turn out to be nonneutral.

"But we were shocked by the large number of such mutations," he said. "Our results imply that synonymous mutations are nearly as important as nonsynonymous mutations in causing disease and call for strengthened effort in predicting and identifying pathogenic synonymous mutations."

Read more at Science Daily

Quantum mechanics could explain why DNA can spontaneously mutate

The molecules of life, DNA, replicate with astounding precision, yet this process is not immune to mistakes and can lead to mutations. Using sophisticated computer modelling, a team of physicists and chemists at the University of Surrey have shown that such errors in copying can arise due to the strange rules of the quantum world.

The two strands of the famous DNA double helix are linked together by subatomic particles called protons -?the nuclei of atoms of hydrogen -- which provide the glue that bonds molecules called bases together. These so-called hydrogen bonds are like the rungs of a twisted ladder that makes up the double helix structure discovered in 1952 by James Watson and Francis Crick based on the work of Rosalind Franklin and Maurice Wilkins.

Normally, these DNA bases (called A, C, T and G) follow strict rules on how they bond together: A always bonds to T and C always to G. This strict pairing is determined by the molecules' shape, fitting them together like pieces in a jigsaw, but if the nature of the hydrogen bonds changes slightly, this can cause the pairing rule to break down, leading to the wrong bases being linked and hence a mutation. Although predicted by Crick and Watson, it is only now that sophisticated computational modelling has been able to quantify the process accurately.

The team, part of Surrey's research programme in the exciting new field of quantum biology, have shown that this modification in the bonds between the DNA strands is far more prevalent than has hitherto been thought. The protons can easily jump from their usual site on one side of an energy barrier to land on the other side. If this happens just before the two strands are unzipped in the first step of the copying process, then the error can pass through the replication machinery in the cell, leading to what is called a DNA mismatch and, potentially, a mutation.

In a paper published this week in the journal Nature Communications Physics, the Surrey team based in the Leverhulme Quantum Biology Doctoral Training Centre used an approach called open quantum systems to determine the physical mechanisms that might cause the protons to jump across between the DNA strands. But, most intriguingly, it is thanks to a well-known yet almost magical quantum mechanism called tunnelling -- akin to a phantom passing through a solid wall -- that they manage to get across.

It had previously been thought that such quantum behaviour could not occur inside a living cell's warm, wet and complex environment. However, the Austrian physicist Erwin Schrödinger had suggested in his 1944 book What is Life? that quantum mechanics can play a role in living systems since they behave rather differently from inanimate matter. This latest work seems to confirm Schrödinger's theory.

In their study, the authors determine that the local cellular environment causes the protons, which behave like spread out waves, to be thermally activated and encouraged through the energy barrier. In fact, the protons are found to be continuously and very rapidly tunnelling back and forth between the two strands. Then, when the DNA is cleaved into its separate strands, some of the protons are caught on the wrong side, leading to an error.

Dr Louie Slocombe, who performed these calculations during his PhD, explains that:

" The protons in the DNA can tunnel along the hydrogen bonds in DNA and modify the bases which encode the genetic information. The modified bases are called "tautomers" and can survive the DNA cleavage and replication processes, causing "transcription errors" or mutations."

Read more at Science Daily

Genetic mutation may identify women with difficulty producing breast milk

Leading health care organizations recommend exclusive breastfeeding for six months after birth, yet some mothers report stopping due to a perceived lack of milk supply. Penn State College of Medicine researchers found in a recent study that women who stopped breastfeeding because they believed they had inadequate milk supply -- a condition called perceived inadequate milk supply (PIMS) -- are more likely to have a specific mutation in a gene found in mammary tissue. These women were also more likely to have babies who gained less weight. The researchers said that screening for this mutation, when combined with maternal characteristics like age and body mass index, could be useful in identifying mothers at risk for stopping breastfeeding prematurely due to a perceived lack of milk supply.

"The World Health Organization, the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists recommend exclusive breastfeeding for at least six months because it provides developing infants with optimum nutrition and is associated with improved health outcomes," said Dr. Steven Hicks, lead researcher and pediatrician at Penn State Health Children's Hospital. "While 83% of women initiate breastfeeding, only a reported 57% continue to six months. Socioeconomic and environmental factors may contribute to early cessation, but milk supply is also an often-cited reason. Identifying women who are more likely to have low milk supply could help get them resources to continue breastfeeding such as lactation consultation services."

Previous research has linked maternal genetics with nutrients in breast milk, but few studies have explored how genetics may relate to supply. The researchers studied 18 genes highly expressed in mammary, or milk-producing, tissue in women. They looked for mutations in those genes to see whether mutations were associated with mothers' perceived milk supply.

The study team followed 88 women between 19 and 42 years old for the first year of their baby's life. The mothers completed surveys about their infant's feeding habits at one, four, six and twelve months of age that asked questions about perceived milk supply, whether women supplemented their child's diet with formula and reasons why they did so. Decreased or low milk production, signs of allergies from breastfeeding and other personal reasons such as work, day care or time constraints were included as possible reasons for why women began to supplement with formula. Mothers also provided a DNA sample by having saliva collected.

Using responses from the surveys, the researchers classified the mothers as having either PIMS or perceived adequate milk supply (PAMS). They found that the 45 mothers with PIMS were more likely to breastfeed for shorter periods, report lower milk supply and have infants who were not gaining adequate weight.

The researchers analyzed the mothers' DNA samples and looked for mutations among 18 genes that are involved in the secretion of breast milk. Although modifications in 10 of the genes studied were found among some women, the team found that only one, a variant in the milk fat globule EGF and factor V/VIII domain containing gene (MFGE8), occurred more frequently in women with PIMS. Those without the mutation were more likely to have adequate milk supply and report a longer duration of breastfeeding.

Using statistical modeling, the researchers found that maternal characteristics like age, previous breastfeeding duration and body mass index alone could not differentiate between mothers with PIMS and PAMS. However, when adding in MFGE8 mutation status into the model, it strongly predicted which women reported adequate or inadequate milk supplies. The researchers published their results in the journal Breastfeeding Medicine.

"Identifying risk of PIMS at the outset of breastfeeding could provide opportunities for early, targeted interventions such as guidance from a trained lactation support professional," Hicks said. He noted that current assessment of PIMS is guided by subjective reports and that counseling may help identify foods and medications that help or hinder milk production.

Hicks said that the study's findings will need to be validated in a larger study that includes more mothers. He also said that more research is needed to uncover the biological processes that determine how this particular gene affects milk supply in moms in order to better understand its association with PIMS status.

"Moms with this mutation still produce milk, even if it may be less than women without the mutation, but challenges like poor diet, hydration or sleep could be enough to hinder the supply that they do have," Hicks said. "Screening for this variant and combining that with maternal reports and characteristics could help identify moms and babies that may need additional support."

Read more at Science Daily

CRISPR-Cas9 can generate unexpected, heritable mutations

CRISPR-Cas9, the "genetic scissors," creates new potential for curing diseases; but treatments must be reliable. In a new study, researchers have discovered that the method can give rise to unforeseen changes in DNA that can be inherited by the next generation. These scientists therefore urge caution and meticulous validation before using CRISPR-Cas9 for medical purposes.

CRISPR-Cas9 is an effective tool for genome modification in microorganisms, as well as animals and plants. In health care, the method creates scope for curing numerous genetic diseases, provided the DNA is modified correctly and undergoes no unexpected changes. To date, such unwanted mutations have been studied in cells, but knowledge of the consequences in living organisms remains limited.

"In this project, we studied the effects of CRISPR-Cas9 in zebrafish, a small aquarium fish. Since DNA molecules and their mechanisms are similar in all animals, we think the results should be similar in humans, for example," says Adam Ameur, associate professor at Uppsala University and the Science for Life Laboratory (SciLifeLab).

When they studied the genome of more than 1,000 zebrafish from two generations, the researchers found unexpected mutations of various types. In some cases, DNA fragments that were larger than anticipated underwent changes, while in other cases mutations occurred in the wrong location in the genome. Unforeseen mutations were found in first-generation zebrafish, but also in their offspring.

"Knowing these unexpected mutations are heritable is important, since they can have long-term consequences for future generations. But that can happen only if you change the genome of embryos or germ cells," says Ida Höijer, PhD of Uppsala University and SciLifeLab.

In healthcare, methods tailored to correct genes in a particular tissue or cell type are now being developed. Although such treatments pose no risk to future generations, caution is advisable.

"CRISPR-Cas9 can be an amazingly valuable tool in health care. But we need to minimise the risk of unwanted effects, and we can do this by carefully validating the modified cells with the latest DNA sequencing technologies," Ameur says.

Read more at Science Daily

Study challenges evolutionary theory that DNA mutations are random

A simple roadside weed may hold the key to understanding and predicting DNA mutation, according to new research from University of California, Davis, and the Max Planck Institute for Developmental Biology in Germany.

The findings, published January 12 in the journal Nature, radically change our understanding of evolution and could one day help researchers breed better crops or even help humans fight cancer.

Mutations occur when DNA is damaged and left unrepaired, creating a new variation. The scientists wanted to know if mutation was purely random or something deeper. What they found was unexpected.

"We always thought of mutation as basically random across the genome," said Grey Monroe, an assistant professor in the UC Davis Department of Plant Sciences who is lead author on the paper. "It turns out that mutation is very non-random and it's non-random in a way that benefits the plant. It's a totally new way of thinking about mutation."

Researchers spent three years sequencing the DNA of hundreds of Arabidopsis thaliana, or thale cress, a small, flowering weed considered the "lab rat among plants" because of its relatively small genome comprising around 120 million base pairs. Humans, by comparison, have roughly 3 billion base pairs.

"It's a model organism for genetics," Monroe said.

Lab-grown plants yield many variations

Work began at Max Planck Institute where researchers grew specimens in a protected lab environment, which allowed plants with defects that may not have survived in nature be able to survive in a controlled space.

Sequencing of those hundreds of Arabidopsis thaliana plants revealed more than 1 million mutations. Within those mutations a nonrandom pattern was revealed, counter to what was expected.

"At first glance, what we found seemed to contradict established theory that initial mutations are entirely random and that only natural selection determines which mutations are observed in organisms," said Detlef Weigel, scientific director at Max Planck Institute and senior author on the study.

Instead of randomness they found patches of the genome with low mutation rates. In those patches, they were surprised to discover an over-representation of essential genes, such as those involved in cell growth and gene expression.

"These are the really important regions of the genome," Monroe said. "The areas that are the most biologically important are the ones being protected from mutation."

The areas are also sensitive to the harmful effects of new mutations. "DNA damage repair seems therefore to be particularly effective in these regions," Weigel added.

Plant evolved to protect itself

The scientists found that the way DNA was wrapped around different types of proteins was a good predictor of whether a gene would mutate or not. "It means we can predict which genes are more likely to mutate than others and it gives us a good idea of what's going on," Weigel said.

The findings add a surprising twist to Charles Darwin's theory of evolution by natural selection because it reveals that the plant has evolved to protect its genes from mutation to ensure survival.

"The plant has evolved a way to protect its most important places from mutation," Weigel said. "This is exciting because we could even use these discoveries to think about how to protect human genes from mutation."

Future uses

Knowing why some regions of the genome mutate more than others could help breeders who rely on genetic variation to develop better crops. Scientists could also use the information to better predict or develop new treatments for diseases like cancer that are caused by mutation.

"Our discoveries yield a more complete account of the forces driving patterns of natural variation; they should inspire new avenues of theoretical and practical research on the role of mutation in evolution," the paper concludes.

Co-authors from UC Davis include Daniel Kliebenstein, Mariele Lensink, Marie Klein, from the Department of Plant Sciences. Researchers from the Carnegie Institution for Science, Stanford University, Westfield State University, University of Montpellier, Uppsala University, College of Charleston, and South Dakota State University contributed to the research.

Read more at Science Daily

Male animals are subject to stronger evolutionary pressures than females

Male animals are subject to stronger selection pressures than females, which may allow populations to adapt to environmental change more efficiently, according to a report published in the open-access journal eLife.

The study supports one of the long-standing assumptions underpinning the idea that sexual selection bolsters adaptation: that stronger selection on males allows them to purge the population of genetic mutations that reduce survival fitness.

Sexual selection is selection arising from competition for mating partners and/or their reproductive cells (their eggs or sperm). For almost a century, researchers have thought that sexual selection is the ultimate selective force that generates the differences we see between male and female animals in terms of reproductive fitness and life history. Yet, little is known about how sexual selection combines with other environmental pressures to impact population demography and adaptive ability.

Living organisms accumulate mutations throughout life - some of which help them become fitter for survival, and some of which provide no benefit and may even cause a disadvantage (called deleterious mutations). Sexual selection is thought to promote evolutionary adaptation if it gives rise to stronger net selection - that is, the total purifying selection against deleterious mutations - in males rather than females. This is because a population's productivity relies on females' ability to reproduce, so that stronger net selection on males allows a population to get rid of the deleterious mutations quickly and adapt to their environment with a lower cost to the population, which may eventually reduce the risk of extinction.

"Our knowledge on whether such stronger sexual selection on males translates into stronger net selection to females is still limited," says first author Lennart Winkler, a PhD student at TU Dresden, Germany. "Previous studies have used the phenotypic variance of fitness to measure net selection, but its relevance has been questioned. An alternative measure is the organism's genetic variance of fitness. We used both measures to show whether net selection is generally stronger on males across a broad range of species."

The team ran a systematic literature search and compiled 101 paired estimates of male and female genetic variances across 26 species for two important components of an organism's fitness: reproductive success and lifespan.

They then tested whether the phenotypic variances were aligned to the genetic variances, and whether genetic variances show consistent sex differences. They predicted that males would show larger genetic variance in reproductive success but not in lifespan.

They found that the phenotypic variance of lifespan but not of reproductive success predicted the genetic variance in either males or females. Importantly, however, the phenotypic variance of reproductive success was larger in males than females, and this translated into a male bias in genetic variance. This sex difference could be detected in polygamous but not monogamous species. By contrast, there were no consistent sex differences in phenotypic or genetic variance for lifespan.

Read more at Science Daily