This year’s Nobel Prize in Physiology or Medicine has been awarded to evolutionary scientist Professor Svante Pääbo, “for his discoveries concerning the genome of extinct hominins and human evolution”.
As explained by the Nobel Assembly at Karolinska Institutet: “Through his pioneering research, Svante Pääbo achieved something seemingly impossible: sequencing the genome of the Neanderthal, an extinct relative of present-day humans. He also made the sensational discovery of a previously unknown hominin, Denisova.” Prof Pääbo further made the important discovery that cross-breeding occurred between Homo sapiens and our extinct relatives after the migration out of Africa some 70 000 years ago. The gene transfers from extinct hominins that have left traces among present-day humans outside Africa have proven physiologically significant, for example, for human resistance to infections.
Prof Pääbo received a doctorate in medicine in 1986 from Uppsala University. He has returned several times to the University as visiting professor and has also been a member of the University Board.
Uppsala University Vice-Chancellor Anders Hagfeldt thinks Prof Pääbo is an excellent and pleasing choice.
“His research identifying and mapping human origins is tremendously fascinating and of course it’s very pleasing that he is connected with Uppsala. I’m sure many people at the University are as happy as I am today, we have many fine researchers following in his footsteps,” he said.
Mattias Jakobsson, professor at the Department of Organismal Biology, who is also engaged in research on human evolution, had thought that ProfPääbo was bound to win the prize sooner or later, though his name had not been mentioned much this year.
“It’s fantastic, both for him and for the entire field of research. And it’s very appropriate that it’s the prize in medicine, his latest work has focused on patterns of genetic variation due to our Neanderthal heritage. Some of these patterns relate to COVID, for example,” he said.
An international research effort has developed a new strategy to treat Huntington disease, which demonstrated that converting the disease-causing protein to its disease-free form results in it still retaining its original function. This discovery, published in the Journal of Clinical Investigation Insight, provides new avenues to approach Huntington disease.
Huntington disease is a rare neurodegenerative disorder with a worldwide prevalence of 2.7 per 100 000. Huntington’s disease is a dominantly inherited neurodegenerative disease and is caused by a mutation in a protein called ‘huntingtin’, which adds a distinctive feature of an expanded stretch of glutamine amino acids called polyglutamine to the protein. The patients would suffer a decade of regression before death, and, thus far, there is no known cure for the disease.
The cleavage near the stretched polyglutamine in mutated huntingtin is known to be the cause of the Huntington disease. However, as huntingtin protein is required for the development and normal function of the brain, it is critical to specifically eliminate the disease-causing protein while maintaining the ones that are still normally functioning. The research team showed that huntingtin delta 12 – the converted form of huntingtin that is resistant to developing cleavages at the ends of the protein, known to be the cause of Huntington disease – alleviated the disease’s symptoms while maintaining the functions of normal huntingtin.
Although low physical activity and greater time spent sitting are well known to be linked to a higher risk of death, a study published in Journal of Aging and Physical Activity showed that a genetic predisposition to longevity was not a substitute for sitting less and greater physical activity, which can benefit even those not gifted with such genes.
“The goal of this research was to understand whether associations between physical activity and sedentary time with death varied based on different levels of genetic predisposition for longevity,” said doctoral student Alexander Posis, lead author of the study.
In 2012, as part of the Women’s Health Initiative Objective Physical Activity and Cardiovascular Health study (OPACH), researchers began measuring the physical activity of 5446 women aged 63 and older, following them through 2020 to determine mortality. Participants wore a research-grade accelerometer for up to seven days to measure how much time they spent moving, the intensity of physical activity, and sedentary time.
Higher levels of light physical activity and moderate-to-vigorous physical activity were found to be associated with lower risk of death. Higher sedentary time was associated with higher risk of mortality. These associations were consistent among women who had different levels of genetic predisposition for longevity.
“Our study showed that, even if you aren’t likely to live long based on your genes, you can still extend your lifespan by engaging in positive lifestyle behaviours such as regular exercise and sitting less,” said Assistant Professor Aladdin H. Shadyab, PhD, senior author. “Conversely, even if your genes predispose you to a long life, remaining physically active is still important to achieve longevity.”
Given the ageing adult population in the United States, and longer time spent engaging in lower intensity activities, the study findings support recommendations that older women should participate in physical activity of any intensity to reduce the risk of disease and premature death, wrote the authors.
A new study published in Nature Genetics has revealed 60 genes linked to autism spectrum disorder (ASD) that may provide important clues to the causes of autism across the full spectrum of the disorder. Five of these genes are heritable instead of new mutated versions, helping explain why autism appears to run in some families.
“Overall, the genes we found may represent a different class of genes that are more directly associated with the core symptoms of ASD than previously discovered genes,” said Professor Wendy Chung, MD, PhD.
Previously, several genes have been linked to autism and as a group are responsible for about 20% of all cases. Most individuals who carry these genes have profound forms of autism and additional neurological issues, such as epilepsy and intellectual disability.
To uncover hidden autism genes that can explain the majority of cases, the researchers tapped into data from nearly 43 000 people with autism.
Five of the genes identified by the new study have a more moderate impact on autism characteristics, including cognition, than previously discovered genes.
“We need to do more detailed studies including more individuals who carry these genes to understand how each gene contributes to the features of autism, but we think these genes will help us unravel the biological underpinnings that lead to most cases of autism,” Prof Chung said.
The five newly identified genes also explain why autism often seems to run in families. Unlike previously known autism genes, which are due to de novo mutations, genetic variants in the five new genes were often inherited from the participant’s parents.
Prof Chung said that many more moderate-effect genes are yet to be discovered, which would help researchers better understand the biology of the brain and behaviour across the full spectrum of autism.
New research with yeast strains carrying ‘silent’ gene mutations, where misspellings occur but do not affect the protein they code for, shows that they are not harmless as previously assumed – rather, they are mostly harmful. The findings, which appear in the journal Nature, could overturn decades of thinking if they are applicable to organisms such as humans.
In the early 1960s, University of Michigan alumnus Marshall Nirenberg and a few other scientists deciphered the genetic code, determining the rules by which information in DNA molecules is translated into proteins.
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 occur, which are known as point mutations. Point mutations that alter the resulting protein sequences are called nonsynonymous mutations, while those that do not are called silent or synonymous mutations.
Around one-quarter to 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 a new study involving the genetic manipulation of yeast cells in the laboratory demonstrates 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 the study’s senior author, Professor Jianzhi “George” Zhang at the University of Michigan.
“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, which Prof Zhang and his colleagues wanted to investigate.
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.
With gene editing, they constructed more than 8000 mutant yeast strains, each carrying a synonymous, nonsynonymous or nonsense mutation in one of 21 selected genes.
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 Prof 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.”
Prof Zhang said the researchers knew beforehand, based on the anecdotal reports, that some synonymous mutations were likely 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.”
The U-M-led team said that while there is no particular reason why their results would be restricted to yeast, confirmations in diverse organisms are required to verify the generality of their findings.
Around one in 500 men could be carrying an extra sex chromosome (X or Y), putting them at increased risk of diseases such as type 2 diabetes, atherosclerosis and thrombosis, according to a study published in Genetics in Medicine.
Researchers from the universities of Cambridge and Exeter analysed genetic data on 200 000 men aged 40 to 70 from UK Biobank. They found 356 men who carried either an extra X chromosome or an extra Y chromosome.
Some men have an extra X or Y chromosome – XXY or XYY, which is usually not obvious without a genetic test. Men with extra X chromosomes, a condition known as Klinefelter syndrome, are sometimes identified during investigations of delayed puberty and infertility; however, most are unaware that they have this condition. Men with an extra Y chromosome tend to be taller as boys and adults, but otherwise they have no distinctive physical features.
In today’s study, the researchers identified 213 men with an extra X chromosome and 143 men with an extra Y chromosome. As the participants in UK Biobank tend to be ‘healthier’ than the general population, this suggests that around one in 500 men may carry an extra X or Y chromosome.
Only a small minority of these men had a diagnosis of sex chromosome abnormality on their medical records or by self-report: fewer than one in four (23%) men with XXY and only one of the 143 XYY men (0.7%) had a known diagnosis.
By linking genetic data to routine health records, the team found that men with XXY have much higher chances of reproductive problems, including a three-fold higher risk of delayed puberty and a four-fold higher risk of being childless. These men also had significantly lower blood concentrations of testosterone. Men with XYY appeared to have a normal reproductive function.
Men with either XXY or XYY had higher risks of several other health conditions: a three-fold higher risk of developing type 2 diabetes, six-fold risk of venous thrombosis, three-fold risk of pulmonary embolism, and four-fold risk of chronic obstructive pulmonary disease (COPD).
It is unclear why an extra chromosome should increase the risk, said the researchers, or why the risks were so similar regardless of which sex chromosome was duplicated.
Yajie Zhao, a PhD student at the Medical Research Council (MRC) Epidemiology Unit at the University of Cambridge, the study’s first author, said: “Even though a significant number of men carry an extra sex chromosome, very few of them are likely to be aware of this. This extra chromosome means that they have substantially higher risks of a number of common metabolic, vascular, and respiratory diseases — diseases that may be preventable.”
Professor Ken Ong, also from the MRC Epidemiology Unit at Cambridge and joint senior author, added: “Genetic testing can detect chromosomal abnormalities fairly easily, so it might be helpful if XXY and XYY were more widely tested for in men who present to their doctor with a relevant health concern.
“We’d need more research to assess whether there is additional value in wider screening for unusual chromosomes in the general population, but this could potentially lead to early interventions to help them avoid the related diseases.”
Professor Anna Murray, at the University of Exeter, said: “Our study is important because it starts from the genetics and tells us about the potential health impacts of having an extra sex chromosome in an older population, without being biased by only testing men with certain features as has often been done in the past.”
Previous studies have found that around one in 1,000 females have an additional X chromosome, which can result in delayed language development and accelerated growth until puberty, as well as lower IQ levels compared to their peers.
A new study published in Brain shows that a genetic mutation which causes blindness in humans also increases intelligence, possibly through an increase in synaptic activity between the very same neurons damaged by the mutation.
The present study came about when Professors Tobias Langenhan and Manfred Heckmann, came across a paper on a mutation that damages a synaptic protein. The mutation caused patients to go blind, but then doctors noticed that the patients were also of above-average intelligence, something which piqued the two neurobiologists’ interest. “It’s very rare for a mutation to lead to improvement rather than loss of function,” said Prof Langenhan.
The two neurobiologists have been using fruit flies to analyse synaptic functions for many years. “Our research project was designed to insert the patients’ mutation into the corresponding gene in the fly and use techniques such as electrophysiology to test what then happens to the synapses. It was our assumption that the mutation makes patients so clever because it improves communication between the neurons which involve the injured protein,” explained Prof Langenhan. “Of course, you can’t conduct these measurements on the synapses in the brains of human patients. You have to use animal models for that.”
“75 per cent of genes that cause diseases in humans also exist in fruit flies”
Professor Tobias Langenhan
First, in collaboration with Oxford researchers, the scientists showed that the fly protein called RIM looks molecularly identical to that of humans. This was essential in order to be able to study the changes in the human brain in the fly. In the next step, the neurobiologists inserted the genetic mutation into flies. They then took electrophysiological measurements of synaptic activity. “We actually observed that the animals with the mutation showed a much increased transmission of information at the synapses. This amazing effect on the fly synapses is probably found in the same or a similar way in human patients, and could explain their increased cognitive performance, but also their blindness,” concludes Professor Langenhan.
The scientists also found out how the increased transmission at the synapses occurs: the molecular components in the transmitting nerve cell that trigger the synaptic impulses move closer together as a result of the mutation effect and lead to increased release of neurotransmitters. A novel method, super-resolution microscopy, was one of the techniques used in the study. “This gives us a tool to look at and even count individual molecules and confirms that the molecules in the firing cell are closer together than they normally are,” said Prof Langenhan.
“The project beautifully demonstrates how an extraordinary model animal like the fruit fly can be used to gain a very deep understanding of human brain disease. The animals are genetically highly similar to humans. It is estimated that 75% of the genes involving disease in humans are also found in the fruit fly,” explained Professor Langenhan, pointing to further research on the topic: “We have started several joint projects with human geneticists, pathologists and the team of the Integrated Research and Treatment Center (IFB) Adiposity Diseases; based at Leipzig University Hospital, they are studying developmental brain disorders, the development of malignant tumours and obesity. Here, too, we will insert disease-causing mutations into the fruit fly to replicate and better understand human disease.”
A Monash University-led research team has developed a risk score based on individuals’ genetic data to predict their likelihood of needing hip or knee replacement surgery for osteoarthritis. The team validated the score’s predictive ability in a study published in Arthritis & Rheumatology.
The score incorporates 10 genetic sequence variants for predicting a person’s risk of needing knee replacement surgery and 37 genetic sequence variants for predicting the risk of needing hip replacement surgery.
Among 12093 individuals of European genetic descent aged 70 years or older, 1422 (11.8%) had knee replacements and 1,297 (10.7%) had hip replacements. Participants with high risk scores had a 1.44-times higher odds of knee replacement and a 1.88-times higher odds of hip replacement, compared with those with low risk scores.
“Genetic scores, such as the one we developed, do not change over a person’s life. They provide an individual with further information about their risk of severe osteoarthritis in later life and have the potential to improve prevention of severe knee and hip osteoarthritis by identifying those who may benefit from early intervention,” said senior author Flavia Cicuttini, PhD, of Monash University.
New research published in Human Geneticsshows that people with blue eyes trace their ancestry back to a single individual. Researchers tracked down a genetic mutation which took place 6–10 000 years ago and is the cause of the eye colour of all blue-eyed humans without albinism alive on the planet today.
While blue eyes evolved only once, blonde hair has evolved at least twice: in Melanesian populations, blonde hair evolved independently to European populations, involving a mutation in a different gene.
“Originally, we all had brown eyes,” said Professor Hans Eiberg from the University of Copenhagen. “But a genetic mutation affecting the OCA2 gene in our chromosomes resulted in the creation of a ‘switch’, which literally ‘turned off’ the ability to produce brown eyes.” The OCA2 gene codes for the P protein, which is involved melanin production. This ‘switch’, located in the gene next to OCA2, does not completely shut off production but instead is limited to reducing the production of melanin in the iris, effectively ‘diluting’ brown eyes to blue. The switch’s effect on OCA2 is very specific therefore. If the OCA2 gene is completely destroyed or turned off, albinism would be the result.
Eye colours from brown to green depend on the amount of melanin in the iris, but blue-eyed individuals only have a small degree of variation in the amount of melanin in their eyes. “From this we can conclude that all blue-eyed individuals are linked to the same ancestor,” said Professor Eiberg. “They have all inherited the same switch at exactly the same spot in their DNA.” Brown-eyed individuals, by contrast, have considerable individual variation in the area of their DNA that controls melanin production.
Professor Eiberg and his team studied mitochondrial DNA and compared the eye colour of blue-eyed individuals in countries as diverse as Jordan, Denmark and Turkey. His research stretches back to 1996, when he first implicated the OCA2 gene as being responsible for eye colour.
The mutation of brown to blue eyes does not confer any evolutionary advantage, as with others such as hair colour.
As Professor Eiberg explained, “it simply shows that nature is constantly shuffling the human genome, creating a genetic cocktail of human chromosomes and trying out different changes as it does so.”
Scientists have discovered that the rare blood clot side-effect associated with some COVID vaccines could be the result of a specific gene variant, which could make a genetic screening test possible.
Vaccine-induced thrombotic thrombocytopenia (VITT), a rare disorder causing thrombosis and thrombocytopenia (low blood platelet counts), was linked to AstraZeneca’s COVID vaccine in early 2021, leading some countries to pause or restrict its use. It is also associated with the Johnson & Johnson vaccine, which also uses a viral vector.
Now, a new study may help to explain what’s causing the rare side effect. The study by Flinders University and SA Pathology is now available on the medRxiv preprint server and is awaiting peer review.
Examining five unrelated individuals who all had the clotting complication after vaccination, the researchers found that all of the patients had unusually structured antibodies against a protein called platelet factor 4 (PF4), which is involved in blood clotting.
In addition, all five shared a specific version of a gene responsible for producing these antibodies.
“We knew previously that PF4 was directly involved in the clotting disorder, and we knew that aberrant antibodies against PF4 are responsible, but what we don’t know is how and why some people develop them,” explained lead author Dr Jing Jing Wang.
The antibodies were all found to be derived from the same amino acid sequence. The researchers then found that all of the patients carried a specific variant of one gene, called IGLV3-21*02, most commonly occurring in people of European descent.
“The other specific amino acid sequences of these antibodies from each patient were derived from separate basic sequences but had all evolved to carry very similar properties, making them very potent attackers of the PF4 protein,” explained research team leader Professor Tom Gordon.
“Together, this suggests that it is the combination of a variant in a gene and the evolution of this antibody towards targeting the PF4 protein in a destructive manner, which is leading to this harmful side-effect.”
Though why the antibody is found in such a tiny number of vaccine recipients remains unknown, the identification of the gene could enable a genetic screening tool to identify patients who are at risk of this severe complication.
“It also provides a unique opportunity for targeted, specific therapy development aimed at neutralising this highly damaging but very specific antibody,” said Dr Wang.
