New research published in the Annals of Clinical and Translational Neurology has identified three genes and their expressed proteins that may be involved in the pathogenesis of multiple sclerosis.
By comparing information on the genes and proteins expressed in the brains of thousands of individuals with and without multiple sclerosis, investigators discovered different expression levels of the SHMT1, FAM120B, and ICA1L genes (and their proteins) in brain tissues of patients versus controls.
Protein abundance alteration in human brain has linked to MS. For instance, protein abundance of glial fibrillary acidic protein (GFAP), myelin basic protein (MBP)3 and thymosin β-46 was dysregulated in lesions from MS patients’ brain, and these proteins have been used for disease severity prediction and targeted therapy lately. In addition, compared to bodily fluid samples like cerebrospinal fluid and plasma, human brain tissue directly reflects the pathophysiology changes of MS and has become increasingly important in disease biomarker identification. However, few studies focused on specific subregions of the brain, ignoring the possible differences in protein types and abundance between subregions with distinct functions.
Studying the functions of these genes may uncover new information on the mechanisms involved in the development and progression of multiple sclerosis. “Our findings shed new light on the pathogenesis of MS and prioritised promising targets for future therapy research,” the authors wrote.
Researchers propose in The American Journal of Human Geneticsa new way of looking at Down syndrome, suggesting that when an extra chromosome is present, the impact on the cell depends less on which chromosome is duplicated and more on the presence of extra DNA.
“Understanding the complexity and general nature of disease phenotypes allows us to see a bigger picture and not get stuck focusing on a single gene, due to its presence on the extra chromosome,” says lead author Maria Krivega, developmental biologist at Heidelberg University.
Every cell starts out with extra chromosomes during early embryogenesis; however, this DNA gets sorted into pairs after about a week of growth. When this process goes awry, it often leads to death of the embryo, with only a few being able to survive with the extra DNA, like in the case of Down syndrome.
By taking a step back and looking at the entire cell, researchers were able to create a new understanding of these syndromes. Krivega and her collaborators took a critical look at recent evidence suggesting that Down syndrome phenotypes arise not only because of increased dosage of genes on chromosome 21 but also because of global effects of chromosome gain.
The researchers sifted through published datasets of proteins and RNA of individuals with Down syndrome and compared these to laboratory made cells with trisomies of chromosomes 3, 5, 12, and 21. What they found from this comparison was that it didn’t matter which chromosome was in excess, the cells all had decreased ability to replicate, survive, and maintain their DNA.
“We were interested to find out why cells with imbalanced chromosomal content – in other words, aneuploid – are capable of surviving,” says Krivega. “It was particularly exciting to me to learn if viable aneuploid embryonic cells have similarities with aneuploid cancer cells or cell lines, derived in the laboratory.”
Additionally, they found that the adaptive T cell immune system was underdeveloped in all cells, while the innate immune system seemed to be overactive. The authors suggest that this is a consequence of general chromosome gain. This research can be expanded into autoimmune diseases, such as Alzheimer disease or acute leukemias in trisomy chr. 8 or 21, that also exist without any connection to aneuploidy.
“We hope that our work elucidating a complex trisomy phenotype should help to improve such kids’ development,” says Krivega.
The common chemotherapy drug ifosfamide could leave a lasting toxic legacy for children and grandchildren of adolescent cancer survivors, suggests a study published online in iScience.
Researchers from Washington State University found that male rats given ifosfamide during adolescence had offspring and grand-offspring with increased incidence of disease. Other studies have shown that cancer treatments can increase patients’ chance of developing disease later in life, this is one of the first-known studies showing that susceptibility can be passed down to a third generation of unexposed offspring.
“The findings suggest that if a patient receives chemotherapy, and then later has children, that their grandchildren, and even great-grandchildren, may have an increased disease susceptibility due to their ancestors’ chemotherapy exposure,” said corresponding author Michael Skinner, a WSU biologist and corresponding author on the study.
Skinner emphasised that the findings should not dissuade cancer patients from undertaking chemotherapy since it can be a very effective treatment. Chemotherapy drugs kill cancerous cells and stop multiplication, but have many side effects, including on reproductive systems.
The researchers therefore recommend that cancer patients who plan to have children later take precautions, such as using cryopreservation to freeze sperm or ova before having chemotherapy.
In the study, researchers exposed a set of young male rats to ifosfamide over three days, mimicking a course of treatment an adolescent human cancer patient might receive. Those rats were later bred with unexposed female rats. The resulting offspring were bred again with another set of unexposed rats.
The first-generation offspring had some exposure to the chemotherapy drug since their fathers’ sperm was exposed, but researchers found greater incidence of disease in not only the first- but also the second-generation, who had no direct exposure to the drug. While there were some differences by generation and sex, the associated problems included greater incidence of kidney and testis diseases as well as delayed onset of puberty and abnormally low anxiety, indicating a lowered ability to assess risk.
The researchers also looked for epigenetic changes. Previous research has shown that exposure to toxicants, particularly during development, can create epigenetic changes that can be passed down through sperm and ova.
The results of the researchers’ analysis showed epigenetic changes in two generations linked to the chemotherapy exposure of the originally exposed rats. The fact that these changes could be seen in the grand-offspring, who had no direct exposure to the chemotherapy drug, indicates that the negative effects were passed down through epigenetic inheritance.
Skinner and colleagues at Seattle Children’s Research Institute are currently working on a human study with former adolescent cancer patients to learn more about the effects chemotherapy exposure has on fertility and disease susceptibility later in life.
A better knowledge of chemotherapy’s epigenetic shifts could also help inform patients of their likelihood of developing certain diseases, creating the possibility of earlier prevention and treatment strategies, Skinner said.
“We could potentially determine if a person’s exposure had these epigenetic shifts that could direct what diseases they’re going to develop, and what they’re going to potentially pass on to their grandchildren,” he said. “We could use epigenetics to help diagnose whether they’re going to have a susceptibility to disease.”
Many estimates of how strongly traits and diseases share genetic signals may be inflated, according to a new study published in Science that indicates current methods for assessing genetic relationships between traits fail to account for mating patterns.
With genome sequencing technology, scientists have been seeking out the genetic associations between traits and disease risk, hoping to find clues in treating diseases. However, UCLA researchers said their new studycautions against relying too much on genetic correlation estimates. They say that such estimates are confounded by non-biological factors more than has been previously appreciated.
Genetic correlation estimates typically assume that mating is random. But in the real world, partners tend to pair up because of many shared interests and social structures. As a result, some genetic correlations in previous work that have been attributed to shared biology may instead represent incorrect statistical assumptions. For example, previous estimates of genetic overlap between body mass index (BMI) and educational attainment are likely to reflect this type of population structure, induced by “cross-trait assortative mating,” or how individuals of one trait tend to partner with individuals of another trait.
The study authors said genetic correlation estimates deserve more scrutiny, since these estimates been used to predict disease risk, glean for clues for potential therapies, inform diagnostic practices, and shape arguments about human behaviour and societal issues. The authors said some in the scientific community have placed too much emphasis on genetic correlation estimates based on the idea that studying genes, because they are unalterable, can overcome confounding factors.
“If you just look at two traits that are elevated in a group of people, you can’t conclude that they’re there for the same reason,” said lead author Richard Border, a postdoctoral researcher in statistical genetics at UCLA. “But there’s been a kind of assumption that if you can track this back to genes, then you would have the causal story.”
Based on their analysis of two large databases of spousal traits, researchers found that cross-trait assortative mating is strongly associated with genetic correlation estimates and plausibly accounts for a “substantial” portion of genetic correlation estimates.
“Cross-trait assortative mating has affected all of our genomes and caused interesting correlations between DNA you inherit from your mother and DNA you inherit from your father across the whole genome,” said study co-author Noah Zaitlen, professor at UCLA Health.
The researchers also examined genetic correlation estimates of psychiatric disorders, which have sparked debate in the psychiatric community because they appear to show genetic relationships among disorders that seemingly have little similarity, such as attention-deficit hyperactivity disorder and schizophrenia. The researchers found that genetic correlations for a number of unrelated traits could be plausibly attributed to cross-trait assortative mating and imperfect diagnostic practices. On the other hand, their analysis found stronger links for some pairs of traits, like anxiety disorders and major depression, suggesting that there truly is at least some shared biology.
“But even when there is a real signal there, we’re still suggesting that we’re overestimating the extent of that sharing,” Border said.
An important new clue for preventing and treating gliomas has been identified in research published in the journal Science, providing a rare window into the biological changes behind glioma development.
In animal models, a team of researchers from Mayo Clinic and Mount Sinai Hospital found that those with a change in DNA known as germline alteration rs55705857 developed gliomas much more frequently and twice as fast compared to animal models without the alteration. In addition to brain tumours, the findings are relevant to other cancers and diseases.
“While we understand much of the biologic function of germline alterations within genes that code for proteins, we know very little about the biologic function of germline alterations outside of genes that code for proteins. In some way, these germline alterations interact with other mutations in cells to accelerate tumour formation,” said co-lead author Robert Jenkins, MD, PhD. “Based on this new understanding of its mechanism of action, future research may lead to novel and specific therapies that target the rs55705857 alteration.”
The study offers new knowledge that may help clinicians determine, pre-surgery, whether a patient has a glioma.
“We expected that rs55705857 would accelerate low-grade glioma development, but we were surprised by the magnitude of that acceleration,” said co-lead author Daniel Schramek, PhD.
There are many alterations, likely thousands, outside of genes associated with the development of cancer and other diseases, but the mechanism of action is only understood for very few, Dr Schramek said.
This study demonstrates that, with the tools of modern molecular/cell biology, it is possible to decipher much of the mechanism of action of such alterations.
There is an elaborate interplay between genes, sex, the environment during growth, and age and how they influence variation in longevity, according to a study published in the journal Science. These findings are an important step in understanding why some people live longer than others and provide a basis for future studies to improve a healthy lifespan.
Robert Williams, PhD, at the University of Tennessee Health Science Center (UTHSC), along with Johan Auwerx, MD, PhD, at the École Polytechnique Fédérale de Lausanne (EPFL) in Switzerland, began a program in 2016 to define genetic factors involved in agieng and lifespan. “Finding common molecular pathways that control differences in rate of aging is critical to our understanding of how individuals differ in their health and lifespan,” Dr Williams said. “Such insights may help us work out ways to intervene rationally.”
Drs Williams and Auwerx received DNA of over 12 000 mice from the National Institute of Aging. Each of the 27 574 genetically heterogeneous mice studied is a full sibling, sharing half its genetic inheritance with each other mouse in the programme, and each has a known lifespan, making them an ideal system to study.
The research team analysed the genes of over 3 000 mice, all of them genetic brothers or sisters which were allowed to live until their natural death. Comparing their DNA to lifespan, the researchers defined stretches of DNA in genomes that affect longevity. The results show the DNA segments, or loci, associated with longevity are largely sex-specific, with females having a region in chromosome 3 that affects lifespan. When the males who died early due to non-aging-related reasons were removed from the analysis, additional genetic signals started to emerge, suggesting some genetic variations only affect lifespan after a certain age.
In addition to finding genetic determinants of longevity, the researchers explored other contributors. In general, bigger mice die younger. The researchers found that some, but not all, of the genetic effects on longevity are through effects on growth. One of the non-genetic effects may be how early access to food affects growth. They observed that mice from smaller litters tended to be heavier adults and live shorter lives. Mice from larger litters that had to share their mother’s milk with more siblings, grew more slowly and lived longer on average. The researchers corroborated these trends of early growth versus longevity in large human datasets with hundreds of thousands of participants.
Beyond characterising how longevity is affected, the researchers worked to find genes most likely to play a role in longevity determination. They measured the effect of DNA variation on how genes are expressed and compared their analyses with multiple human and non-human databases. From this they nominated a few genes likely to modulate aging rates. They then tested the effects of manipulating these genes in roundworms and found that a subset of gene perturbations did in fact affect the lifespan. The results of this study will be a rich resource of aging genes that will hopefully guide the design of therapies that not only extend lifespan, but also healthspan.
Mucus is ubiquitous in nature, from saliva to slugs, and serves many useful functions such as protection of tissues and lubrication. A new study published in Science Advances reveals just how these gooey substances evolved in nature, and how they easily evolve from genes that code for normal proteins.
Comparing mucin genes in 49 mammal species, scientists identified 15 instances in which new mucins appear to have evolved through an additive process that transformed a non-mucin protein into a mucin.
The scientists propose that each of these “mucinisation” events began with a non-mucin protein. At some point, evolution tacked a new section onto this non-mucin base: one consisting of a short chain of amino acids that are decorated with sugar molecules. Over time, this new region got duplicated, with multiple copies added on to elongate the protein even further, making it a mucin.
The doubled regions, called “repeats,” are key to a mucin’s function, say University at Buffalo researchers.
The sugars coating these sections protrude outward like the bristles of a bottle brush, granting mucins the slimy property key to many important tasks that these proteins carry out.
“I don’t think it was previously known that protein function can evolve this way, from a protein gaining repeated sequences. A protein that isn’t a mucin becomes a mucin just by gaining repeats. This is an important way that evolution makes slime. It’s an evolutionary trick, and we now document this happening over and over again,” said Omer Gokcumen, PhD, associate professor of biological sciences.
“The repeats we see in mucins are called ‘PTS repeats’ for their high content of the amino acids proline, threonine and serine, and they aid mucins in their important biological functions that range from lubricating and protecting tissue surfaces to helping make our food slippery so that we can swallow it,” said Stefan Ruhl, DDS, PhD, interim dean of the UB School of Dental Medicine and professor of oral biology. “Beneficial microbes have evolved to live on mucus-coated surfaces, while mucus can at the same time also act as a protective barrier and defend against disease by shielding us from unwanted pathogenic intruders.”
“Not many people know that the first mucin which had been purified and biochemically characterised came from a salivary gland,” Prof Ruhl added. “My lab has been studying mucins in saliva for the last 30 years, mostly because they protect teeth from decay and because they help balance the microbiota in the oral cavity.”
While studying saliva, the team noticed that a small salivary mucin in humans called MUC7 was not present in mice, but they had a similarly sized salivary mucin called MUC10.
It turned out the two mucins were not evolutionarily related. But what the research uncovered next was a surprise. While MUC10 did not appear to be related to MUC7, a protein found in human tears called PROL1 did share a portion of MUC10’s structure. PROL1 looked a lot like MUC10, minus the sugar-coated bottlebrush repeats that make MUC10 a mucin.
“We think that somehow that tear gene ends up repurposed,” Assoc Prof Gokcumen said. “It gains the repeats that give it the mucin function, and it’s now abundantly expressed in mouse and rat saliva.”
The scientists wondered whether other mucins might have formed the same way. They began to investigate and discovered multiple examples of the same phenomena. Though many mucins share common ancestry among various groups of mammals, the team documented 15 instances in which evolution appeared to have converted non-mucin proteins into mucins via the addition of PTS repeats.
And this was “with a pretty conservative look,” Assoc Prof Gokcumen said, noting that the study focused on one region of the genome in a few dozen mammal species. Slime is an “amazing life trait,” he said, curious whether the same evolutionary mechanism might have driven the formation of some mucins in slugs, slime eels and other critters. More research is needed to find an answer.
“How new gene functions evolve is still a question we are asking today,” said Petar Pajic, a UB PhD student in biological sciences and the study’s first author. “Thus, we are adding to this discourse by providing evidence of a new mechanism, where gaining repeated sequences within a gene births a novel function.”
“I think this could have even broader implications, both in understanding adaptive evolution and in possibly explaining certain disease-causing variants,” Pajic added. “If these mucins keep evolving from non-mucins over and over again in different species at different times, it suggests that there is some sort of adaptive pressure that makes it beneficial. And then, at the other end of the spectrum, maybe if this mechanism goes ‘off the rails’ – happening too much, or in the wrong tissue – then maybe it can lead to disease like certain cancers or mucosal illnesses.”
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.
University of College London researchers have used gene therapy to partially restore the function of cone receptors in two children with achromatopsia, a rare genetic disorder which can cause partial or complete colourblindness.
The findings, published in Brain, suggest that treatment activates previously dormant communication links between the retina and the brain, thanks to the developing adolescent brain’s plastic nature.
The academically-led study has been running alongside a phase 1/2 clinical trial in children with achromatopsia, using a new way to test whether the treatment is changing the neural pathways specific to the cones.
Achromatopsia is caused by disease-causing variants to one of a few genes. As it affect the cones in the retina, are responsible for colour vision, people with achromatopsia are completely colourblind, while they also have very poor vision and photophobia. Their cone cells do not send signals to the brain, but many remain present, so researchers have been seeking to activate the dormant cells.
Lead author Dr Tessa Dekker said: “Our study is the first to directly confirm widespread speculation that gene therapy offered to children and adolescents can successfully activate the dormant cone photoreceptor pathways and evoke visual signals never previously experienced by these patients.
“We are demonstrating the potential of leveraging the plasticity of our brains, which may be particularly able to adapt to treatment effects when people are young.”
The study involved four young people with achromatopsia aged 10 to 15 years old.
The two trials, which each target a different gene implicated in achromatopsia, are testing gene therapies with the primary aim of establishing that the treatment is safe, while also testing for improved vision. Their results have not yet been fully compiled so the overall effectiveness of the treatments remains to be determined.
The accompanying academic study used a novel functional magnetic resonance imaging (fMRI) mapping approach to separate emerging post-treatment cone signals from existing rod-driven signals in patients, allowing the researchers to pinpoint any changes in visual function, after treatment, directly to the targeted cone photoreceptor system. They employed a ‘silent substitution’ technique using pairs of lights to selectively stimulate cones or rods. The researchers also had to adapt their methods to accommodate eye movements due to nystagmus, another symptom of achromatopsia. The results were compared to tests involving nine untreated patients and 28 volunteers with normal vision.
Each of the four children was treated with gene therapy in one eye, enabling doctors to compare the treatment’s effectiveness with the untreated eye.
For two of the four children, there was strong evidence for cone-mediated signals in the brain’s visual cortex coming from the treated eye, six to 14 months after treatment. Before the treatment, the patients showed no evidence of cone function on any tests. After treatment, their measures closely resembled those from normal sighted study participants.
The study participants also completed a test to distinguish between different levels of contrast. This showed there was a difference in cone-supported vision in the treated eyes in the same two children.
The researchers say they cannot confirm whether the treatment was ineffective in the other two study participants, or if there may have been treatment effects that were not picked up by the tests they used, or if effects are delayed.
Co-lead author Dr Michel Michaelides (UCL Institute of Ophthalmology and Moorfields Eye Hospital), who is also co-investigator on both clinical trials, said: “In our trials, we are testing whether providing gene therapy early in life may be most effective while the neural circuits are still developing. Our findings demonstrate unprecedented neural plasticity, offering hope that treatments could enable visual functions using signalling pathways that have been dormant for years.
“We are still analysing the results from our two clinical trials, to see whether this gene therapy can effectively improve everyday vision for people with achromatopsia. We hope that with positive results, and with further clinical trials, we could greatly improve the sight of people with inherited retinal diseases.”
Dr Dekker added: “We believe that incorporating these new tests into future clinical trials could accelerate the testing of ocular gene therapies for a range of conditions, by offering unparalleled sensitivity to treatment effects on neural processing, while also providing new and detailed insight into when and why these therapies work best.”
One of the study participants commented: “Seeing changes to my vision has been very exciting, so I’m keen to see if there are any more changes and where this treatment as a whole might lead in the future.
“It’s actually quite difficult to imagine what or just how many impacts a big improvement in my vision could have, since I’ve grown up with and become accustomed to low vision, and have adapted and overcome challenges (with a lot of support from those around me) throughout my life.”
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.
