Posts Tagged ‘gene’

Elephants’ secret to their low rates of cancer might be explained in part by a so-called zombie gene—one that was revived during evolution from a defunct duplicate of another gene. In the face of DNA damage, elephant cells fire up the activity of the zombie gene LIF6 to kill cells, thereby destroying any cancer-causing genetic defects, researchers reported in Cell Reports.

“From an evolutionary biology perspective, it’s completely fascinating,” Joshua Schiffman, a pediatric oncologist at the University of Utah who was not involved in the work, tells National Geographic.

The better-known LIF gene has a number of functions in mammals, including as an extracellular cytokine. In elephants, LIF is duplicated numerous times as pseudogenes, which don’t have the proper sequence to produce functioning transcripts. For the latest study, the researchers wanted to see whether the duplications might have anything to do with elephant cells’ unusual response to DNA damage: indiscriminant destruction.

The team found that one of the pseudogenes, LIF6, evolved after LIF was duplicated in a way that produces a transcript, and that the gene product is controlled by TP53, a tumor suppressor. When the researchers overexpressed LIF6 in elephant cells, the cells underwent apoptosis. The same thing happened with they introduced the gene to Chinese hamster ovary cells, indicating that LIF6 has a role in elephants’ defense against DNA damage.

More work needs to be done to determine whether the LIF6 revival is responsible for elephants’ low cancer rates. There are likely to be other contributors, says coauthor Vincent Lynch, an evolutionary biologist at the University of Chicago, in an interview with The New York Times. “There are lots of stories like LIF6 in the elephant genome, and I want to know them all.”

https://www.the-scientist.com/news-opinion/elephants-revived-a-zombie-gene-that-perhaps-fends-off-cancer-64643

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by Matthew Herper

A Harvard scientist thinks he’s reached a new milestone: a genetic test that helps identify people who are at high risk of having a heart attack. Can he convince doctors to use it?

“I think–in a few years, I think everybody will know this number, similar to the way we know our cholesterol right now,” muses Sekar Kathiresan, director of the Cardiovascular Disease Initiative at the Broad institute and a professor at Harvard Medical School.

Not everyone else is so sure. “I think it’s a brilliant approach,” says Harlan Krumholz, the Harold H. Hines Jr. professor of cardiology at Yale University and one of Kathiresan’s collaborators. But he worries about whether Kathiresan’s tests are ready to compete with the plethora of diagnostic tests, from AI-boosted CT scans to new types of “bad” cholesterol proteins, that are on offer. And he worries about cost. There is no commercial version of the gene test. But the very idea that such a test is not only available, but also near, is the result of a cresting wave of new genetic science, the result of large efforts to gather genetic information from millions of volunteers.

The number in question is what is called a polygenic risk score. Instead of looking for one miswritten gene that causes heart attacks, or, for that matter, other health problems, geneticists are increasingly looking at thousands of genetic alterations without even being sure what each does. In the case of Kathiresan’s polygenic score, the test looks for 6.6 million single-letter genetic changes that are more prevalent in people who have had early heart attacks.

Our genetic inheritances, the current thinking goes, are not so much a set of declarative orders as a cacophony of noise. There are big genetic changes that can have a big effect, but most diseases are the result of lots of tiny changes that add up. In Kathiresan’s words, it’s mostly a gemish (Yiddish for “a mixture”). And it’s not clear which changes are biologically important – Kathiresan says only 6,000 or so of the 6.6 million genetic changes are probably actually causing heart attacks. But finding those specific changes will take a long time. The risk score could be used now.

The effect of this genetic cacophony can be huge. The most common single mutation that increases the risk of heart disease is a gene that causes a disease called heterozygous familial hypercholesterolemia (literally: inherited high cholesterol) that occurs in one person in 250 and triple’s a person’s risk of having a heart attack. But today, in a paper in Nature Genetics, Kathiresan and his colleagues present data that 5% to 8% have a polygenic score that also at least triples their risk of having a heart attack. That’s about 20 times as many people, Kathiresan says.

“These patients are currently unaware of their risk because the polygenic patients don’t have higher levels of the usual risk factors,” Kathiresan says. “Their cholesterol is not high. Their blood pressure is not that high. They are hidden from the current risk assessment tools.”

In the Nature Genetics paper, Kathiresan’s team tested the 6-million-variant polygenic score in two groups of patients numbering, respectively, 120,280 and 288,978 people, from the U.K. BioBank, a government-backed effort in the United Kingdom to collect genetic data. For some patients, the risk was even higher, with the genetic changes predicting a fivefold increase in heart attack risk. The paper also argues that polygenic risk scores could be used to predict risk of conditions such as type 2 diabetes and breast cancer.

Another study, yet to be published, looked at the prevalence of both familial hypercholesterolemia and the polygenic score in a population of people who had heart attacks in their 40s and 50s, Katherisan says. Only 2% had familial hypercholesterolemia, but 20% had a high polygenic risk score. Knowing one’s polygenic risk score might matter. A 2016 paper in the New England Journal of Medicine showed that people with high polygenic scores had fewer heart attacks if they had healthier lifestyles, and a 2017 paper in the medical journal Circulation showed that patients with high polygenic risk scores got an outsize benefit from cholesterol-lowering statin drugs. Those papers, both by Kathiresan’s group, used a score that included only a few dozen gene variants.

Doctors should be skeptical of such a test. There’s a long history of tests in medicine that have done more harm than good by leading to people to take drugs they do not need. Cardiologists have gotten used to even higher standards for data. For instance, many might want to see if the test can show a benefit in a large study in which people are tested at random. Many will want more evidence that the test can identify people at high risk they’d otherwise miss, as Kathiresan says, and that it doesn’t lead to treatment in those who don’t need it. Kathiresan says he hopes to do a study in the highest-risk individuals to prove that statin drugs can lower their risk. If the test becomes a commercial prospect, more studies will drive up the eventual cost.

Kathiresan is hoping to follow a less expensive path. He notes that 17 million people have already used genotyping services like 23andMe and Ancestry. He hopes that people who use those services (23andMe costs $99, Ancestry $59) will submit their data to a portal he’ll build for free. He also says he’s in discussions with commercial providers, but he’s hoping that people will be able to get their polygenic scores for about as much as the cost of a cholesterol test. For the people at the highest risk, he argues, this is information that could be important. For others, he argues, why deny people information that has been scientifically validated?

Whether Kathiresan can really pull off a low-cost version in a medical system that is optimized to make money is as big a question as whether the test is ready for prime time. Krumholz worried about the cost of the test until a reporter told him of Kathiresan’s planned website. “If you say it’s free, I’m going, ‘Why not?'” Krumholz says. “It’s a better family history,” he says, comparing the test to asking whether a relative has had a heart attack. But that may be the biggest ‘if’. If anything is more puzzling than genetics, it is the economics of healthcare in the U.S.A.
https://www.forbes.com/sites/matthewherper/2018/08/13/a-harvard-scientist-thinks-he-has-a-gene-test-for-heart-attack-risk-he-wants-to-give-it-away-free/#557490e85959


Lung cancer seen on chest X ray.

Researchers have identified a gene that when inhibited or reduced, in turn, reduced or prevented human non-small cell lung cancer tumors from growing.

When mice were injected with non-small cell lung cancer cells that contained the gene NOVA1, three of four mice formed tumors. When the mice were injected with cancer cells without NOVA1, three of four mice remained tumor-free.

The fourth developed a tumor, but it was very small compared to the mice with the NOVA1 tumor cells, said Andrew Ludlow, first author on the study and assistant professor at the University of Michigan School of Kinesiology.

The research appears online today in Nature Communications. Ludlow did the work while a postdoctoral fellow at the University of Texas Southwestern Medical Center, in the shared lab of Woodring Wright, professor of cell biology and internal medicine, and Jerry Shay, professor of cell biology.

The study found that in cancer cells, the NOVA1 gene is thought to activate telomerase, the enzyme that maintains telomeres—the protective caps on the ends of chromosomes that preserve genetic information during cell division (think of the plastic aglets that prevent shoelace ends from fraying).

Telomerase isn’t active in healthy adult tissues, so telomeres degrade and shorten as we age. When they get too short, the body knows to remove those damaged or dead cells.

In most cancers, telomerase is reactivated and telomeres are maintained, thus preserving the genetic material, and these are the cells that mutate and become immortal.

Telomerase is present in most cancer types, and it’s an attractive therapeutic target for cancer. However, scientists haven’t had much luck inhibiting telomerase activity in cancer, Ludlow said.

Ludlow’s group wanted to try a new approach, so they screened lung cancer cell lines for splicing genes (genes that modify RNA) that might regulate telomerase in cancer, and identified NOVA1.

They found that reducing the NOVA1 gene reduced telomerase activity, which led to shorter telomeres, and cancer cells couldn’t survive and divide.

Researchers only looked at non-small cell lung cancers, and NOVA1 was present in about 70 percent of them.

“Non-small cell lung cancer is the most prevalent form of age-related cancer, and 80 to 85 percent of all lung cancers are non-small cell,” Ludlow said. “But there really aren’t that many treatments for it.”

According to the American Cancer Society, lung cancer causes the most cancer deaths among men and women, and is the second most common cancer, aside from skin cancer.

Before researchers can target NOVA1 or telomerase splicing as a serious potential therapy for non-small cell lung cancer, they must gain a much better understanding of how telomerase is regulated. This research is a step in that direction.

Ludlow’s group is also looking at ways to directly impact telomerase splicing, in addition to reducing NOVA1.

Explore further: Blocking two enzymes could make cancer cells mortal

More information: Andrew T. Ludlow et al, NOVA1 regulates hTERT splicing and cell growth in non-small cell lung cancer, Nature Communications (2018). DOI: 10.1038/s41467-018-05582-x

https://medicalxpress.com/news/2018-08-nova1-gene-tumor-growth-common.html

Scientists have revealed a new link between alcohol, heart health and our genes.

The researchers investigated faulty versions of a gene called titin which are carried by one in 100 people or 600,000 people in the UK.

Titin is crucial for maintaining the elasticity of the heart muscle, and faulty versions are linked to a type of heart failure called dilated cardiomyopathy.

Now new research suggests the faulty gene may interact with alcohol to accelerate heart failure in some patients with the gene, even if they only drink moderate amounts of alcohol.

The research was carried out by scientists from Imperial College London, Royal Brompton Hospital, and MRC London Institute of Medical Sciences, and published this week in the latest edition of the Journal of the American College of Cardiology.

The study was supported by the Department of Health and Social Care and the Wellcome Trust through the Health Innovation Challenge Fund.

In the first part of the study, the team analysed 141 patients with a type of heart failure called alcoholic cardiomyopathy (ACM). This condition is triggered by drinking more than 70 units a week (roughly seven bottles of wine) for five years or more. In severe cases the condition can be fatal, or leave patients requiring a heart transplant.

The team found that the faulty titin gene may also play a role in the condition. In the study 13.5 per cent of patients were found to carry the mutation – much higher than the proportion of people who carry them in the general population.

These results suggest this condition is not simply the result of alcohol poisoning, but arises from a genetic predisposition – and that other family members may be at risk too, explained Dr James Ware, study author from the National Heart and Lung Institute at Imperial.

“Our research strongly suggests alcohol and genetics are interacting – and genetic predisposition and alcohol consumption can act together to lead to heart failure. At the moment this condition is assumed to be simply due to too much alcohol. But this research suggests these patients should also be checked for a genetic cause – by asking about a family history and considering testing for a faulty titin gene, as well as other genes linked to heart failure,” he said.

He added that relatives of patients with ACM should receive assessment and heart scans – and in some cases have genetic tests – to see if they unknowingly carry the faulty gene.

In a second part of the study, the researchers investigated whether alcohol may play a role in another type of heart failure called dilated cardiomyopathy (DCM). This condition causes the heart muscle to become stretched and thin, and has a number of causes including viral infections and certain medications. The condition can also be genetic, and around 12 per cent of cases of DCM are thought to be linked to a faulty titin gene.

In the study the team asked 716 patients with dilated cardiomyopathy how much alcohol they consumed.

None of the patients consumed the high-levels of alcohol needed to cause ACM. But the team found that in patients whose DCM was caused by the faulty titin gene, even moderately increased alcohol intake (defined as drinking above the weekly recommended limit of 14 units), affected the heart’s pumping power.

Compared to DCM patients who didn’t consume excess alcohol (and whose condition wasn’t caused by the faulty titin gene), excess alcohol was linked to reduction in heart output of 30 per cent.

More research is now needed to investigate how alcohol may affect people who carry the faulty titin gene, but do not have heart problems, added Dr Paul Barton, study co-author from the National Heart and Lung Institute at Imperial:

“Alcohol and the heart have a complicated relationship. While moderate levels may have benefits for heart health, too much can cause serious cardiac problems. This research suggests that in people with titin-related heart failure, alcohol may worsen the condition.

“An important wider question is also raised by the study: do mutations in titin predispose people to heart failure when exposed to other things that stress the heart, such as cancer drugs or certain viral infections? This is something we are actively seeking to address.”

The research was supported by the Department of Health and Social Care and Wellcome Trust through the Health Innovation Challenge Fund, the Medical Research Council, the NIHR Cardiovascular Biomedical Research Unit at Royal Brompton & Harefield NHS Foundation Trust and the British Heart Foundation.

Reference: Ware, J. S., Amor-Salamanca, A., Tayal, U., Govind, R., Serrano, I., Salazar-Mendiguchía, J., … Garcia-Pavia, P. (2018). Genetic Etiology for Alcohol-Induced Cardiac Toxicity. Journal of the American College of Cardiology, 71(20), 2293–2302. https://doi.org/10.1016/j.jacc.2018.03.462

https://www.technologynetworks.com/genomics/news/faulty-gene-leads-to-alcohol-induced-heart-failure-304365?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=63228690&_hsenc=p2ANqtz-9oqDIw3te1NPoj51s94kxnA1ClK8Oiecfela6I4WiITEbm_-SWdmw6pjMTwm2YP24gqSzRaBvUK1kkb2kZEJKPcL5JtQ&_hsmi=63228690

By Tereza Pultarova

About 4 percent of the people on Earth experience a mysterious phenomenon called synesthesia: They hear a sound and automatically see a color; or, they read a certain word, and a specific hue enters their mind’s eye. The condition has long puzzled scientists, but a small new study may offer some clues.

The study, published March 5 in the journal Proceedings of the National Academy of Sciences, offers insight into what might be happening in the brains of people with synesthesia.

Previous “studies of brain function using magnetic resonance imaging confirm that synesthesia is a real biological phenomenon,” said senior study author Simon Fisher, director of the Max Planck Institute for Psycholinguistics in the Netherlands. For example, when people with synesthesia “hear” color, brain scans show that there’s activity in the parts of the brain linked to both sight and sound, he said. (Not all people with the condition “hear” sights, however; the condition can also link other senses.)Indeed, the brains of people with synesthesia previously have been shown to be more connected across different regions than the brains of people whose senses are not cross-linked, Fisher told Live Science. The question, however, was what causes this different brain wiring, he said.

To answer that question, Fisher and his team looked to genetics.

Synesthesia frequently runs in families, so the researchers decided to look for genes that might be responsible for the development of the condition. They chose three families, in which multiple members across at least three generations had a specific type of synesthesia, the so-called sound-color synesthesia, meaning that hearing sounds evokes perceptions of colors. Typically, a specific sound or musical tone is consistently associated with a specific color for people who have this type of synesthesia. However, different members of a single family can see different colors when hearing the same sound, Fisher said.

The scientists used DNA sequencing to study the participants’ genes, Fisher said. Then, to identify genes that might be responsible for the condition, the scientists compared the genes of family members with synesthesia to the genes of family members without it, he said.

But the findings didn’t yield a straightforward result: “There was not a single gene that could explain synesthesia in all three families,” Fisher said. Instead, “there were 37 candidate variants,” or possible gene variations, he said.

Because the study included only a small number of people, there wasn’t enough data to single out the specific genes, of the 37 possibilities, that played a role in synesthesia. So, instead, the scientists looked at the biological functions of each gene to see how it could be related to the development of the condition. “There were just a few biological themes that were significantly enriched across the candidate genes identified,” Fisher said. “One of those was axonogenesis, a crucial process helping neurons get wired up to each other in the developing brain.” Axonogenesis refers to the development of neurons.

This is consistent with prior findings of altered connectivity in brain scans of people with synesthesia, Fisher said. In other words, the genes identified in the study play a role in how the brain is wired, offering a potential explanation for why the brains of people with synesthesia appear to be wired differently.

https://www.livescience.com/61930-synesthesia-hear-colors-genes.html

A group of genes and genetic switches involved in age-related brain deterioration have been identified by scientists at the Babraham Institute, Cambridge and Sapienza University, Rome. The research, published online today (5th March) in Aging Cell, found that changes to one of these genes, called Dbx2, could prematurely age brain stem cells, causing them to grow more slowly. The study was led jointly by Giuseppe Lupo and Emanuele Cacci in Italy and Peter Rugg-Gunn in the UK.

Cells in the brain are constantly dying and being replaced with new ones produced by brain stem cells. As we age, it becomes harder for these stem cells to produce new brain cells and so the brain slowly deteriorates. By comparing the genetic activity in brain cells from old and young mice, the scientists identified over 250 genes that changed their level of activity with age. Older cells turn some genes, including Dbx2, on and they turn other genes off.

By increasing the activity of Dbx2 in young brain stem cells, the team were able to make them behave more like older cells. Changes to the activity of this one gene slowed the growth of brain stem cells. These prematurely aged stem cells are not the same as old stem cells but have many key similarities. This means that many of the genes identified in this study are likely to have important roles in brain ageing.

The research also identified changes in several epigenetic marks – a type of genetic switch – in the older stem cells that might contribute to their deterioration with age. Epigenetic marks are chemical tags attached to the genome that affect the activity of certain genes. The placement of these marks in the genome change as we age and this alters how the cells behave. The researchers think that some of these changes that happen in the brain may alter causing brain stem cells to grow more slowly.

First author on the paper, Dr Giuseppe Lupo, Assistant Professor at Sapienza University said: “The genes and gene regulators that we identified are corrupted in neural stem cells from older mice. By studying the Dbx2 gene we have shown that these changes may contribute to ageing in the brain by slowing the growth of brain stem cells and by switching on the activity of other age-associated genes.”

Co-lead scientist Dr Peter Rugg-Gunn at the Babraham Institute said: “Ageing ultimately affects all of us and the societal and healthcare burden of neurodegenerative diseases is enormous. By understanding how ageing affects the brain, at least in mice, we hope to identify ways to spot neural stem cell decline. Eventually, we may find ways to slow or even reverse brain deterioration – potentially by resetting the epigenetic switches – helping more of us to stay mentally agile for longer into old age.”

Co-lead scientist Dr Emanuele Cacci at Sapienza University said: “We hope this research will lead to benefits for human health. We have succeeded in accelerating parts of the ageing process in neural stem cells. By studying these genes more closely, we now plan to try turning back the clock for older cells. If we can do this in mice, then the same thing could also be possible for humans.”

This article has been republished from materials provided by the Babraham Institute. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference: Lupo, G., Nisi, P. S., Esteve, P., Paul, Y.-L., Novo, C. L., Sidders, B., … Rugg-Gunn, P. J. (n.d.). Molecular profiling of aged neural progenitors identifies Dbx2 as a candidate regulator of age-associated neurogenic decline. Aging Cell, n/a-n/a. https://doi.org/10.1111/acel.12745

https://www.technologynetworks.com/genomics/news/these-genes-are-involved-in-age-linked-brain-deterioration-298221?utm_campaign=Newsletter_TN_BreakingScienceNews&utm_source=hs_email&utm_medium=email&utm_content=61138279&_hsenc=p2ANqtz-_FeiFbqi-SP5EqlFOOosvK1dViRCt4fG_ztTzGnpct1WLd4sY0BUbdkcuE7-2clIdZwQsKU1fdtv-8HDaJoh76WD9KwA&_hsmi=61138279

A single genetic mutation may increase a person’s risk of developing a rare, severe form of multiple sclerosis (MS) by roughly 60 percent, according to a study published recently in the journal Neuron.

That’s an unusually straightforward result for a complex disease like MS, which has previously been traced to hundreds of mutations that each increases the risk of developing the disease only slightly.

“That’s why our finding is unprecedented,” Carles Vilariño-Güell, Ph.D., an assistant professor of medical genetics at The University of British Columbia and one of the paper’s senior authors, told Healthline.

His team found the mutation by combing through a database of Canadians with MS who had donated blood samples as part of the Canadian Collaborative Project on Genetic Susceptibility to MS.

Some of these samples belonged to a family that was disproportionately diagnosed with the disease. Four first cousins and two parents developed MS.

The team isolated a common mutation from their DNA, and looked for that mutation in other individuals in the database.

That’s how they found a second family similarly afflicted. Three first cousins and two parents were diagnosed with MS.

Having so many cases of MS within a family is rare. The disease is not considered truly heritable, although a person’s risk does increase if a parent or sibling has the disease.

The families shared another rare trait. Most had the more severe version of the disease known as primary progressive MS, which makes up 10 to 15 percent of all MS cases.

Treatments for primary progressive MS have so far eluded scientists, although there are promising clinical trials underway of a drug called Ocrelizumab.


Future Research

The study found the mutation only in a handful of people, all of whom were diagnosed with a rare form of the disease.

Therefore, the researchers don’t suggest they have found the genetic basis of MS.

But they do think they’ve discovered a way to study how the disease progresses in the body and what drugs could be developed to slow or even stop it

Bruce Bebo, Ph.D., vice president of research at the National Multiple Sclerosis Society, agrees.

“Studying the genetics of a very rare form that is inherited can give us clues about pathways involved in MS in the general population,” he told Healthline.

The mutation appears to disable a regulatory gene called NR1H3, which codes for a protein that helps regulate the inflammation and the metabolism of lipids.

The researchers now plan to engineer a similar mutation in mice so they can study the outcome of a disabled NR1H3 gene and test potential new drugs in an animal model.

And because the NR1H3 pathway has already been implicated in diseases like atherosclerosis and heart disease, there are already drugs in clinical trials for safety that could be repurposed for treating MS, Vilariño-Güell said.

“Understanding the genetics of MS could help us get closer to individualizing therapy to people for better outcomes,” Bebo said.

Getting Personal with Treatment

People with a disease like MS, which appears in so many different ways and can be linked to so many different genetic components, could benefit by personalized medicine.

If the mechanism of each disease causing mutation or group of mutations is pinpointed, scientists could potentially design more effective, targeted treatments rather than the standard one-size-fits-all therapies.

That means tracking down the many different genetic hotspots that are linked to MS.

Overall, genetic predisposition accounts for only about a third of a person’s risk of developing the disease, Bebo said. Within that category only about half the genes responsible can be identified.

Researchers don’t know where the other half of that genetic risk comes from, Bebo said, but it makes sense that it would include rare mutations like this one that help explain risk in a small fraction of MS patients.

And there could be many different versions of these mutations.

“Odds are if you look at a different family the genetic risk would probably be something different than this,” Bebo said.

Speeding Through the Genome

The Canadian database has been available since the late 1990s, but only recently has the team had access to exome sequencing, a powerful, efficient tool that makes searching for tiny genetic changes easier.

This technique sequences only the DNA that codes for proteins — leaving the other 98 percent behind. It’s like speed reading the genome.

Exome sequencing has been particularly helpful for finding so-called “Mendelian” diseases — diseases that can be traced to a single, heritable mutation just like Gregor Mendel’s purple and white pea flowers. Cystic fibrosis and sickle cell anemia are two examples of these diseases.

With this discovery, the researchers say that have found a Mendelian form of MS.

That doesn’t mean the discovery won’t be beneficial for the 85 percent of people diagnosed with relapsing remitting MS. In many of those patients, the disease eventually changes course and becomes progressive.

Whatever is learned about primary progressive MS — a condition that doesn’t respond to treatments for other types of MS — could also potentially help those with secondary progressive MS, the researchers say.

http://www.healthline.com/health-news/form-of-ms-could-be-caused-by-single-genetic-mutation#5