Category Archives: Gene Medicine

Previous articles in this series focused on handling very large text files. At some point, you may be interested in searching for a specific pattern in those large files. Manually searching through a large text file is a non-starter, so leveraging the incredible tools of the developers trade is where we turn for help in todays article.

Regular expressions (Regex) are built for this task. They are encoded text strings focused on matching and manipulating patterns in the text. They were born into our world in the 1970s. They are extremely useful and considered the key to powerful text processing.

To be more precise, a regular expression is a string that contains a combination of normal characters and special metacharacters. The normal characters are present to match themselves. On the other hand, the metacharacters represent ideas such as quantity and location of characters.

Regex is a language in and of itself, with special syntax and instructions to implement. It can be used with programming languages, like Ruby, to accomplish different tasks, such as:

These are just a few of the example tasks that are possible. Such tasks can range in complexity from a simple text editors search command to a powerful text processing language.

The bottom line is that you, as a Ruby programmer, will be armed with a very versatile tool that can be used to perform all sorts of text processing tasks.

The example today will focus on the main types of tasks regex performs: Search (locate text) and Replace (edit located text).

Regex comes in handy when searching text, especially when the text is not a straightforward match. As we mentioned above, you may be interested in finding the text ==ant==. This is simple. But when the location of ==ant== matters, such that you want ant but not want, regex is perfect.

Replacing in regex is a power on itself to be added to the search capability of regex. An example when replacing may be needed is when you want to replace extracted (searched) URLs with clickable URLs, that is, a URL having the HTML href attribute.

Lets do some simple examples with regex to warm up. You can use these tables as a reference for some of the metacharacters well use. Also, as a way to test your regex, use Rubular, an online Ruby-based regular expression editor for testing regular expressions.

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Ruby on Medicine: Hunting For The Gene Sequence

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Newswise BIRMINGHAM, Ala. Amjad Javed, Ph.D., of the University of Alabama at Birmingham, has taken a major step forward in understanding the bone development function of a gene called runx2, which could lead to future ways to speed bone healing, aid bone bioengineering, stem osteoporosis and reduce arthritis.

Javed, a professor in the UAB School of Dentistrys Department of Oral and Maxillofacial Surgery, says the results will contribute to future personalized medicine. This month, Javed presented this work to a standing-room-only audience at the International Association for Dental Research Annual Meeting in Boston. The work was published recently in two articles in the Journal of Bone and Mineral Research.

It was well-known that the deletion of both copies of the runx2 gene is lethal and the organism cannot form bone, teeth or cartilage.

To learn about the function of runx2 in specific cells types, Javed and his colleagues developed mice in which both copies of the runx2 gene were removed in only one of two key cells for bone tissue either chondrocytes or osteoblasts.

Our objective was to dissect and tease out which cell is really contributing what in bone development, Javed said. Runx2 is vital. But when we talk up personalized medicine, we need to identify which specialized cells to target within bone tissue.

Study of these mice (technically known as the next-generation conditional knockout runx2 model) shows that chondrocytes and osteoblasts have surprisingly different functions in bone formation during gestation or after birth:

Chondrocytes are involved in bone mineralization during embryonic development. Osteoblasts are involved in bone growth during postnatal development. This is a major step forward in understanding the biology of bones the dynamic, complex organs that are actively remodeled throughout life. Bones have cartilage-producing cells (chondrocytes), bone-creating cells (osteoblasts), bone-eating cells (osteoclasts), neuronal cells and blood-forming (hematopoietic) cells. Connective tissue and muscle surround the bones.

Chondrocytes Javeds model began with the cartilage-producing cells. We first removed the runx2 gene in chondrocytes, cells that are fundamental for every cartilage tissue in the body, Javed said. Our first surprise was lethality at birth.

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UAB Researcher Probes Role of a Master Gene in Skeletal Formation

By Dennis Thompson HealthDay Reporter

WEDNESDAY, March 25, 2015 (HealthDay News) -- Researchers say they've discovered a new genetic cause of autism, singling out a rare gene mutation that appears to hamper normal brain development early on in powerful ways.

The gene, CTNND2, provides instructions for making a protein called delta-catenin, which plays crucial roles in the nervous system, said senior author Aravinda Chakravarti, a professor in the Johns Hopkins University School of Medicine's Institute of Genetic Medicine.

His research team found that a group of girls with severe autism carried CTNND2 mutations that appeared to reduce the effectiveness of delta-catenin, potentially affecting their neurological development.

"There are many, many proteins that in fact 'moonlight,' doing many, many different things," Chakravarti said. "Maybe the severity of the effect of delta-catenin comes from the fact that when you lose function of this protein, you lose not just one function but many functions. Although that remains to be shown, it is strongly implicated by our study."

Autism spectrum disorder is a neurological and developmental disorder that begins early in life. The cause is not known, although scientists suspect genes play a role.

The researchers discovered the CTNND2 gene's link to autism using an approach that focuses on rare and extreme cases of autism, according to the study released online March 25 in the journal Nature.

By focusing on extreme cases, they believe they will discover genes that have a more powerful effect on brain development and help explain the root causes of autism.

"If we study rare and extreme forms, they are both genetic and they represent very early neurodevelopmental events," Chakravarti said.

The researchers chose to study girls with autism because they are far less likely to have autism than boys. When girls do develop the disorder, their symptoms tend to be severe.

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Scientists Spot Gene Tied to Severe Autism in Girls

PITTSBURGH, March 25, 2015 - Fetal ultrasound exams on more than 87,000 mice that were exposed to chemicals that can induce random gene mutations enabled developmental biologists at the University of Pittsburgh School of Medicine to identify mutations associated with congenital heart disease in 61 genes, many not previously known to cause the disease. The study, published online today in Nature, indicates that the antenna-like cellular structures called cilia play a critical role in the development of these heart defects.

The findings are the culmination of an effort to find the genetic determinants of structural heart disease in the "Bench to Bassinet" program, launched six years ago by the National Heart, Lung, and Blood Institute (NHLBI), part of the National Institutes of Health, led at Pitt by principal investigator Cecilia Lo, Ph.D., professor and chair of the Department of Developmental Biology, Pitt School of Medicine.

"This project has given us new insights into the biological pathways involved in development of the heart," Dr. Lo said. "The genes and pathways identified in our study will have clinical importance for interrogating the genetic causes of congenital heart disease in patients."

For the study, Dr. Lo's team mated mice exposed to chemicals that could create random genetic mutations, resulting in 87,355 pregnancies. They scanned each fetus using noninvasive ultrasound and recovered over 3,000 independent cases of congenital heart defects, all incompatible with life. They sequenced the genes of mutant animals and compared them to those of unaffected offspring to identify 91 recessive mutations in 61 genes.

"We were surprised to learn many of these genes were related to the cilia, or cilia-transduced cell signaling," Dr. Lo said. "These findings suggest cilia play a central role in the regulation of heart development, including patterning left-right asymmetry in the cardiovascular system critical for efficient oxygenation of blood."

She added that pathways recovered in the mouse study show overlap with those associated with de novo, or spontaneous, mutations identified in congenital heart disease patients. Co-investigators of the project include other researchers from the University of Pittsburgh; the University of Massachusetts Medical School; the Jackson Laboratory; and Children's National Medical Center.

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The project was funded NHLBI grants HL098180 and HL098188; National Institute of Mental Health grant MH094564; National Human Genome Research Institute grant HG000330; and the University of Pittsburgh School of Medicine.

About the University of Pittsburgh School of Medicine

As one of the nation's leading academic centers for biomedical research, the University of Pittsburgh School of Medicine integrates advanced technology with basic science across a broad range of disciplines in a continuous quest to harness the power of new knowledge and improve the human condition. Driven mainly by the School of Medicine and its affiliates, Pitt has ranked among the top 10 recipients of funding from the National Institutes of Health since 1998. In rankings recently released by the National Science Foundation, Pitt ranked fifth among all American universities in total federal science and engineering research and development support.

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Pitt team identifies mutations associated with development of congenital heart disease

Angelina Jolie told the story yesterday of her decision to have her ovaries and fallopian tubes surgically removed to reduce the risk of ovarian cancer due to the faulty BRCA1 gene she was born with. This follows a similar decision to undergo a double mastectomy in 2013 to reduce the even higher risk of breast cancer the mutant BRCA1 gene bestows.

As a human being, its hard not to feel enormous sympathy with her for facing such a decision a thoroughly 21stCentury decision that no-one ever had to face until the advent of molecular medicine. For centuries humanity has had to face the many adversities of life head on, but for the most part without much forewarning and even less hope of intervention.

The knowledge that certain mutations in this BRCA1 gene confer such high risks of cancer (as much as 87% chance over a lifetime for breast cancer and 50% for ovarian cancer) has the potential to be empowering or frightening (and perhaps both at the same time) in equal measure.

The interventions are hugely invasive. The surgeries themselves are major, and come with short-term risks. The hormonal imbalances that will result can change not only health but also the person. But perhaps hardest of all to quantify is the psychological and emotional impact.

In addition to sympathy for having to face such a decision, Ms Jolie also deserves admiration for her self-awareness and the clarity of her thinking that has allowed her to make such a clear choice the right choice uniquely for her. Not everyone is blessed with such gifts.

That matters because we all of us are going to face these kind of decisions much more frequently in the future.

We hear from all sides about the benefits of personalized medicine the product of refined molecular diagnostics that offer a glimpse into the future health of the individual. But Ms Jolies experience of personalized medicine highlights some of the challenges that also remain.

The biggest hurdle seems to be one of education. The default state of humans is to be pretty bad at understanding risks and the output of all precision medicine algorithms is precisely that: an estimate of individual risk. While science can make the estimate more accurate, what it cannot provide is the calibration of what that risk estimate means to the individual. A 50% risk of ovarian cancer over a lifetime sounds, on the face of it, like a death sentence. But it needs some context. First and most importantly we have to remember we are all born with a death sentence. The only questions are when and how. Something like 33% of everyone alive today will suffer cancer in their lifetime.

Of course, BRCA1 mutations carry a material risk of an early death and no doubt that influenced Ms Jolies decision (as it would likely have done for most of us). But the important point is that properly understanding the implications of the genetic diagnosis is a complex education process. It cannot be nicely packaged up into a single number or a simple decision.

And BRCA1 carries one of the larger risks associated with any single genetic marker. As molecular diagnostics are refined (as they are being at an impressive rate), that picture will become more complex still and the decisions facing the patient ever more challenging.

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What Angelina Jolie's Very Personal Medicine Tells Us About Personalized Medicine

A University of Colorado Cancer Center study published today in the journal Nature Genetics describes a newly-discovered, heritable genetic cause of acute lymphoblastic leukemia (ALL), namely mutation of the gene ETV6. Much like mutation of the gene BRCA marks people at risk to develop breast and ovarian cancers, identification of mutations in the gene ETV6 may allow doctors to predict the development of ALL, allowing increased monitoring and in the future, perhaps strategies to prevent the disease. There are just over 30,000 cases of ALL diagnosed in the United States each year, with the majority of those cases being in children ages 2-5.

"These people are born with a broken gene and it sets them up for leukemia," says Chris Porter, MD, investigator at the CU Cancer Center and associate professor in the Department of Pediatrics at the CU School of Medicine.

The finding started with a family that had an abnormally high rate of ALL.

"All of them had big red blood cells, low platelet counts and propensity to bleed," Porter says.

This familial link to abnormal blood dynamics and predisposition to ALL implied a common genetic denominator. The question was what, exactly, in this family's genes created these blood problems. To answer the question, the group performed "whole exome sequencing" of family members to, effectively, take snapshots of each protein-producing gene in the chromosomes of these people predisposed to ALL.

Working at the CU Cancer Center, bioinformaticist Ken Jones, PhD, sifted through the data to compare these high-risk genomes with normal-risk genomes. The key difference between healthy genomes and those predisposed to develop ALL was mutation of the gene ETV6.

The gene is involved in the development of blood cells. "Somatic" mutations of the gene, meaning mutations that are not present in the genome at birth but develop later, have previously been implicated in the development of blood cancers. In fact, somatic ETV6 translocation is the most common gene rearrangement in childhood leukemia. Porter explains that somatic mutation of the gene ETV6 requires the presence of other "helper" mutations to cause ALL.

This study is one of two new reports to show that "germline" mutation of ETV6, meaning abnormality that is heritable and present in the genome at birth, can also cause cancers. (Thus the mutation and the risk can run in families.) Unlike somatic mutation of the gene, it seems as if the germline mutation puts the patient one important step closer to the development of leukemia from the time of birth.

Porter and colleagues hope that future work will show the prevalence of this mutation.

"It's not common in a general population," Porter says, "but we think it might be much more common in people who develop ALL."

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Like Angelina Jolie, study pinpoints genetic cause of increased leukemia risk

Researchers at Duke University have identified a protein that may help determine whether a person will develop an apple- or pear-shaped body, which could point to his or her risk of diabetes or heart disease.

In the study, published Monday in the journal Proceedings of the National Academy of Sciences, scientists analyzed zebrafish with and without the Plexin D1 gene, and found that those missing the gene had less visceral fat and were less likely to develop insulin resistance, a precursor of diabetes, even after eating a high-fat diet, according to a news release. A study published in February in the journal Nature also linked Plexin D1, among dozens of other genomic hotspots, to waist-to-hip regulation.

Heart disease is tied to greater visceral fat accumulation in the belly, or an apple-shaped body, compared to subcutaneous fat accumulation in the hips and thighs, which are characteristics of pear-shaped bodies. Fat concentration in the midsection is thought to induce inflammation and trigger metabolic diseases including high blood pressure, stroke and diabetes.

"This work identifies a new molecular pathway that determines how fat is stored in the body, and as a result, affects overall metabolic health," senior study author John F. Rawls, associate professor of molecular genetics and microbiology at Duke University School of Medicine, said in the news release. "Moving forward, the components of that pathway can become potential targets to address the dangers associated with visceral fat accumulation."

Rawls and postdoctoral fellow James E. Minchin studied the zebrafish because they found that mice died when they knocked out the Plexin D1 gene. According to the news release, the zebrafish were easy to study because they are transparent for most of their lives, so researchers could visualize fat distribution differences between those that contained the gene and those that were genetically engineered to lack it.

Scientists used a chemical dye that fluorescently stained the animals fat cells, which indicated that the mutant zebrafish had less visceral fat than those that still contained the Plexin D1 gene. Researchers also observed that those without the gene had visceral fat tissue composed of smaller but more numerous cells a factor known to reduce the risk of metabolic disease in humans compared to the fish that still had the gene.

After study authors fed the fish a high-fat diet for a few weeks, they saw even stronger differences of fat distribution between the groups of fish. When they gave the fish glucose, the genetically modified fish also cleared sugar from their bloodstream more efficiently, which in humans points to a reduced risk of diabetes and heart disease. Researchers at the Karolina Institute in Sweden analyzed human patient samples and similarly discovered a link between elevated Plexin D1 levels and a greater risk of type 2 diabetes.

"We think that Plexin D1 is functioning within blood vessels to pattern the environment in visceral fat tissue," Minchin, who was lead author of the study, said in the news release. That is, the genes that build blood vessels are also setting up structures to house fat cells. And this role skews the distribution and shape of fat in one direction or another. It is probably just one of many of different genes that each contribute to overall body shape and metabolic health."

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Gene may influence body shape, metabolic disease risk, study finds

IMAGE:Yellow coloring highlights the location of fat cells in this pair of zebrafish. In the adult fish at the top, which is about 10 mm, fat is deposited throughout the... view more

Credit: James E. Minchin

DURHAM, N.C. - Scientists have known for some time that people who carry a lot of weight around their bellies are more likely to develop diabetes and heart disease than those who have bigger hips and thighs. But what hasn't been clear is why fat accumulates in different places to produce these classic "apple" and "pear" shapes.

Now, researchers have discovered that a gene called Plexin D1 appears to control both where fat is stored and how fat cells are shaped, known factors in health and the risk of future disease.

Acting on a pattern that emerged in an earlier study of waist-to-hip ratios in 224,000 people, the study, which appears March 23 in the Proceedings of the National Academy of Sciences, found that zebrafish that were missing the Plexin D1 gene had less abdominal or visceral fat, the kind that lends some humans a characteristic apple shape. The researchers also showed that these mutant zebrafish were protected from insulin resistance, a precursor of diabetes, even after eating a high-fat diet.

"This work identifies a new molecular pathway that determines how fat is stored in the body, and as a result, affects overall metabolic health," said John F. Rawls, Ph.D., senior author of the study and associate professor of molecular genetics and microbiology at Duke University School of Medicine. "Moving forward, the components of that pathway can become potential targets to address the dangers associated with visceral fat accumulation."

Unlike the subcutaneous fat that sits beneath the skin of the hips, thighs, and rear of pear-shaped individuals, visceral fat lies deep within the midsection, wedged between vital organs like the heart, liver, intestine, and lungs. From there, the tissue emits hormones and other chemicals that cause inflammation, triggering metabolic diseases like high blood pressure, heart attack, stroke, and diabetes.

Despite the clear health implications of body fat distribution, relatively little is known about the genetic basis of body shape. A large international study that appeared in Nature in February began to fill in this gap by looking for regions of the human genome associated with a common metric known as the waist-to-hip ratio, which uses waist measurements as a proxy for visceral fat and hip measurements as a proxy for subcutaneous fat. The researchers analyzed samples from 224,000 people and found dozens of hot spots linked to their waist-hip ratio, including a few near a gene called Plexin D1 which is known to be involved in building blood vessels.

Rawls and his postdoctoral fellow James E. Minchin, Ph.D., were curious about how a gene for growing blood vessels might control the storage and shape of fat cells. When they knocked out the Plexin D1 gene in mice, all of the mutant animals died at birth. So they turned to another model organism, the zebrafish, to conduct the rest of their experiments. Because these small aquarium fish are transparent for much of their lives, the researchers could directly visualize how fat was distributed differently between animals that had been genetically engineered to lack Plexin D1 and those with the gene still intact.

By using a chemical dye that fluorescently stained all fat cells, the researchers could see that the mutant zebrafish had less visceral fat than their normal counterparts. They also noticed that the shape or morphology of the fat cells themselves was different. The zebrafish without the Plexin D1 gene had visceral fat tissue that was composed of smaller, but more numerous cells, a characteristic known to decrease the risk of insulin resistance and metabolic disease in humans. In contrast, their normal siblings had visceral fat tissue containing larger, but fewer fat cells of the kind known to be more likely to leak inflammatory substances that contribute to illness.

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New gene influences apple or pear shape, risk of future disease

Findings could pave way for precision medicine approach to treatment of neurological diseases

PHILADELPHIA- Penn Medicine researchers have discovered that hypermethylation - the epigenetic ability to turn down or turn off a bad gene implicated in 10 to 30 percent of patients with Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration (FTD) - serves as a protective barrier inhibiting the development of these diseases. Their work, published this month in Neurology, may suggest a neuroprotective target for drug discovery efforts.

"This is the first epigenetic modification of a gene that seems to be protective against neuronal disease," says lead author Corey McMillan, PhD, research assistant professor of Neurology in the Frontotemporal Degeneration Center in the Perelman School of Medicine at the University of Pennsylvania.

Expansions in the offending gene, C9orf72, have been linked with TAR DNA binding protein (TDP-43) which is the pathological source that causes ALS and FTD. "Understanding the role of C9orf72 has the possibility to be truly translational and improve the lives of patients suffering from these devastating diseases," says senior author, Edward Lee, MD, PhD, assistant professor of Neuropathology in Pathology and Laboratory Medicine at Penn.

McMillan and team evaluated 20 patients recruited from both the FTD Center and the ALS Center at the University of Pennsylvania who screened positive for a mutation in the C9orf72 gene and were clinically diagnosed with FTD or ALS. All patients completed a neuroimaging study, a blood test to evaluate C9orf72 methylation levels, and a brief neuropsychological screening assessment. The study also included 25 heathy controls with no history of neurological or psychiatric disease.

MRI revealed reduced grey matter in several regions that were affected in patients compared to controls. Grey matter is needed for the proper function of the brain in regions involved with muscle control, memory, emotions, speech and decision-making. Critically, patients with hypermethylation of C9orf72 showed more dense grey matter in the hippocampus, frontal cortex, and thalamus, regions of the brain important for the above described tasks and affected in ALS and FTD, suggesting that hypermethylation is neuroprotective in these regions.

To validate these findings, the Penn team also looked at autopsies of 35 patients with C9orf72 expansions and found that their pathology also suggested that increased methylation was associated with reduced neuronal loss in both the frontal cortex and hippocampus.

Longitudinal analysis was performed in 11 of the study patients to evaluate the neuroprotective effects of hypermethylation in individuals over their disease course. This showed reduced changes in grey matter of the hippocampus, thalamus, and frontal cortex, associated with hypermethlation suggesting that disease progresses more slowly over time in individuals with C9orf72 hypermethylation. Longitudinal neuropsychological assessments also showed a correlation between protected memory decline and hypermethylation.

These findings are consistent with a growing number of studies which have suggested the neuroprotective effects of the hypermethylation of C9orf72. "We believe that this work provides additional data supporting the notion that C9orf72 methylation is neuroprotective and therefore opens up the exciting possibility of a new avenue for precision medicine treatments and targets for drug development in neurodegenerative disease," says McMillan.

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Penn Medicine: Potential new drug target may protect against certain neurodegenerative diseases

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Newswise PHILADELPHIA- Penn Medicine researchers have discovered that hypermethylation - the epigenetic ability to turn down or turn off a bad gene implicated in 10 to 30 percent of patients with Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal Degeneration (FTD) - serves as a protective barrier inhibiting the development of these diseases. Their work, published this month in Neurology, may suggest a neuroprotective target for drug discovery efforts.

This is the first epigenetic modification of a gene that seems to be protective against neuronal disease, says lead author Corey McMillan, PhD, research assistant professor of Neurology in the Frontotemporal Degeneration Center in the Perelman School of Medicine at the University of Pennsylvania. Expansions in the offending gene, C9orf72, have been linked with TAR DNA binding protein (TDP-43) which is the pathological source that causes ALS and FTD.

Understanding the role of C9orf72 has the possibility to be truly translational and improve the lives of patients suffering from these devastating diseases, says senior author, Edward Lee, MD, PhD, assistant professor of Neuropathology in Pathology and Laboratory Medicine at Penn.

McMillan and team evaluated 20 patients recruited from both the FTD Center and the ALS Center at the University of Pennsylvania who screened positive for a mutation in the C9orf72 gene and were clinically diagnosed with FTD or ALS. All patients completed a neuroimaging study, a blood test to evaluate C9orf72 methylation levels, and a brief neuropsychological screening assessment. The study also included 25 heathy controls with no history of neurological or psychiatric disease.

MRI revealed reduced grey matter in several regions that were affected in patients compared to controls. Grey matter is needed for the proper function of the brain in regions involved with muscle control, memory, emotions, speech and decision-making. Critically, patients with hypermethylation of C9orf72 showed more dense grey matter in the hippocampus, frontal cortex, and thalamus, regions of the brain important for the above described tasks and affected in ALS and FTD, suggesting that hypermethylation is neuroprotective in these regions.

To validate these findings, the Penn team also looked at autopsies of 35 patients with C9orf72 expansions and found that their pathology also suggested that increased methylation was associated with reduced neuronal loss in both the frontal cortex and hippocampus.

Longitudinal analysis was performed in 11 of the study patients to evaluate the neuroprotective effects of hypermethylation in individuals over their disease course. This showed reduced changes in grey matter of the hippocampus, thalamus, and frontal cortex, associated with hypermethlation suggesting that disease progresses more slowly over time in individuals with C9orf72 hypermethylation. Longitudinal neuropsychological assessments also showed a correlation between protected memory decline and hypermethylation.

These findings are consistent with a growing number of studies which have suggested the neuroprotective effects of the hypermethylation of C9orf72. "We believe that this work provides additional data supporting the notion that C9orf72 methylation is neuroprotective and therefore opens up the exciting possibility of a new avenue for precision medicine treatments and targets for drug development in neurodegenerative disease, says McMillan.

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Penn Medicine Researchers Pinpoint Potential New Drug Target for Protection against Certain Neurodegenerative Diseases