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Category Archives: Gene Medicine

Scientists find a striking number of genetic changes can occur early in human development – Medical Xpress

Posted: February 25, 2017 at 2:49 pm

February 24, 2017 Dr. Pengfei Liu holding human DNA treated with fluorescent dyes prepared for copy number variant analysis. Credit: Baylor College of Medicine

The genetic material of an organism encodes the instructions that guide its development. These codes are not written in stone; they can change or mutate any time during the life of the organism. Single changes in the code can occur spontaneously, as a mutation, causing developmental problems. Others, as an international team of researchers has discovered, are too numerous to be explained by random mutation processes present in the general population. When such multiple genetic changes occur before or early after conception, they may inform scientists about fundamental knowledge underlying many diseases. The study appears in Cell.

“As a part of the clinical evaluation of young patients with a variety of developmental issues, we performed clinical genomic studies and analyzed the genetic material of more than 60,000 individuals. Most of the samples were analyzed at Baylor Genetics laboratories,” said lead author Dr. Pengfei Liu, assistant professor of molecular and human genetics Baylor College of Medicine and assistant laboratory director of Baylor Genetics. “Of these samples, five had extreme numbers of genetic changes that could not be explained by random events alone.”

The researchers looked at a type of genetic change called copy number variants, which refers to the number of copies of genes in human DNA. Normally we each have two copies of each gene located on a pair of homologous chromosomes.

“Copy number variants in human DNA can be compared to repeated or missing paragraphs or pages of text in a book,” said senior author Dr. James R. Lupski, Cullen Professor of Molecular and Human Genetics at Baylor. “For instance, if one or two pages are duplicated in a book it could be explained by random mistakes. On the other hand, if 10 different pages are duplicated, you have to suspect that it did not happen by chance. We want to understand the basic mechanism underlying these multiple new copy number variant mutations in the human genome.”

A rare, early and transitory phenomenon that can affect human development

The researchers call this phenomenon multiple de novo copy number variants. As the name indicates, the copy number variants are many and new (de novo). The latter means that the patients carrying the genetic changes did not inherit them from their parents because neither the mother nor the father carries the changes.

In this rare phenomenon, the copy number variants are predominantly gains duplications and triplications rather than losses of genetic material, and are present in all the cells of the child. The last piece of evidence together with the fact that the parents do not carry the alterations suggest that the extra copies of genes may have occurred either in the sperm or the egg, the parent’s germ cells, and before or very early after fertilization.

“This burst of genetic changes happens only during the early stages of embryonic development and then it stops,” Liu said. “Interestingly, despite having a large number of mutations, the young patients present with relatively mild neurological problems.”

The researchers are analyzing more patient samples looking for additional cases of multiple copy number variants to continue their investigation of what may trigger this rare phenomenon.

“We hope that as more researchers around the world learn about this and confirm it, the number of cases will increase,” Liu said. “This will improve our understanding of the underlying mechanism and of why and how pathogenic copy number variants arise not only in developmental disorders but in cancers.”

A new era of clinical genomics-supported medicine and research

This discovery was made possible in great measure thanks to the breadth of genetic testing performed and genomic data available at Baylor Genetics laboratory.

“The diagnostics lab Baylor Genetics is one of the pioneers in this new era of clinical genomics-supported medical practice and disease gene discovery research,” Lupski said. “They are developing the clinical genomics necessary to foster and support the Precision Medicine Initiative of the National Institutes of Health, and generating the genomics data that further drives human genome research.”

Using state-of-the art technologies and highly-trained personnel, Baylor Genetics analyzes hundreds of samples daily for genetic evaluation of patients with conditions suspected to have underlying genetic factors potentially contributing to their disease. Having this wealth of information and insight into the genetic mechanisms of disease offers now the possibility of advancing medicine and basic research in ways that were not available before.

“There is so much that both clinicians and researchers can learn from the data generated in diagnostic labs,” Liu said. “Clinicians receive genomic information that can aid in diagnosis and treatment of their patients, and researchers gather data that can help them unveil the mechanisms underlying the biological perturbations resulting in the patients’ conditions.”

Explore further: Largest study of its kind finds rare genetic variations linked to schizophrenia

More information: An Organismal CNV Mutator Phenotype Restricted to Early Human Development. Cell, DOI: dx.doi.org/10.1016/j.cell.2017.01.037

Journal reference: Cell

Provided by: Baylor College of Medicine

Many of the genetic variations that increase risk for schizophrenia are rare, making it difficult to study their role in the disease. To overcome this, the Psychiatric Genomics Consortium, an international team led by Jonathan …

Scientists at Baylor College of Medicine, Baylor Genetics, the University of Texas Health Science Center at Houston and Texas Children’s Hospital are combining descriptions of patients’ clinical features with their complex …

Scientists have linked a gene called PKD1L1 with disarrangement of human internal organs, known as laterality defects, and complex congenital heart disease. This discovery contributes to a better understanding of the genetic …

A team of scientists from a number of institutions around the world, including Baylor College of Medicine, has discovered that rare neurological syndromes for which there was no cause can be the result of variations in the …

A team of researchers at Baylor College of Medicine has developed a family-based association test that improves the detection in families of rare disease-causing variants of genes involved in complex conditions such as Alzheimer’s. …

An international team of scientists has identified variants of the gene EBF3 causing a developmental disorder with features in common with autism. Identification of these gene variants leads to a better understanding of these …

The genetic material of an organism encodes the instructions that guide its development. These codes are not written in stone; they can change or mutate any time during the life of the organism. Single changes in the code …

A research team from the United States and Canada has developed and successfully tested new computational software that determines whether a human DNA sample includes an epigenetic add-on linked to cancer and other adverse …

Gene discovery research is uncovering new information about similarities and differences underlying various neurodevelopmental disorders.

A University of Toronto (U of T) study on fruit flies has uncovered a gene that could play a key role in obesity in humans.

Our genes play a significant role in how anxious we feel when faced with spatial and mathematical tasks, such as reading a map or solving a geometry problem, according to a new study by researchers from King’s College London.

Gene editing techniques developed in the last five years could help in the battle against cancer and inherited diseases, a University of Exeter scientist says.

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Scientists find a striking number of genetic changes can occur early in human development – Medical Xpress

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Discovery of genetic mutation may boost cancer therapies – Medical Xpress

Posted: at 2:49 pm

February 24, 2017 by Geri Clark Killer T cells surround a cancer cell. Credit: NIH

A newly discovered type of genetic mutation that occurs frequently in cancer cells may provide clues about the disease’s origins and offer new therapeutic targets, according to research from Weill Cornell Medicine and the New York Genome Center.

Using next-generation sequencing technology, scientists have previously traced cancer’s roots to mutations that disrupt the sequence of proteins. As a result, the cell either creates hyperactive or dysfunctional versions of proteins, or fails to produce them at all, leading to cancer. Now, a study published Jan. 12 in Cell illuminates a possible new type of driver of the disease: small (one- to 50-letter) insertions or deletions of DNA sequence, also called “indels,” in regions of the genome that do not code for protein.

“Those noncoding regions are still important because they contain sequences that affect how genes are regulated, which is critical for normal cell development,” said lead author Dr. Marcin Imielinski, an assistant professor of pathology and laboratory medicine at Weill Cornell Medicine and a core member at the New York Genome Center. “We already know they are biologically important. The question is whether they can impact cancer development.”

In the study, Imielinski and his colleagues analyzed sequencing data from several publicly available databases of tumor samples, focusing on the 98 percent of the genome that does not code for protein. They initially looked at lung adenocarcinoma, the most common type of lung cancer, and found that the most frequent indel-mutated regions in their genomes landed in genes encoding surfactant proteins.

Though these genes are essential for healthy lung function, they had not previously been associated with lung cancer. However, they are highly and specifically expressed by the cell type that gives rise to lung adenocarcinoma.

The researchers then looked at the genomes of 12 other cancer types and found similar patterns in liver, stomach and thyroid tumors.

“In each cancer, noncoding indels clustered in genes that are critical to organ function, but had not been associated with the cancer,” said Imielinski, who is also an assistant professor of computational genomics in the HRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicine and a member of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

Most strikingly, these noncoding indels are very common, occurring in 20 to 50 percent of the associated cancers.

“They occur as frequently as the most famous cancer-causing mutations,” said Imielinski, a paid consultant for the company 10X Genomics, which sells devices and technology to analyze genetic information. “Any gene or any sequence that mutated at this frequency has been shown to play a causal role in cancer. That would be an exciting outcome, if we can prove it.”

Even if these mutations are not shown to cause cancer, they can be used in the future to improve cancer diagnosis and treatment.

“These mutations can be biomarkers that help us to diagnose a cancer early, or they could be used to pinpoint a primary cancer when there are metastases and we can’t find the original cancer,” Imielinski said. “There are a lot of potential clinical implications from these findings.”

Explore further: Researchers pinpoint key regulatory role of noncoding genes in prostate cancer development

More information: Marcin Imielinski et al. Insertions and Deletions Target Lineage-Defining Genes in Human Cancers, Cell (2017). DOI: 10.1016/j.cell.2016.12.025

Journal reference: Cell

Provided by: Cornell University

Prostate cancer researchers studying genetic variations have pinpointed 45 genes associated with disease development and progression.

The steroid dexamethasone could potentially deter the growth of a prostate cancer subtype that was previously thought to be difficult to treat with medications, Weill Cornell Medicine researchers report. Their findings were …

New research shows that current approaches to genome analysis systematically miss detecting a certain type of complex mutation in cancer patients’ tumors. Further, a significant percentage of these complex mutations are found …

Researchers from several major U.S. universities and ITMO University in Russia have identified a number of new driver mutations in lung cancer cells that may be responsive to genomically targeted therapies and to immunotherapy.

A Yale-led study describes how a known cancer gene, EGFR, silences genes that typically suppress tumors. The finding, published in Cell Reports, may lead to the development of more effective, individualized treatment for …

Short, unstable stretches of DNA, called microsatellites, may play a far greater role in the development and progression of cancer than previously thought, UW Medicine researchers report in a study appearing Oct. 3 in the …

Massachusetts General Hospital (MGH) researchers have identified a mechanism that controls the expression of genes regulating the growth of the most aggressive form of medulloblastoma, the most common pediatric brain tumor. …

A new discovery by researchers at the Fred Hutchinson Cancer Research Center in Seattle makes an important step in identifying which specific T cells within the diverse army of a person’s immune system are best suited to …

An interaction between two proteins enables cancer cells to use the physical forces of healthy cells to start spreading to other parts of the body.

Scientists at The Wistar Institute and Inovio Pharmaceuticals, Inc. have devised a novel DNA vaccine approach through molecular design to improve the immune responses elicited against one of the most important cancer antigen …

A newly discovered type of genetic mutation that occurs frequently in cancer cells may provide clues about the disease’s origins and offer new therapeutic targets, according to research from Weill Cornell Medicine and the …

(Medical Xpress)One major challenge in pathology is to determine if a group of cells are cancerous. By ‘cancerous’ one generally means that they have the potential to grow and spread, or that they have already spread from …

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Study finding suggests new ways in which genetic mutations may cause brain disorders – News-Medical.net

Posted: at 2:49 pm

February 25, 2017 at 5:31 AM

Many kids say they love their mom and dad equally, but there are times when even the best prefers one parent over the other. The same can be said for how the body’s cells treat our DNA instructions. It has long been thought that each copy – one inherited from mom and one from dad – is treated the same. A new study from scientists at the University of Utah School of Medicine shows that it is not uncommon for cells in the brain to preferentially activate one copy over the other. The finding breaks basic tenants of classic genetics and suggests new ways in which genetic mutations might cause brain disorders.

In at least one region of the newborn mouse brain, the new research shows, inequality seems to be the norm. About 85 percent of genes in the dorsal raphe nucleus, known for secreting the mood-controlling chemical serotonin, differentially activate their maternal and paternal gene copies. Ten days later in the juvenile brain, the landscape shifts, with both copies being activated equally for all but 10 percent of genes.

More than an oddity of the brain, the disparity also takes place at other sites in the body, including liver and muscle. It also occurs in humans.

“We usually think of traits in terms of a whole person, or animal. We’re finding that when we look at the level of cells, genetics is much more complicated than we thought,” says Christopher Gregg, Ph.D., assistant professor of neurobiology and anatomy and senior author of the study which publishes online in Neuron on Feb. 23. “This new picture may help us understand brain disorders,” he continues.

Among genes regulated in this unorthodox way are risk factors for mental illness. In humans, a gene called DEAF1, implicated in autism and intellectual disability, shows preferential expression of one gene copy in multiple regions of the brain. A more comprehensive survey in primates, which acts as a proxy for humans, indicates the same is true for many other genes including some linked to Huntington’s Disease, schizophrenia, attention deficit disorder, and bipoloar disorder.

What the genetic imbalance could mean for our health remains to be determined, but preliminary results suggest that it could shape vulnerabilities to disease, explains Gregg. Normally, having two copies of a gene acts as a protective buffer in case one is defective. Activating a gene copy that is mutated and silencing the healthy copy – even temporarily – could be disruptive enough to cause trouble in specific cells.

Supporting the idea, Gregg’s lab found that some brain cells in transgenic mice preferentially activate mutated gene copies over healthy ones. “It has generally been assumed that there is correlation between both copies of a gene,” says Elliott Ferris, a computer scientist who co-led the study with graduate student Wei-Chao Huang. Instead, they found something unexpected. “We developed novel methods for mining big data, and discovered something new,” Huang explains.

The investigators screened thousands of genes in their study, quantifying the relative levels of activation for each maternal and paternal gene copy and discovered that expression of the two is different for many genes. Surprised by what they saw, they developed statistical methods to rigorously test their validity and determined that they were not due to technical artifacts, nor genetic noise. Following up on their findings, they examined a subset of genes more closely, directly visualized imbalances between gene copies at the cellular level in the mouse and human brain.

Results from Gregg and colleagues build on previous research, expanding on scenarios in which genes play favorites. Imprinted genes and X-linked genes are specific gene categories that differentially activate their maternal and paternal gene copies. Studies in cultured cells had also determined that some genes vary which copy they express. The results from this study, however, suggests that silencing one gene copy may be a way in which cells fine tune their genetic program at specific times during the lifecycle of the animal, or in discrete places.

“Our new findings reveal a new landscape of diverse effects that shape the expression of maternal and paternal gene copies in the brain according to age, brain region, and tissue type,” explains Gregg. “The implication is a new view of genetics, one that starts up close.”

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Gene mutations in brain linked to OCD-like behavior – Medical News … – Medical News Today

Posted: February 24, 2017 at 5:52 pm

Researchers provide further evidence of how gene mutations in a certain brain region might fuel behaviors associated with obsessive-compulsive disorder. The findings could pave the way for new treatments for the condition.

Obsessive-compulsive disorder is a condition characterized by uncontrollable thoughts, obsessions, and compulsions.

Obsessions include repetitive thoughts or mental images that trigger anxiety, while compulsions refer to the urge to repeat certain behaviors in response to obsessions. Common examples of compulsions include excessive hand-washing, arranging items in a particular way, and compulsive counting.

OCD is estimated to affect around 1 percent of adults in the United States. Of these adults, 50 percent have severe OCD, which can significantly interfere with daily life.

While the precise causes of OCD are unclear, previous studies have suggested that the disorder may be caused by specific gene mutations.

In the new study, researchers from Northwestern University in Chicago, IL, have pinpointed gene mutations in the corticostriatal region of the brain that led to OCD-like behaviors in mice.

Lead author Anis Contractor, associate professor of physiology at Feinberg School of Medicine, and colleagues recently reported their findings in the journal Cell Reports.

In humans and mice, the corticostriatal brain region is responsible for regulating repetitive behavior. “People with OCD are known to have abnormalities in function of corticostriatal circuits,” notes Contractor.

By analyzing this brain region in mice, Contractor and colleagues identified a number of synaptic receptors – called kainate receptors (KARs) – that play a key role in the development of the corticostriatal region.

The researchers then set out to investigate whether disrupting KAR genes in mice – thereby eliminating KARs – might induce repetitive behavior in the rodents. They found this was the case.

Mice whose KAR genes were erased displayed a number of OCD-like behaviors, such as over-grooming and repeatedly digging in their bedding.

The team says these findings provide further evidence that KAR genes play a role in OCD in humans, and a possible biological mechanism.

“A number of studies have found mutations in the kainate receptor genes that are associated with OCD or other neuropsychiatric and neurodevelopmental disorders in humans.

I believe our study, which found that a mouse with targeted mutations in these genes exhibited OCD-like behaviors, helps support the current genetic studies on neuropsychiatric and neurodevelopmental disorders in humans.”

Anis Contractor

The team suggests that in the future, KAR genes could be a target for the development of new drugs to treat OCD.

Learn how exposure therapy might help treat people with OCD.

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Gene mutations in brain linked to OCD-like behavior – Medical News … – Medical News Today

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CRISPR Patent Ruling: 3 Different Takes – KQED

Posted: at 5:52 pm

Solast week the feds may have dashedUC Berkeleys billion-dollar dreams when it decided not to give the universitypatent rights over CRISPR-Cas9, a revolutionary gene-editing technology.

The Feb. 15ruling from the U.S. Patent and Trademark Office let Berkeleys rivaltheBroad Institutejointly owned by Harvard and MITkeep itsexisting patents issued in 2014.UC Berkeleyhas yet to say whether or not it will appeal.

Berkeley was seeking to have some of those patents repealedbecause the university says they conflict with its pending patent application for CRISPR.

The judges reasoned that Berkeleys patent request doesnt affect Broads existing patents because the two are based on different gene editing techniques.

Berkeleys patent request is for editing genes in bacteria, whereas Broads existing patents are for editing genes in eukaryotic cells, i.e. cells found in plants and animals, including humans.

But Berkeleyargues that its research toolcan easily be extended to use in non-bacterial cells.

That distinction is key since potentially lucrative applications of gene editing in medicine and health will involve eukaryotic cells found in humans.

UC Berkeley biologist Jennifer Doudna, who is credited with co-inventingCRISPR-Cas9 now has two options:

1) Appeal to the U.S. Court of Appeals for the Federal Circuit 2) Go back to the U.S. Patent and Trademark Office

If Berkeley appeals, the court could overrule the patent office decision in favor of Berkeley.

If Berkeley loses, it could go backto the patent office, where itcould be required to narrow itsclaims, i.e., specifying that its technique is only intended to be used in bacteria.

Or it could get a broad patentthat still doesnt specifyhow to use CRISPRin eukaryotic cells. But according to Jacob Sherkow, a law professor at New York Law School, that could lead to future legal challenges.

Its not going to be that strong because anyone who wants to challenge it later can say, that patent doesnt disclose how to use the tool in eukaryotic cells,’ says Sherkow.

And the money is in altering those specific cells.

So whats next? Only Berkeley knows; the university has said it will carefully consider all options.

Science journalists are abuzz about what this means for biotech. Heres a sampling of what theyre saying:

1.Berkeley + Broad = VirtualMonopoly on CRISPR-Cas9 (Gizmodo)

Why does this matter? While academic researchers can still use CRISPR for free, companies hoping to harness the gene editing tool to fight disease, solve agricultural problems, or for myriad other potential applications, may have to pay not one, but both institutions, a hefty fee. Its a decision that has caused some to wonder whether the rights to such revolutionary technology dont really belong to a third party: the people.

2. Could the Case Encourage Scientiststo Be Less Honest?(STAT)

The patent judges concluded that the inventors themselves were uncertain about making CRISPR work in human cells.

That could send a terrible message to scientists, said Dr. Robert Cook-Deegan of Arizona State University, an expert on legal and ethical issues surrounding biotechnology. I hope this does not become the poster child that patent offices use to coach scientists not to be honest about uncertainties about their discoveries, he said. The fact that Doudnas quotes were used by the judges mainly tells me Doudna was being honest. I hope scientists will continue to be honest and not succumb to being told they cant say things that might undermine a broad patenting strategy.

3. Fogettaboutit, Companies Can SidestepBerkeleyand Broad(Nature)

Researchers in academia and industry have been pushing CRISPR gene editing beyond the scope of the Broad and Berkeley patents.

Both patent families cover the use of CRISPRCas9, which relies on the Cas9 enzyme to cut DNA. But there are alternatives to Cas9 that provide other functions, and a way to sidestep the BerkeleyBroad patent fight.

One attractive alternative is Cpf1, an enzyme that may be simpler to use and more accurate than Cas9 in some cases. The Broad has already filed patents on applications of Cpf1 in gene editing, and has licensed them to biotech company Editas Medicine in Cambridge, Massachusetts.

Remember, my friends, if UC Berkeley appeals, this whole process could last through 2020. Or longer.

Lindsey Hoshaw is an interactive producer for KQED Science. Before joining KQED, Lindsey was a science correspondent for The New York Times, The Boston Globe, Forbes and Scientific American. On Twitter @lindseyhoshaw

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CRISPR Patent Ruling: 3 Different Takes – KQED

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New Type of Genetic Mutation Identified in Cancer – Cornell Chronicle

Posted: at 5:52 pm

A newly discovered type of genetic mutation that occurs frequently in cancer cells may provide clues about the diseases origins and offer new therapeutic targets, according to new research from Weill Cornell Medicine and the New York Genome Center.

Using next-generation sequencing technology, scientists have previously traced cancers roots to mutations that disrupt the sequence of proteins. As a result, the cell either creates hyperactive or dysfunctional versions of proteins, or fails to produce them at all, leading to cancer. Now, a study published Jan. 12 in Cell illuminates a possible new type of driver of the disease: small (one-50 letter) insertions or deletions of DNA sequence, also called indels, in regions of the genome that do not code for protein.

Dr. Marcin Imielinski Photo credit: John Abbott

Those non-coding regions are still important because they contain sequences that affect how genes are regulated, which is critical for normal cell development, said lead author Dr. Marcin Imielinski, an assistant professor of pathology and laboratory medicine at Weill Cornell Medicine and a core member at the New York Genome Center. We already know they are biologically important. The question is whether they can impact cancer development.

In the study,Dr.Imielinski and colleagues from the Broad Institute of MIT and Harvard and the Dana-Farber Cancer Institute analyzed sequencing data from several publicly available databases of tumor samples, focusing on the 98 percent of the genome that does not code for protein. They initially looked at lung adenocarcinoma, the most common type of lung cancer, and found that the most frequent indel-mutated regions in their genomes landed in genes encoding surfactant proteins. Though these genes are essential for healthy lung function, they had not previously been associated with lung cancer. However, they are highly and specifically expressed by the cell type that gives rise to lung adenocarcinoma.

The researchers then looked at the genomes of 12 other cancer types and found similar patterns in liver, stomach and thyroid tumors. In each cancer, noncoding indels clustered in genes that are critical to organ function, but had not been associated with the cancer, said Dr. Imielinski, who is also an assistant professor of computational genomics in theHRH Prince Alwaleed Bin Talal Bin Abdulaziz Al-Saud Institute for Computational Biomedicineand a member of theSandra and Edward Meyer Cancer Centerat Weill Cornell Medicine.

This image shows genetic mutations (blue) in the context of their surrounding DNA sequence, highlighting a sequence motif (red) that Dr. Imielinski discovered.

Most strikingly, these non-coding indels are very common, occurring in 20-50 percent of the associated cancers. They occur as frequently as the most famous cancer-causing mutations, said Dr. Imielinski, who is a paid consultant for the company 10X Genomics, which sells devices and technology to analyze genetic information. Any gene or any sequence that mutated at this frequency has been shown to play a causal role in cancer. That would be an exciting outcome, if we can prove it.

Even if these mutations are not shown to cause cancer, they can be used in the future to improve cancer diagnosis and treatment. These mutations can be biomarkers that help us to diagnose a cancer early, or they could be used to pinpoint a primary cancer when there are metastases and we cant find the original cancer, Dr. Imielinski said. There are a lot of potential clinical implications from these findings.

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New Type of Genetic Mutation Identified in Cancer – Cornell Chronicle

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Playing favorites: Brain cells prefer one parent’s gene over the other’s – Medical Xpress

Posted: at 5:52 pm

February 23, 2017 Many cells in the brain express two copies of each gene, one inherited from mom and one from dad. Others express just one copy. If the single copy happens to carry a genetic mutation, it may cause the cell to become sick. The discovery from the University of Utah offers a previously undescribed nuanced view of genetics that has consequences at the cellular level. Credit: Christopher Gregg

Most kids say they love their mom and dad equally, but there are times when even the best prefers one parent over the other. The same can be said for how the body’s cells treat our DNA instructions. It has long been thought that each copy – one inherited from mom and one from dad – is treated the same. A new study from scientists at the University of Utah School of Medicine shows that it is not uncommon for cells in the brain to preferentially activate one copy over the other. The finding breaks basic tenants of classic genetics and suggests new ways in which genetic mutations might cause brain disorders.

In at least one region of the newborn mouse brain, the new research shows, inequality seems to be the norm. About 85 percent of genes in the dorsal raphe nucleus, known for secreting the mood-controlling chemical serotonin, differentially activate their maternal and paternal gene copies. Ten days later in the juvenile brain, the landscape shifts, with both copies being activated equally for all but 10 percent of genes.

More than an oddity of the brain, the disparity also takes place at other sites in the body, including liver and muscle. It also occurs in humans.

“We usually think of traits in terms of a whole person, or animal. We’re finding that when we look at the level of cells, genetics is much more complicated than we thought,” says Christopher Gregg, Ph.D., assistant professor of neurobiology and anatomy and senior author of the study which publishes online in Neuron on Feb. 23. “This new picture may help us understand brain disorders,” he continues.

Among genes regulated in this unorthodox way are risk factors for mental illness. In humans, a gene called DEAF1, implicated in autism and intellectual disability, shows preferential expression of one gene copy in multiple regions of the brain. A more comprehensive survey in primates, which acts as a proxy for humans, indicates the same is true for many other genes including some linked to Huntington’s Disease, schizophrenia, attention deficit disorder, and bipoloar disorder.

What the genetic imbalance could mean for our health remains to be determined, but preliminary results suggest that it could shape vulnerabilities to disease, explains Gregg. Normally, having two copies of a gene acts as a protective buffer in case one is defective. Activating a gene copy that is mutated and silencing the healthy copy – even temporarily – could be disruptive enough to cause trouble in specific cells.

Supporting the idea, Gregg’s lab found that some brain cells in transgenic mice preferentially activate mutated gene copies over healthy ones. “It has generally been assumed that there is correlation between both copies of a gene,” says Elliott Ferris, a computer scientist who co-led the study with graduate student Wei-Chao Huang. Instead, they found something unexpected. “We developed novel methods for mining big data, and discovered something new,” Huang explains.

The investigators screened thousands of genes in their study, quantifying the relative levels of activation for each maternal and paternal gene copy and discovered that expression of the two is different for many genes. Surprised by what they saw, they developed statistical methods to rigorously test their validity and determined that they were not due to technical artifacts, nor genetic noise. Following up on their findings, they examined a subset of genes more closely, directly visualized imbalances between gene copies at the cellular level in the mouse and human brain.

Results from Gregg and colleagues build on previous research, expanding on scenarios in which genes play favorites. Imprinted genes and X-linked genes are specific gene categories that differentially activate their maternal and paternal gene copies. Studies in cultured cells had also determined that some genes vary which copy they express. The results from this study, however, suggests that silencing one gene copy may be a way in which cells fine tune their genetic program at specific times during the lifecycle of the animal, or in discrete places.

“Our new findings reveal a new landscape of diverse effects that shape the expression of maternal and paternal gene copies in the brain according to age, brain region, and tissue type,” explains Gregg. “The implication is a new view of genetics, one that starts up close.”

Explore further: Genetic tug of war in brain subregions influences parental control over offspring behavior

More information: The study publishes in Neuron as “Diverse Non-Genetic Allele Specific Expression Effects Shape Genetic Architecture at the Cellular Level in the Mammalian Brain”. DOI: 10.1016/j.neuron.2017.01.033 , http://www.cell.com/neuron/fulltext/S0896-6273(17)30057-0

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Early this year, about 30 neuroscientists and computer programmers got together to improve their ability to read the human mind.

Most kids say they love their mom and dad equally, but there are times when even the best prefers one parent over the other. The same can be said for how the body’s cells treat our DNA instructions. It has long been thought …

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Diabetes, heart-disease risks rise with ‘apple-shape’ body gene variant – Genetic Literacy Project

Posted: at 5:52 pm

A study from Massachusetts General Hospital (MGH) researchers has found that a pattern of gene variants associated with an apple-shaped body type.

In this body type, weight is deposited around the abdomen, rather than in the hips and thighs.This body shape increases the risk for type 2 diabetes and coronary heart disease, as well as the incidence of several cardiovascular risk factors.

[W]e call [this condition] abdominal adiposity, says Sekar Kathiresan, MD, director of the MGH Center for Genomic Medicine. We tested whether genetic predisposition to abdominal adiposity was associated with the risk for type 2 diabetes and coronary heart disease and found that the answer was a firm yes.

No association was found between the genetic risk score and lifestyle factors, and testing confirmed that only the abdominal adiposity effects of the identified gene variants were associated with cardiometabolic risk.

The lack of association between the body type genetic risk score and confounding factors such as diet and smoking provides strong evidence that abdominal adiposity itself contributes to causing type 2 diabetes and heart disease, says lead author Connor Emdin, of the MGH Center for Genomic Medicine and the Cardiology Division.

[The study can be found here.]

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Diabetes, heart-disease risks rise with ‘apple-shape’ body gene variant – Genetic Literacy Project

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Neanderthal DNA contributes to human gene expression – Phys.Org

Posted: February 23, 2017 at 12:46 pm

February 23, 2017 This visual abstract depicts the findings of McCoy et al., who show genome-wide interrogation of the functional differences between modern human and Neanderthal alleles reveals that Neanderthal-inherited sequences are not silent remnants of ancient interbreeding but have a measurable impact on gene expression that may contribute to phenotypic variation in modern humans. Credit: McCoy et al./Cell 2017

The last Neanderthal died 40,000 years ago, but much of their genome lives on, in bits and pieces, through modern humans. The impact of Neanderthals’ genetic contribution has been uncertain: Do these snippets affect our genome’s function, or are they just silent passengers along for the ride? In Cell on February 23, researchers report evidence that Neanderthal DNA sequences still influence how genes are turned on or off in modern humans. Neanderthal genes’ effects on gene expression likely contribute to traits such as height and susceptibility to schizophrenia or lupus, the researchers found.

“Even 50,000 years after the last human-Neanderthal mating, we can still see measurable impacts on gene expression,” says geneticist and study co-author Joshua Akey of the University of Washington School of Medicine. “And those variations in gene expression contribute to human phenotypic variation and disease susceptibility.”

Previous studies have found correlations between Neanderthal genes and traits such as fat metabolism, depression, and lupus risk. However, figuring out the mechanism behind the correlations has proved difficult. DNA can be extracted from fossils and sequenced, but RNA cannot. Without this source of information, scientists can’t be sure exactly if Neanderthal genes functioned differently than their modern human counterparts. They can, however, look to gene expression in modern humans who possess Neanderthal ancestry.

In this study, researchers analyzed RNA sequences in a dataset called the Genotype-Tissue Expression (GTEx) Project, looking for people who carried both Neanderthal and modern human versions of any given geneone version from each parent. For each such gene, the investigators then compared expression of the two alleles head-to-head in 52 different tissues.

“We find that for about 25% of all those sites that we tested, we can detect a difference in expression between the Neanderthal allele and the modern human allele,” says the study’s first author, UW postdoctoral researcher Rajiv McCoy.

Expression of Neanderthal alleles tended to be especially low in the brain and the testes, suggesting that those tissues may have experienced more rapid evolution since we diverged from Neanderthals approximately 700,000 years ago. “We can infer that maybe the greatest differences in gene regulation exist in the brain and testes between modern humans and Neanderthals,” says Akey.

One example uncovered by this study is a Neanderthal allele of a gene called ADAMTSL3 that decreases risk of schizophrenia, while also influencing height. “Previous work by others had already suggested that this allele affects alternative splicing. Our results support this molecular model, while also revealing that the causal mutation was inherited from Neanderthals,” says McCoy. Alternative splicing refers to a process in which mRNAs are modified before they leave the cell’s nucleus. When the Neanderthal mutation is present, the cell’s machinery removes a segment of the mRNA that is expressed in the modern human version. The cell ends up making a modified protein because of a single mutation from a Neanderthal ancestor.

The connection between that modified protein, height, and schizophrenia still requires more investigation, but it’s an example of how small differences between modern humans and Neanderthals can contribute to variation in people.

“Hybridization between modern humans and Neanderthals increased genomic complexity,” explains Akey. “Hybridization wasn’t just something that happened 50,000 years ago that we don’t have to worry about anymore. Those little bits and pieces, our Neanderthal relics, are influencing gene expression in pervasive and important ways.”

Next steps may include investigating whether Denisovansanother species of hominins that crossbred with modern humansare contributing to gene expression, as well as applying the side-by-side method of expression analysis more broadly. For this study, McCoy and his colleagues had to develop a new statistical approach to sift through the immense amount of RNA data, but the same technique could be used to compare gene expression differences between modern human alleles.

Explore further: Long ago humans and Neanderthals Interbred: What happened to Neanderthal genes?

More information: Cell, McCoy et al.: “Impacts of Neanderthal-introgressed sequences on the landscape of human gene expression” http://www.cell.com/cell/fulltext/S0092-8674(17)30128-9 , DOI: 10.1016/j.cell.2017.01.038

Journal reference: Cell

Provided by: Cell Press

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Neanderthal DNA contributes to human gene expression – Phys.Org

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Many people with harmful genetic variants show no ill effects – Spectrum

Posted: at 12:46 pm

Crowd control: Nearly 4 percent of people carry at least one genetic variant tied to a serious medical condition.

brainmaster / Getty Images

Most adults with genetic variants tied to certain conditions, such as heart disease or cancer, go undiagnosed, according to a study of more than 50,000 people1.

The variants silence leaves these people unaware of their risk of developing the conditions later in life, says lead investigator David Carey, director of the Weis Center for Research at Geisinger Health System in Danville, Pennsylvania.

Careys team looked for genetic variants associated with 27 chronic conditions. The list of conditions does not include autism, but does include tuberous sclerosis complex. As many as half of all people with tuberous sclerosis complex have autism. Other teams are studying the same population to gauge the effects of variants linked to autism.

The value lies in the huge population, all captured within the same healthcare system. Its really fantastic, says Dan Arking, associate professor of genetic medicine at Johns Hopkins University in Baltimore, Maryland, who was not involved in the new work.

The variants in the study are clinically significant: Some increase the risk of the linked condition by up to 70 percent. But variants interact with many other genetic and environmental factors, and these interactions may cause the conditions features to be more or less severe or even absent.

People used to say anytime there is a [spontaneous] variant or something really rare, that it must cause disease, says Arking. The new study instead suggests that, on the contrary, some rare variants have weak ties to conditions such as autism, he says. The results appeared 23 December in Science2.

Carey and his team looked at data from the MyCode Community Health Initiative, launched in 2007 by Geisinger Health System in central Pennsylvania. MyCode researchers have collected DNA samples and up to 14 years worth of medical records from the participants.

The researchers probed the 50,726 participants genomes for inserted or deleted sequences, and for single nucleotide variants, called SNVs, in the code. Their analysis revealed that each individual harbors about 21,409 SNVs, consistent with findings from previous studies.

The researchers then narrowed their analysis to 76 genes known to contribute to life-threatening conditions such as cancer or cardiovascular disease. The list includes three genes tied to tumor growth and to autism: PTEN, TSC1 and TSC2. (Clinicians are obligated to counsel individuals with variants in any of these 76 genes.)

Nearly 4 percent of the general population carries variants in at least one of these genes, the researchers found. But more than one-third of these people show no symptoms and have no family history of the linked condition. For example, most of the individuals who carry a variant linked to an inherited condition that causes high cholesterol have normal cholesterol levels, according to a second study by Careys team in the same issue of Science.

The findings could mean the individual will develop the condition later in life or not, Carey says. Other variants in her genome might mitigate the risk, he says.

We generally look at one gene at a time, but we have about 20,000 genes and they all work in concert, Carey says. Were not sophisticated enough yet to be able to tease out all the genetic interactions, but we know that they exist.

Last year, another team of researchers used the MyCode data to show that genetic changes tied to autism also crop up in many people without the condition. At the 2016 American Society of Human Genetics annual meeting in Vancouver, Canada, last year, they presented results showing that about 2,000 of the MyCode participants carry large deletions or duplications of genetic material associated with autism, intellectual disability or schizophrenia. But less than 5 percent of this group has received treatment for any of the conditions.

The finding suggests that genetic variants can confer features so subtle that they go unrecognized well into adulthood. Researchers could study this group to understand the mildest end of the autism spectrum.

This cohort could help us describe the full picture of autism, the breadth of the phenotype, says Christa Lese Martin, director of the Autism and Developmental Medicine Institute at Geisinger Health System in Lewisburg, Pennsylvania. Martin was a lead investigator on the autism study but was not involved in the new work.

About 125,000 people have enrolled in MyCode so far. By early next year, researchers expect to have sequencing data for 90,000 of the individuals.

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