Category Archives: Gene Medicine

Researchers may be one step closer to determining the cause of schizophrenia, after uncovering an abnormal genetic process associated with the disease that begins in the womb.

By transforming skin cells from patients with schizophrenia into neuronal progenitor cells - cells that form neurons in early development - researchers identified an abnormal gene pathway called nuclear FGFR1 (nFGFR1) that impairs early brain development.

Senior study author Michal K. Stachowiak, Ph.D., of the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo in New York, and colleagues say that their findings may bring us closer to treatments that could prevent schizophrenia in utero.

The researchers recently reported their results in the journal Schizophrenia Research.

According to the National Institute of Mental Health, around 1.1 percent of adults in the United States have schizophrenia - a mental health disorder characterized by hallucinations, delusions, and abnormal thoughts.

While the exact causes of schizophrenia remain unclear, researchers have long known that the condition can run in families, suggesting a genetic origin. Furthermore, an increasing number of studies have uncovered genetic mutations associated with an increased risk of schizophrenia.

For their study, Stachowiak and colleagues sought to learn more about the genomic processes that occur in utero that might influence the risk of schizophrenia development.

To reach their findings, the researchers collected skin cells from four adults with schizophrenia and four adults without the disorder.

The skin cells were reprogrammed into induced pluripotent stem cells, and these differentiated into neuronal progenitor cells. This enabled the team to assess the processes that occur during early brain development in people with schizophrenia.

The researchers pinpointed a dysregulated nFGFR1 pathway that targets and mutates numerous genes associated with schizophrenia. The team explains that just one of these gene mutations can impact brain development.

According to the authors, these findings provide proof of concept that schizophrenia may be caused by a dysregulated genomic pathway that influences the brain before birth.

"In the last 10 years, genetic investigations into schizophrenia have been plagued by an ever-increasing number of mutations found in patients with the disease. We show for the first time that there is, indeed, a common, dysregulated gene pathway at work here."

Michal K. Stachowiak, Ph.D.

Furthermore, the team says that these findings open the door to new schizophrenia treatments. For example, a drug could be administered to expectant mothers, whose offspring has a high risk of developing schizophrenia, that prevents processes related to the disease occurring in the developing fetus.

In future studies, the researchers plan to grow "mini brains" using the same processes used in the current study, with the aim of gaining a deeper understanding of how dysregulation of the nFGFR1 pathway influences early brain development, as well as to provide a model to test possible treatments.

Learn how B vitamins might improve symptoms of schizophrenia.

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Schizophrenia begins in the womb, study suggests - Medical News Today

February 28, 2017 Credit: Cardiff University

Researchers at Cardiff University have discovered that genetic variation is the reason why some immune systems overreact to viruses.

Previous research had already revealed that a gene called Ifitm3 influences how sensitive people are to the influenza virus, with a variant form of the gene making cells more susceptible to viral infection. The new research reveals that Ifitm3 also plays an important role in controlling the extent of the inflammatory response triggered by virus infection.

The study suggests that individuals with deficiencies in Ifitm3 may have an overactive immune response to viral infection and may therefore be helped by a combination of anti-inflammatory drugs in addition to medicine that directly targets the virus.

World-wide the frequency of the variant Ifitm3 gene is 1 in 400, although it is much more common in certain ethnicities.

Dr Ian Humphreys from Cardiff University's School of Medicine said: "Now we know that genetic make-up influences how the immune system copes with infections, not only by influencing how the body controls an infection but also by controlling how strongly the body's immune system reacts, we can design therapeutic strategies for individuals who are seriously ill with infections, which are tailored to the individual based on their genetic profile."

The data were collected using immune cells from mice with and without the variant form of Ifitm3, to observe how the immune system responds to a virus called cytomegalovirus. The results could also be relevant for other viral infections such as influenza epidemics/pandemics.

Explore further: Genetics of flu susceptibility: Researchers find gene that can transform mild influenza to a life-threatening disease

More information: Maria A. Stacey et al. The antiviral restriction factor IFN-induced transmembrane protein 3 prevents cytokine-driven CMV pathogenesis, Journal of Clinical Investigation (2017). DOI: 10.1172/JCI84889

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Genetic variant linked to overactive inflammatory response - Medical Xpress

February 28, 2017 A South African child is evaluated as part of a Stellenbosch University study. Credit: Stellenbosch University

A child's genetic make-up can play a large, hidden role in the success of efforts to maximize his or her development, South African research suggests.

The study, published February 28 in PLoS Medicine and supported by the Government of Canada through Grand Challenges Canada's Saving Brains program, sheds new light on why some children benefit more than others from interventions and raises complex questions about psychosocial intervention programs in future.

In a study led by Professor Mark Tomlinson of Stellenbosch University, the study followed-up an intervention implemented between 1999 and 2003, in which expectant mothers underwent mentoring to improve attachment with their childrenattachment being a measure of a child's psychological security, and predictive of future wellbeing. In the original study, a control group of roughly equal size was composed of expectant mothers who did not receive mentoring.

The original study concluded that the intervention had a small-to-moderate effect on mother-child attachment, evaluated once the children reached 18 months of age.

The follow-up study, conducted thirteen years after the intervention, re-examined the original attachment results and revealed something surprising: the intervention had in fact worked well for toddlers who had a particular genetic characteristic.

Conducted in collaboration with colleagues from the University of Reading, University College London, and Western University, the study re-enrolled and conducted genetic tests on 279 of the original 449 children.

220 children had both genetic and attachment data, enabling the investigators to test whether the original attachment outcomes were influenced by their genes.

The researchers factored in whether the child had the short or long form of gene SLC6A4the serotonin transporter gene, which is involved in nerve signalling, and which other studies have linked to anxiety, depression and other conditions. Serotonin is popularly thought to contribute to feelings of well-being and happiness.

The attachment of children with the short form of the gene, and whose pregnant mothers were mentored, were almost four times more likely to be securely attached to their mothers at 18 months old (84 percent were secure) than children carrying the short form whose mothers did not receive mentoring (58 percent were secure).

Meanwhile, children with the long gene were apparently unaffected by their mother's training or lack thereof: in both cases, the rate of secure attachment was almost identical (70 and 71 percent).

Subject to further validation, says Professor Tomlinson, the insight has "important implications for scientists designing and evaluating interventions to benefit as many people as possible in South Africa and worldwide."

"Without taking genetics into account, it is possible that other studies have under-estimated the impact of their interventions, as we originally did."

Says lead author Dr. Barak Morgan of the University of Cape Town: "The immediate significance of this research is the revelation that in principle, and probably in many cases in practice too, the effectiveness of interventions has been mis-measuredunder-estimated for genetically susceptible individuals and over-estimated for those who are genetically less susceptible. But even more worrying is the implication that the negative consequences of not receiving an intervention also differ by genotype."

"This is an enormously important insight because, in this case, the subgroup with the short form of the SLC6A4 gene is also the one with the most to lose if not helped."

"Individuals with the long form of the gene, on the other hand, appear less sensitive and derived little benefit from the same intervention, and little detriment from not getting it."

Adds Professor Tomlinson: "In the original study, we did not see such a big impact from this intervention because only those with the short gene improved, and this improvement was 'diluted' by the large number of children with the long gene who did not improve."

The researchers caution that, among other limitations, this study involved a relatively small sample and only measured one gene and one outcome (attachment).

Dr. Morgan stressed: "We are certainly not saying that only some people should receive the interventionthose who are 'susceptible' to improving from it. There is little scientific justification for this. For example, many children with the non-susceptible long genotype of the SLC6A4 gene may carry the susceptible form of another gene which renders them much more likely to benefit from the same intervention but for a different but equally important outcome.

"Going forward, the implications are therefore two-fold. Firstly, measuring genetic differences allows for proper assessment of the effectiveness or lack of effectiveness of an intervention for a particular outcome in different individuals. Secondly, this information can then be used to find out how to intervene effectively for allto guide what might be done to improve outcomes for a non-responsive gene-intervention interaction while continuing to optimise outcomes for the responsive one."

Says Dr. Karlee Silver, Vice President Programs of Grand Challenges Canada: "This work is fundamentally about better understanding the impact of interventions which is an important step forward to creating a world where every child can survive and thrive."

Says Dr. Peter A. Singer, Chief Executive Officer of Grand Challenges Canada: "This is a startling finding that changes the way I think about child development. Why is it important? Because child development is the ladder of social mobility used to climb out of the hole of inequity by millions of children around the world."

Explore further: Study explores how to tell children they have HIV

More information: "Serotonin Transporter Gene (SLC6A4) Polymorphism and Susceptibility to a Home-Visiting Maternal-Infant Attachment Intervention Delivered by Community Health Workers in South Africa: Re-analysis of a Randomized Controlled Trial" DOI: 10.1371/journal.pmed.1002237

Journal reference: PLoS Medicine

Provided by: Grand Challenges Canada

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A child's genetic make-up can play a large, hidden role in the success of efforts to maximize his or her development, South African research suggests.

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To maximize a child's development, genetics provide important insight - Medical Xpress

In the case of patients with low risk of lung cancer, the current diagnostic procedure can sometimes be invasive and unnecessary. However, new research may have uncovered a less invasive, less costly way to screen these patients.

A team of researchers from Boston University School of Medicine (BUSM) in Massachusetts may have found a more convenient way to determine whether lung lesions are malignant. The findings were published in the Journal of the National Cancer Institute.

Lung lesions - or solitary pulmonary nodules - are small growths in the lungs that are usually detected incidentally when a patient has an X-ray for other reasons. Although physicians are typically worried about cancer upon discovering the lesions, these are benign in the majority of cases.

For instance, of all the patients screened using computed tomography (CT) as part of the National Lung Cancer Screening Trial, 25 percent had a lung lesion, but approximately 95 percent of these cases were, in the end, found to be benign.

As the authors of the new study point out, many of the patients who ultimately receive a benign diagnosis undergo invasive medical procedures such as surgical lung biopsy. The new research, however, uncovers a genomic tool that could enable physicians to tell whether a patient has a malignant lesion by simply taking a swab of their nose.

BUSM researchers collected nasal epithelial brushings from patients who were in the process of having their lung lesions evaluated. These participants were people who currently and formerly smoked, and who were enrolled in the two Airway Epithelium Gene Expression in the Diagnosis of Lung Cancer clinical trials.

The epithelium is a membrane of cellular tissue that, in this case, encloses and protects the nasal cavity. Scientists examined these nasal epithelial brushings and profiled the participants' gene expression by using microarrays - a genetic tool commonly used to detect gene mutations, such as in BRCA1 or BRCA2, in a person's DNA.

The researchers found cancer-associated gene expressions to be altered in a similar way across the two airway sites. This led them to believe that the nasal airway epithelial field in people who smoke extends all the way to the nose, and that the brushings could be a biomarker for lung cancer.

Marc Lenburg, Ph.D., a professor of medicine at BUSM and co-senior author of the study, explains the significance of the findings:

"Our findings clearly demonstrate the existence of a cancer-associated airway field of injury that also can be measured in nasal epithelium. We find that nasal gene expression contains information about the presence of cancer that is independent of standard clinical risk factors, suggesting that nasal epithelial gene expression might aid in lung cancer detection. Moreover, the nasal samples can be collected non-invasively with little instrumentation or advanced training."

Corresponding author Dr. Avrum Spira, a professor of medicine, pathology, and bioinformatics at BUSM, also weighs in:

"There is a clear and growing need to develop additional diagnostic approaches for evaluating pulmonary lesions to determine which patients should undergo CT surveillance or invasive biopsy," Dr. Spira says. The ability to test for molecular changes in this 'field of injury' allows us to rule out the disease earlier without invasive procedures."

This research builds on previous work by the same team, who located another biomarker for lung cancer, found in the epithelium of the bronchus.

"Our group previously derived and validated a bronchial epithelial gene-expression biomarker to detect lung cancer in current and former smokers," Dr. Spira explains. "This innovation [...] is measurably improving lung cancer diagnosis. Given that bronchial and nasal epithelial gene expressions are similarly altered by cigarette smoke exposure, we sought to determine in this study if cancer-associated gene expression might also be detectable in the more readily accessible nasal epithelium."

Learn how a colorful compound in fruits and vegetables could lower smokers' lung cancer risk.

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Nasal swab could help diagnose lung cancer - Medical News Today

February 27, 2017

Obesity often leads to insulin resistance, a hallmark of type 2 diabetes. The anti-diabetic drug rosiglitazone counters insulin resistance in diabetic patients by targeting PPAR, a nuclear receptor that senses hormones and other molecules to help regulate the expression of genes. Rosiglitazone's ability to reverse insulin resistance is not fully understood, but prior work has implicated its effects on fat cells as a key driver of therapeutic success.

Research led by Mitch Lazar at the Perelman School of Medicine at University of Pennsylvania examined how rosiglitazone treatment altered gene expression in fat cells from an obesity-prone strain of mice (B6 mice) that were fed a high-fat diet.

In work published this week in the JCI, the researchers showed that although developing obesity was associated with marked changes in gene expression in the visceral fat of these mice, treatment with rosiglitazone had little effect on these changes.

Rather, the drug affected subcutaneous fat, specifically increasing the expression of genes associated with brown fat, a metabolically-active type of fat characterized by the key gene Ucp1.

An obesity-resistant strain, 129 mice, displayed elevated Ucp1 expression compared to B6 mice. A cross of B6 and 129 mice exhibited showed biased expression of Ucp1 genes derived from the 129 parent, indicating that Ucp1 may be defective in the obesity-prone B6 strain. In the B6/129 crossed mice, rosiglitazone eliminated this bias and restored expression levels of the B6 parent-derived Ucp1 gene.

These findings suggest that environmental changes, including drug therapies, may be able to reverse some genetic alterations that are associated with obesity.

Explore further: Anti-aging gene identified as a promising therapeutic target for older melanoma patients

More information: Raymond E. Soccio et al, Targeting PPAR in the epigenome rescues genetic metabolic defects in mice, Journal of Clinical Investigation (2017). DOI: 10.1172/JCI91211

Journal reference: Journal of Clinical Investigation

Provided by: JCI Journals

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Medication improves obesity-associated gene expression in mice - Medical Xpress

February 27, 2017 by Ellen Goldbaum Credit: University at Buffalo

The skin cells of four adults with schizophrenia have provided an unprecedented "window" into how the disease began while they were still in the womb, according to a recent paper in Schizophrenia Research.

The paper was published online in January by researchers at the Jacobs School of Medicine and Biomedical Sciences at the University at Buffalo in collaboration with the Icahn School of Medicine at Mount Sinai. It provides what the authors call the first proof of concept for their hypothesis that a common genomic pathway lies at the root of schizophrenia.

The researchers say the work is a first step toward the design of treatments that could be administered to pregnant mothers at high risk for bearing a child with schizophrenia, potentially preventing the disease before it begins.

Multiple mutations

"In the last 10 years, genetic investigations into schizophrenia have been plagued by an ever-increasing number of mutations found in patients with the disease," said Michal K. Stachowiak, PhD, senior author on the paper, and professor in the Department of Pathology and Anatomical Sciences in the Jacobs School of Medicine and Biomedical Sciences at UB.

PHOTO available here.

"We show for the first time that there is, indeed, a common, dysregulated gene pathway at work here," he said.

The authors gained insight into the early brain pathology of schizophrenia by using skin cells from four adults with schizophrenia and four adults without the disease that were reprogrammed back into induced pluripotent stem cells and then into neuronal progenitor cells.

"By studying induced pluripotent stem cells developed from different patients, we recreated the process that takes place during early brain development in utero, thus obtaining an unprecedented view of how this disease develops," said Stachowiak. "This work gives us an unprecedented insight into those processes."

A central intersection point

The research provides what he calls proof of concept for the hypothesis he and his colleagues published in 2013. They proposed that a single genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection point for multiple pathways involving more than 100 genes believed to be involved in schizophrenia.

"This research shows that there is a common dysregulated gene program that may be impacting more than 1,000 genes and that the great majority of those genes are targeted by the dysregulated nuclear FGFR1," Stachowiak said.

When even one of the many schizophrenia-linked genes undergoes mutation, by affecting the INFS it throws off the development of the brain as a whole, similar to the way that an entire orchestra can be affected by a musician playing just one wrong note, he said.

The next step in the research is to use these induced pluripotent stem cells to further study how the genome becomes dysregulated, allowing the disease to develop.

"We will utilize this strategy to grow cerebral organoids - mini-brains in a sense - to determine how this genomic dysregulation affects early brain development and to test potential preventive or corrective treatments," he said.

Explore further: Stem cell research helps to identify origins of schizophrenia

More information: S.T. Narla et al, Common developmental genome deprogramming in schizophreniaRole of Integrative Nuclear FGFR1 Signaling (INFS), Schizophrenia Research (2017). DOI: 10.1016/j.schres.2016.12.012

New University at Buffalo research demonstrates how defects in an important neurological pathway in early development may be responsible for the onset of schizophrenia later in life.

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By turning skin cells into brain neurons, researchers at the Icahn School of Medicine at Mount Sinai have identified that certain tiny molecules aiding in gene expression, known as microRNAs (miRNAs), are under-expressed ...

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The skin cells of four adults with schizophrenia have provided an unprecedented "window" into how the disease began while they were still in the womb, according to a recent paper in Schizophrenia Research.

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Faulty genomic pathway linked to schizophrenia developing in utero, study finds - Medical Xpress

In 2012, Madurai-based Avinash Shetty, then 30, was busy making arrangements for his wedding. But festivities were not the only thing on his familys mind. With serious health scares on both sides, his fiance and he were aware they had the odds stacked against them in the genetic department. My mother-in-law had succumbed to leukaemia and my mother was suffering from lung carcinoma and diabetes. Plus, I was (and still am) a smoker, says Shetty. My mother, a nurse, insisted that my future bride and I get genetic testing done, he says. Blood and tissue samples were sent for testing. Fortunately, there was nothing amiss. The couple married and now have two daughters.

The 46 chromosomes or genetic material that we inherit from our parents are responsible for more than just shaping our physical characteristics. They can give us insight into the kind of diseases we could be exposed to. With a single blood test, doctors are now able to analyse our risk to disease at the DNA level and tell in advance the kind of illness you might possibly develop, says Mumbai-based Priyanka Raina, genetic counsellor at Positive Bioscience, a clinical genomics company, and consultant at Saifee Hospital.

The study of a persons DNA to identify various mutations is called genetic testing. Genomic medicine is the broad disciplinebasically medical care attuned to the bodys unique genetic make-up. So, when you get tested for disease based on your genetic coding, it is called genetic testing. The medical care that results is genomic medicine.

Advances in genomic medicine are the results of ground-breaking research. We expect it to transform the very fabric of healthcare, says Samarth Jain, founder and chief executive officer of Positive Bioscience, which offers genetic testing and evaluation of ones risk for disease.

Perhaps the most famous example of genetic diagnosis is Angelina Jolies preventive breast surgeries in 2013. A simple blood test showed the actor carried the BRCA1 gene, which meant she had an 87% risk of contracting breast cancer and a 50% risk of ovarian cancer. She knew she had a strong family risk for both diseases, since her mother and aunts had succumbed to them. Jolie removed her breasts, uterus and fallopian tubes in successive operations.

Shortly afterwards, there were reports of a steady rise in demand for pre-emptive surgeries by women. Doctors still advise caution, however; they say pre-emptive surgery necessitates a thorough assessment of risk factors, age and family history.

While pre-emptive surgery isnt the norm in India yet, there is a growing awareness about genetic diagnosis, especially in the area of cancer prediction and treatment, says Vikas Goswami, senior oncologist at the Fortis Hospital in Noida, near Delhi. But in many cases, even as were able to assess our risk to cancer, we wont always have the medicine to treat it. And that is a very real vulnerability.

To be able to diagnose whether we may be at risk of the disease is only part of the story. We need to be able to answer questions such as what the nature of this disease would be, what drugs would be effective, can we predict whether the cancer would spread or recur. We hope that genetic research can provide answers to these in the days ahead, says Dr Goswami.

In addition to cancer, genomic testing has opened up our world to many other diseases that could possibly be diagnosed or predicted, such as cardiovascular diseases, diabetes, autism spectrum diseases and neurological disorders, says Radhika Vaishnav, a Vadodara-based genetic scientist and executive editor of the International Journal Of Molecular ImmunoOncology. Being able to treat previously untreatable conditions is becoming a reality today, she adds. However, though far more accessible (with costs half of what they were in 2011), genetic testing is still in its infancy in India. This is because genomic medicine relies on Big Data (comparing the genetic data of millions of people) for its accuracy in the prediction of disease. There are concerns that there is not enough Indian population-specific data to compare and accurately predict disease risk.

Prenatal care

Since the 1970s, blood tests have been conducted routinely during pregnancy in India to rule out genetic diseases such as Downs Syndrome. Today, were able to catch rare genetic disorders earlier, says Seema Thakur, senior consultant, genetics and foetal diagnosis, at the Indraprastha Apollo Hospitals in New Delhi. Diseases like thalassemia (an inherited blood disorder requiring frequent blood transfusion), dwarfism and Gauchers (an inherited disorder in which the bodys ability to store fats is compromised, accumulating it in the bodys tissues, cells and organs) are now being identified early.

Great strides have also been made in the treatment of muscular dystrophy (MD), a genetic disorder which causes progressive muscular degeneration and weakness. Of the nine kinds of muscular dystrophy, Duchenne Muscular Dystrophy (DMD) the most common oneis manageable after prenatal genetic testing. DMD can begin as early as the age of 3. By the time a child reaches his/her teens, their muscles progressively waste away and they will find themselves in a wheelchair. By the age of 21, the disease can prove fatal, says Berty Ashley, senior research associate at the Dystrophy Annihilation Research Trust, a non-profit in Bengaluru. DMD occurs because a certain gene in our bodies (incidentally the largest gene we have) called the dystrophin gene is not copied in its entirety when it is passed on to the child in the womb. The gene is made of 79 exons, structures that fit like a jigsaw puzzle. When the gene is transferred to the child, any exon, for example, is missing or deleted, says Ashley.

In September, the US food and drug administration approved the use of new medication (dystrophy eteplirsen) for this. Taking this drug during pregnancy will introduce the missing genetic strand in the child. It wont cure the disease but it could effectively hamper its progression, says Ashley. A child will still have weak limbs, but he will be spared a life in a wheelchair or premature death.

Dr Thakur, however, believes that genetic testing without sustained counselling both before and afterwards could lead to greater stress for patients.

Genetic testing is extremely expensive (ranging from Rs12,000 to Rs1.5 lakh) and not all (diagnostic) labs offer standardized results. If you are faced with an incurable disease, there is little you can do. It could cause great anxiety, she says.

It is disturbing that people are requesting tests on their own because emotionally, they may not be equipped to handle the results. Adequate counselling and follow-up on treatment/medication are important, Dr Thakur explains, adding, There is no doubt that our knowledge of genetic diagnosis will bring with it greater responsibility.

Where to go

Places that provide prenatal diagnostic services and genetic diagnosis

The Indian Council of Medical Research in Mumbai provides prenatal diagnostic services (www.icmr.nic.in)

The genetics unit, department of paediatrics, All India Institute of Medical Sciences, New Delhi (a World Health Organization collaborating centre) offers genetic diagnosis, prenatal diagnosis and counselling (www.aiims.edu)

Genetic blood tests and counselling are offered at hospitals across the country such as Apollo (Madurai, Chennai), Saifee (Mumbai), Kokilaben Dhirubhai Ambani Hospital, Breach Candy (Mumbai) and MedantaThe Medicity (Gurugram).

First Published: Mon, Feb 27 2017. 05 44 PM IST

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Taking the gene test - Livemint

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 gene -- one 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 Denisovans -- another species of hominins that crossbred with modern humans -- are 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.

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Neanderthal DNA contributes to human gene expression - Science Daily

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

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

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

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Discovery of genetic mutation may boost cancer therapies - Medical Xpress