Tag: Genetics

Identifying the Underlying Causes of Ovarian Cancer

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Newswise — Two new discoveries led by Cedars-Sinai Cancer investigators help improve the understanding of what drives the development of ovarian cancer and why some women’s tumors do not respond to therapy.

“Understanding the relationship between molecular profiles and clinical presentation of ovarian cancer not only can help guide the development of personalized therapeutic approaches, but can also help us identify women who are at the highest risk so we can intervene before the cancer even develops,” said Simon Gayther, PhD, professor of Biomedical Sciences, director of the Center for Bioinformatics and Functional Genomics at Cedars-Sinai and senior author of both studies.

Scientists Identify Mutations Tied to Increase Risk of Ovarian Cancer

The first study, published today in the Journal of the National Cancer Institute, identified four new regions of the human genome that harbor genetic variants or mutations that put women at an increased risk of developing epithelial ovarian cancer, the most common type of ovarian cancer.

“When it comes to ovarian cancer, prevention is how we’re really going to impact mortality,” said Michelle Jones, PhD, a research scientist in the Center for Bioinformatics and Functional Genomics and corresponding author of the study. “This study helps us accurately identify women who carry cancer-causing mutations, which can help physicians develop preventive strategies for these women.”

To pinpoint the mutations, the team of investigators used new methods to analyze the structural variation of the genome, which is made up of 23 pairs of chromosomes where an individual’s genetic code is stored.

While most research focuses on analyzing the change in the sequence of the gene, the team looked at the number of copies of the gene an individual has—known as a copy number variant.

When the genome gets copied, structural variation can occur, and stretches of the genome can get deleted, duplicated or rearranged to another position. These changes can lead to diseases, like cancer.

The researchers collaborated with scientists at the University of Cambridge to specifically look at deletions and duplications in 13,000 women with ovarian cancer and compared them to 17,000 women without ovarian cancer from the Ovarian Cancer Association Consortium to identify copy number variants that were associated with ovarian cancer risk.

They found significant deletions and duplications in the BRCA1 gene, BRCA2 gene, and RAD51C gene, all of which are known to harbor changes in a patient’s DNA sequence that increase risk for ovarian cancer. Also found: four new genes that have not been previously linked to an increased risk for ovarian cancer.

The study, which is the largest to date to evaluate the contribution of copy number variants to ovarian cancer risk, will likely lead to more accurate genetic testing for women.

“We have the technology that can pick up these deletions and duplications, but it’s not always done consistently in clinical genetic testing,” said Jones. “We hope these findings highlight the value of looking at copy number variants in clinical genetic testing.”

Gene Expression Unlikely to Drive Chemotherapy Resistance in Ovarian Cancer

The second study, published in the Journal of Experimental & Clinical Cancer Research, gives investigators a deeper understanding as to how ovarian tumors develop resistance to chemotherapy, which occurs in about 80% of high-grade serous ovarian cancer patients and ultimately leads to their succumbing to the disease.

Previously, researchers believed that ovarian tumors evolve after they are exposed to chemotherapy, and that they change their gene expression to adapt and survive through the treatment.

However, using whole genome sequencing, they found for the first time that this is not the case. Instead, it seems more likely that most high-grade serous ovarian tumors have the capacity to survive chemotherapy from a very early stage, said Jones, who is also the co-first author on this study.

“This study has changed our understanding of how tumors respond to chemotherapy,” Jones said. “Previously it was thought that we could probably find a way to treat chemo-resistant tumors with other drugs after they have been treated with the standard therapy, but this study suggests that may not be the best approach.”

“By improving our understanding as to how tumors doing survive chemotherapy, and even continue growing throughout treatment, as well as finding vulnerabilities in the tumors, will give us an opportunity to design better drugs and save the lives of women with ovarian cancer,” added Gayther.

Cedars-Sinai Cancer High-Risk BRCA Clinic

As researchers at Cedars-Sinai Cancer explore how to more accurately identify women who carry cancer-causing mutations, clinicians are simultaneously working to monitor, and rapidly treat as needed, BRCA-positive patients.

Under the leadership of B.J. Rimel, MD, a gynecological oncologist and medical director of the Cedars-Sinai Cancer Clinical Trials Office, Cedars-Sinai recently launched a high-risk BRCA clinic—known as a previvor clinic—for BRCA1 and 2 carriers at high-risk for developing ovarian cancer.

The goal, Rimel says, is to arm BRCA-positive patients with regular screening and risk-reducing prevention strategies—in a one-stop clinic setting.

“Our multidisciplinary care team, comprised of a reproductive and infertility physician, a gynecologist oncologist and a genetic counselor, spends time with each high-risk patient during the clinic visit,” said Rimel. “We provide transvaginal screening onsite, review results from relevant lab work and ensure questions are addressed in real-time.”

Modeled by an existing and highly successful high-risk BRCA breast cancer program, the ovarian cancer previvor clinic remains a significant focus at Cedars-Sinai.

“Alterations in genes such as BRCA in either the cancer or the patient’s germline have profound implications for treatment and prevention,” said Dan Theodorescu, MD, PhD, director of Cedars-Sinai Cancer and the PHASE ONE Foundation Distinguished Chair and professor of Surgery and Pathology and Laboratory Medicine. “As our research propels, so do our translational findings that impact and improve patient lives.”

Funding: The first study was funded in part by the National Institute of General Medicine Sciences of the National Institutes of Health under award number 5T32GM118288-03, the Cedars-Sinai Medical Center Precision Health Initiative, and the Tell Every Amazing Lady about Ovarian Cancer Louisa M. McGregor Ovarian Cancer Foundation. The second study was funded in part by the National Institutes of Health under award number R01CA211575 and the Cedars-Sinai Medical Center Precision Health Initiative.

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October 9, 2022
Age vs. genetics: Which is more important for determining how we age?

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Newswise — Amid much speculation and research about how our genetics affect the way we age, a University of California, Berkeley, study now shows that individual differences in our DNA matter less as we get older and become prone to diseases of aging, such as diabetes and cancer.

In a study of the relative effects of genetics, aging and the environment on how some 20,000 human genes are expressed, the researchers found that aging and environment are far more important than genetic variation in affecting the expression profiles of many of our genes as we get older. The level at which genes are expressed — that is, ratcheted up or down in activity — determines everything from our hormone levels and metabolism to the mobilization of enzymes that repair the body.

“How do your genetics — what you got from your sperm donor and your egg donor and your evolutionary history — influence who you are, your phenotype, such as your height, your weight, whether or not you have heart disease?” said Peter Sudmant, UC Berkeley assistant professor of integrative biology and a member of the campus’s Center for Computational Biology. “There’s been a huge amount of work done in human genetics to understand how genes are turned on and off by human genetic variation. Our project came about by asking, ‘How is that influenced by an individual’s age?’ And the first result we found was that your genetics actually matter less the older you get.”

In other words, while our individual genetic makeup can help predict gene expression when we are younger, it is less useful in predicting which genes are ramped up or down when we’re older — in this study, older than 55 years. Identical twins, for example, have the same set of genes, but as they age, their gene expression profiles diverge, meaning that twins can age much differently from each other.

The findings have implications for efforts to correlate diseases of aging with genetic variation in humans, Sudmant said. Such studies should perhaps focus less on genetic variants that impact gene expression when pursuing drug targets.

“Almost all human common diseases are diseases of aging: Alzheimer’s, cancers, heart disease, diabetes. All of these diseases increase their prevalence with age,” he said. “Massive amounts of public resources have gone into identifying genetic variants that predispose you to these diseases. What our study is showing is that, well, actually, as you get older, genes kind of matter less for your gene expression. And so, perhaps, we need to be mindful of that when we’re trying to identify the causes of these diseases of aging.”

Sudmant and his colleagues reported their results this week in the journal Nature Communications.

Medawar’s hypothesis

The findings are in line with Medawar’s hypothesis: Genes that are turned on when we are young are more constrained by evolution because they are critical to making sure we survive to reproduce, while genes expressed after we reach reproductive age are under less evolutionary pressure. So, one would expect a lot more variation in how genes are expressed later in life.

“We’re all aging in different ways,” Sudmant said. “While young individuals are closer together in terms of gene expression patterns, older individuals are further apart. It’s like a drift through time as gene expression patterns become more and more erratic.”

This study is the first to look at both aging and gene expression across such a wide variety of tissues and individuals, Sudmant said. He and his colleagues built a statistical model to assess the relative roles of genetics and aging in 27 different human tissues from nearly 1,000 individuals and found that the impact of aging varies widely — more than twentyfold — among tissues.

“Across all the tissues in your body, genetics matters about the same amount. It doesn’t seem like it plays more of a role in one tissue or another tissue,” he said. “But aging is vastly different between different tissues. In your blood, colon, arteries, esophagus, fat tissue, age plays a much stronger role than your genetics in driving your gene expression patterns.”

Sudmant and colleagues also found that Medawar’s hypothesis does not hold true for all tissues. Surprisingly, in five types of tissues, evolutionary important genes were expressed at higher levels in older individuals.

“From an evolutionary perspective, it is counterintuitive that these genes should be getting turned on, until you take a close look at these tissues,” Sudmant said. These five tissues happen to be the ones that constantly turn over throughout our lifespan and also produce the most cancers. Every time these tissues replace themselves, they risk creating a genetic mutation that can lead to disease.

“I guess this tells us a little bit about the limits of evolution,” he said. “Your blood, for instance, always has to proliferate for you to live, and so these super-conserved, very important genes have to be turned on late in life. This is problematic because it means that those genes are going to be susceptible to getting somatic mutations and getting turned on forever in a bad, cancerous way. So, it kind of gives us a little bit of a perspective on what the limitations of living are like. It puts bounds on our ability to keep living.”

Sudmant noted that the study indirectly indicates the effect on aging of one’s environment, which is the impact of everything other than age and genetics: the air we breathe, the water we drink, the food we eat, but also our levels of physical exercise. Environment amounts to up to a third of gene expression changes with age.

Sudmant is conducting similar analyses of the expressed genes in several other organisms — bats and mice — to see how they differ and whether the differences are related to these animals’ different lifespans.

UC Berkeley graduate students Ryo Yamamoto and Ryan Chung are co-first authors of the paper. Other co-authors are Juan Manuel Vazquez, Huanjie Sheng, Philippa Steinberg and Nilah Ioannidis. The work was supported by the National Institute of General Medical Sciences (R35GM142916) of the National Institutes of Health.

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University of California, Berkeley

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October 7, 2022
Mapping human brain development

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Newswise — The human brain is probably the most complex organ in the entire living world and has long been an object of fascination for researchers. However, studying the brain, and especially the genes and molecular switches that regulate and direct its development, is no easy task.

To date, scientists have proceeded using animal models, primarily mice, but their findings cannot be transferred directly to humans. A mouse’s brain is structured differently and lacks the furrowed surface typical of the human brain. Cell cultures have thus far been of limited value in this field, as cells tend to spread over a large area when grown on a culture dish; this does not correspond to the natural three-dimensional structure of the brain.

Mapping molecular fingerprints

A group of researchers led by Barbara Treutlein, ETH Professor at the Department of Biosystems Science and Engineering in Basel, has now taken a new approach to studying the development of the human brain: they are growing and using organoids – millimetre-sized three-dimensional tissues that can be grown from what are known as pluripotent stem cells.

Provided these stem cells receive the right stimulus, researchers can program them to become any kind of cell present in the body, including neurons. When the stem cells are aggregated into a small ball of tissue and then exposed to the appropriate stimulus, they can even self-organise and form a three-dimensional brain organoid with a complex tissue architecture.

In a new study just published in Nature, Treutlein and her colleagues have now studied thousands of individual cells within a brain organoid at various points in time and in great detail. Their goal was to characterise the cells in molecular-genetic terms: in other words, the totality of all gene transcripts (transcriptome) as a measure of gene expression, but also the accessibility of the genome as a measure of regulatory activity. They have managed to represent this data as a kind of map showing the molecular fingerprint of each cell within the organoid.

However, this procedure generates immense data sets: each cell in the organoid has 20,000 genes, and each organoid in turn consists of many thousands of cells. “This results in a gigantic matrix, and the only way we can solve it is with the help of suitable programs and machine learning,” explains Jonas Fleck, a doctoral student in Treutlein’s group and one of the study’s co-lead authors. To analyse all this data and predict gene regulation mechanisms, the researchers developed their own program. “We can use it to generate an entire interaction network for each individual gene and predict what will happen in real cells when that gene fails,” Fleck says.

Identifying genetic switches

The aim of this study was to systematically identify those genetic switches that have a significant impact on the development of neurons in the different regions of brain organoids.

With the help of a CRISPR-Cas9 system, the ETH researchers selectively switched off one gene in each cell, altogether about two dozen genes simultaneously in the entire organoid. This enabled them to find out what role the respective genes played in the development of the brain organoid.

“This technique can be used to screen genes involved in disease. In addition, we can look at the effect these genes have on how different cells within the organoid develop,” explains Sophie Jansen, also a doctoral student in Treutlein’s group and the second co-lead author of the study.

Checking pattern formation in the forebrain

To test their theory, the researchers chose the GLI3 gene as an example. This gene is the blueprint for the transcription factor of the same name, a protein that docks onto certain sites on DNA in order to regulate another gene. When GLI3 is switched off, the cellular machinery is prevented from reading this gene and transcribing it into an RNA molecule.

In mice, mutations in the GLI3 gene can lead to malformations in the central nervous system. Its role in human neuronal development was previously unexplored, but it is known that mutations in the gene lead to diseases such as Greig cephalopolysyndactyly and Pallister Hall Syndromes.

Silencing this GLI3 gene enabled the researchers both to verify their theoretical predictions and to determine directly in the cell culture how the loss of this gene affected the brain organoid’s further development. “We have shown for the first time that the GLI3 gene is involved in the formation of forebrain patterns in humans. This had previously been shown only in mice,” Treutlein says.

Model systems reflect developmental biology

“The exciting thing about this research is that it lets you use genome-wide data from so many individual cells to postulate what roles individual genes play,” she explains. “What’s equally exciting in my opinion is that these model systems made in a Petri dish really do reflect developmental biology as we know it from mice.”

Treutlein also finds it fascinating how the culture medium can give rise to self-organised tissue with structures comparable to those of the human brain – not only at the morphological level but also (as the researchers have shown in their latest study) at the level of gene regulation and pattern formation. “Organoids like this are truly an excellent way to study human developmental biology,” she points out.

Versatile brain organoids

Research on organoids made up of human cell material has the advantage that the findings are transferable to humans. They can be used to study not only basic developmental biology but also the role of genes in diseases or developmental brain disorders. For example, Treutlein and her colleagues are working with organoids of this type to investigate the genetic cause of autism and of heterotopia; in the latter, neurons appear outside their usual anatomical location in the cerebral cortex.

Organoids may also be used for testing drugs, and possibly for culturing transplantable organs or organ parts. Treutlein confirms that the pharmaceutical industry is very interested in these cell cultures.

However, growing organoids takes both time and effort. Moreover, each clump of cells develops individually rather than in a standardised way. That is why Treutlein and her team are working to improve the organoids and automate their manufacturing process.

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ETH Zurich

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October 7, 2022
Watching Plants Switch on Genes

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The Science

Biologists often use green fluorescent protein (GFP) to see what happens inside cells. GFP, which scientists first isolated in jellyfish, is a protein that changes light from one color into another. Attaching it to other proteins allows researchers to find out if cells produce those proteins and where within cells to find them. This in turn shows how cells deliver and use genes. The problem is that this usually requires expensive equipment, such as fluorescence microscopes, and it can be time consuming. In this study, researchers describe how a special type of GFP can be used to ‘see’ protein production with the unaided eye. Modifying the genes of plants allowed the team to see GFP production using a simple black light to provide long-wave ultraviolet (UV) light.

The Impact

The research demonstrates real-time imaging of cellular and molecular events in a wide range of plants with the unaided eye and a black-light flashlight. This will enable quick and affordable screening for research and development or for real time monitoring of molecular events in mature plants.

Summary

Reporter genes are attached to other genes of interest to provide an inexpensive, rapid, and sensitive assay for studying gene delivery and gene expression. These reporters have long been an essential tool for live-cell imaging. Today, imaging and analysis are becoming more accessible through the development of UV-visible fluorescent reporters. This research from scientists at Oak Ridge National Laboratory aimed to advance the use and efficiency of these reporters in two herbaceous plant species (Arabidopsis and tobacco) and two woody plant species (poplar and citrus).

After designing and building a GFP UV reporter protein (eYGFPuv) that provides enhanced signals for all tested plant species, the researchers demonstrated that strong fluorescence could be captured using either a fluorescence microscope or UV light. Moreover, this UV‐excitable reporter can be observed across a wide range of scales from sub‐meter level seedlings to whole plants without need for special emission filters. For instance, by using a simple UV flashlight, the scientists demonstrated how this new reporter can facilitate rapid quantification of transformation efficiency in plant systems. These improved features will make this newly developed GFP-UV reporter a valuable tool for a wide range of applications in plant science research.

Funding

The research was supported by the Center for Bioenergy Innovation (CBI), a Department of Energy (DOE) Research Center and the Secure Ecosystem Engineering and Design (SEED) project funded by the Genomic Science Program of the DOE Office of Science, Office of Biological and Environmental Research (BER) as part of the Secure Biosystems Design Science Focus Area (SFA).

SEE ORIGINAL STUDY

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Department of Energy, Office of Science

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October 7, 2022
3D map reveals DNA organization within human retina cells

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Newswise — National Eye Institute researchers mapped the organization of human retinal cell chromatin, the fibers that package 3 billion nucleotide-long DNA molecules into compact structures that fit into chromosomes within each cell’s nucleus. The resulting comprehensive gene regulatory network provides insights into regulation of gene expression in general, and in retinal function, in both rare and common eye diseases. The study published in Nature Communications.

“This is the first detailed integration of retinal regulatory genome topology with genetic variants associated with age-related macular degeneration (AMD) and glaucoma, two leading causes of vision loss and blindness,” said the study’s lead investigator, Anand Swaroop, Ph.D., senior investigator and chief of the Neurobiology Neurodegeneration and Repair Laboratory at the NEI, part of the National Institutes of Health.

Adult human retinal cells are highly specialized sensory neurons that do not divide, and are therefore relatively stable for exploring how the chromatin’s three-dimensional structure contributes to the expression of genetic information.

Chromatin fibers package long strands of DNA, which are spooled around histone proteins and then repeatedly looped to form highly compact structures. All those loops create multiple contact points where genetic sequences that code for proteins interact with gene regulatory sequences, such as super enhancers, promoters, and transcription factors.

Such non-coding sequences were long considered “junk DNA.” But more advanced studies demonstrate ways these sequences control which genes get transcribed and when, shedding light on the specific mechanisms by which non-coding regulatory elements exert control even when their location on a DNA strand is remote from the genes they regulate.

Using deep Hi-C sequencing, a tool used for studying 3D genome organization, the researchers created a high-resolution map that included 704 million contact points within retinal cell chromatin. Maps were constructed using post-mortem retinal samples from four human donors.

The researchers then integrated that chromatin topology map with datasets on retinal genes and regulatory elements. What emerged was a dynamic picture of interactions within chromatin over time, including gene activity hot spots and areas with varying degrees of insulation from other regions of DNA.

They found distinct patterns of interaction at retinal genes suggesting how chromatin’s 3D organization plays an important role in tissue-specific gene regulation.

“Having such a high-resolution picture of genomic architecture will continue to provide insights into the genetic control of tissue-specific functions,” Swaroop said.

Furthermore, similarities between mice and human chromatin organization suggest conservation across species, underscoring the relevance of chromatin organizational patterns for retinal gene regulation. More than a third (35.7%) of gene pairs interacting through a chromatin loop in mice also did so in human retina.

The researchers integrated the chromatin topology map with data on genetic variants identified from genome-wide association studies for their involvement in AMD and glaucoma, two leading causes of vision loss and blindness. The findings point to specific candidate causal genes involved in those diseases.

The integrated genome regulatory map will also assist in evaluating genes associated with other common retina-associated diseases such as diabetic retinopathy, determining missing heritability and understanding genotype-phenotype correlations in inherited retinal and macular diseases.

The study was supported by the NEI Intramural Research Program, grants ZIAEY000450 and ZIAEY000546.

Reference: Marchal C, Singh N, Batz Z, Advani J, Jaeger C, Corso-Diaz X, and Swaroop A. “High-resolution genome topology of human retina uncovers super enhancer-promoter interactions at tissue-specific and multifactorial disease loci.” Published October 7, 2022, Nature Communications. DOI:10.1038/s41467-022-33427-1

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This press release describes a basic research finding. Basic research increases our understanding of human behavior and biology, which is foundational to advancing new and better ways to prevent, diagnose, and treat disease. Science is an unpredictable and incremental process— each research advance builds on past discoveries, often in unexpected ways. Most clinical advances would not be possible without the knowledge of fundamental basic research. To learn more about basic research, visit https://www.nih.gov/news-events/basic-research-digital-media-kit.

NEI leads the federal government’s efforts to eliminate vision loss and improve quality of life through vision research…driving innovation, fostering collaboration, expanding the vision workforce, and educating the public and key stakeholders. NEI supports basic and clinical science programs to develop sight-saving treatments and to broaden opportunities for people with vision impairment. For more information, visit https://www.nei.nih.gov.

About the National Institutes of Health (NIH): NIH, the nation’s medical research agency, includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. NIH is the primary federal agency conducting and supporting basic, clinical, and translational medical research, and is investigating the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit https://www.nih.gov/.

NIH…Turning Discovery Into Health®

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NIH, National Eye Institute (NEI)

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October 7, 2022
Strand Life Sciences Announces the Release of Strand NGS v3.1 at ASHG 2017

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Strand NGS now supports large scale RNA- and small-RNA-Seq and Unique Molecular Identifiers (UMIs) for DNA-, RNA-, and small-RNA-Seq.

Press Release
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updated: Oct 17, 2017

Orlando, FL, October 17, 2017 (Newswire.com)
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Strand Life Sciences announced the latest version release of its bioinformatics flagship product, Strand NGS, at the Annual Meeting of the American Society of Human Genetics today. Two major themes in Strand NGS v3.1 address recent challenges in next generation sequencing (NGS).

The first theme is large-scale RNA-Seq data analysis. Current cross-cohort RNA- and small-RNA-Seq studies span tens of replicates and batches across hundreds of samples, sometimes conducted across several different institutions. For such studies, Strand NGS v3.1 includes confounding variable analysis to eliminate technical effects, including batch effects; the t-SNE plot; profile and heat-map plots of gene-body coverage; and several other notable visual enhancements.

The second new feature is support for Unique Molecular Identifiers, or UMIs, for DNA-, RNA- and small-RNA-Seq. UMI support in Strand NGS is end-to-end, spanning alignment to variant calling in DNA-Seq, and alignment to quantification in RNA- and small-RNA-Seq. The Bioo Scientific, Qiagen, and Rubicon UMI protocols are natively supported, and an intuitive interface allows the specification of custom UMI protocols.

“For liquid biopsies and low-grade FFPE samples, UMI support in DNA-Seq enables the detection of somatic variants at low concentrations. In RNA-Seq, large-scale and UMI support can be used in single-cell-based studies that reveal tumor-cell heterogeneity, even at low concentrations”, says Dr. Vamsi Veeramachaneni, Chief Scientific Officer, Strand Life Sciences.

“At Strand, we are continuously working towards improving the accuracy and efficiency of NGS data analysis. Customers can look forward to Strand NGS becoming available on the cloud in the near future”, says Dr. Ramesh Hariharan, Chief Executive Officer, Strand Life Sciences.

Visit Strand Life Sciences at ASHG booth #1017 to know more about Strand NGS v3.1 and other products and service offerings from Strand Life Sciences. Click here to access detailed agenda and v3.1 release notes. To know more about Strand NGS, visit www.strand-ngs.com.

About Strand Life Sciences
Strand Life Sciences is a premier life science informatics innovation company. Founded in 2000, Strand is a leader in technology innovations for healthcare using genomics. By enhancing sequence-based diagnostics and clinical genomic data interpretation using a strong foundation of computational, scientific, and medical expertise, Strand is bringing individualized medicine to the world. To know more, visit www.strandls.com

Source: Strand Life Sciences

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October 17, 2017