Monthly Archives: June 2021

UNIVERSITY PARK, Pa. Some regions of the human genome where the DNA can fold into unusual three-dimensional structures called G-quadruplexes (G4s) show signs that they are preserved by natural selection. When G4s are located in the regulatory sequences that control how genes are expressed or in other functional, but non-protein coding, regions of the genome, they are maintained by selection, are more common, and their unusual structures are more stable, according to a new study. Conversely, the structures are less common, less stable, and evolve neutrally outside of these regions, including within the protein-coding regions of genes themselves.

Together, these lines of evidence suggest that G4 elements should be added to the list of functional elements of the genome along with genes, regulatory sequences, and non-protein coding RNAs, among others. A paper describing the study, by a team of researchers led by Penn State scientists, appears June 29 in the journal Genome Research.

There have been only a handful of studies that provided experimental evidence for individual G4 elements playing functional roles, said Wilfried Guiblet, first author of the paper, a graduate student at Penn State at the time of research, and now a postdoctoral scholar at the National Cancer Institute. Our study is the first to look at G4s across the genome to see if they show the characteristics of functional elements as a general rule.

As much as 1% of the genome can fold into G4s, rather than the typical double helix (in comparison, protein-coding genes occupy approximately 1.5% of the genome). G4s are one of several non-canonical shapes into which DNA can fold, collectively known as non-B DNA. The G4 structure forms in DNA sequences rich in the nucleotide guanine, the G in the ACGT alphabet of the genome. G4s have been implicated in several key cellular processes and have been suggested to play a role in several human diseases, including neurological disorders and cancer.

To better understand the function of G4s at a genome-wide scale, the research team looked at their distribution across the genome, their thermostability, and whether or not they showed signs of being under the influence of natural selection, all in relation to other functional elements of the genome. They confirmed that, as a rule, G4s are more common in regions of the genome known to have important cellular functions and that the G4s in these regions are more stable than elsewhere in the genome.

The three-dimensional structure of G4s can form transiently and how stable their structure is depends on their underlying DNA sequence and other factors, said Guilbet. We found that, usually, G4s located within functional regions of the genome tend to be more stable. In other words, its more likely that the DNA is folded into a G4 at any given time and thus, more likely that the G4 is there for a functional reason.

Functional regions of the genome are generally maintained by a type of natural selection called purifying selection. Mutations in these regions could disrupt their function and be harmful to the organism. The mutations therefore are usually eliminated by purifying selection, which keeps the DNA sequence relatively unchanged over time. In nonfunctional regions of the genome, a mutation may have no impact and can persist in the genome without any consequences. These regions of the genome are said to evolve neutrally. Where G4s fall in this spectrum depends on their location in the genome.

We can look at the patterns of change in a DNA sequence among human individuals and between humans and our close primate relatives as a test of natural selection and then use selection as an indicator of function, said Yi-Fei Huang, assistant professor of biology at Penn State and a leader of the research team. Our tests show that G4s located within functional regions of the genome appear to be under purifying selections, which is further evidence that G4s should be considered as functional elements.The only exception from this pattern were protein-coding regions of genes, where G4s are relatively uncommon, rather unstable, and do not evolve under purifying selection. G4s in protein-coding regions of genes might be nonfunctional and costly to maintain.

The research team has recently shown that G4s, along with other types of non-B DNA, have increased mutation rates. The fact that G4s located outside of protein-coding regions are maintained by purifying selection, despite their high mutagenic potential, adds further weight to the evidence for classifying G4s as functional elements.

We think that we are seeing evidence for a paradigm shift for how scientists define function in the genome, said Kateryna Makova, Verne M. Willaman Chair of Life Sciences at Penn State and a leader of the research team. First, geneticists focused almost exclusively on protein-coding genes, then we became aware of many functional non-coding elements, and now we have G4s and possibly other non-B DNA elements. Three-dimensional structure may be just as important for defining function as the underlying DNA sequence.

Defining the full complement of functional genome elements is crucial for interpreting the potential disease consequences not only of inherited genetic variants but also of mutations arising within tissues over the lifetime of individuals, said Kristin Eckert, professor of pathology at the Penn State College of Medicine, co-author of the paper, and member of the research team. The identification of G4s as novel functional elements within the human genome is key to advancing the use of genetics in precision medicine.

In addition to Guiblet, Huang, Makova and Eckert, the research team includes Xiaoheng Cheng (now a postdoctoral researcher at the University of Chicago) and Francesca Chiaromonte, at Penn State, and Michael DeGiorgio at Florida Atlantic University. The study was funded by the U.S. National Institutes of Health, the Clinical and Translational Sciences Institute, the Institute of Computational and Data Sciences, the Huck Institutes of the Life Sciences at Penn State, the Penn State Eberly College of Science, and the U.S. National Science Foundation, and it also was supported by the CBIOS Predoctoral Training Program awarded to Penn State by the National Institutes of Health.

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A new class of functional elements in the human genome? | Penn State University - Penn State News

Twenty years ago, the first draft of the human genome was published in Nature and Science. The Human Genome Project was the most costly and ambitious biological enterprise in history. Astoundingly, it came in under the budget of $3 billion allocated by the United States Congress in 1990.

In 2003, a more complete genome was publicly released, but gaps remained. At the time, eight per cent of the most challenging and repetitive parts of the 3.057 billion chemical letters of DNA that make up the human genome remained unmapped. Those challenging gaps were finally sequenced and posted this May to much less fanfare.

In the early days of the Human Genome Project, DNA sequences were handwritten in notebook pages and faxed between groups. Keeping pace with early history of the Internet, the Human Genome Project sparked collaboration, open sharing of data, and made bioinformatics mainstream to all biologists.

Also Read: Scientifically Speaking | Knowing how coronavirus hacks cells will help stop it

However, the race to sequence the human genome didnt simply catalyse the creation of the infrastructure and tools needed to handle large amounts of data. It also accelerated the development of new fields such as genomics, systems biology, and computational biology. Today, sequencing genomes is a million times cheaper than it was two decades ago. Consequently, millions of people have had their genomes sequenced.

Genomes have helped in ancestry analyses and in identifying risk factors for diseases. With faster and cheaper DNA sequencing, we have entered the era of personalised medicine, which allows for individualised therapies that target molecular signatures of diseases that vary from person to person. Next-generation sequencing has also allowed us to design molecular vaccines, and to track mutations in viruses and variants during the current pandemic.

Genes are the functional units of the genome that contain instructions for how to make proteins. Scientists initially thought that the human genome would contain 50,000 to 100,000 genes. It came as a surprise to us that our genomes are nowhere close to being the largest, nor do they contain the most genes. With a genome of 43 billion base pairs (14 times larger than the human genome), the Australian lungfish an air-breathing distant relative of the first fish that walked on land 380 million years ago holds the distinction of the largest animal genome sequenced.

Humans have around 20,000 to 30,000 gene (depending on how a gene is actually defined) and each gene gives rise to three proteins on average. But even at the higher end of the range, this means that genes make up only one per cent of our genomes.

We made pivotal discoveries in the first decade of the draft human genome. We know that the 99% of the genome that doesnt code for genes is not fluff. Parts of it act as dials controlling the activity of genes. We also know there are switches that arent embedded in DNA which can respond to environmental signals to change the fate of cells. This extra layer on top of our genetics is spawning research in the field of epigenetics.

But in my view, the biggest development in genomics came in the second decade of the century from outside the field, with the discovery of the tools to edit the genome itself. This genome editing technology, called CRISPR, which won its discoverers the Nobel Prize in Chemistry last year, allows us to edit any part of the human genome.

Earlier this year, the New England Journal of Medicine published landmark research on two patients who received CRISPR gene-editing based therapy for sickle-cell disease and beta thalassemia. Both patients seem to have been cured of these severely debilitating genetic disorders, a truly monumental breakthrough. Doctors removed stem cells from bone marrow and edited a faulty gene using CRISPR. Billions of gene-edited cells were introduced into patients bodies.

On Saturday, the same journal published interim results on the treatment of amyloidosis with CRISPR. With the ability to edit genes inside the body directly, we have entered the genome editing era.

We know we can edit human genomes. But we do not know enough about the effects of making gene changes for complex diseases. Most diseases are not like sickle cell disease and beta thalassemia: they do not have a clear relationship between one gene and its effects. Instead, most diseases progress through the effects of multiple genes and environmental factors.

Right now, much of the medical applications of genomics are geared to genes of known function. But there are many genes for which we dont know function yet. An ambitious goal for the next decade would be to find out what the remaining genes actually do. An even more ambitious (and likely unachievable) goal would be to map the network of how genes interact with one another and with the rest of our cells.

In addition, some of the unbridled optimism that many diseases would be cured easily once the genome had been sequenced is gone, firmly replaced by the understanding that human biology is more complex and messy than we had realised back then.

Finally, we cannot lose sight of concerns in science that correlate with inequities in broader society. Who benefits from discoveries made from genomics? People of African ancestry, for example, are the most genetically diverse people on the planet. The rest of us are descendants of small populations that survived the journey out of Africa around 60,000 years ago. Yet people of African ancestry are underrepresented in genomic databases, which contain a disproportionate number of sequenced genomes of people of European ancestry. Just as vaccines are a common resource for all humans, so should genomes be.

Anirban Mahapatra, a microbiologist by training, is the author of COVID-19: Separating Fact From Fiction.

The views expressed are personal

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Scientifically Speaking | 20 years later, what we know about the human genome - Hindustan Times

What you now see is that every cancer is a rarecancer.

So says Emile Voest, professor of medical oncology at the Netherlands Cancer Institute, who was writing in the journal Nature. Voest was highlighting a revolutionary change in cancer treatment over the past decade: the advancement ofgenomics.

Genomics is the study of how genes interact with one another and the environment. It has already had a massive impact in oncology. For example, Voest notes that 12 years ago, lung cancer was classified as either small cell or non-small cell. Today, its identified by nearly 30 genomic mutations orchanges.

Identifying specific mutations in patients marks a radical shift from one-size-fits-all treatment towards more personalised therapy. For example, it could provide treatments for colorectal cancer with mutations in the so-called KRAS gene, which dont respond to some standard therapies. Likewise, acute myeloid leukaemia carries mutations that make it resistant to drugs known as isocitrate dehydrogenase inhibitors; genomics could offeranswers.

Cancer is far more complex than even the most visionary of scientists everimagined.

Twenty years ago, for example, researchers speculated that germ cell testicular cancer might be attributable to a single gene. However, a team led by Professor Clare Turnbull of the Institute of Cancer Research in London has found more than 40 genomic variants associated with thedisease.

Small wonder, then, that so many experts see such importance in genomics. And there has been significant progress. For example, Turnbull was clinical lead on the 100,000 Genome Project, which sequenced 100,000 genomes from more than 80,000 NHS patients with cancer or a rare disease. This yielded potential research leads in nearly half the cancer patients takingpart.

To understand why all this is so remarkable, its important to understand the context. The initial sequencing of the full human genome took more than 10 years and cost in excess of 2 billion. Using a blood sample, an individuals genome can now be sequenced in a day for less than 700.

Genomic medicine is already saving lives in a multitude of ways. Take DYPD, a gene mutation carried by roughly 10% of the UK population that can make chemotherapy harmful to the bone marrow, potentially killing the patient. Genomics advances mean doctors can now test patients for the mutation at a cost of 50 each, saving lives and cutting costs for the NHS, notes Andrew Beggs, professor of cancer genetics and surgery in the Institute of Cancer and Genomics Sciences at the University of Birmingham.

However, Beggs worries about a lack of public and even professional awareness about the scope for cancer prevention. For example, Lynch syndrome is a genetic condition that can increase the risk of bowel cancer by up to 80%. It also increases the risk of ovarian, womb and other cancers. Beggs, who runs a Lynch syndrome clinic, says its a relatively common condition, affecting about 1% of the UK population, but most are not aware ofit.

One reason for this is cultural. Most people think of the NHS as an institution they turn to when they are feeling sick, but genomic medicine points to a future when there will be an ever bigger emphasis on preventive medicine. Increasingly, families with a history of genetically linked cancers will be asked to undergo testing and any necessary treatment to prevent the cancers developing at all. But Beggs says that some patients fear screening because they do not want to face up to the idea that they could be at risk from a fataldisease.

Most people want to find out if they are at risk, but the people who dont want to know tend to be in their late teens and early 20s. You can understand this. They are young and believe it will never happen to them. But some are scared, heexplains.

The answer, he says, lies in education of both healthcare professionals and patients. GPs have a critical role to play in identifying families atrisk.

There are advantages to the NHS too. A single round of chemotherapy in a private hospital can cost up to 3,000, while cancer drugs cost the NHS more than 2bn a year. While a single genomic treatment could cost up to 20,000, thats cheaper than putting a patient through hospital admissions with say five or six rounds of chemotherapy that dont work and that cause significant side effects, Beggsnotes.

Oncology used to be like sharp-pointed sticks and rocks. We now have more finesse and have moved to the medical equivalent of ascalpel

Statins, the widely prescribed cholesterol-lowering drugs, are another example of a cheap therapy that has been found to have a beneficial effect in genomic treatment. Costing as little as four pence per tablet, statins have been shown to reduce levels of P53, a tumour suppressor gene. P53 mutations can cause cancer cells to grow andspread.

Statins are an example of repurposed drugs old medicines used in new ways that have long-established safety records. They can avoid the need for expensive new medicines. About 25,000 new substances are tested for every marketed medicine that makes enough money to pay for its development.

Genomic drug testing is also changing clinical trial design. Traditional trials usually compare one drug with another, with patients divided into treatment groups. They remain on the trial from the start to the end perhaps for several years irrespective of whether it is helpingthem.

The ongoing National Lung Matrix Trial could change this. Through the trial which is based on 11 treatment arms using different drugs University of Birmingham researchers match various treatments to different groups of lung cancer patients according to genetic changes in their cancers. If a particular drug isnt working, that treatment arm is closed and a new one may be introduced. If a patient doesnt respond to drug A, they can be switched to drug B. They may be in and out of the trial within twomonths.

In a traditional trial, patients receive broad spectrum chemotherapies that dont work half the time, Beggs says. Oncology used to be like sharp-pointed sticks and rocks. We now have more finesse and have moved to the medical equivalent of ascalpel.

Thirteen regional genomic centres are now operating in England. One of their goals is to identify the patients who may benefit most from from genomic testing. Another is to ensure more effective use of medicines, not just in cancer, but in all health care. The NHS medicines bill was about 17 billion a year. However, 50 per cent of medicines are not taken as prescribed and one in 15 hospital admissions occur because of adverse drug reactions according to a recent report in the Pharmaceutical Journal.

What is also disturbing is that the effectiveness of drugs overall ranges between 30 to 50 per cent. Advances in cancer genomics is explaining why so much conventional chemotherapy fails it does not target the right mutations. Hopefully, genomics will also lead to kinder treatments. Severe side effects arising from cancer therapy are all toocommon.

There is, of course, still a long way to go before the genomic revolution meets its full potential, but the success so far would have been unimaginable just a few yearsago.

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The personal touch: genomics and the fight against cancer - Raconteur

IRVINE, Calif.--(BUSINESS WIRE)--Genomic Testing Cooperative, a first-in-class diagnostic company based on a cooperative business model (Co-Op) using the most recent advances in NGS technology, announced today a collaboration with Elevation Oncology to enhance identification of patients with any solid tumor harboring an NRG1 fusion who may be eligible for enrollment in the Phase 2 CRESTONE study.

GTCs business is based on a cooperation model and has partnerships with multiple Co-Op members, all offering identical menus as GTC. This identification of patients with tumors harboring an NRG1 fusion is extended to all Co-Op members laboratories including Anthology Diagnostics in Edison, NJ and Key Genomics Laboratory at the John Theurer Cancer Center. Patients identified at these sites may be eligible for referral into the CRESTONE study.

Our goal is to provide comprehensive actionable molecular profiling so patients and their treating physicians can personalize therapy and select the proper treatment that has the potential of improving outcome, stated Dr. Maher Albitar, GTC Chief Executive Officer and Chief Medical Officer. The Co-Op model allows us to enable all members of the Co-Op to update their offering and make testing for NRG1 fusion available to their patients.

We believe that comprehensive biomarker testing of DNA and RNA is critical to give each patient their best chance of getting matched with a precision medicine, said Shawn Leland, PharmD, RPh, Founder and Chief Executive Officer of Elevation Oncology. We are pleased to add Genomic Testing Cooperative to our growing community of collaborators, who share our vision of profiling every patients tumor to identify genomic driver alterations that may be actionable.

The Solid Tumor Profile Plus offered by GTC combines the analysis of DNA with RNA to provide comprehensive evaluation of cancer that includes detection of single nucleotide variation, copy number variation, expression and fusion. This includes testing of abnormalities in 434 DNA genes and 1408 RNA genes.

Under the terms of the agreement, GTC will help Elevation Oncology identify patients with advanced solid tumors that harbor an NRG1 fusion for participation in Elevation Oncologys CRESTONE trial. Eligible patients will be referred to active clinical trial sites in Elevation Oncologys Phase 2 CRESTONE trial of seribantumab in adult patients with recurrent, locally advanced or metastatic solid tumors that harbor an NRG1 fusion.

Patients and physicians can learn more about the CRESTONE study at http://www.nrg1fusion.com or on http://www.ClinicalTrials.gov under the NCT number NCT04383210.

About Genomic Testing Cooperative, LCA

Genomic Testing Cooperative (GTC) is a privately-owned molecular testing company located in Irvine, CA. The company operates based on a cooperative (co-op) business model. Members of the co-op hold type A shares with voting rights. The company offers its patron members a full suite of comprehensive genomic profiling based mainly on next generation sequencing. Molecular alterations are identified based on rigorous testing with the aid of specially developed algorithms to increase accuracy and efficiency. The clinical relevance of the detected alterations is pulled from numerous databases using internally developed software. Relevance of findings to diagnosis, prognosis, selecting therapy, and predicting outcome are reported to members. The co-op model allows GTC to make the testing and information platform available to members at a lower cost because of a lower overhead. For more information, please visit https://genomictestingcooperative.com/.

Forward Looking Statements

All of the statements, expectations and assumptions contained in this press release are forward-looking statements. Such forward-looking statements are based on the GTC managements current expectations and includes statements regarding the value of comprehensive genomic profiling, RNA profiling, DNA profiling, algorithms, therapy, the ability of testing to provide clinically useful information. All information in this press release is as of the date of the release, and GTC undertakes no duty to update this information unless required by law.

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Genomic Testing Cooperative Announces Collaboration with Elevation Oncology to Expand Comprehensive Genomic Testing for NRG1 Fusions Across Solid...

NEW YORK Euformatics said Wednesday that it is continuing its global expansion by moving into China via a distribution deal with INSVAST. INSVAST, an acronym for its official name of Shanghai Yi Shuo Information Technology, sells bioinformatics products to next-generation sequencing laboratories in China.

The distribution agreement covers Euformatics' entire Omnomics suite of interpretation and validation software for NGS. It gives Shanghai-based INSVAST, which already distributes products from secondary analysis firm Sentieon, a more complete line of genomic interpretation software to sell.

"INSVAST already has a strong network of connections with the NGS bioinformatics sphere in China, and we are sure that they are well placed to bridge the gap between those labs looking for quality NGS bioinformatics tools and what we have to offer," Euformatics CEO Tommi Kaasalainen said in a statement. "The fact that INSVAST is already successfully working with other bioinformatics providers which our products complement means that the value proposition to customers is even stronger."

Eric Lee, cofounder and chief engineer of INSVAST, said that Euformatics allows his firm to round out its NGS bioinformatics product line. "We believe that by combining [Euformatics'] OmnomicsQ with the analytical power of OmnomicsNGS, we can ensure that laboratories running NGS in China produce impactful results, making a real difference to patient lives and the way we treat diseases," Lee said.

Espoo, Finland-based Euformatics has struck several distribution deals in the last two years.

A month ago, thefirm entered into a distribution agreement with A&C Group to offer its products in Bolivia, Peru, and Paraguay. That deal expanded Euformatics' presence in Latin America, which already included Brazil by virtue of a Marchdistribution agreement with Sntese Biotecnologia.

Euformatics moved into Central Asia, the Middle East, and Africa in late 2019 via anagreementwith Dubai-based Alliance Global (AGBLGroup).

The company has also expressed a desire to sell its products in Southeast Asia. Kaasalainenspecifically namedSingapore, Thailand, and Malaysia as near-term targetsbut did not rule out other countries.

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Euformatics Expands to China With INSVAST Distribution Deal - GenomeWeb

What You Should Know:

FoundationMedicine(FMI)announced todayit will begin integrating with Flatiron Health and other electronic medical record (EMR) systems to make it easier for oncologists to order comprehensive genomic tests (CGP), review results, continually access clinical and genomic information and share among their care teams in order to quickly and efficiently develop personalized treatment plans for their patients.

This integration, the first of a series planned by Flatiron, will support more efficient clinical decision making by allowing electronic ordering, order tracking and receipt ofFoundationMedicines CGP test results all within the OncoEMR platform.

Why It Matters

With the number of targeted cancer treatments growing exponentially, CGP is often the first step to determine the best treatment options for patients based on the genomic make-up of their cancer. As 95% of all oncology practices use an EMR system, integrating CGP within these medical record systems will streamline a doctors ability to order and track these tests, which can then help guide them in making personalized treatment plans for their patients.

The two companies are planning similar integrations with other CGP platforms and EMRs, respectively, in the oncology space, with the goal of helping every patient to realize the benefit of precision cancer care. These workflow-streamlining integrations are being designed by clinical and product experts in partnership with oncology practices.

With the number of targeted treatments growing exponentially, the opportunity for cancer care transformation has never been greater. Clinicians increasingly rely on genomic insights to guide clinical decision-making, andFoundationMedicineis committed to implementing new solutions that enable widespread access to CGP, said Kathleen Kaa, Interim Chief Commercial Officer atFoundationMedicine. The integration ofFoundationMedicinetests into OncoEMR, and other leading EMR systems to follow, is just one way were improving our offerings to fuel precisionmedicinefor cancer patients. The integrations will create efficiencies for oncology healthcare teams to deliver precision treatment plans based on individual genomic insights to their patients.

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Foundation Medicine Integrates Genomic Profiling with Flatiron Health's EMR - HIT Consultant