Monthly Archives: May 2023

23andMe Co-founder & CEO Anne Wojcicki says weve only seen the tip of the iceberg for human genomics and DNA research.

Look at all the explosion of all these new technologies with gene therapy, with CRISPR (CRSP), with RNA technologies and understanding the human genome, Wojcicki told Yahoo Finance at the Milken Global Conference in Beverly Hills, California.

Wojcicki says shes disappointed in the lack of progress around genomics, despite having just crossed a significant milestone, 20 years since the first complete sequencing of the human genome.

I think part of the reason is that genetics tells you a lot about what you're at risk for and it doesn't necessarily financially pay to get you that preventative information and to intervene in that way versus just treating people once they have a disease.

The 23andMe (ME) CEO also says they are looking into building new partnerships with pharmaceutical giants once the companys partnership with GlaxoSmithKline (GSK) ends in July.

Interview Highlights:

1:29

How genetics can tell us more about human diversity

2:20

Why 23andMe CEO is disappointed about genome adoption

5:00

Wojcicki on 23andMe partnership with pharma giant GSK

7:15

Genetics needs to be part of medical school training

8:26

Whats next for 23andMe

BRIAN SOZZI: I'm really interested in what 23 is-- 23andMe is working on at this point in its life. But you have said, you see the world through the lens of genetics. What is this world telling you right now?

ANNE WOJCICKI: Oh. Well, genetics-- so I should say, we're on the 20th anniversary of when the first human genome was sequenced. And it has, you know, it's a big milestone of like when it costs billions of dollars to get a single person sequenced and what you can learn from that to where we are today, where 23andMe has over 13 million people. You can learn a tremendous amount from your genome. And you can start to account for like all of this incredible diversity we see in life and all of the variation we have in our health, and like why some people do so well on a treatment, why some people don't, why some people get a disease, why some people don't.

Story continues

So I'm excited about the 20th anniversary and like, where it can go from here. But I do look at everything with that perspective of genetics, because it's almost like a digital code way of looking at all of the diversity that we see in life. And I look around a room, and I do think about like, I look at your eyes right now, and I'm like, ah--

[LAUGHTER]

I know he's an AG.

BRIAN SOZZI: What's AG?

ANNE WOJCICKI: It's just me, like you have like greenish eyes.

BRIAN SOZZI: Ha, what does that say about my DNA?

ANNE WOJCICKI: Well, just like you're not a GG.

BRIAN SOZZI: OK. Is one better than the other?

ANNE WOJCICKI: No, no. It's all-- no, that's the thing about diversity. Like, it's not-- you know, the diversity that we have of humans is about our story of survival, which is like a really beautiful story of like how we as, like, humans are made to keep living on this planet. Like, some people are made for cold, some people are made for hot. Some people have darker skin, and that protects them from sun. Some people are fair skin, and they can absorb more sun. Like, it's just like diversity is amazing.

BRIAN SOZZI: I wasn't going to go here, but are you a-- when you go into a room, are you assessing people like this? I didn't even realize anything. You just told me.

ANNE WOJCICKI: [LAUGHS]

[INTERPOSING VOICES]

[LAUGHTER]

ANNE WOJCICKI: I mean, I do-- I do sometimes see people, then I'm like, and they'll say, they're like, oh, yeah, I haven't done 23andMe yet. And I'll be kind of chomping at the bit. I'd be like I'm dying to see your DNA.

BRIAN SOZZI: Wow. OK, let me go-- let me get back on topic here. We're at the Milken Conference. And there's so much focus on health care because of the efforts by Michael Milken. I went to the doctor recently, just a checkup, didn't tell me anything about my genetics. Didn't even tell me where I can go, what I can do, what I may not do. Is it-- is it interwoven in health care right now? Or is there something missing here?

ANNE WOJCICKI: No. I mean, again, I'd say that's the disappointment I have of the 20 years having been around when they first sequenced the human genome that it's not broadly adopted. And I think part of that reason is that genetics tells you a lot about what you're at risk for. And it doesn't necessarily financially pay to get you that preventative information and to intervene in that way versus just treating people once they have a disease.

And so that's frankly it's my disappointment here is that we don't look at genetics, for instance, when you're getting a prescription and say, like, are you likely to respond? Should you have a different dose? You look at the epidemic of depression. There's all kinds of, you know, you can look at your genetics, look at a number of the drug, you know, interaction genes and see what medication you're likely to most respond to.

It's a tragedy to me that people are not first tested before they are prescribed something. I think also there's all kinds of other conditions like hereditary, you know, colon cancer. People should actually know whether or not they have something like that. And they can have increased screening. Familial hypercholesterolemia is where you have like really high, you know, cholesterol levels, and you need to get screened.

So things like that you could actually really start to, you know, see it for yourself.

BRIAN SOZZI: All of that makes a lot of sense to me.

ANNE WOJCICKI: Yeah.

BRIAN SOZZI: What's the biggest roadblock preventing health care from adopting these things?

ANNE WOJCICKI: It's a good question. I'd say there's two things. Like, one is it's not in the workflow. So meaning like when you go to your doctor, it's not necessarily part of the workflow, the processes. Like, if you said you're interested in having children, it isn't necessarily part of that workflow for actually how your doctor would follow up, how insurance would pay-- be paid. Does the doctor-- is the doctor educated about genetics? And what, you know, why they should do it, what you're potentially going to learn, how to potentially deal with the results if they get them.

I think for a long time we were really just used to genetic counselors and saying, like, hey, it's going to be put on a genetic counselor if you have this particular issue. And more and more, it's going into the mainstream. It should be your primary care physician really integrating it with primary care.

So I think that insurance and payment is a big obstacle. And I would say that physician education is a main-- is a significant obstacle as well as like being part of the workflow.

BRIAN SOZZI: Last time you talked to you around the time of the IPO 2021, you were just starting, I guess, getting going on a partnership with GSK and drug development. Where is that now? And when is that first drugs from this deal coming to market?

ANNE WOJCICKI: Well, that is thriving. GSK is actually-- it's done extraordinarily well. We have over 50 programs underway with GSK. We do have one that is in a phase I study that GSK now controls. We've-- it's co-developed, but we-- they're taking lead now. So, and there's a huge number of programs behind it.

23andMe also has our own wholly owned program. It's an immunotherapy program. So super excited about it. It is definitely exciting to see that you can go from understanding the genetic variation-- that makes me so excited-- to saying, wow, some people are, you know, genetically not likely to develop, you know, a certain kind of condition. And then can I understand that and turn that actually into a drug to help either treat people who have that condition?

BRIAN SOZZI: Is that the holy grail in health care, looking out over the next decade, the ability to match up your genetics with figuring out the cure for cancer or some other disease?

ANNE WOJCICKI: I look at all the explosion of all these new technologies with gene therapy, with CRISPR, with RNA technologies, and understanding the human genome. And I think what 23andMe can really bring to the table here is the understanding of the human genome.

So for instance, one thing that we can do really well is we study healthy people, meaning that you might have a particularly interesting mutation that the scientific world thinks like they don't know. Maybe it's potentially disease-causing. But because I can study you, and I can say, OK, you have finished a knockout mutation, you're doing really well. You have no other health issues.

We potentially know that that, like, changing that or modifying that gene is not going to create any other kinds of issues. So it's a way to help the pharmaceutical industry study essentially what's naturally going on in humans. So we find like studying huge populations and huge numbers helps us just understand that natural variability in people.

BRIAN SOZZI: How do you-- how do you go about championing this in the educational system? Do you see the things you're talking about today being embedded in our education system?

ANNE WOJCICKI: I think that, you know, genetics to be really successful, I think it needs to be part of medical school training. And it needs to be integrated not as a single subject but throughout all aspects of the curriculum. So when you're doing, you know, cardiovascular health, that it's part of that. When you're doing renal health, it's part of that.

That everything, every aspect of health care has a genetic component and helping realize, you know, the personalization that comes with it. Like, every patient that is coming also is unique and different. And so we're all going to metabolize drugs in a different way. You're going to have potentially, like, your blood values are naturally going to be different than my blood values based on your genetics.

There's just a lot of variability that we're going to understand from your genetics. And that's going to manifest in different ways in each of us. So what your baseline is going to be different than what my baseline is. So I do see that it needs to be integrated throughout all aspects of health care, not just as a specialty in genetics.

BRIAN SOZZI: Lastly, what's next for your company?

ANNE WOJCICKI: I'm excited-- there's two big areas. One is consumer, which is really about helping. We have over 13 million people and helping them do more with the information that we already provided. So one thing that we've gotten the feedback from our customers. Is that it's almost an overwhelming amount of information. So how do you translate all this into a care plan?

And there's a lot of lifestyle information we're also collecting from our customers about how they eat, how much they sleep, how much they walk, exercise, happiness. So helping people understand their health in the context of what they've self-reported, their genetics, and then all of their lifestyle information, so that then you can know what things should you change. And some of that might be more proactive screening in the medical system. Some of it might be changing how you sleep. Some of it might be changing how you eat.

So I see a real opportunity for us to deliver a type of personalized prevention that's grounded in your genetics. But we take all that other information about you. And we really help you be as healthy as you can.

I think the second slide, I think, we see this from the work that we've done with GSK. Having a large-- you know, a large amount of genetic information with really, really broad phenotypic data is incredibly powerful for drug discovery. And the end of the GSK collaboration comes in July. And it opens up all kinds of doors for us to, you know, start to do more partnerships with more companies. And I feel a responsibility to my customers that if you're somebody who has a family history of Alzheimer's, it's on me.

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Why the human genome could be healthcares holy grail - Yahoo Finance

It has been 20 years since scientists put together the first rough draft of the human genome, the three billion genetic letters of DNA tightly wound inside most of our cells. Today, scientists are still struggling to decipher it.

But a batch of studies published in Science on Thursday has cast a bright light into the dark recesses of the human genome by comparing it with those of 239 other mammals, including narwhals, cheetahs and screaming hairy armadillos.

By tracing this genomic evolution over the past 100 million years, the so-called Zoonomia Project has revealed millions of stretches of human DNA that have changed little since our shrew-like ancestors scurried in the shadows of dinosaurs. These ancient genetic elements most likely carry out essential functions in our bodies today, the project found, and mutations within them can put us at risk of a range of diseases.

The projects strength lies in the huge amount of data analyzed not just the genomes, but experiments on thousands of pieces of DNA and information from medical studies, said Alexander Palazzo, a geneticist at the University of Toronto who was not involved in the work. This is the way it needs to be done.

The mammalian genomes also allowed the Zoonomia team to pinpoint pieces of human DNA with radical mutations that set them apart from other mammals. Some of these genetic adaptations may have had a major role in the evolution of our big, complex brains.

The researchers have only scraped the surface of potential revelations in their database. Other researchers say it will serve as a treasure map to guide further explorations of the human genome.

Evolutions crucible sees all, said Jay Shendure, a geneticist at the University of Washington who was not involved in the project.

Scientists have long known that just a tiny fraction of our DNA contains so-called protein-coding genes, which make crucial proteins like digestive enzymes in our stomach, collagen in our skin and hemoglobin in our blood. All of our 20,000 protein-coding genes make up just 1.5 percent of our genome. The other 98.5 percent is far more mysterious.

Scientists have found that some bits of that inscrutable DNA help determine which proteins get made at certain places and at certain times. Other pieces of DNA act like switches, turning on nearby genes. And still others can amplify the production of those genes. And still others act like off switches.

Through painstaking experiments, scientists have uncovered thousands of these switches nestled in long stretches of DNA that seem to do nothing for us what some biologists call junk DNA. Our genome contains thousands of broken copies of genes that no longer work, for example, and vestiges of viruses that invaded the genomes of our distant ancestors.

But its not yet possible for scientists to look directly at the human genome and identify all the switches. We dont understand the language that makes these things work, said Steven Reilly, a geneticist at the Yale School of Medicine and one of more than 100 members of the Zoonomia team.

When the project began over a decade ago, the researchers recognized that evolution could help them decipher this language. They reasoned that switches that endure for millions of years are probably essential to our survival.

In every generation, mutations randomly strike the DNA of every species. If they hit a piece of DNA that isnt essential, they will cause no harm and may be passed down to future generations.

Mutations that destroy an essential switch, on the other hand, probably wont get passed down. They may instead kill a mammal, such as by turning off genes essential for organ development. You just wont get a kidney, said Kerstin Lindblad-Toh, a geneticist at the Broad Institute and Uppsala University who initiated the Zoonomia Project.

Dr. Lindblad-Toh and her colleagues determined that they would need to compare more than 200 mammal genomes to track these mutations over the past 100 million years. They collaborated with wildlife biologists to get tissue from species spread out across the mammalian evolutionary tree.

The scientists worked out the sequence of genetic letters known as bases in each genome, and compared them with the sequences of other species to determine how mutations arose in different mammalian branches as they evolved from a common ancestor.

It took a lot of computer churn, said Katherine Pollard, a data scientist at Gladstone Institutes who helped build the Zoonomia database.

The researchers found that a relatively small number of bases in the human genome 330 million, or about 10.7 percent gained few mutations in any branch of the mammalian tree, a sign that they were essential to the survival of all of these species, including our own.

Our genes make up a small portion of that 10.7 percent. The rest lies outside our genes, and probably includes elements that turn genes on and off.

Mutations in these little-changed parts of the genome were harmful for millions of years, and they remain harmful to us today, the researchers found. Mutations linked to genetic diseases typically alter bases that the researchers found had evolved little in the past 100 million years.

Nicky Whiffin, a geneticist at the University of Oxford who was not involved in the project, said that clinical geneticists struggle to find disease-causing mutations outside of protein-coding genes.

Dr. Whiffin said the Zoonomia Project could guide geneticists to unexplored regions of the genome with health relevance. That could massively narrow down the number of variants youre looking at, she said.

The DNA that governs our essential biology has changed remarkably little over the past 100 million years. But of course, we are not identical to kangaroo rats or blue whales. The Zoonomia Project is allowing researchers to pinpoint mutations in the human genome that help make us unique.

Dr. Pollard is focused on thousands of stretches of DNA that have not changed over that period of time except in our own species. Intriguingly, many of these pieces of fast-evolving DNA are active in the developing human brain.

Based on the new data, Dr. Pollard and her colleagues think they now understand how our species broke with 100 million years of tradition. In many cases, the first step was a mutation that accidentally created an extra copy of a long stretch of DNA. By making our DNA longer, this mutation changed the way it folded.

As our DNA refolded, a genetic switch that once controlled a nearby gene no longer made contact with it. Instead, it now made contact with a new one. The switch eventually gained mutations allowing it to control its new neighbor. Dr. Pollards research suggests that some of these shifts helped human brain cells grow for a longer period of time during childhood a crucial step in the evolution of our large, powerful brains.

Dr. Reilly, of Yale, has found other mutations that might have also helped our species build a more powerful brain: those that accidentally snip out pieces of DNA.

Scanning the Zoonomia genomes, Dr. Reilly and his colleagues looked for DNA that survived in species after species but were then deleted in humans. They found 10,000 of these deletions. Most were just a few bases long, but some of them had profound effects on our species.

One of the most striking deletions altered an off switch in the human genome. It is near a gene called LOXL2, which is active in the developing brain. Our ancestors lost just one base of DNA from the switch. That tiny change turned the off switch into an on switch.

Dr. Reilly and his researchers ran experiments to see how the human version of LOXL2 behaved in neurons compared with the standard mammalian version. Their experiments suggest that LOXL2 stays active in children longer than it does in young apes. LOXL2 is known to keep neurons in a state where they can keep growing and sprouting branches. So staying switched on longer in childhood could allow our brains to grow more than ape brains.

It changes our idea of how evolution can work Dr. Reilly said. Breaking stuff in your genome can lead to new functions.

The Zoonomia Project team has plans to add more mammalian genomes to their comparative database. Zhiping Weng, a computational biologist at UMass Chan Medical School in Worcester, is particularly eager to look at 250 additional species of primates.

Her own Zoonomia research suggests that virus-like pieces of DNA multiplied in the genomes of our monkey-like ancestors, inserting new copies of themselves and rewiring our on-off switches in the process. Comparing more primate genomes will let Dr. Weng get a clearer picture of how those changes may have rewired our genome.

Im still very obsessed with being a human, she said.

Read more here:
Scientists Compare Genomes of 240 Mammals to Understand Human DNA - The New York Times

There are more than 6,000 mammalian species on Earth, each of them different. Over the past 100 million years, mammals have evolved to adapt to their surrounding environment, resulting in diverse features.However, certain parts of the genome have remained the same across species and over millions of years, a large international collaboration of 30 research teams has found. This suggests that these regions are important, and the researchers believe these could hold the key to understanding human disease better.

The findings were recently published in 11 papers in the journal Science. The collaboration, called Zoonomia Project, investigated the genomic basis of shared and specialised traits in mammals.

The reason why the authors compared 240 mammalian genomes is to observe which parts remained unchanged across species during the course of evolution. Since evolution is a natural phenomenon that helps species adapt over time in response to the changing environment, any part of the genome that remains unchanged must be important.

A genome is the complete set of genetic information in an organism, and provides all of the information the organism requires to function. It consists of two broad parts. One is the genes, which are responsible for manufacture of protein molecules by the organism.

The other part consists of regulatory elements. These regions do not code for proteins, but instruct other genes where, when and how many proteins they must produce.

The scientists hypothesised that mutations in these regions of the genome may give rise to new diseases, or may be responsible for some unique mammalian features.

One of the paper is about the sled dog Balto, who was partly descended from the Siberian Husky, and was one of the most famous dogs in the world.

In 1925, during an outbreak of diphtheria in Nome, Alaska, Balto helped deliver serum to children. The study examined Baltos genome and compared it with the genomes of other dogs of that time and the present. It found that sled dogs of that time (including Balto) were genetically healthier than modern dogs, while Balto had more genetic diversity than his contemporaries and also modern dogs.

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The scientists have found some genetic variants that may be responsible for rare and common human diseases, including cancer. They studied a disease called medulloblastoma. It is a type of brain cancer that originates in the cerebellum, and is the most common type of cancerous brain tumour in children.

In one of the papers, scientists studied patients with medulloblastoma and found mutations in regions of the human genome which are otherwise conserved across all mammalian species. According to the researchers, these mutations may be associated with the disease, or may slow down the treatment of the illness.

The fact that the regions are conserved across mammalian species, but show mutations in patients with medulloblastoma, supports the hypothesis that the reason these portions are conserved is because they are important.

Therefore, scientists may use this approach in future to identify genetic changes that could be responsible for diseases.

Other papers have described how some parts of the conserved genomic regions are associated with exceptional mammalian traits such as a superior sense of smell, the ability to hibernate in winters and an extraordinary brain size, among others.

According to one of the studies, mammals started changing and diverging about 65 million years ago. This was even before the Chicxulub impactor, the asteroid that killed dinosaurs, hit Earth.

Another study found a link between more than 10,000 genetic deletions in human genomes and the function of neurons.

One paper said that species that have had a small population size historically are at a higher risk of extinction in the present day.

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Genomes From 240 Mammalian Species Help Explain 100 Years Of Evolution And Human Disease - ABP Live

What the human genome is lacking compared with the genomes of other primates might have been as crucial to the development of humankind as what has been added during our evolutionary history, according to a new study led by researchers at Yale and the Broad Institute of MIT and Harvard.

The new findings, published April 28 in the journal Science, fill an important gap in what is known about historical changes to the human genome. While a revolution in the capacity to collect data from genomes of different species has allowed scientists to identify additions that are specific to the human genome such as a gene that was critical for humans to develop the ability to speak less attention has been paid to whats missing in the human genome.

For the new study researchers used an even deeper genomic dive into primate DNA to show that the loss of about 10,000 bits of genetic information most as small as a few base pairs of DNA over the course of our evolutionary history differentiate humans from chimpanzees, our closest primate relative. Some of those deleted pieces of genetic information are closely related to genes involved in neuronal and cognitive functions, including one associated with the formation of cells in the developing brain.

These 10,000 missing pieces of DNA which are present in the genomes of other mammals are common to all humans, the Yale team found.

The fact that these genetic deletions became conserved in all humans, the authors say, attests to their evolutionary importance, suggesting that they conferred some biological advantage.

Often we think new biological functions must require new pieces of DNA, but this work shows us that deleting genetic code can result in profound consequences for traits make us unique as a species, said Steven Reilly, an assistant professor of genetics at Yale School of Medicine and senior author of the paper.

The paper was one of several published in Science from the Zoonomia Project, an international research collaboration that is cataloging the diversity in mammalian genomes by comparing DNA sequences from 240 species of mammals that exist today.

In their study, the Yale team found that some genetic sequences found in the genomes of most other mammal species, from mice to whales, vanished in humans. But rather than disrupt human biology, they say, some of these deletions created new genetic encodings that eliminated elements that would normally turn genes off.

The deletion of this genetic information, Reilly said, had an effect that was the equivalent of removing three characters nt from the word isnt to create a new word, is.

[Such deletions] can tweak the meaning of the instructions of how to make a human slightly, helping explain our bigger brains and complex cognition, he said.

The researchers used a technology called Massively Parallel Reporter Assays (MPRA), which can simultaneously screen and measure the function of thousands of genetic changes among species.

These tools have the capability to allow us to start to identify the many small molecular building blocks that make us unique as a species, Reilly said.

James Xue of the Broad Institute is lead author of the study.

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'Deletions' from the human genome may be what made us human - Yale News

STAMFORD, Conn., May 04, 2023 (GLOBE NEWSWIRE) -- GeneDx (Nasdaq: WGS), a leader in delivering improved health outcomes through genomic and clinical insights, today announced the availability of its GenomeXpress and GenomeSeqDx whole genome sequencing tests with buccal swabs as an alternative sample collection option for biological parents or other immediate family members. Sequencing biological parent genomes alongside patient genomes known as trio analysis - aids in disease diagnosis and greatly increases diagnostic yield rates.

"We are continuously looking for ways to broaden adoption of genome sequencing and facilitate convenient access to families to aid in disease diagnosis, said Paul Kruszka, M.D., Chief Medical Officer at GeneDx. Research shows diagnostic rates are highest when we can include genomic data of biological parents to classify variants of unknown significance based on inheritance patterns. Adding buccal swab as an additional sample collection method for our GenomeSeqDx and GenomeXpress whole genome sequencing tests can make it easier for providers to collect parent samples for trio testing.

Buccal swab is a convenient, non-invasive method to collect DNA from cells found inside a persons cheek. In the case of trio testing, the diagnostic yield for positively identifying a disease-causing variant increases from 19% to 30%.1 In addition to its whole genome sequencing tests, GeneDx also makes buccal swab available as an alternative DNA collection method for its XomeDx and XomeDxXpress whole exome sequencing tests for patients and biological parent samples.

We continue to turn to GeneDx for whole genome sequencing testing to accurately identify pathogenic variants that explain our patients illnesses, said Tara Lynn Wenger, M.D., Ph.D., Associate Professor in the Department of Pediatrics at the University of Washington and Associate Medical Director for Inpatient Genetics Services at Seattle Childrens Hospital. Collecting DNA from biological parents or other relatives is not always so easy. Buccal swab DNA collection for parents will streamline the process and prevent delays in testing and enable us to do a more thorough whole genome analysis.

About GeneDx GenomeSeqDx and GenomeXpress Whole Genome Sequencing GenomeSeqDx and GenomeXpress clinical whole genome tests by GeneDx include evaluation and analysis of both the protein-coding and non-coding regions of the human nuclear genome, allowing for the broadest potential detection of characterized/pathogenic variants contributing to the molecular basis of a genetic disorder in an affected individual. Detecting and characterizing variants that may contribute to the molecular basis of a genetic disorder is most effective when at least one or both biological parents are included in the analysis. Several large, evidenced-based studies have demonstrated that genome sequencing identifies a causal variant in more than 40% of cases, with higher yields for cases that specifically include samples from family members for analysis.2,3,4

About GeneDxGeneDx (Nasdaq: WGS) delivers personalized and actionable health insights to inform diagnosis, direct treatment and improve drug discovery. The company is uniquely positioned to accelerate the use of genomic and large-scale clinical information to enable precision medicine as the standard of care. GeneDx is at the forefront of transforming healthcare through its industry-leading exome and genome testing and interpretation, fueled by one of the worlds largest, rare disease data sets. For more information, please visit http://www.genedx.com and connect with us on LinkedIn, Twitter, Facebook, and Instagram.

Investor ContactTricia TruehartInvestors@GeneDx.com

Media ContactMaurissa MessierPress@GeneDx.com

1 Data on file.2 Manickam K, McClain MR, Demmer LA, et al. Exome and genome sequencing for pediatric patients with congenital anomalies or intellectual disability: an evidence-based clinical guideline of the American College of Medical Genetics and Genomics (ACMG). Genet Med. 2021 Nov;23(11):2029-2037. doi: 10.1038/s41436-021-01242-6. Epub 2021 Jul 1.3 Sheidley BR, Malinowski J, Bergner AL, et al. Genetic testing for the epilepsies: A systematic review. Epilepsia. 2022 Feb;63(2):375-387. doi: 10.1111/epi.17141. Epub 2021 Dec 10.4 Dimmock D, Caylor S, Waldman B, et al. Project Baby Bear: Rapid precision care incorporating rWGS in 5 California childrens hospitals demonstrates improved clinical outcomes and reduced costs of care. Am J Hum Genet. 2021 Jul 1;108(7):1231-1238. doi:10.1016/j.ajhg.2021.05.008. Epub 2021 Jun 4.Yang et al. (2014) JAMA 312 (18):1870-9 (PMID: 25326635)

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GeneDx Adds Buccal Swab as Non-Invasive Whole Genome ... - GlobeNewswire

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by Bob Yirka , Medical Xpress

Proportion of the glioma exploratory cohort (green) or control cohort (blue) with variants in seven cancer genes and overall. P values were calculated with Fishers exact test and Bonferroni correction. Credit: Science Advances (2023). DOI: 10.1126/sciadv.ade2675

A team of gene therapists, oncologists, genetic sequencing experts and neurosurgeons affiliated with a host of institutions in the U.S. and one in Sweden has uncovered gene variants that appear to be responsible for passing on familial glioma from parent to offspring. In their study, reported in the journal Science Advances, the group sequenced the genomes of members of glioma-affected families.

Glioma is a form of cancerous brain tumor with a generally poor prognosis. Familial glioma is a subclass of glioma that persists along family lines, strongly suggesting a genetic component. In this new effort, the researchers set their sights on tracking down the specific genes responsible for passing on a propensity for developing glioma.

The researchers took tissue samples from 203 volunteers from 189 families with a history of glioma and performed whole-genome sequencing. They then repeated the whole exercise using tissue samples from another 122 people from 115 families. Once sequencing was completed, germline variants were compared with sequences done on more than 1,000 people who did not have a family history of glioma.

The researchers found 54 variants appearing in 28 genes that appeared to be overrepresented in families with a history of glioma. They found them in 50 of the families involved in the testing. More specifically, they found copy number changes in HERC2. They also found an overlap between genes they identified as possibly related to familial glioma and genes that have previously been associated with other kinds of cancer.

The data also showed variants they described as suspicious in some noncoding genes, which they suggest could play a role in mediating the activity of other genes. Such variants, they further note, appeared to coincide with heightened levels of transcription factor bind mutations upstream of some of the involved genes.

The researchers conclude by noting that theirs is the first study to link the HERC2 gene to predisposition to any type of cancer and the first to look at the role noncoding variants may play in glioma.

More information: Dong-Joo Choi et al, The genomic landscape of familial glioma, Science Advances (2023). DOI: 10.1126/sciadv.ade2675

Journal information: Science Advances

2023 Science X Network

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Whole-genome sequencing used to track down genes behind familial glioma - Medical Xpress

Tiny pores in the cell nucleus play an essential role for healthy aging by protecting and preserving the genetic material. A team in Germany from the Department of Theoretical Biophysics at the Max Planck Institute of Biophysics in Frankfurt am Main and the Synthetic Biophysics of Protein Disorder Group at Johannes Gutenberg University Mainz has literally filled a hole in the understanding of the structure and function of these nuclear pores. The scientists found out how intrinsically disordered proteins in the center of the pore can form a spaghetti-like mobile barrier that is permeable for important cellular factors but blocks viruses or other pathogens.

Human cells shield their genetic material inside the cell nucleus, protected by the nuclear membrane. As the control center of the cell, the nucleus must be able to exchange important messenger molecules, metabolites or proteins with the rest of the cell. About 2000 pores are therefore built into the nuclear membrane, each consisting of about 1000 proteins.

For decades, researchers have been fascinated by the three-dimensional structure and function of these nuclear pores, which act as guardians of the genome: substances that are required for controlling the cell are allowed to pass, while pathogens or other DNA-damaging substances are blocked from entry. The nuclear pores can therefore be thought of as molecular bouncers, each checking many thousands of visitors per second. Only those who have an entrance ticket are allowed to pass.

How do the nuclear pores manage this enormous task? About 300 proteins attached to the pore scaffold protrude deep into the central opening like tentacles. Until now, researchers did not know how these tentacles are arranged and how they repel intruders. This is because these proteins are intrinsically disordered and lack a defined three-dimensional structure. They are flexible and continuously moving -- like spaghetti in boiling water.

Combination of microscopy and computer simulations

As these intrinsically disordered proteins (IDPs) are constantly changing their structure, it is difficult for scientists to decipher their three-dimensional architecture and their function. Most experimental techniques that researchers use to image proteins only work with a defined 3D structure. So far, the central region of the nuclear pore has been represented as a hole because it was not possible to determine the organization of the IDPs in the opening.

The team led by Gerhard Hummer, Director at the Max Planck Institute of Biophysics, and Edward Lemke, Professor for Synthetic Biophysics at Johannes Gutenberg University Mainz, and Adjunct Director at the Institute of Molecular Biology Mainz has now used a novel combination of synthetic biology, multidimensional fluorescence microscopy and computer-based simulations to study nuclear pore IDPs in living cells.

"We used modern precision tools to mark several points of the spaghetti-like proteins with fluorescent dyes that we excite by light and visualize in the microscope," Lemke explains. "Based on the glow patterns and duration, we were able to deduce how the proteins must be arranged." Hummer adds, "We then used molecular dynamics simulations to calculate how the IDPs are spatially organized in the pore, how they interact with each other and how they move. For the first time, we could visualize the gate to the control center of human cells."

Dynamic protein network as transport barrier

The tentacles in the transport pore take on a completely different behavior compared to what we knew before, because they interact with each other and with the cargo. They move permanently like the aforementioned spaghetti in boiling water. So, in the center of the pore there is no hole, but a shield of wiggly, spaghetti-like molecules. Viruses or bacteria are too big to get through this sieve. However, other large cellular molecules needed in the nucleus can pass as they carry very specific signals. Such molecules have an entry ticket, whereas pathogens usually do not. "By disentangling the pore filling, we enter a new phase in nuclear transport research," adds Martin Beck, collaborator and colleague at the Max Planck Institute of Biophysics.

"Understanding how the pores transport or block cargo will help us identify errors. After all, some viruses manage to enter the cell nucleus despite the barrier," Hummer sums up. "With our combination of methods, we can now study IDPs in more detail to find why they are indispensable for certain cellular functions, despite being error-prone. In fact, IDPs are found in almost all species, although they carry the risk of forming aggregates during the aging process which can lead to neurodegenerative diseases such as Alzheimer's," Lemke says. By learning how IDPs function, researchers aim to develop new drugs or vaccines that prevent viral infections and help healthy aging.

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Wiggly proteins guard the genome: Dynamic network in the pores of ... - Science Daily

Alternative RNA splicing is an essential mechanism linking genetic variation to human diseases. While the signals from genome-wide association studies (GWAS) have been linked to expression quantitative trait loci (eQTL) in previous studies, further work is needed to better elucidate the relationship to other genetic regulatory mechanisms, such as splicing QTLs (sQTL). Here, we performed a genome-wide sQTL analysis to identify variants that might affect RNA splicing in 1,010 nonsmall cell lung cancer (NSCLC) samples from The Cancer Genome Atlas. The identified sQTLs were largely independent of eQTLs and were predominantly enriched in exonic regions, genetic regulatory elements, RNA-binding protein (RBP) binding sites, and known NSCLC risk loci. In addition, target genes affected by sQTLs (sGenes) were involved in multiple processes in cancer, including cell growth, apoptosis, metabolism, immune infiltration, and drug responses, and sGenes were frequently altered genetically in NSCLC. Systematic screening of sQTLs associated with NSCLC risk using GWAS data from 15,474 cases and 12,375 controls identified an sQTL variant rs156697-G allele that was significantly associated with an increased risk of NSCLC. The association between the rs156697-G variant and NSCLC risk was further validated in two additional large population cohorts. The risk variant promoted inclusion of GSTO2 alternative exon 5 and led to higher expression of the GSTO2 full-length isoform (GSTO2-V1) and lower expression of the truncated GSTO2 isoform (GSTO2-V2), which was induced by RBP quaking (QKI). Mechanistically, compared with GSTO2-V1, GSTO2-V2 inhibited NSCLC cells proliferation by increasing S-glutathionylation of AKT1 and thereby functionally blocking AKT1 phosphorylation and activation. Overall, this study provides a comprehensive view of splicing variants linked to NSCLC risk and provides a set of genetic targets with therapeutic potential.

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Genome-Wide Splicing Quantitative Expression Locus Analysis ... - Cancer Discovery