Category Archives: Human Genetics

The sweetness of sugar is one of life's great pleasures. People's love for sweet is so visceral, food companies lure consumers to their products by adding sugar to almost everything they make: yogurt, ketchup, fruit snacks, breakfast cereals and even supposed health foods like granola bars.

Schoolchildren learn as early as kindergarten that sweet treats belong in the smallest tip of the food pyramid, and adults learn from the media about sugar's role in unwanted weight gain. It's hard to imagine a greater disconnect between a powerful attraction to something and a rational disdain for it. How did people end up in this predicament?

Insights into our species' evolutionary history can provide important clues about why it's so hard to say no to sweet.

The basic activities of day-to-day life, such as raising the young, finding shelter and securing enough food, all required energy in the form of calories. Individuals more proficient at garnering calories tended to be more successful at all these tasks. They survived longer and had more surviving children - they had greater fitness, in evolutionary terms.

One contributor to success was how good they were at foraging. Being able to detect sweet things - sugars - could give someone a big leg up.

In nature, sweetness signals the presence of sugars, an excellent source of calories. So foragers able to perceive sweetness could detect whether sugar was present in potential foods, especially plants, and how much.

This ability allowed them to assess calorie content with a quick taste before investing a lot of effort in gathering, processing and eating the items. Detecting sweetness helped early humans gather plenty of calories with less effort. Rather than browsing randomly, they could target their efforts, improving their evolutionary success.

Sweet taste genesEvidence of sugar detection's vital importance can be found at the most fundamental level of biology, the gene. Your ability to perceive sweetness isn't incidental; it is etched in your body's genetic blueprints. Here's how this sense works.

Sweet perception begins in taste buds, clusters of cells nestled barely beneath the surface of the tongue. They're exposed to the inside of the mouth via small openings called taste pores.

Different subtypes of cells within taste buds are each responsive to a particular taste quality: sour, salty, savory, bitter or sweet. The subtypes produce receptor proteins corresponding to their taste qualities, which sense the chemical makeup of foods as they pass by in the mouth.

One subtype produces bitter receptor proteins, which respond to toxic substances. Another produces savory (also called umami) receptor proteins, which sense amino acids, the building blocks of proteins. Sweet-detecting cells produce a receptor protein called TAS1R2/3, which detects sugars. When it does, it sends a neural signal to the brain for processing. This message is how you perceive the sweetness in a food you've eaten.

Genes encode the instructions for how to make every protein in the body. The sugar-detecting receptor protein TAS1R2/3 is encoded by a pair of genes on chromosome 1 of the human genome, conveniently named TAS1R2 and TAS1R3.

Comparisons with other species reveal just how deeply sweet perception is embedded in human beings. The TAS1R2 and TAS1R3 genes aren't only found in humans - most other vertebrates have them, too. They're found in monkeys, cattle, rodents, dogs, bats, lizards, pandas, fish and myriad other animals. The two genes have been in place for hundreds of millions of years of evolution, ready for the first human species to inherit.

Geneticists have long known that genes with important functions are kept intact by natural selection, while genes without a vital job tend to decay and sometimes disappear completely as species evolve. Scientists think about this as the use-it-or-lose-it theory of evolutionary genetics. The presence of the TAS1R1 and TAS2R2 genes across so many species testifies to the advantages sweet taste has provided for eons.

The use-it-or-lose-it theory also explains the remarkable discovery that animal species that don't encounter sugars in their typical diets have lost their ability to perceive it. For example, many carnivores, who benefit little from perceiving sugars, harbor only broken-down relics of TAS1R2.

Sweet taste liking

The body's sensory systems detect myriad aspects of the environment, from light to heat to smell, but we aren't attracted to all of them the way we are to sweetness.

A perfect example is another taste, bitterness. Unlike sweet receptors, which detect desirable substances in foods, bitter receptors detect undesirable ones: toxins. And the brain responds appropriately. While sweet taste tells you to keep eating, bitter taste tells you to spit things out. This makes evolutionary sense.

So while your tongue detects tastes, it is your brain that decides how you should respond. If responses to a particular sensation are consistently advantageous across generations, natural selection fixes them in place and they become instincts.

Such is the case with bitter taste. Newborns don't need to be taught to dislike bitterness - they reject it instinctively. The opposite holds for sugars. Experiment after experiment finds the same thing: People are attracted to sugar from the moment they're born. These responses can be shaped by later learning, but they remain at the core of human behavior.

Sweetness in humans' futureAnyone who decides they want to reduce their sugar consumption is up against millions of years of evolutionary pressure to find and consume it. People in the developed world now live in an environment where society produces more sweet, refined sugars than can possibly be eaten.

There is a destructive mismatch between the evolved drive to consume sugar, current access to it and the human body's responses to it. In a way, we are victims of our own success.

The attraction to sweetness is so relentless that it has been called an addiction comparable to nicotine dependence - itself notoriously difficult to overcome.

It is worse than that. From a physiological standpoint, nicotine is an unwanted outsider to our bodies. People desire it because it plays tricks on the brain. In contrast, the desire for sugar has been in place and genetically encoded for eons because it provided fundamental fitness advantages, the ultimate evolutionary currency.

Sugar isn't tricking you; you are responding precisely as programmed by natural selection.

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Why do we love sugar so much? Here is a genetic connection to your sweet addiction - Economic Times

On November 24, 2021, scientists in South Africa revealed that they had discovered a worrying new variant of SARS-CoV-2.

They reported that the variant was spreading very rapidly in southern Africa and contained a large number of unusual mutations likely to make the virus more infectious than previous variants.

Within days of the scientists announcement, the World Health Organization (WHO) declared that the new variant, called Omicron, was a variant of concern.

Confirming the scientists early fears, by early January 2022, Omicron was driving an unprecedented surge in cases worldwide.

Many of the mutations that health experts identified in Omicron are rare among previously sequenced variants of the virus.

This presents a puzzle for scientists because there are no known intermediate variants to reveal how Omicron evolved. It is almost as if the new variant appeared out of nowhere.

There are three alternative theories for the origin of Omicron:

The second theory is the most popular among virologists and epidemiologists.

However, some experts have argued that other viruses, such as the influenza virus, tend to become less infectious over time in individuals with compromised immune systems.

They cite evidence that while such viruses evolve adaptations to their hosts immune system, they accumulate other mutations that make them less able to cause infections in other people.

However, Omicron appears to be more infectious than all previously known variants.

Researchers at the Chinese Academy of Sciences in Beijing have now found evidence that Omicron may have evolved its large collection of unusual mutations in mice.

They believe that an earlier variant, from the lineage known as B.1.1, jumped from a human into a mouse in mid-2020. Over time, it evolved a range of adaptations to its new host before causing an infection in another human in late 2021.

They identified 45 point mutations in the RNA of Omicron that they propose occurred after the variant split from its last known common ancestor in humans.

Point mutations are substitutions of single chemical letters, known as bases, in the four-letter genetic code.

Past research suggests RNA viruses tend to pick up more mutations in particular bases, according to which animal host they are replicating inside.

Using this knowledge, the authors of the new paper have previously identified the mutation signature of different animal hosts of SARS-CoV-2.

Their new study found that the relative frequency of the new point mutations in Omicron is characteristic of evolution in a mouse host rather than a human host.

They discovered that the mutation signature of Omicron is different from several variants known to have evolved in humans, including three variants isolated from patients with chronic COVID-19.

The scientists also found that several mutations in Omicrons spike protein, which SARS-CoV-2 uses to cause infection in host cells, help the virus bind more tightly to its target receptor in mice.

They have published their findings in the Journal of Genetics and Genomics.

In the paper, they conclude:

Collectively, our results suggest that the progenitor of Omicron jumped from humans to mice, rapidly accumulated mutations conducive to infecting that host, then jumped back into humans, indicating an inter-species evolutionary trajectory for the Omicron outbreak.

Biologist Matt Ridley, author of Viral: The Search for the Origin of COVID-19, responded to the study on Twitter:

Looks like Omicron developed from a human variant in a mouse. The question is: what mice and where? House mice in homes? Or lab mice in labs?

We believe that Omicron likely evolved in a wild mouse population, the senior author of the study, Wenfeng Qian, Ph.D., told Medical News Today.

He said that mutations in the spike protein of Omicron significantly overlapped with mutations in SARS-CoV-2 viruses that have adapted to a mouse host.

However, 18 out of a total of 25 mutations in the Omicron spike were not present in any of the SARS-CoV-2 viruses they studied that were adapted to lab mice.

In addition, he pointed out that Omicron appears to have diverged from the B.1.1 lineage, with which it shares seven mutations.

It is implausible that a lab will use a B.1.1 variant for their mouse adaptation experiments, he commented. Instead, he said they would most likely use a strain of SARS-CoV-2 that researchers sequenced at the start of the pandemic, known as Wuhan-Hu-1.

Evolutionary biologist Mike Worobey, Ph.D., of the University of Arizona in Tucson, said the most plausible theory remained that Omicron evolved in an immune-compromised patient with a protracted [SARS-CoV-2] infection.

I think their approach is really interesting, but I still think it is more likely that the unusual array of mutations in Omicron occurred in a chronically human [with the infection], he told MNT.

For live updates on the latest developments regarding the novel coronavirus and COVID-19, click here.

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COVID-19: Did Omicron evolve in mice? - Medical News Today

On Wednesday, January 26 from 12:00 12:45pm, Marty Soehnlen, PhD, MPH, PHLD(ABB), and Heather Blankenship, PhD, will provide a presentation on the Omicron variant's concerning rise in Michigan, how whole genome testing is performed, impacts upon diagnostic tests, current data trends, and impacts upon therapies.

Doctor Soehnlen is the Director of Infectious Disease at the Michigan Department of Health and Human Services, Bureau of Laboratories. She began her laboratory career at Ohio State University where she received a BS in Medical Technology followed by an MPH is Hospital and Molecular Epidemiology with a sub-specialization in public health genetics. Doctor Soehnlen went on to the Centers for Disease Control and Prevention as an APHL/CDC Class XII Emerging Infectious Diseases Fellow in the Rabies group before obtaining a PhD in Pathobiology from Penn State University. She spent 4 years in Landstuhl, Germany with the US Army Public Health Command Region in Europe. She also directs three local health department labs and one small commercial lab.

Doctor Blankenship is Section Manager of Bioinformatics and Sequencing at the Michigan Department of Health and Human Services, Bureau of Laboratories. She received her BS in Biology from George Mason University and her PhD from Michigan State University. She gained expertise for her career through study of human and prokaryotic genetics. Her post graduate studies focused on molecular genetics, epidemiology, biotechnology, and bioinformatics.

Approved for .75AMA PRA Category 1 Credit(s)

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Grand Rounds: Omicron The Next Variant of Concern and Responses in the COVID Pandemic Efforts - Michigan State Medical Society

Work type: Full-timeDepartment: Li Ka Shing Faculty of Medicine (20000)Categories: Academic-related Staff

Assistant Research Officer (holding the functional title of Bioinformatic Scientist II) in the LKS Faculty of Medicine (Ref.: 511404)(to commence as soon as possible, on a two-year fixed-term basis with contract-end gratuity and University contribution to a retirement benefits scheme, totalling up to 10% of basic salary, with the possibility of renewal)

Applicants should possess a Ph.D. degree in Genetics, Molecular Biology or Computational Biology/Bioinformatics. Experience with next-generation sequencing data analysis, proficiency in Python, R and Linux scripting, including evidence of the use of source code management repositories are essential. Applicants should have solid knowledge of molecular and human genetics, and demonstrated ability to effectively communicate scientific results in presentations and publications.

The appointee will work with a multi-disciplinary team including clinicians and scientists to study undiagnosed disorders and cancers through analysis of whole genome sequencing data coupled with clinical information as part of the Hong Kong Genome Project Partnering Centre based at The University of Hong Kong and Queen Mary Hospital. Responsibilities include to implement bioinformatics pipelines for the processing and management of genomics data, design workflow for the prioritisation and validation of genomic variants of potential significance, provide advanced scientific support for the interpretation of potential variants of significance in relation to the disease of individual patients. Enquiries about the duties of the post should be sent to Professor Suet Yi Leung at suetyi@hku.hk.

A highly competitive salary commensurate with qualifications and experience will be offered, in addition to annual leave and medical benefits.

The University only accepts online application for the above post. Applicants should apply online and upload an up-to-date C.V. Review of applications will start from January 19, 2022 and continue untilJanuary 31, 2022, or until the post is filled, whichever is earlier.

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Assistant Research Officer, Li Ka Shing Faculty of Medicine job with THE UNIVERSITY OF HONG KONG | 276845 - Times Higher Education (THE)

The spike protein of the coronavirus, or SARS-CoV-2, binds to a receptor on the host cells, called ACE2, which allows the virus to enter the cells and infect it. Binding is the first step for infection, and several mutations in previous variants of concern have been shown to be important for increasing the spike's binding to human ACE2.

We use a fully quantum mechanical model to theoretically assess how different mutations in the spike can contribute to its increased, or decreased, binding strength to human ACE2, Momeni said. The modeling shows that Omicron binds to receptor proteins stronger than the currently dominant Delta variant.

In addition to Momeni, Boston College Professor of Biology Welkin Johnson and post-doctoral researcher Marco Zaccaria, Luigi Genovese of French CEA - University of Grenoble Alpes, and Professor Michael Farzan of the Scripps Research Institute, contributed to the report"Investigating the mutational landscape of the SARS-CoV-2 Omicron variant viaab initioquantum mechanical modeling,which is available at the pre-print host site bioRxiv.

We find that Omicron has not reached its full potential to bind human host cells, Momeni said. We identify mutations that can strengthen the virus affinity for the human cell, which could increase infectivity and evasion of antibodies. He cautioned that increased infectivity is only one important aspect in variants of concern; it is also important to monitor the severity of symptoms and the ability of the variant to evade antibodies and vaccines.

While the study found that Omicrons spike proteins bind better than the Delta variant to the human ACE2 receptor, not all mutations in the spike proteins targeting systemknown as a receptor binding domainare beneficial for binding, which suggests factors other than binding may also be involved in determining how the variant evolves.

One possible explanation is that the variant has acquired mutations to evade host antibodies, Momeni said. Such mutations can be detrimental to its binding to the host receptor and were followed by additional compensatory mutations to recover, or even improve, its receptor binding.

Momeni said the team was surprised to see a range of mutationssome beneficial, some neutral, and some detrimentalto hACE2 binding. He said the teams next steps are to experimentally validate the predictions of the model.

The teams findings on Omicron build upon a prior analysis of the Wuhan and Delta variants by the team. There, modeling found that E484 was actually a weak link in the original Wuhan strain, but it has evolved through mutation to better bind to human host cells and to evade some antibodies, Momeni said. Additionally, the team found that the Wuhan strain bindingto ACE2 in bats was more optimized than the human counterpart. The team predicted further E484K mutation added to the Delta variant would produce a future variant of concern.

Ed Hayward | University Communications | December 2021

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Predicting the future of COVID - Boston College Chronicle

East Lyme The Board of Selectmen on Wednesday raised numerous objections to a draft resolution on racism and public health that was brokered by new First Selectman Kevin Seery and a local, grassroots social justice group.

The wording was similar to documents identifying racism as a public health crisis that already have been authorized in 22 cities and towns in the state, plus the Mashantucket Pequot Tribal Nation. Officials in towns including Old Saybrook, New London and Norwich passed resolutions, and Gov. Ned Lamont in June signed into law a sweeping bill addressing the effect of racism on public health at the state level.

The issues were raised locally by the grassroots Southeastern Connecticut Organization for Racial Equity, known asSCORE. Seery described members of the group as committed to their beliefs and willing to talk as is he.

He's been involved in the conversation since the group first proposed the resolution in April of last year.

"The one thing we kept making sure we did is, no matter what, keep talking," Seery, a Republican,said. "Because we want to hear their input and address their concerns."

SCOREwas formed in 2020 as East Lyme for Black Lives Matter. It emerged following the death of George Floyd, who was killed by then-Minneapolis police Officer Derek Chauvin.

Anneliese Lapides, a town native who is a student at the University of Vermont's Larner College of Medicine and SCORE's director of community engagement, said in a phone call Thursday that there are profound disparities in health outcomes among people of color.

"Not everyone has equitable access to that right that they have as a living, breathing human being," she said. "Everyone deserves to be able to live healthy lives and so whatever we can do to actually make that a reality, I think, is important."

The American Medical Association's House of Delegates in November 2020 approved a policy denouncing racism as an urgent threat to public health. According to Ledge Light Health District Deputy Director Jennifer Muggeo, the health district also considers racism a public health crisis and has put the issue at the center of its plan for improving the overall health of the community.

Selectman Dan Cunningham, a Democrat,on Wednesday told his fellow selectmen the draft resolution was created to show that the community as a whole is concerned about the issues brought forth by SCORE. He worked with Seery and the social justice group on what he described as "negotiations" about the wording of the resolution.

According to Cunningham, passing a resolution shows East Lyme is "a place that is receptive to all communities, all ethnic groups, all races; that we are a town that respects people."

The resolution is based in part on a template created by Hartford-based Health Equity Solutions, an organization that advocates for equitable health care access in Connecticut. It comprises eight action steps, ranging from fostering a "justice-oriented" community, to "dismantling racism" as it affects town services, to solidifying partnerships with other organizations at the local, state and national levels.

Seery and Cunningham were given the go-ahead by former First Selectman Mark Nickerson back in April to form an "unofficial subcommittee" to look at ways of enhancing equity and inclusion in the community, according to meeting minutes. SCORE during the previous meeting had givenits presentation with the stated goal of getting a resolution passed declaring racism a public health crisis.

The draft resolution never came up on the agenda during Nickerson's administration. Seery was sworn in on Dec. 6, bringing with him a commitment to a continued conversation on the issue.

The issue of racism has been a high-profile one at East Lyme High School this year, manifesting in incidents in the girls' bathrooms that included verbal and then physical assaults against a student, who wasaccused of making racist statements online. Videos of the incidents were shared on social media. The situation underscored racial tensions at the school that students say have been ignored by the administration. In November, roughly a quarter of the high school's students walked out of class to protest what they described as school officials' failure to denounce racist statements and actions.

Over in neighboring Old Lyme, former Democratic Selectwoman Mary Jo Nosal brought up the idea of a similar resolution 24 times in a roughly 1.5-year span, asking repeatedly for discussion and ideas for compromise. It never came up for a vote on the three-member, Republican-dominated board.

Objections

The other four members of East Lyme's six-member Board of Selectmen expressed various reservations about the draft resolution.

Unaffiliated member Rose Ann Hardy a former Democrat who ran last year under the Republican banner said she didn't believe racism itself is a public health crisis. Republican William Weber was troubled that the resolution addressed race and not other forms of division. Anne Santoro, also a Republican, said the resolution didn't offer specific solutions to the broad problem.

Democrat Ann Cicchiello asked for more time to review the issue.

The draft resolution describes race as a "social construct with no biological basis." The statement echoes a concept published by the American Society of Human Genetics in 2018 challenging the idea that different races are biologically separate and distinct.

Also in the resolution are statements identifying racism as both individual and systemic, as a root cause of poverty and as a cause of disproportionate illness and mortality.

Santoro objected to broad statements that could be cause for debate. "There's lots of room for disagreement, and I'm really trying to get beyond that," she said.

She instead suggested inviting departments such as police, the school system, human resources, parks and recreation and the library to come before the Board of Selectmen to talk about what they're doing to address racism.

"I think it would help the public to understand that the complaint or the concern doesn't exist in a vacuum," she said. "There is a system in place to address some of these things and some are being addressed. In fact, some quite well."

Weber asked why the resolution focused on race to the exclusion of issues like sexual orientation, religion, military veteran status, age and disability. "We should say that everybody needs to be treated equally, not this group needs to be treated equally," he said.

Ultimately, members agreed to put the issue on a future agenda.

Seery said he wants to "keep the conversation going" and will reach out to members of SCORE.

Lapides, one of the SCORE members who worked with Seery and Cunningham on the language, said she looks forward to the opportunity for SCORE to make a presentation to the new Board of Selectmen that includes facts, figures and an opportunity to answer questions.

She said racism is not something that was created by the town or its leaders but it is everyone's job to address it.

"It's a systemic issue that exists in our country," she said."This is a problem everywhere and no one is immune to it. It's our responsibility to practice anti-racism efforts."

Acknowledging Weber's concerns that it's important to promote positive health outcomes for everyone, she said the focus at this moment is on anti-racism.

"It's important for everybody, but we are focusing on racism that was recently, nationally declared a public health crisis," she said.

e.regan@theday.com

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East Lyme officials resist resolution identifying racism as public health crisis - theday.com

Nottingham Forest host Arsenal in the FA Cup in Sunday in what will top off a great week for the Championship club.

Forest have secured a great signing in Steve Cook from Bournemouth and manager Steve Cooper is pleased he could get the deal over the line.

He told the club website: Were delighted. As soon as we knew of his possible availability, we went for it as much as we could to see if we could make it happen, he told the clubs official website.

We feel this is an important signing as Steve is a fantastic player and brings a good level of experience, both in the Championship and the level above.

Hes played in a team that has won a lot of games and I think thats important. We want our group to be young and hungry along with players of experience that can drive the team forward and thats what were building.

Heres all you need to know about the upcoming tie.

When is it?

The match will kick off at 5.10pm on Sunday, 9 January at the City Ground.

How can I watch?

The game will be available for fans to watch on ITV 1 with coverage starting at 4.20pm.

Team news

For the hosts Jordi Osei-Tutu and Alex Mighten are out until February with knee injuries. While Djed Spence is expected to feature after returning against Huddersfield last time out.

Meanwhile for Arsenal Nicolas Pepe, Thomas Partey, Mohamed Elneny and Pierre-Emerick Aubameyang are away on international duty at the Africa Cup of Nations. Sead Kolasinac is injured and not expected to feature while Calum Chambers is in doubt due to Covid.

Predicted line-ups

Nottingham: Samba; Worrall, Yates, McKenna; Spence, Garner, Cafu, Colback; Johnson, Taylor, Zinckernagel

Arsenal: Leno; Tomiyasu, White, Holding, Tavares; Xhaka, Lokonga; Saka, Odegaard, Smith Rowe; Nketiah

Odds

Nottingham 26/5

Draw 3/1

Arsenal 18/25

Prediction

Arsenals form of late has been impressive and they have bounced back from their disastrous start to the season. While Nottingham provides a challenge for the Premier league side, the top-flight club should come out on top. Nottingham 0-2 Arsenal.

Link:
Nottingham Forest vs Arsenal predicted line-ups: Team news ahead of FA Cup fixture today - newsconcerns

MENLO PARK, Calif.--(BUSINESS WIRE)--Jan 6, 2022--

Personalis, Inc. (Nasdaq: PSNL), a leader in advanced genomics for cancer and population sequencing, today reported unaudited preliminary revenue for the fourth quarter and full year ended December 31, 2021.

Personalis estimates revenue of approximately $20.7 million for the fourth quarter of 2021 and approximately $85.5 million for the full year of 2021.

Fourth Quarter Highlights

Full Year 2021 Revenue

Im proud that preliminary revenue for our oncology business has exceeded $15 million in the fourth quarter of 2021 and was nearly $40 million for the full year 2021, despite all the headwinds from the COVID-19 pandemic. Customer orders from our oncology business were once again significantly above preliminary revenue estimates for both the fourth quarter and full year of 2021, which puts us in position to grow our oncology revenue by more than 50% in 2022 compared to 2021, said John West, Chief Executive Officer. In addition, we recently launched NeXT Personal, our MRD liquid biopsy offering, which is expected to be an important growth driver for both biopharma and diagnostic test revenue in the future.

The above information is preliminary and subject to Personalis normal quarter and year-end accounting procedures and external audit by the company's independent registered public accounting firm.

About Personalis, Inc.

Personalis, Inc. is a leader in advanced cancer genomics for enabling the next generation of precision cancer therapies and diagnostics. The Personalis NeXT Platform is designed to adapt to the complex and evolving understanding of cancer, providing its biopharmaceutical customers and clinicians with information on all of the approximately 20,000 human genes, together with the immune system, from a single tissue sample. In population sequencing, Personalis operates one of the largest sequencing laboratories globally and is currently the sole sequencing provider to the VA MVP. To enable cancer and population sequencing, the Personalis Clinical Laboratory was built with a focus on clinical accuracy, quality, big data, scale, and efficiency. The laboratory is GxP aligned as well as CLIA88-certified and CAP-accredited. For more information, please visit http://www.personalis.com and follow Personalis on Twitter ( @PersonalisInc ).

Forward-Looking Statements

This press release contains forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Actual results may differ materially from the results predicted, and reported results should not be considered an indication of future performance. Forward-looking statements include all statements that are not historical facts and can be identified by terms such as estimate, expect, should, target, will, or would or similar expressions and the negatives of those terms. These statements include, but are not limited to, statements regarding the companys estimated revenues for the fourth quarter and full year of 2021, unfulfilled orders for the VA MVP, and preliminary cash, cash equivalents, and short-term investments as of December 31, 2021. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause our actual results, performance or achievements to be materially different from any future results, performance or achievements expressed or implied by the forward-looking statements. These risks, uncertainties and other factors relate to, among others: additional adjustments to our expected fourth quarter and full year 2021 revenue that may be identified during our regular financial closing and audit procedures and other developments, the timing and pace of new orders from customers, including from the U.S. Department of Veterans Affairs Million Veteran Program, which was the companys largest customer in 2018, 2019, 2020, and 2021; the launch and market adoption of new products and new product features, such as NeXT Personal; the timing of tissue, blood, and other specimen sample receipts from customers, which can materially impact revenue quarter over quarter and year over year; whether orders for the NeXT Platform and revenue from biopharmaceutical customers increase in future periods; the success of Personalis collaborations including with Mayo Clinic; the success of the companys international expansion plans; the evolution of cancer therapies and market adoption of the companys services; the companys expectations regarding future performance; and the ongoing COVID-19 pandemic, which may significantly impact the companys business and operations and the business and operations of our customers and suppliers. In addition, other potential risks and uncertainties that could cause actual results to differ from the results predicted include, among others, those risks and uncertainties included under the captions Risk Factors and Managements Discussion and Analysis of Financial Condition and Results of Operations in our Quarterly Report on Form 10-Q for the period ended September 30, 2021, and risk factors included within the Prospectus Supplement filed January 3, 2022. All information provided in this release is as of the date of this press release, and any forward-looking statements contained herein are based on assumptions that we believe to be reasonable as of this date. Undue reliance should not be placed on the forward-looking statements in this press release, which are based on information available to us on the date hereof. Personalis undertakes no duty to update this information unless required by law.

PERSONALIS, INC.

PRELIMINARY REVENUE RESULTS (unaudited)

(in thousands)

Three Months EndedDecember 31,

Year Ended December 31,

2021

2020

2021

2020

(preliminary)

(preliminary)

VA MVP

$

5,304

$

12,556

$

45,671

$

56,154

All other customers

15,363

7,620

39,808

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Personalis Reports Preliminary Fourth Quarter and Full Year 2021 Revenue - The Bakersfield Californian

When Keegan Joines was born as a low-birthweight baby, his parents saw the rough start as a mere bump in the road.

He plumped up quickly and everything seemed fine, said his mom, Susan Joines, an elementary school assistant and pediatric nurse by trade who lives in Castle Rock.

But by the time he was a year and a half, the Joineses were noticing developmental delays, including in walking and speech. A year later he would be diagnosed with Type 1 diabetes, an autoimmune disorder that destroys the bodys ability to create insulin, a vital hormone that allows the body to use glucose for energy.

We noticed more global abnormalities and we always just kept thinking, Something is related here. These are not all separate instances occurring.

Little did they know that, half a decade later, Keegan would be diagnosed with a rare genetic disorder KCNJ11, which affects the pancreas and the brain, resulting in developmental delay and juvenile-onset diabetes; the diagnosis was one of only 30 identified cases in the world at the time similar to his.

Even with the diagnosis, the search for answers continues, as the Joineses await therapies that could unlock his potential, allowing him to develop beyond the kindergarten-to-first grade level he functions at as a 10-year-old or could have no effect at all.

Unfortunately we dont know what his future is and you never can, even with a well-researched disorder, his mom said. Of course, the skys the limit for these kids. But, without having much research, we just dont know what to expect.

Theres just not enough kids like him to know.

Diagnostic odyssey

Alone, rare disease can be isolating. The U.S. National Institutes of Health defines a rare disorder as one that affects fewer than 200,000 people nationwide a definition created by Congress in the 1983 Orphan Drug Act, which established financial incentives for drug companies to develop medications for such conditions.

Collectively, however, rare is common, with approximately 7,000 known diseases affecting an estimated 25 million-30 million Americans nearly 10% of the population, according to the National Human Genome Research Institute. Worldwide,263 million to 446 million people are affected by rare disorders at any point in time between 3.5% and 6% of the global population, according to a 2019 article in the European Journal of Human Genetics.

With nearly 1 in 10 Americans and Coloradans affected by rare disorders, we likely encounter them daily at schools, at grocery shops, at places of worship, at workplaces. Some prefer to keep quiet, realizing the likelihood of being misunderstood is much greater than that of finding common ground. Others become vocal advocates, on a quest to raise awareness of a disease very few if any others have been diagnosed with. Others yet are oblivious to their disorders, on a quest for an answer to their health maladies that may never materialize.

The quest for a diagnosis the Joineses were on seemed foreign, rare, esoteric. But patients with rare disorders, on average, spent six to eight years and often untold thousands of dollars searching for an answer. While waiting, there's the uncertain no man's land of "undiagnosed," a label that can call into question one's symptoms and even one's sanity.

And when a diagnosis is finally received, it's not always the right one.

It's hard to diagnose people (with rare disorders) it takes a really long time, said Dr. Anne Pariser, director of the Office of Rare Diseases Research at the National Institutes of Healths National Center for Advancing Translational Sciences.

This happens so often in rare diseases. We call it the diagnostic odyssey.

Beyond frustration, accompanying the diagnostic odyssey are consequences that have the potential to take a toll on health and finances.

Being undiagnosed carries a substantial monetary and also human cost, Pariser said. People are treated for the wrong disease. They don't receive therapies that may be available, or there arent specific ways that we can intervene to lessen suffering.

Pariser cited a 2019 study by the EveryLife Foundation for Rare Diseases that estimated the economic cost of nearly 400 rare diseases in the U.S. that year at nearly $1 trillion, surpassing the estimated economic burdens for diabetes, heart disease and cancer among the costliest common chronic diseases.

Theres a mental cost, as well. Without a diagnosis, Susan Joines spent years attributing Keegans issues to pregnancy complications.

She blamed herself.

I had to go on beta blockers just for myself to survive because I wasnt profusing to him well, she said. He just wasnt thriving super well in my body. As we started seeing the gap widening between him and his peers, I was just like, I should have done better. That mom guilt just never goes away, because it always feels like you could do more. Even with your neurotypical kids, you always feel like youre not doing things well enough.

Its especially hard with a kiddo with extra needs because there's always so much you feel like you should or could be doing.

Complicating each patients search for answers is the reality that every rare-disease patient is unique. A patients symptoms can be caused by a single gene or chromosomal abnormality; multiple genetic errors; nongenetic factors; or a combination thereof. Even those considered to have the same disorder can have similar but distinct genetic errors that result in different presentations and health outcomes.

When we think about rare disease, each patient is essentially unique in their characteristics and that makes studying them, diagnosing them and understanding the public health impacts of rare disease patients very, very challenging, said Melissa Haendel, chief research informatics officer at the University of Colorado Anschutz Medical Campus and director of the National Center for Data to Health.

Case in point: Youll find differing estimates of the number of rare diseases, depending on the source and the country the data originates in more than 7,000, according to the National Institutes of Health; between 5,000 and 8,000, according to the World Health Organization; more than 6,000, according to Rare Diseases Europe.

Why do we care about how many rare diseases there are? Despite having 10% of the population potentially having a rare disease, the inability to count them really underlies an inability to identify them in the first place,Haendel said.

Its not the count that we care about. The fact that we cant count them is an indication of our inability to understand and define them, to diagnose them, to treat them.

Zebras, not horses

For Elliott Wellnitz, 3, of Colorado Springs, the diagnostic odyssey was blessedly short seven or eight months, as his mom, Christine, recalls.

A few things were off during the pregnancy Christine had only one artery in her umbilical cord instead of two, and Elliott was born prematurely but we didnt know at the time we were going to have a special-needs kid, she recalls.

But soon medical providers began to point out other anomalies a widely spaced big toe, port wine stains under his lips, an abnormally large head.

A basic genetic test showed no abnormalities, nor did a more sophisticated test.

The Wellnitzs were sent home with a tank of oxygen, a myriad of specialist appointments and no answers.

Several months later they learned he had Megalencephaly-capillary malformation syndrome an exceedingly rare genetic syndrome involving developmental delay, intellectual disability, poor muscle tone, parts of the body that are larger than usual and epilepsy. The disorder places patients at risk of fluid buildup in the brain and of cancerous tumors.

For Christine, the diagnosis has meant wearing more hats than parents already wear those of honorary therapist and educator, and that of an actual nurse.

When we got out of the hospital, no one pointed me in the right direction, said Christine, a hospice nurse whose husband stays home and cares for their son. I kind of had to figure it all out on my own. To me, thats the most frustrating aspect of this journey.

Susan Joines ran a group for special needs families where she lived last, working as a parent liaison to the early childhood education system. She found that many parents of children with rare disorders are desperate for answers and support and help.

I feel like very rarely do we get all three of those or even two out of three of those from providers.

Shes encountered a wide variety of personality types in doctors over countless visits, from the kind who say, Wait, give it time, theyll be fine, and then theyre 16 and end up with an autism diagnosis to the ones who say, Here you go, heres your childs list of problems, and well see you later, completing writing a kid off.

The former have served as roadblocks, the latter sources of immense hurt and devastation.

A psychologist once administered an IQ test on Keegan without Susan's permission or understanding, then delivered dismal news.

"Essentially they just said he was in the bottom 15th percentile, so probably under 40," she said of his score. "Just basically, 'Here is his IQ, and most likely he'll never live alone, he'll never be able to have a job or live independently,' and they just kind of left it there. We were like, 'Should we follow up with you?' They were like, 'No, this is it.'

"I feel like they gave him a life sentence."

With myriad rare disorders and such fuzzy definitions of many, its often a struggle to find a provider equipped to diagnose, no less treat, a rare disorder.

The problem at least partially originates in medical schools, where doctors in training are taught that when you hear hoofbeats, think horses, not zebras common things occur commonly. Dont give somebody a rare diagnosis if they probably have a common problem, Pariser said.

Providers need to be trained to look for zebra triggers, she said, invoking a symbol of the rare disease community: zebras, which each have a unique stripe pattern, as humans do fingerprints.

We want (doctors) to think of zebras, and we want them to think of zebras when they start seeing certain clusters of things: young age, high (medical system) utilization, multiple consults, having to travel great distances. Also, some of these what we call basket (medical) codes, like developmental delay or motor delay.

Rare diseases we have many, many diseases that affect small numbers of patients each and very few treatments. But when you consider this collectively, it really is a large public health problem.

How long is my child going to live?

Even with a diagnosis, the future is uncertain for Keegan.

Now 10, he performs in school three to four years behind grade level, even with extensive developmental services, Susan said.

Weve exhausted just about everything we think we can think to do for him. He struggles greatly with academics. He still cant write his name. He still isnt reading well," she said, adding that, regardless, Keegan is a joyful, humorous child who loves life, his family, school and friends.

To get him to recognize the word the thats a (school) goal for him, to have an 85% success rate on just recognizing that word. Hes in a severe special-needs program. We arent seeing progress like we hope. Just from the little bit we do know, early to late elementary school is typically, developmentally, where they see him maxing out."

For Christine Wellnitz, receiving a diagnosis was comfortingbut it didnt come with a road map of what to expect.

It was definitely a huge relief when there was actually a name for what he had, she said. I cried. But there wasnt a whole lot of information, even on life expectancy.

How long is my child going to live?

A Facebook group Christine joined, for those affected and their families, has a couple of older patients in their 30s and 40s, and that makes me happy.

But beyond that, we dont really know, and thats pretty scary. I always tell my husband, 'Right now were doing pretty good, and things are going pretty well, but I never hold my breath,' because every time I think that, something else pops up, or we need to see another specialist.

Elliotts pediatrician is supportive but doesnt have much to offer in the way of specialized knowledge.

Our pediatric doctor basically just goes with whatever I want, Christine said. If I call and say, I think I need this, she usually does it. I think part of it is because Im a nurse. I love our pediatric doctor, but I feel like there should be more specialists in town.

I really have no idea exactly where my child is when it comes to development. "I just know that hes somewhat delayed.

When it comes to enrolling her child in school and ensuring he receives proper education and support, I dont even know what the next steps are. I hear the school districts arent great when it comes to working with special needs children, and that just puts fear in my heart.

"I havent heard of one good district in this town, unfortunately."

For Susan Joines, looking to the future is equally tough.

My husband and I frequently think we might be forever-nesters, she said. Theres such a grieving process we will never put a cap on him, of course, but it is a process of this potential grief of maybe not achieving the life we hope for him. He may never drive. He may never graduate. He may never have a job. He may never get married. We may never see grandkids from him.

"Maybe we will," she added hopefully.

Susan leans on her personal faith in the fact that God made her son for a purpose and has plans for him.

"But its definitely not without grief," she said. "Its the heaviest and hardest thing we deal with on a regular basis."

Continued here:
Diagnostic odyssey: The lonely road walked by thousands of Coloradans with rare disorders - Colorado Springs Gazette

Abstract

Nuclear noncoding RNAs (ncRNAs) are key regulators of gene expression and chromatin organization. The progress in studying nuclear ncRNAs depends on the ability to identify the genome-wide spectrum of contacts of ncRNAs with chromatin. To address this question, a panel of RNADNA proximity ligation techniques has been developed. However, neither of these techniques examines proteins involved in RNAchromatin interactions. Here, we introduce RedChIP, a technique combining RNADNA proximity ligation and chromatin immunoprecipitation for identifying RNAchromatin interactions mediated by a particular protein. Using antibodies against architectural protein CTCF and the EZH2 subunit of the Polycomb repressive complex 2, we identify a spectrum of cis- and trans-acting ncRNAs enriched at Polycomb- and CTCF-binding sites in human cells, which may be involved in Polycomb-mediated gene repression and CTCF-dependent chromatin looping. By providing a protein-centric view of RNADNA interactions, RedChIP represents an important tool for studies of nuclear ncRNAs.

The majority of the eukaryotic genome is transcribed into coding and noncoding RNAs (ncRNAs). ncRNAs fulfill various functions both in the cytoplasm and the cell nucleus. Nuclear ncRNAs are attracted to different genomic regions and mediate the activation or repression of genes located in these regions and are also implicated in the genome three-dimensional organization (1, 2). In particular, recent studies indicate that RNA is essential for the chromatin targeting of Polycomb repressive complexes (3) and the organization of CTCF-dependent chromatin loops (4). However, these studies do not show which particular RNAs are involved.

Helpful in studying nuclear functions of ncRNAs are methods that map the sites of ncRNA associations with the genome. Initially developed for probing genomic interactions of one particular RNA, these methods are now available in an all-vs.-all version allowing simultaneous detection of the sites of chromosomal locations for all RNA molecules present in the nucleus (reviewed in ref. 1). An important drawback of these techniques, however, is that they do not disclose the proteins involved in RNADNA interactions.

To identify RNAs that could be involved in the functioning of DNA-bound proteins, we developed a hybrid approachRedChIPcombining an RNADNA proximity ligation technique [Red-C (5)] with chromatin immunoprecipitation (ChIP). Using antibodies against CTCF and EZH2, we identified various ncRNAs interacting with DNA at the sites of deposition of the above-mentioned proteins.

The RedChIP experimental procedure is analogous to HiChIP used for protein-centric mapping of DNADNA interactions (6), with the difference being that RNADNA interactions are analyzed instead of DNADNA interactions. Briefly, RNAproteinDNA complexes are cross-linked in living cells, and RNA and DNA fragments are ligated in situ using a bridge adapter. Ligated complexes are solubilized by sonication and subjected to IP using antibodies against a protein of interest. RNADNA chimeric molecules are then purified and sequenced, thus reporting RNADNA interactions that may be mediated by a particular protein and proteinDNA interactions that may be mediated by various RNAs (Fig. 1A). An aliquot of the material (input fraction) is processed without an IP step to record the total set of RNADNA interactions mediated by any proteins, as in a regular Red-C experiment.

RedChIP technique. (A) Outline of the experimental procedure. (B) A region of Chr17 encompassing Hoxb genes showing distribution of DNA and RNA portions in IP (RedChIP) and input (RedC) fractions from experiments with EZH2 and CTCF antibodies. Shown alongside are ChIP-seq peaks of EZH2 in H1-hESCs (human embryonic stem cells) and ChIP-seq peaks of CTCF in K562 cells as well as total RNA-seq profiles for H1-hESCs and K562 cells (from ENCODE). (C) Distribution of DNA portions around EZH2 peaks in hESCs and CTCF peaks in K562. (D) Ratio of the number of RNA contacts detected in different chromatin types in IP fraction to the number of RNA contacts detected in the same chromatin types in input fraction.

We used antibodies against EZH2, a catalytic subunit of the PRC2 complex, to study the Polycomb-dependent RNADNA interactome in human embryonic stem cells. We also used antibodies against CTCF to study the CTCF-dependent RNADNA interactome in human K562 cells. DNA portions of the chimeric molecules showed a clear preference for the binding sites of corresponding proteins in the IP fraction (Fig.1 B and C), indicating successful IP. Accordingly, we observed an enrichment of DNA portions in chromatin types typical for poised promoters and Polycomb-repressed regions in the IP fraction from the EZH2 experiment and an enrichment of DNA portions in chromatin types typical for insulators and promoters in the IP fraction from the CTCF experiment (Fig. 1D). Meanwhile, RNA portions of the chimeric molecules showed correlation with RNA-sequencing (RNA-seq) profiles both in IP and input fractions (Fig. 1B), reflecting the origination of RNA portions from various transcripts. We combined the contacts of RNA portions originating from a single gene, thus obtaining a whole-genome contact profile for each annotated RNA.

We then focused on the analysis of contacts of individual RNAs in the experiment with EZH2 antibodies. We first aimed to identify cis-acting RNAs that fulfill their functions in the vicinity of an encoding gene. For each RNA, we selected a fraction of cis contacts established with DNA regions surrounding the gene (1 Mb of gene boundaries including the gene) and compared the number of cis contacts between EZH2-precipitated and input fractions. We found that the degree of enrichment in the IP fraction correlated with the percentage of contacts detected in Polycomb-specific and poised promoter-specific chromatin types but not any other chromatin types in the area under study (Fig. 2A). We identified 10 long intergenic ncRNAs (lincRNAs) with a fold enrichment of >1.3 in both replicates (Fig. 2C). Among the identified RNAs is Kcnq1ot1 (fold change = 1.5), a well-known example of antisense lincRNA involved in the Polycomb-mediated silencing of several genes in the same locus (7). High fold enrichment was also observed for AC078778, antisense lincRNAs from the HOXC locus. Notably, antisense RNAs, on average, demonstrate higher fold enrichment than other lincRNAs and mRNAs of protein-coding genes (Fig. 2G), indicating the enrichment of the group of antisense RNAs with RNAs that may mediate Polycomb targeting.

Identification of ncRNAs associated with genomic regions occupied by EZH2 in hESCs and by CTCF in K562 cells. (A) Ratio of the number of cis contacts of individual RNAs between EZH2-precipitated and input fractions (x axis) vs. the percentage of cis contacts detected in different chromatin types in EZH2-precipitated fraction (y axis). (B) The same as A for CTCF-precipitated fraction. (C and D) Ratio of the number of cis (C) or trans (D) contacts of individual RNAs between EZH2-precipitated and input fractions for rep1 and rep2. (E and F) Ratio of the number of cis (E) or trans (F) contacts of individual RNAs between CTCF-precipitated and input fractions for rep1 and rep2. (G) Distribution of fold changes from C for different RNA biotypes (antisense, n = 44; linc, n = 162; protein coding, n = 4,184). *P < 0.05, ***P < 0.001. (H) Intersection of RNAs enriched in RedChIP and fRIP-seq.

At the final step of the analysis, we searched for trans-acting RNAs that could participate in Polycomb functioning genome-wide. We compared the number of trans contacts (contacts with nonparental chromosomes) for each RNA between EZH2-precipitated and input fractions and looked for RNAs showing an elevated number of contacts in the IP fraction. The highest enrichment was observed for antisense RNA KIF5C-AS1, snRNA RNU5B-1, and SNORD3a RNA (Fig. 2D). These RNAs are good candidates to act as global mediators of Polycomb activity.

The above types of analysis were then performed for the data from the experiment with CTCF antibodies. In the analysis of cis-acting RNAs, we observed a correlation of RNA enrichment in the CTCF-precipitated fraction with the percentage of contacts detected in promoter-, enhancer-, and insulator-specific chromatin type (Fig. 2B). We identified seven lincRNAs with a fold enrichment of >1.3 in both replicates (Fig. 2E). These lincRNAs might participate in loading CTCF to its DNA sites and organization of promoter-enhancer specific and other chromatin loops within genomic loci from where lincRNAs are produced. In the analysis of trans-acting RNAs, the highest fold enrichment was observed for snRNA RNU12 (Fig. 2F). Notably, U12 RNA is the second top by the total number of contacts among all RNAs in K562 cells (1.1% of all contacts). The potential involvement of RNU12 RNA in the functions of CTCF requires further experimental evidence.

Remarkably, the set of RNAs enriched in RedChIP significantly intersects the set of RNAs enriched in RNA IP (formaldehyde RNA IP-sequencing, fRIP-seq) experiments (Fig. 2H). Importantly, 18 of 22 ncRNAs overrepresented in CTCF- and EZH2-RedChIP samples are fRIP-positive, indicating these ncRNAs indeed interact with the studied proteins.

Collectively, the present study results demonstrate the utility of the RedChIP protocol for identifying RNAs that may target nonhistone proteins to various locations on chromosomes or mediate interactions of these proteins with DNA. The identification of RNAs that are known to target Polycomb complexes to repressed genomic domains strongly supports the validity of the experimental approach, whereas identifying a set of RNAs possessing similar characteristics will stimulate studies of their possible role in Polycomb and CTCF functioning. The RedChIP technique can be used for identifying RNAs associated with genomic regions occupied by any protein of interest.

Cells are fixed with formaldehyde, DNA is fragmented with NlaIII restriction enzyme, and the ends are blunted and A-tailed. RNA 3 ends are ligated to a biotinylated bridge adapter followed by ligation of the opposite ends of the bridges with DNA ends in spatial proximity. Ligated complexes are solubilized by sonication, immunoprecipitated, and washed. RNADNA chimeras are purified, and DNA is digested with MmeI restriction enzyme. After biotin pull-down, reverse transcription is initiated from the bridge with template switching at the RNA 5 end, allowing for the incorporation of an Illumina adapter. Another Illumina adapter is ligated to DNA ends, and the chimeras are amplified and paired-end sequenced. The detailed protocol and sequencing data processing are described in SI Appendix. For sample processing statistics, refer to Dataset S1. For read processing statistics, refer to Dataset S2.

Raw fastq reads and processed TSV files with contacts are available at Gene Expression Omnibus (accession no. GSE174474). The code for read processing is available as RedClib on GitHub: https://github.com/agalitsyna/RedClib.

This work was supported by the Russian Science Foundation (21-64-00001) and by the Russian Ministry of Science and Higher Education (075-15-2021-1062).

Author contributions: A.A. Gavrilov, E.L.A., and S.V.R. designed research; A.A. Gavrilov and E.B.D. performed research; A.A. Gavrilov, R.I.S., M.D.M., and A.A. Galitsyna analyzed data; and A.A. Gavrilov and S.V.R. wrote the paper.

The authors declare no competing interest.

This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2116222119/-/DCSupplemental.

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RedChIP identifies noncoding RNAs associated with genomic sites occupied by Polycomb and CTCF proteins - pnas.org