Category Archives: Genetics

Genetics

Genetic clue to pericarditis inflammation points to promising new treatments – News-Medical.Net

Sequence variants that protect against pericarditis have been discovered at a genomic locus encoding interleukin-1 immune cytokines. A newly approved drug treatment for pericarditis inhibits these cytokines and new a study from deCODE genetics and collaborators can contribute to the further development of this treatment.

A new study called "Variants at the interleukin-1 gene locus and pericarditis" was published today in the journal JAMA Cardiology, by scientists at deCODE genetics, a subsidiary of Amgen, and their collaborators from Denmark, USA, and Iceland.

The study involves a genome-wide search for variants affecting the risk of pericarditis, a disease characterized by often painful inflammation of the fibrous sack surrounding the heart. A subset of patients experiences recurrent pericarditis that does not respond well to traditional treatment with unspecific anti-inflammatory drugs. The role of specific immune processes in pericarditis is poorly understood and the aim of the study was to use human genetics to shed light on the pathogenesis of the disease.

The scientists found common variants in the genome that protect against pericarditis. They are located in a region with genes encoding interleukin-1 inflammatory cytokines. Drugs inhibiting these cytokines have previously been used to treat other inflammatory diseases and recently they have been tested in clinical studies of recurrent pericarditis with good results. One of these drugs was approved by the US Food and Drug Administration for use in recurrent pericarditis as recently as 2021.

The results of the genetic study provide important insights. They suggest that interleukin-1 may be an important contributor to pericarditis in general, as the identified variants are common (up to approximately 50% frequency). Furthermore, the results provide the foundation for future studies, such as those aimed at understanding which interleukin-1 cytokines are most important and whether response to treatment is affected by genotype.

Source:

Journal reference:

Thorolfsdottir, R. B., et al. (2023). Variants at the Interleukin 1 Gene Locus and Pericarditis. JAMA Cardiology. doi.org/10.1001/jamacardio.2023.4820

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Genetic clue to pericarditis inflammation points to promising new treatments - News-Medical.Net

Genetics

Understanding the genetic basis of hereditary diffuse gastric cancer – News-Medical.Net

Gastric cancer, a significant global health burden, claims over 7% of cancer-related deaths annually. Although only 1-3% of cases have a genetic basis, understanding these genetic drivers is crucial for developing preventative strategies.

Gastric cancer, a formidable foe in the global health arena, casts a long shadow over millions of lives each year. While its tendrils reach far and wide, a distinct subset hereditary diffuse gastric cancer (HDGC) emerges as a particularly aggressive and enigmatic adversary. This group of cancers, accounting for roughly 10% of all gastric cancer cases, exhibits a chilling pattern of familial clustering, hinting at a deeper genetic melody playing beneath the surface.

Unraveling the secrets of HDGC has led scientists to a crucial player: the CDH1 gene. This gene, the blueprint for a protein called E-cadherin, acts as the glue that binds cells together, forming the tight-knit communities that make up healthy tissues.

Mutations in CDH1 disrupt this delicate dance, causing cells to lose their grip and embark on a journey of uncontrolled growth the hallmark of cancer. Over 100 unique mutations in CDH1 have been identified, each a discordant note in the symphony of a healthy genome. In roughly 40% of families burdened by HDGC, these mutations act as the conductor, orchestrating the tragic progression of the disease.

However, the story of HDGC is not solely etched in the pages of the CDH1 gene. Other players, like CTNNA1 and MAP3K6, join the chorus, adding layers of complexity to the genetic landscape of this cancer. Like a misplaced instrument, each gene mutation contributes to the disharmony that defines HDGC.

Understanding this intricate interplay of genetic factors remains a key challenge, but it holds immense promise for unlocking new avenues of prevention and treatment.

Despite the lingering mysteries, a beacon of hope shines through prophylactic total gastrectomy (PTG). This surgical procedure, though drastic, offers a life-saving option for individuals with a ticking time bomb of CDH1 mutations and a family history of HDGC. By removing the stomach, the potential breeding ground for cancer, PTG effectively silences the discordant melody and prevents the tragic symphony from playing out. While PTG comes with its own set of challenges, it stands as the only definitive preventive measure currently available for these high-risk individuals.

The battle against HDGC is far from over. Unraveling the complexities of its genetic drivers, deciphering the supporting roles of other genes, and refining our understanding of the interplay between genetics and environment are crucial steps in the fight. With continued research and unwavering dedication, we can hope to one day rewrite the script of HDGC, replacing its tragic verses with a triumphant chorus of prevention and cure.

Source:

Journal reference:

Mokhtari-Esbuie, F., et al. (2023). Pioneering use of genetic analysis for CDH1 to identify candidates for prophylactic total gastrectomy to prevent hereditary diffuse gastric cancer. eGastroenterology. doi.org/10.1136/egastro-2023-100017.

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Understanding the genetic basis of hereditary diffuse gastric cancer - News-Medical.Net

Genetics

Clues to preventing Alzheimer’s come from patient who, despite genetics, evaded disease Washington University … – Washington University School of…

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Breaking link between early, late stages of disease may prevent dementia

A woman who never developed Alzheimer's despite a strong genetic predisposition may hold the key to stopping the disease in its tracks. Studying the woman's unique complement of genetic mutations, researchers at Washington University School of Medicine in St. Louis have found clues that could help cut the link between the early, asymptomatic stage and the late stage, when cognitive decline sets in.

Alzheimers disease has plagued one large Colombian family for generations, striking down half of its members in the prime of life. But one member of that family evaded what had seemed would be fate: Despite inheriting the genetic defect that caused her relatives to develop dementia in their 40s, she stayed cognitively healthy into her 70s.

Researchers at Washington University School of Medicine in St. Louis now think they know why. A previous study had reported that, unlike her relatives, the woman carried two copies of a rare variant of the APOE gene known as the Christchurch mutation. In this study, researchers used genetically modified mice to show that the Christchurch mutation severs the link between the early phase of Alzheimers disease, when a protein called amyloid beta builds up in the brain, and the late phase, when another protein called tau accumulates and cognitive decline sets in. So the woman stayed mentally sharp for decades, even as her brain filled with massive amounts of amyloid. The findings, published Dec. 11 in the journal Cell, suggest a new approach to preventing Alzheimers dementia.

Any protective factor is very interesting, because it gives us new clues to how the disease works, said senior author David M. Holtzman, MD, the Barbara Burton and Reuben M. Morriss III Distinguished Professor of Neurology. As people get older, many begin to develop some amyloid accumulation in their brains. Initially, they remain cognitively normal. However, after many years the amyloid deposition begins to lead to the accumulation of the tau protein. When this happens, cognitive impairment soon ensues. If we can find a way to mimic the effects of the APOE Christchurch mutation, we may be able to stop people who already are on the path to Alzheimers dementia from continuing down that path.

Alzheimers develops over the course of about 30 years. The first two decades or so are silent; amyloid slowly accumulates in the brain without causing ill effects. When amyloid levels reach a tipping point, however, they kick off phase two, which involves multiple interrelated destructive processes: A protein called tau forms tangles that spread through the brain; brain metabolism slows down, and the brain begins to shrink; and people start to experience memory and thinking problems. The disease follows the same pattern in people with genetic and nongenetic forms of Alzheimers.

The Colombian families carry a mutation in a gene called presenilin-1 that causes their brains to develop far too much amyloid buildup beginning in their 20s. People who carry the mutation accumulate amyloid so quickly that they reach the tipping point and start showing signs of cognitive decline in middle age. One rare exception is a woman who had more amyloid in her brain in her 70s than her relatives did in their 40s, but only very minimal signs of brain injury and cognitive impairment.

One of the biggest unanswered questions in the Alzheimers field is why amyloid accumulation leads to tau pathology, Holtzman said. This woman was very, very unusual in that she had amyloid pathology but not much tau pathology and only very mild cognitive symptoms that came on late. This suggested to us that she might hold clues to this link between amyloid and tau.

A 2019 study had revealed that, along with a mutation in presenilin-1, the woman also carried the Christchurch mutation in both copies of her APOE gene, another gene associated with Alzheimers disease. But with only one person in the world known to have this particular combination of genetic mutations, there were not enough data to prove that the Christchurch mutation was responsible for her remarkable resistance to Alzheimers and not simply a coincidental finding.

To solve this puzzle, Holtzman and first author Yun Chen, a graduate student, turned to genetically modified mice. They took mice genetically predisposed to overproduce amyloid and modified them to carry the human APOE gene with the Christchurch mutation. Then, they injected a tiny bit of human tau into the mouse brains. Normally, introducing tau into brains already brimming with amyloid seeds a pathological process in which tau collects into aggregates at the site of injection, followed by the spread of such aggregates to other parts of the brain.

Not so in the mice with the Christchurch mutation. Much like the Colombian woman, the mice developed minor tau pathology despite extensive amyloid plaques. The researchers discovered that the key difference was the activity levels of microglia, the brains waste-disposal cells. Microglia tend to cluster around amyloid plaques. In mice with the APOE Christchurch mutation, the microglia surrounding amyloid plaques were revved up and hyperefficient at consuming and disposing of tau aggregates.

These microglia are taking up the tau and degrading it before tau pathology can spread effectively to the next cell, Holtzman said. That blocked much of the downstream process; without tau pathology, you dont get neurodegeneration, atrophy and cognitive problems. If we can mimic the effect that the mutation is having, we may be able to render amyloid accumulation harmless, or at least much less harmful, and protect people from developing cognitive impairments.

Chen Y, Song S, Parhizkar S, Lord J, Zhu Y, Strickland MR, Wang C, Park J, Tabor GT, Jiang H, Li K, Davis AA, Yuede CM, Colonna M, Ulrich JD, Holtzman DM. APOE3ch alters microglial response and suppresses A-induced tau seeding and spread. Cell. Dec. 11, 2023. DOI: 10.1016/j.cell.2023.11.029

This study was supported by the JPB Foundation; Cure Alzheimers Fund; the National Institutes of Health (NIH), grant numbers RF1AG047644 and RF1NS090934; and the Alzheimers Association, grant number AARF-21-850865. This content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Holtzman is an inventor on a patent licensed by Washington University to C2N Diagnostics on the therapeutic use of anti-tau antibodies; co-founded and is on the scientific advisory board of C2N Diagnostics; is on the scientific advisory board of Denali, Genentech, and Cajal Neuroscience; consults for Asteroid; and is on the Advisory Board for Cell. Colonna is a member of the Vigil Neuro scientific advisory board and is a consultant for Cell Signaling Technology and NGM Bio. The rest of the authors have no conflict of interests.

About Washington University School of Medicine

WashU Medicine is a global leader in academic medicine, including biomedical research, patient care and educational programs with 2,800 faculty. Its National Institutes of Health (NIH) research funding portfolio is the third largest among U.S. medical schools, has grown 52% in the last six years, and, together with institutional investment, WashU Medicine commits well over $1 billion annually to basic and clinical research innovation and training. Its faculty practice is consistently within the top five in the country, with more than 1,800 faculty physicians practicing at 65 locations and who are also the medical staffs of Barnes-Jewish and St. Louis Childrens hospitals of BJC HealthCare. WashU Medicine has a storied history in MD/PhD training, recently dedicated $100 million to scholarships and curriculum renewal for its medical students, and is home to top-notch training programs in every medical subspecialty as well as physical therapy, occupational therapy, and audiology and communications sciences.

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Clues to preventing Alzheimer's come from patient who, despite genetics, evaded disease Washington University ... - Washington University School of...

Genetics

Diminished Genetic Resilience in Pandemic-Era Depression Spike – Neuroscience News

Summary: Researchers found that the pandemic doubled the incidence of clinical depression among first-year college students, affecting one-third of the cohort. Even students with genetic resilience factors were not spared, especially young women.

The study utilized an Affect Score tool combining mental health questionnaires and genetic risk prediction, offering potential for early depression prediction and prevention. This research is vital in understanding the long-term mental health implications of the pandemic on young adults and developing targeted support strategies.

Key Facts:

Source: University of Michigan

Living through a historic pandemic while handling the stress of the first year of college sent one-third of students in a new study into clinical depression. Thats double the percentage seen in previous years of the same study.

And while certain genetic factors appeared to shield first-year students in pre-pandemic years from depression, even students with these protective factors found themselves developing symptoms in the pandemic years.

In fact, much of the overall rise in student depression during the pandemic was among young women with this kind of genetic resilience.

But the research has a silver lining.

By studying these students experiences and backgrounds in depth and over time, scientists may have discovered a way to go beyond genetics to predict which students might be more or less vulnerable to stress-related depression.

The new studyis published in theProceedings of the National Academy of Sciencesby a team from theMichigan Neuroscience Instituteat the University of Michigan.

Potential for prediction and prevention

The team used their findings to develop a tool called an Affect Score, that combines answers from a range of standard mental health questionnaires. The score could help colleges and universities offer more social and mental health support to those most at risk.

The score might work in other groups of people, too, alone or in combination with genetic risk prediction for depression. But further research is needed.

The new findings come from a multi-year longitudinal effort to study the mental health, genetics, personal history, physical activity and sleep of successive groups of first-year college students. It began several years before the pandemic and continues today.

These students experiences during such a stressful time can help us understand the factors that contribute to a rise in depression risk, and inform future efforts to prevent it, saidHuda Akil, Ph.D., senior author of the new paper and former co-director of the institute. Understanding enough to predict is a key initial step to prevention, early detection and early treatment of depression.

Lead authorCortney Turner, Ph.D.,an associate research scientist at MNI, says The possibility of preventing depression is what Im most excited about, because the variables at baseline that appear to play the largest role in Affect Score may be modified with training. That might include summer programs before the start of freshman year to help students feel more confident and positive as they arrive on campus.

Harnessing massive data

The team developed the Affect Score with the help of a machine learning tool that was used to comb through all the students responses on thousands of standardized questionnaires and Fitbit data on their activity and sleep.

The data in the paper come from students in three cohorts of students, one that completed their freshman year before the pandemic, and two whose freshman experience was impacted by the pandemic.

At the start of their freshman year, all took 14 standard questionnaires and gave in-depth interviews conducted by Virginia Murphy-Weinberg, N.P., a highly experienced research nurse. They provided samples of blood and/or saliva to be analyzed in U-MsAdvanced Genomics Core.

Samples were obtained on a wide range of biological measures pre-pandemic, but this became more limited for the two COVID-19 cohorts. Nevertheless, they contributed monthly salivary samples to measure stress and other hormones. Each student also received a Fitbit to monitor daily activity and sleep patterns.

The team also followed up with them multiple times with some of the same questionnaires during the rest of their freshman year and into the summer or next academic year to assess symptoms of depression and/or anxiety in each student.

By looking at which genetic variations each student carried on hundreds of thousands of genes, the researchers calculated their individual depression genetic risk score, called an MDD-PRS.

Men and women with a high MDD-PRS score were more likely than their classmates to develop depression as freshmen in the pre-pandemic era. But when the pandemic hit, genetics became less important.

Men with lower MDD-PRS scores were still less likely to develop depression during the pandemic, but not women with similarly low scores. Meanwhile, the overall risk for the group of students with high MDD-PRS scores didnt change much from the pre-pandemic classes.

The pandemic increased not only the incidence of depression in females, but how long it lasts, or its chronicity. No matter their genetic profile, women whose freshman year of college started in 2020 had over eight times the risk of chronic depression symptoms that lasted across that first year and into the summer, compared with those who entered college before the year the pandemic hit, the study shows.

The study also identified what is termed psychological resilience in individuals whose genetic profiles might make them seem more prone to depression, but who didnt develop it despite going through all or part of their freshman year during a pandemic.

This suggests that when the stress gets strong enough, genetic resilience alone is not enough to buffer against it, especially in females, said Akil. But by using machine learning to analyze the components of the psychological profiles at baseline, our ability to predict who became depressed was truly remarkable.

She continued, Both the genetic and nongenetic data tell us that nothing is predestined, and there are multiple kinds of resilience. Colleges and universities need to think about strategies for helping young people walk into their freshman year with the positive state of mind and social support that can help them weather stress, no matter what their background.

The team continues to test the Affect Score tool on freshmen who entered in 2021, 2022 and this fall. Theyre also preparing to test a validated psychiatric intervention digital tool that they hope will help with risk.

The students in the study were all from the University of Michigan, which offers mental health care and mental well-being support through itsCounseling and Psychological Servicesand itsUniversity Health Service.

Akil and Turner are members of the U-M Eisenberg Family Depression Center, which offersmultiple programs to support the mental health of college studentsincluding athletes and veterans. For more than 20 years, the center has sponsored a national conference calledDepression on College Campuses; the next conference will occur in March.

The center also offersa free online Depression Toolkitto support those experiencing depression symptoms and those who want to help them.

In addition to Akil, Turner and Murphy-Weinberg, the research team included Huzefa Khalil, Ph.D. and other MNI faculty, staff and trainees.

Funding: The study was funded by the Office of Naval Research of the U.S. Navy (N00014-09-1-0598, N00014-12-1-0366 and N00014-19-1-2149), and by grants from the Hope for Depression Research Foundation and the Pritzker Neuropsychiatric Disorders Research Consortium Fund LLC. The researchers also used resources from the Michigan Institute for Clinical and Health Research (TR002240).

Author: Kara Gavin Source: University of Michigan Contact: Kara Gavin University of Michigan Image: The image is credited to Neuroscience News

Original Research: Closed access. The impact of COVID-19 on a college freshman sample reveals genetic and nongenetic forms of susceptibility and resilience to stress by Huda Akil et al. PNAS

Abstract

The impact of COVID-19 on a college freshman sample reveals genetic and nongenetic forms of susceptibility and resilience to stress

Using a longitudinal approach, we sought to define the interplay between genetic and nongenetic factors in shaping vulnerability or resilience to COVID-19 pandemic stress, as indexed by the emergence of symptoms of depression and/or anxiety.

University of Michigan freshmen were characterized at baseline using multiple psychological instruments. Subjects were genotyped, and a polygenic risk score for depression (MDD-PRS) was calculated. Daily physical activity and sleep were captured. Subjects were sampled at multiple time points throughout the freshman year on clinical rating scales, including GAD-7 and PHQ-9 for anxiety and depression, respectively.

Two cohorts (2019 to 2021) were compared to a pre-COVID-19 cohort to assess the impact of the pandemic. Across cohorts, 26 to 40% of freshmen developed symptoms of anxiety or depression (N = 331). Depression symptoms significantly increased in the pandemic years and became more chronic, especially in females.

Physical activity was reduced, and sleep was increased by the pandemic, and this correlated with the emergence of mood symptoms. While low MDD-PRS predicted lower risk for depression during a typical freshman year, this genetic advantage vanished during the pandemic. Indeed, females with lower genetic risk accounted for the majority of the pandemic-induced rise in depression.

We developed a model that explained approximately half of the variance in follow-up depression scores based on psychological trait and state characteristics at baseline and contributed to resilience in genetically vulnerable subjects.

We discuss the concept of multiple types of resilience, and the interplay between genetic, sex, and psychological factors in shaping the affective response to different types of stressors.

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Diminished Genetic Resilience in Pandemic-Era Depression Spike - Neuroscience News

Genetics

Intermountain Health study offering free genetic testing will end this month – KSL.com

Estimated read time: 3-4 minutes

SALT LAKE CITY Intermountain Health will be pausing enrollment in the HerediGene: Population Study, which provides people an opportunity to participate in genetic research.

"We have been incredibly appreciative of the community support and willingness to participate in the HerediGene: Population Study. The genetic discoveries from this study have been monumental," Brad Gillman, an Intermountain spokesman, told KSL.com.

"Because of these efforts, we have reached a point where we will be pausing the enrollment of this study as of Dec. 28. This will allow us to focus on returning results to the participants and generating more discoveries," he said.

Until then, people interested in enrolling can sign up online, or simply go to any Intermountain lab and say they want to participate in the research. Less than 2.5 teaspoons of blood is necessary for sequencing, Intermountain Health's website says.

The study is the largest DNA study in the United States, and has been ongoing since mid-2019. It aims to improve health care intervention for anyone at risk of serious diseases, and to help prevent chronic illnesses like diabetes, heart disease and cancer. All U.S. residents 18 and older are eligible for participation.

HerediGene has already changed the lives of many Utahns.

Former KSL-TV reporter Keith McCord discovered through the study he has genetic markers for hereditary hemochromatosis, which can be managed with treatment but may have irreversible health implications if left untreated. He discovered his diagnosis before any symptoms arose.

Three generations of Elissa Smith's family got the free risk assessment after her father survived colon cancer.

The study informed Madison Certonio she has the BRCA2 gene, which causes women to have between a 45% and 85% chance of developing breast cancer in their lives, and men to have between a 20% and 50% chance of developing prostate cancer.

"It's been a little stressful. It's been a little emotional," she said in an promotional video produced by Intermountain. "But then you have to be happy because you know (the risk). Since I'm 25 and I know, I can get all the screenings done to prevent it, because knowledge is power."

Participants who do not bear any genetic markers will not be contacted by Intermountain; but if markers are discovered, they will be contacted by phone or letter to schedule an appointment with a genetic counselor should they wish to find out what the gene is.

A large sequencing sample regardless of whether an individual participant has a harmful gene is useful to doctors and scientists in discovering new genetic risk factors and treating existing patients.

"We anticipate spin-off studies that will target the genetics of specific diseases will occur over the next several years," Gillman said. "Intermountain Health continues to be committed to precision medicine to help our patients, and their families, live the healthiest lives possible."

Correction: The HerediGene study does not provide free genetic testing for any condition, as a previous version might have indicated. It involves research on specific genes, to better predict and prevent serious disease.

Katie Workman is a former KSL.com and KSL-TV reporter who works as a politics contributor. She has degrees from Cambridge and the University of Utah, and she's passionate about sharing stories about elections, the environment and southern Utah.

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Intermountain Health study offering free genetic testing will end this month - KSL.com

Genetics

Origin and evolution of the triploid cultivated banana genome – Nature.com

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Origin and evolution of the triploid cultivated banana genome - Nature.com

Genetics

Genetic architecture of cardiac dynamic flow volumes – Nature.com

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Genetic architecture of cardiac dynamic flow volumes - Nature.com

Genetics

Exploring plant gene regulation: promoters, terminators, and their role in biodesign – EurekAlert

Plant bioengineeringin which plant genes are modified to include desirable characteristicsis the key to solutions for problems concerning crop resilience and food security. Elements like gene promoters and terminators play a pivotal role in high-precision bioengineering. The interplay between these elements influences transcription and gene expression levels in plants and understanding it is pivotal to achieve precision in plant bioengineering.

In an articlethat was published on 7th July 2023, in Volume 5 of the journalBioDesign Research, researchers from the United States explain how different promoterterminator combinations affect gene expression and how new technology can be leveraged to identify and characterize them, thus improving bioengineering tools.

Plant DNA can be fragmented into functional units known as bioparts that consist of promoters, terminators, and cis-regulatory elements that orchestrate gene expression. Promoters, with distinct regions like the core, proximal, and distal regions, interact with transcription machinery to regulate gene expression. Promoters have specific motifs, such as TATA-boxes, which impact their function and specificity, or enhancers and repressors, which modulate gene expression patterns in response to varying conditions. Further, cis-regulatory elements in plant promoters act as specific regulators of gene expression. Terminators, on the other hand, mark the end of RNA transcripts, aiding in their processing, transport, and stability while protecting them from degradation. They also prevent read-through transcription of downstream sequences.

Differences exist between the core promoters present in dicot and monocot plants, highlighting their unique features and performances. The rational engineering of synthetic core promoters by combining specific motifs will significantly boost promoter activity. Cis-regulatory elements in plant promoters, found across proximal and distal promoter regions, offer insights into shared transcriptional regulation mechanisms between dicots and monocots.

Previous studies have characterized numerous native plant promoters, curated this information in databases, and utilized it for constitutive or conditional transgene expression. Combinatorial cis-regulatory elements and their interactions with transcription factors determine the strength and expression patterns of these native promoters. Although computational tools aid in motif discovery, experimental validation remains crucial due to prediction limitations.

"Only a small number of promoters and terminators have been experimentally characterized and validated in plants. Thus, there is high demand to expand the number of functionally characterized promoters and terminators to serve as standard biological parts for plant synthetic biology research and bioengineering", explains Professor Wusheng Liu, the lead author of the review article.

The authors touch upon strategies for evaluating and benchmarking promoters and terminators in plant biodesign, focusing on their temporal and spatial expression patterns, environmental responses, and cross-species variation. Methodologies such as transient and stable expression approaches, reporter gene systems, and dual-reporter systems aid in assessing their performance and attributes. "Transient expression approaches are relatively simple and effective and can be quickly completed in various plant cells and tissues/organs. In contrast, stable expression systems involve complex and lengthy stable plant transformation but provide the most robust information on the function and strength of promoters and terminators,explains Prof. Liu.

Despite challenges in traditional identification methods, sequencing-based approaches like ATAC-seq and the integration of RNA-seq and ATAC-seq offer promising avenues for discovering regulatory elements and refining bioengineering efforts. Benchmarking different regulatory elements with varied expression patterns aids in constructing genetic circuits and pathways in plant biodesign.

In conclusion, the study encapsulates the multifaceted roles of promoters and terminators in plant genetic engineering, showcasing their significance in manipulating gene expression for various applications and highlighting the evolving strategies for their assessment and utilization in plant biodesign.

###

References

Authors

Emily G. Brooks1, Estefania Elorriaga1, Yang Liu2,3, James R. Duduit1, Guoliang Yuan2,3, Chung-Jui Tsai3,4,5,6, Gerald A. Tuskan2,3, Thomas G. Ranney7, Xiaohan Yang2,3, and Wusheng Liu1

Affiliations

1. Department of Horticultural Science, North Carolina State University, Raleigh, NC 27607, USA.

2. Biosciences Division, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA.

3. The Center for Bioenergy Innovation, Oak Ridge National Laboratory, Oak Ridge, TN 37831, USA.

4. Warnell School of Forestry and Natural Resource, University of Georgia, Athens, GA 30602, USA.

5. Department of Plant Biology, University of Georgia, Athens, GA 30602, USA.

6. Department of Genetics, University of Georgia, Athens, GA 30602, USA.

7. Mountain Crop Improvement Lab, Department of Horticultural Science, Mountain Horticultural Crops Research and Extension Center, North Carolina State University, Mills River, NC 28759, USA.

AboutProfessor Wusheng Liu

Dr. Wusheng Liu is currently an Assistant Professor in the Department of Horticultural Science atNorth Carolina State University. He has nearly 20 years of research experience and has published over 38 scientific articles with a focus on plant biotechnology and plant synthetic biology. Professor Liu is interested in novel approaches for non-GMO and genotype-independent delivery of the CRISPR/Cas9 system into crops for gene editing, Molecular mechanisms of agronomic traits, crop trait engineering using genetic engineering and gene editing, and computational tool-assisted de novo motif discovery and synthetic promoter engineering.

Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.

Originally posted here:
Exploring plant gene regulation: promoters, terminators, and their role in biodesign - EurekAlert

Genetics

Salk teams assemble first full epigenomic cell atlas of the mouse brain – EurekAlert

image:

Top left: 3D rendering of anatomical mouse brain divided into sections based onbrain region dissected; Bottom left: 3D rendering of mouse brain divided into multicolored segments (yellow, blue, aqua, green, pink, orange, brown, red) that represent the dissections made in each brain region.

Top right:Vertical slice of mouse brain with different cell types represented by different colors (orange, green, blue, aqua, red, purple)representing the spatial location of specific cell types in that section; Bottom right: Multicolored circles (yellow, blue, aqua, green, pink, orange, brown, red) representingtheamountand diversity of cell types found in the mousewholebrainbased on epigenomic profiling.

Credit: Salk Institute

LA JOLLA (December 14, 2023)Salk Institute researchers, as part of a worldwide initiative to revolutionize scientists understanding of the brain, analyzed more than 2 million brain cells from mice to assemble the most complete atlas ever of the mouse brain. Their work, published December 14, 2023 in a special issue of Nature, not only details the thousands of cell types present in the brain but also how those cells connect and the genes and regulatory programs that are active in each cell.

The efforts were coordinated by the National Institutes of HealthsBrain Research Through Advancing Innovative NeurotechnologiesInitiative, or the BRAIN Initiative, which ultimately aims to produce a new, dynamic picture of mammalian brains.

With this work, we have not only gained a lot of information about what cells make up the mouse brain, but also how genes are regulated within those cells and how that drives the cells functions, says Salk Professor, International Council Chair in Genetics, and Howard Hughes Medical Institute InvestigatorJoseph Ecker, who contributed to four of the new papers. When you take this epigenome-based cell atlas and start to look at genetic variants that are known to cause human disease, you get new insight into what cell types may be most vulnerable in the disease.

The NIH BRAIN Initiative was launched in 2014 and has provided more than $3 billion in funding to researchers to develop transformative technologies and apply them to brain science.

In 2021, researchers supported by the BRAIN Initiativeincluding teams at Salkunveiled the first draft of the mouse brain atlas, which pioneered new tools to characterize neurons and applied those tools to small sections of the mouse brain. Earlier this year, many of the same techniques were used to assemble an initial atlas of the human brain. In the latest work, researchers expanded the number of cells studied and which areas of the mouse brain were included, as well as used new, single-cell technologies that have only emerged in the last few years.

This is the entire brain, which hasnt been done before, says Professor Edward Callaway, a senior author on two of the new papers. There are ideas and principles that come out of looking at the whole brain that you dont know from looking at one part at a time.

To help assist other researchers studying the mouse brain, the new data is publicly available through an online platform, which can not only be searched through a database but also queried using the artificial intelligence tool ChatGPT.

There is an incredibly large community of people who use mice as model organisms and this gives them an incredibly powerful new tool to use in their research involving the mouse brain, adds Margarita Behrens, a Salk research professor who was involved in all four new papers.

The special issue of Nature has 10 total NIH BRAIN Initiative articles, including four co-authored by Salk researchers that describe the cells of the mouse brain and their connections. Some highlights from these four papers include:

Single-cell DNA methylation atlas

To determine all the cell types in the mouse brain, Salk researchers employed cutting-edge techniques that analyze one individual brain cell at a time. These single-cell methods studied both the three-dimensional structure of DNA inside cells and the pattern of methyl chemical groups attached to the DNAtwo different ways that genes are controlled by cells. In 2019, Eckers lab group pioneered approaches to simultaneously make these two measurements, which lets researchers work out not only which genetic programs are activated in different cell types, but also how these programs are being switched on and off.

The team found examples of genes that were activated in different cell types but through different wayslike being able to flip a light on or off with two different switches. Understanding these overlapping molecular circuits makes it easier for researchers to develop new ways of intervening in brain diseases.

If you can understand all the regulatory elements that are important in these cell types, you can also begin to understand the developmental trajectories of the cells, which becomes critical to understanding neurodevelopmental disorders like autism and schizophrenia, says Hanqing Liu, a postdoctoral researcher in Eckers lab and first author of this paper.

The researchers also made new discoveries about which areas of the brain contain which cell types. And when cataloguing those cell types, they additionally found that the brain stem and midbrain have far more cell types than the much larger cortex of the brainsuggesting that these smaller parts of the brain may have evolved to serve more functions.

Other authors of this paper include Qiurui Zeng, Jingtian Zhou, Anna Bartlett, Bang-An Wang, Peter Berube, Wei Tian, Mia Kenworthy, Jordan Altshul, Joseph Nery, Huaming Chen, Rosa Castanon, Jacinta Lucero, Julia Osteen, Antonio Pinto-Duarte, Jasper Lee, Jon Rink, Silvia Cho, Nora Emerson, Michael Nunn, Carolyn OConnor, and Jesse Dixon of Salk; Yang Eric Li, Songpeng Zu, and Bing Ren of UC San Diego; Zhanghao Wu and Ion Stoica of UC Berkley; Zizhen Yao, Kimberly Smith, Bosiljka Tasic, and Hongkui Zeng of the Allen Institute; and Chongyuan Luo of UC Los Angeles.

Single-cell chromatin maps

Another way of indirectly determining the structure of DNA, and which stretches of genetic material are being actively used by cells, is testing what DNA is physically accessible to other molecules that can bind to it. Using this approach, called chromatin accessibility, researchers led by Bing Ren of UC San Diegoincluding Salks Ecker and Behrensmapped the structure of DNA in 2.3 million individual brain cells from 117 mice.

Then, the group used artificial intelligence to predict, based on those patterns of chromatin accessibility, which parts of DNA were acting as overarching regulators of the cells states. Many of the regulatory elements they identified were in stretches of DNA that have already been implicated in human brain diseases; the new knowledge of exactly which cell types use which regulatory elements can help pin down which cells are implicated in which diseases.

Other authors of this paper include co-first authors Songpeng Zu, Yang Eric Li, and Kangli Wang of UC San Diego; Ethan Armand, Sainath Mamde, Maria Luisa Amaral, Yuelai Wang, Andre Chu, Yang Xie, Michael Miller, Jie Xu, Zhaoning Wang, Kai Zhang, Bojing Jia, Xiaomeng Hou, Lin Lin, Qian Yang, Seoyeon Lee, Bin Li, Samantha Kuan, Zihan Wang, Jingbo Shang, Allen Wang, and Sebastian Preissl of UC San Diego, Hanqing Liu, Jingtian Zhou, Antonio Pinto-Duarte, Jacinta Lucero, Julia Osteen, and Michael Nunn of Salk; and Kimberly Smith, Bosiljka Tasic, Zizhen Yao, and Hongkui Zeng of the Allen Institute.

Neuron projections and connections

In another paper, co-authored by Behrens, Callaway, and Ecker, researchers mapped connections between neurons throughout the mouse brain. Then, they analyzed how these maps compared to patterns of methylation within the cells. This let them discover which genes are responsible for guiding neurons to which areas of the brain.

We discovered certain rules dictating where a cell projects to based on their DNA methylation patterns, says Jingtian Zhou, a postdoctoral researcher in Eckers lab and co-first author of the paper.

The connections between neurons are critical to their function and this new set of rules may help researchers study what goes awry in diseases.

Other authors of this paper include co-first author Zhuzhu Zhang of Salk; May Wu, Hangqing Liu, Yan Pang, Anna Bartlett, Wubin Ding, Angeline Rivkin, Will Lagos, Elora Williams, Cheng-Ta Lee, Paula Assakura Miyazaki, Andrew Aldridge, Qiurui Zeng, J. L. Angelo Salida, Naomi Claffey, Michelle Liem, Conor Fitzpatrick, Lara Boggeman, Jordan Altshul, Mia Kenworthy, Cynthia Valadon, Joseph Nery, Rosa Castanon, Neelakshi Patne, Minh Vu, Mohammed Rashid, Matthew Jacobs, Tony Ito, Julia Osteen, Nora Emerson, Jasper Lee, Silvia Cho, Jon Rink, Hsiang-Hsuan Huang, Antnio Pinto-Duarte, Bertha Dominguez, Jared Smith, Carolyn OConnor, and Kuo-Fen Lee of Salk; Zhihao Peng of Nanchang University in China; Zizhen Yao, Kimberly Smith, Bosiljka Tasic, and Hongkui Zeng of the Allen Institute; Shengbo Chen of Henan University in China; Eran Mukamel of UC San Diego; and Xin Jin of East China Normal University in China and New York University Shanghai.

Comparing mouse, monkey, and human motor cortexes

The motor cortex is the part of the mammalian brain involved in the planning and carrying out of voluntary body movements. Researchers led by Behrens, Ecker, and Ren studied the methylation patterns and DNA structure in more than 200,000 cells from the motor cortexes of humans, mice, and nonhuman primates to better understand how motor cortex cells have changed throughout human evolution.

They were able to identify correlations between how particular regulatory proteins have evolved and how, in turn, the expression patterns of genes evolved. They also discovered that nearly 80 percent of the regulatory elements that are unique to humans are transposable elementssmall, mobile sections of DNA that can easily change position within the genome.

Other authors of this paper include co-first authors Nathan Zemke and Ethan Armand of UC San Diego; Wenliang Wang, Jingtian Zhou, Hanqing Liu, Wei Tian, Joseph Nery, Rosa Castanon, Anna Bartlett, Julia Osteen, Jonathan Rink, and Edward Callaway of Salk; Seoyeon Lee, Yang Eric Li, Lei Chang, Keyi Dong, Hannah Indralingam, Yang Xie, and Michael Miller of UC San Diego; Daofeng Li, Xiaoyu Zhuo, Vincent Xu, and Ting Wang of Washington University in Missouri; Fenna Krienen of Princeton University and Harvard Medical School; Qiangge Zhang and Guoping Feng of the Broad Institute and MIT; Steven McCarroll of Harvard Medical School and the Broad Institute; and Naz Taskin, Jonathan Ting, and Ed Lein of the Allen Institute and University of Washington in Seattle.

Summary

I think in general this whole package serves as a blueprint for other peoples future studies, says Callaway, also the Vincent J. Coates Chair in Molecular Neurobiology at Salk. Someone studying a particular cell type can now look at our data and see all the ways those cells connect and all the ways theyre regulated. Its a resource that allows people to ask their own questions.

The work was supported by the National Institutes of Health BRAIN Initiative (U19MH11483, U19MH114831-04s1, 5U01MH121282, UM1HG011585, U19MH114830).

About the Salk Institute for Biological Studies:

Unlocking the secrets of life itself is the driving force behind the Salk Institute. Our team of world-class, award-winning scientists pushes the boundaries of knowledge in areas such as neuroscience, cancer research, aging, immunobiology, plant biology, computational biology, and more. Founded by Jonas Salk, developer of the first safe and effective polio vaccine, the Institute is an independent, nonprofit research organization and architectural landmark: small by choice, intimate by nature, and fearless in the face of any challenge. Learn more atwww.salk.edu.

For more information

Visit all 10 papers in the Nature package here.

Journal title: Nature

Paper title: Single-cell DNA Methylome and 3D Multiomic Atlas of the Adult Mouse Brain

Authors: Hanqing Liu, Qiurui Zeng, Jingtian Zhou, Anna Bartlett, Bang-An Wang, Peter Berube, Wei Tian, Mia Kenworthy, Jordan Altshul, Joseph R. Nery, Huaming Chen, Rosa G. Castanon, Songpeng Zu, Yang Eric Li, Jacinta Lucero, Julia K. Osteen, Antnio Pinto-Duarte, Jasper Lee, Jon Rink, Silvia Cho, Nora Emerson, Michael Nunn, Carolyn OConnor, Zhanghao Wu, Ion Stoica, Zizhen Yao, Kimberly A. Smith, Bosiljka Tasic, Chongyuan Luo, Jesse R. Dixon, Hongkui Zeng, Bing Ren, M. Margarita Behrens, Joseph R Ecker

DOI: 10.1038/s41586-019-0000-0

Journal title: Nature

Paper title: Single-cell analysis of chromatin accessibility in adult mouse brain

Authors: Songpeng Zu, Yang Eric Li, Kangli Wang, Ethan Armand, Sainath Mamde, Maria Luisa Amaral, Yuelai Wang, Andre Chu, Yang Xie, Michael Miller, Jie Xu, Zhaoning Wang, Kai Zhang, Bojing Jia, Xiaomeng Hou, Lin Lin, Qian Yang, Seoyeon Lee, Bin Li, Samantha Kuan, Hanqing Liu, Jingtian Zhou, Antonio Pinto-Duarte, Jacinta Lucero, Julia Osteen, Michael Nunn, Kimberly A. Smith, Bosiljka Tasic, Zizhen Yao, Hongkui Zeng, Zihan Wang, Jingbo Shang, M. Margarita Behrens, Joseph R. Ecker, Allen Wang, Sebastian Preissl, Bing Ren

DOI: 10.1038/s41586-023-06824-9

Journal title: Nature

Paper title: Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections

Authors: Jingtian Zhou, Zhuzhu Zhang, May Wu, Hanqing Liu, Yan Pang, Anna Bartlett, Zhihao Peng, Wubin Ding, Angeline Rivkin, Will N. Lagos, Elora Williams, Cheng-Ta Lee, Paula Assakura Miyazaki, Andrew Aldridge, Qiurui Zeng, J.L. Angelo Salinda, Naomi Claffey, Michelle Liem, Conor Fitzpatrick, Lara Boggeman, Zizhen Yao, Kimberly A. Smith, Bosiljka Tasic, Jordan Altshul, Mia A. Kenworthy, Cynthia Valadon, Joseph R. Nery, Rosa G. Castanon, Neelakshi S. Patne, Minh Vu, Mohammad Rashid, Matthew Jacobs, Tony Ito, Julia Osteen, Nora Emerson, Jasper Lee, Silvia Cho, Jon Rink, Hsiang-Hsuan Huang, Antonio Pinto-Duarte, Bertha Dominguez, Jared B. Smith, Carolyn OConnor, Hongkui Zeng, Shengbo Chen, Kuo-Fen Lee, Eran A. Mukamel, Xin Jin, M. Margarita Behrens, Joseph R. Ecker, Edward M. Callaway

DOI: 10.1038/s41586-019-0000-0

Journal title: Nature

Paper title: Conserved and divergent gene regulatory programs of the mammalian neocortex

Authors: Nathan R. Zemke, Ethan J. Armand, Wenliang Wang, Seoyeon Lee, Jingtian Zhou, Yang Eric Li, Hanqing Liu, Wei Tian, Joseph R. Nery, Rosa G. Castanon, Anna Bartlett, Julia K. Osteen, Daofeng Li, Xiaoyu Zhuo, Vincent Xu, Lei Chang, Keyi Dong, Hannah Indralingam, Jonathan A. Rink, Yang Xie, Michael Miller, Fenna M. Krienen, Qiangge Zhang, Naz Taskin, Jonathan Ting, Guoping Feng, Steven A. McCarroll, Edward M. Callaway, Ting Wang, Ed S. Lein, M. Margarita Behrens, Joseph R. Ecker, Bing Ren

DOI: 10.1038/s41586-023-06819-6

Brain-wide Correspondence Between Neuronal Epigenomics and Long-Distance Projections

14-Dec-2023

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Salk teams assemble first full epigenomic cell atlas of the mouse brain - EurekAlert