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

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

Genetics

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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

Genetics

GENEFIT, the First-Ever Fitness Technology to Integrate Personal Genetics with Wearable Tracker Data, Launches to … – Fitt Insider

GENEFIT(GENEs First Integrated Technologies), powered by3X4 Genetics, announces today the public-facing launch of its revolutionary, patented modifier technology that integrates genetic data with training data from wearable devices to give personalized, gene-informed sports performance metrics and goal-based training plans. In an industry dominated by stats and metrics, there has never before been a way to tap into genetics to target specific strengths and weaknesses in a training plan. By combining genetic pathway analysis, advanced exercise physiology and artificial intelligence, GENEFIT makes fitness data truly personalized to the individual.

Research shows that genetics play a large, and in many cases dominant, role in an individuals ability to recover, their risk of injury, and which type of training they best respond to,saysTony Hsu, Chairman & CEO, 3X4 Genetics.With GENEFIT, weve finally found a way to quantify this integral part of an individuals sports performance and integrate it seamlessly into daily training regimens.It truly is the future of sports.

A first in the health & fitness space, GENEFIT alerts users when they are at risk of an injury. This feature, which measures both muscle health and connective tissue health, allows athletes to know, and not guess, their risk for overuse injury on any given day. GENEFIT gives a simple yet comprehensive breakdown of an athletes genetic strengths and weaknesses across six categories of athletic performance: training, recovery, injury risk, body composition, energy levels, and nutrition. Combined with wearable tracker data such as that from Garmin devices, GENEFIT shows specific areas of focus along with recommendations for improvement and daily Steps to Success (short, targeted nutrition and lifestyle recommendations) to boost recovery and tissue health. These small genetic switches have the potential to unlock big leaps in performance.

GENEFIT offers both freemium and premium subscriptions and works with Garmin on both Apple and Android devices, or any wearable heart rate & GPS-enabled fitness tracker that connects to Apple Health. By downloading the GENEFIT app, ordering and taking a genetic test, and linking a tracker complete with workout history, an athletes performance metrics are calculated and displayed in an easy-to-interpret green-orange-red traffic light system. The platform permanently houses the athletes baseline genetic results, how well they are tracking toward their fitness goals, and whether they are at risk for an injury so they can push their body the way its meant to.

The 3X4 product team, led byHarvard-trained geneticist Dr. Gerrida Uys, PhD, and engineering team, led by Mariette Conning, MEng, intentionally designed GENEFIT to have standardized, user-friendly outputs to make the complex science of genetic pathway analysis and physiology accessible and practical. Both world-class triathletes, Uys and Conning recognized that every athlete has unique strengths and weaknesses that take years to identify and develop.

We all know that the differences we observe in athletes, those not explained by data and performance metrics, comes down to genetics,says Dr. Uys.GENEFIT transforms generic big data into genetic-based, hyper-personalized data that can be the difference between winning and losing in competitive sports.

Downloading and using the GENEFIT app without genetics testing is free, and users can still monitor injury risk, assess training load, and analyze workouts using statistical norms and AI. For athletes looking to integrate their genetics, initial testing is$199, and the subscription for personalized injury monitoring, goal-based training plans, and daily nutrition and recovery recommendations is$14.99/month (or$119/year).

GENEFIT also offers enterprise solutions for elite sports organizations, providing practical performance insights for coaching staff and athletes alike. GENEFIT is currently an official partner of the 2022 MLS Cup Champions, the Los Angeles Football Club.

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GENEFIT, the First-Ever Fitness Technology to Integrate Personal Genetics with Wearable Tracker Data, Launches to ... - Fitt Insider

Genetics

A Case of Von Hippel-Lindau Disease With Recurrence of Paraganglioma and No Other Associated Symptoms: The … – Cureus

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A Case of Von Hippel-Lindau Disease With Recurrence of Paraganglioma and No Other Associated Symptoms: The ... - Cureus

Genetics

VA/Yale Researchers Lead Multi-ancestry Study of Genetics of Problematic Alcohol Use – Yale School of Medicine

A study led by VA Connecticut Healthcare Center/Yale researchers reveals ancestries around the world possess a shared genetic architecture for problematic alcohol use (PAU) habitual heavy drinking, accompanied by harmful consequences.

The findings, published in Nature Medicine, could help scientists understand the genetic basis of PAU, a major cause of health problems in many age groups. It is a leading cause of death in those it afflicts.

This study is the largest to date for PAU it identified many new risk genes and uncovered a large amount of new biology. With a better understanding of PAU biology, scientists will have new possibilities in developing treatments.

Hang Zhou, PhD, assistant professor of psychiatry and of biomedical informatics & data science at Yale School of Medicine and VA Connecticut, and first author of the study, said, Research with the primary focus on understanding the molecular mechanism underlying PAU and identification of gene targets for potential pharmacological studies is extremely important for future treatments and could help mitigate the consequences of excessive alcohol use.

Researchers studied more than 1 million people with PAU and included as many genetic ancestral groups as possible, including people with European, African, Latin American, East Asian, and South Asian ancestries.

The Million Veteran Program (MVP), funded by the U.S. Department of Veterans Affairs, was a major source of data for this study MVP data were combined with data from many other sources to create the analyses.

Compared to previous research, this work broadened the findings and demonstrated that the genetic architecture of PAU is substantially shared across these populations. There are genetic differences in different populations for PAU, but the similarities are greater. Cross-ancestry information allowed the researchers to improve the power of gene discovery.

By leveraging the multi-ancestry information, we identified 110 gene regions and had an improved fine-mapping of the potential causal variants in each region, Zhou said.

The researchers also used various methods to prioritize multiple genes with convergent evidence linking association to PAU with brain biology through gene expression (transcriptional-wide association study in 13 brain tissues) and chromatin interaction analyses in the brain. This work will provide valuable resources and targets for future functional analyses and drug development.

Joel Gelernter, MD, Foundations Fund Professor of Psychiatry, and professor of genetics and of neuroscience at Yale School of Medicine and VA Connecticut, was the study's senior author.

One of the most important products of this research is the information provided about PAU risk across the entire genome," Gelernter said. "The resulting data allowed us to understand the biology of PAU better, suggesting some already-approved drugs that might become tools for treating PAU in the future, with additional research. The data we produced will be shared with the research community, and this will aid greatly in future research by other scientists.

The drug-repurposing analyses identified several existing medications as potential treatments for PAU, which are described in the published article.

One of the outputs from this study is genomewide association data, and this kind of information can be used to compute polygenic risk scores, or PRS, that can be used to estimate an individuals genetic risk for PAU.

The researchers stressed that the PRS they computed is not yet ready for use in the clinic, but they also tested the association of the PRS for PAU with hundreds of medical traits in multiple biobanks including Vanderbilt University Medical Centers Biobank, Mount Sinais BioMe, the Mass General Brigham Biobank, and Penn Medicine Biobank. This analysis identified genetic correlations between PAU and many other mental and neurological disorders.

Other Yale contributors include Joseph D. Deak, Lu Wang, Jiayi Xu, Keira J.A. Johnston, Marco Galimberti, Cecilia Dao, Daniel F. Levey, Cassie Overstreet, Ke Xu, Hongyu Zhao, Laura M. Huckins, John H. Krystal, and Amy C. Justice. The investigators also worked with scientists from the University of Pennsylvania and many other institutions.

Funding was provided by the U.S. Department of Veterans Affairs and National Institutes of Health.

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VA/Yale Researchers Lead Multi-ancestry Study of Genetics of Problematic Alcohol Use - Yale School of Medicine

Genetics

Study reveals genetic roots of hodgkin lymphoma, offering hope for new treatments – News-Medical.Net

A Stanford Medicine-led, international study of hundreds of samples from patients with Hodgkin lymphoma has shown that levels of tumor DNA circulating in their blood can identify who is responding well to treatment and others who are likely to experience a disease recurrence -; potentially letting some patients who are predicted to have favorable outcomes forgo lengthy treatment.

Surprisingly, the study also revealed that Hodgkin lymphoma, a cancer of the lymph nodes, can be divided into two groups, each with distinct genetic changes and slightly different prognoses. These changes hint at weaknesses in the cancer's growth mechanisms that could be targeted by new, less toxic therapies.

The idea of establishing molecular profiles of tumors is not new. But unlike other cancers, Hodgkin lymphoma has resisted these types of analyses. That's because Hodgkin lymphoma cells are relatively scarce -; even within a large tumor.

This approach offers our first significant look at the genetics of classical Hodgkin lymphoma. Compared with other cancers, finding Hodgkin lymphoma cancer cells or cancer DNA to study is like searching for a needle in a haystack. A patient can have a football-sized tumor in their chest, but only about 1% of the cells in the mass are cancer cells, with the remainder representing an inflammatory response to the tumor. This has made it very difficult to find the smoking guns that drive the disease."

Ash Alizadeh, MD, PhD, professor of medicine, Stanford

Alizadeh, who is the Moghadam Family Professor, and Maximilian Diehn, MD, PhD, professor of radiation oncology and the Jack, Lulu, and Sam Willson Professor, are the senior authors of the research, which will be published Dec. 11 in Nature. Former postdoctoral scholar Stefan Alig, MD; instructor of medicine Mohammad Shahrokh Esfahani, PhD; and graduate student Andrea Garofalo are the lead authors, as is graduate student Michael Yu Li at British Columbia Cancer.

About 8,500 people are diagnosed with Hodgkin lymphoma each year in the United States. The disease primarily affects people between the ages of 15 and 35, and people older than 55.

Just over 60 years ago, Stanford radiologist Henry Kaplan, MD pioneered the use of targeted radiation to treat Hodgkin lymphoma. The new therapy, delivered by a high-energy linear accelerator Kaplan developed in the 1950s for medical use, was the first step in a Stanford-driven effort to turn the once fatal cancer of the lymph nodes into one that is now highly curable. Soon thereafter, Kaplan was joined by medical oncologist Saul Rosenberg, MD, and the two worked out ways to combine radiation therapy with chemotherapy regimens, including one known simply as the Stanford 5 (named because it was the fifth in a series of gradually less toxic treatments).

During the subsequent decades, however, the genetic changes that cause the cancer have remained mysterious. That's because, unlike many other cancers, Hodgkin lymphoma tumors are made up primarily of immune cells that have infiltrated the cancer, making it difficult to isolate the diseased cells for study. Today, patients are treated with chemotherapy, radiation or a combination of both; about 89% of patients survive five years or more after their initial diagnosis.

Alizadeh, Diehn and their colleagues used an optimized DNA sequencing technique called PhasED-Seq, or phased variant enrichment and detection sequencing, they developed at Stanford Medicine in 2021 to home in on vanishingly rare bits of DNA in a patient's bloodstream to identify genetic changes that drive the growth of Hodgkin lymphoma.

PhasED-Seq builds upon a technique called CAPP-Seq, or cancer personalized profiling by deep sequencing, developed in 2014 by Alizadeh and Diehn to assess lung cancer levels and response to treatment. But PhasED-Seq is much more sensitive.

"CAPP-Seq could detect as few as one cancer DNA sequence in 10,000 non-cancer DNA sequences," Diehn said. "But PhasED-Seq can detect less than one cancer DNA sequence in 1 million non-cancer DNA sequences."

Their goal was to learn more about what drives the cancer and how to make successful treatments even easier for patients.

"We typically can cure most patients with one line of therapy," Alizadeh said. "But we are always trying to figure out less toxic chemotherapeutic agents that are gentler to the bone marrow, lungs and other organs, and ways to more precisely target radiation therapy. And a small minority of patients experience a recurrence that can be challenging to treat successfully."

The researchers used CAPP-Seq and PhasED-Seq to analyze blood samples from 366 people treated for Hodgkin lymphoma at three medical centers including Stanford Medicine. The technique was remarkably sensitive.

"Surprisingly, we detected more cancer DNA in the blood than in the cancer tissue itself," Alizadeh said. "That seemed hard to believe until we had analyzed enough samples to show that it was reproducible."

The researchers used machine learning techniques to categorize the different types of genetic changes present in the cancer cells. They found that patients could be separated into two groups: one that predominantly has mutations in several cancer-associated genes implicated in cellular survival, growth and inflammation, and another with a type of genetic change called copy number alterations that affects larger swathes of the genome, subbing in or excising regions of DNA that influence cell growth and cancer.

"We adapted a method from natural language processing to find these two Hodgkin subtypes, and then used a variety of methods to identify key biological and clinical features and to confirm that the subtypes are also seen in other groups of patients," Esfahani said.

The first group, which makes up about one-half to two-thirds of patients, occurs primarily in younger patients and has a comparatively more favorable outcome. About 85-90% of these people survive for three years without disease recurrence. The second, which makes up about one-half to one-third of the total, occurs in both younger and older patients and has a less favorable, although still good outcome. About 75% of these people live for at least three years without recurrence.

Critically, a subset of both groups contained a unique mutation in a gene for the receptor for cellular signaling proteins called interleukin 4 and interleukin 13.

"We discovered a new class of mutations in the interleukin 4 receptor gene that enhance a key pathway characteristic to Hodgkin lymphoma," Alig said. "These mutations may be indicative of unique vulnerabilities of the tumor that can be exploited therapeutically."

The researchers also showed that patients who had no detectable circulating tumor DNA in their blood shortly after starting treatment were much less likely to have disease recurrence than those who had even small amounts of residual circulating cancer DNA at the same time point -; a distinction researchers had hoped to see, but were unsure about being able to detect even with PhasED-Seq.

"I was surprised that we could predict which patients would recur," Diehn said. "Even with our ultrasensitive assay there was a significant chance that the signal from the cancer DNA could become undetectable after treatment, even in patients who eventually recurred. But this didn't happen."

The researchers seeking to understand more about the biology of Hodgkin lymphoma have one key goal: the improvement of care for patients.

"The number of people who experience recurrence is small, but, like Henry Kaplan and Saul Rosenberg, we want to save every one of them," Diehn said. "They would have been amazed and gratified by these findings, which build upon their important work from decades ago. We look forward to an era in which we can cure every patient with no toxicity."

Researchers from British Columbia Cancer, University Hospital Franois Mitterand, St. Jude Children's Research Hospital, the Oncology Institute of Southern Switzerland, KU Leuven, the University of Strasbourg, Emory University, the Fred Hutchinson Cancer Research Center, the Hospices Civils de Lyon, and the Universit Catholique de Louvain contributed to the work.

This work was supported by the National Institutes of Health (grants R01CA257655, R01CA233975 and R03CA21765), the Department of Defense, the Virginia and D.K. Ludwig Fund for Cancer Research, a Hanna and Michael Murphy family gift, the Stanford Cancer Institute, the Damon Runyon Cancer Research Foundation, an American Society of Hematology Scholar Award, the V Foundation for Cancer Research, the Emerson Collective Cancer Research Fund, a Stinehart/Reed Award, the CRK Faculty Scholar Fund, the Lung Cancer Research Foundation and the SDW/DT, the Shanahan Family Foundations, the Terry Fox Research Institute, the Canadian Institutes of Health Research, an Elizabeth C. Watters Research Fellowship, and the American Syrian Lebanese Associated Charities.

Diehn, Alizadeh, Alig and Esfahani have filed patents related to cancer biomarkers. Diehn has multiple issued and pending patents licensed to Foresight Diagnostics and Roche. He holds interests in CiberMed, Inc.; Foresight Diagnostics; and Gritstone Bio. Alizadeh has multiple issued and pending patents licensed to Foresight Diagnostics, CiberMed Inc. and Idiotype Vaccines. He holds interests in CiberMed, Inc.; Foresight Diagnostics; FortySeven Inc.; and CARGO Therapeutics.

Source:

Journal reference:

Alig, S. K., et al. (2023). Distinct Hodgkin lymphoma subtypes defined by noninvasive genomic profiling. Nature. doi.org/10.1038/s41586-023-06903-x.

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Study reveals genetic roots of hodgkin lymphoma, offering hope for new treatments - News-Medical.Net