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Summary: A new study shows that the DNA repair enzyme Polβ plays a vital role in protecting the developing brain from harmful mutations. Researchers found that without Polβ, insertion-deletion mutations near CpG sites rose sharply, threatening genetic stability during crucial stages of brain growth.

These regions are essential for regulating gene activity and are especially vulnerable during DNA demethylation. The findings shed light on the molecular roots of neurodevelopmental disorders and point to potential new avenues for prevention and treatment.

Key Facts

• Polβ Function: Repairs DNA damage during brain development, preventing harmful indel mutations.
• Mutation Increase: Loss of Polβ causes a ninefold rise in indel mutations at CpG sites.
• Health Impact: Findings link DNA repair deficits to neurodevelopmental disorders, with implications for cancer and aging research.

Source: Osaka University

A research group led by The University of Osaka has discovered that the DNA repair enzyme Polβ plays a crucial role in protecting the developing brain from harmful mutations.

The study found that a lack of Polβ leads to a significant increase in small insertions and deletions of DNA, known as indels near CpG sites, which are important regulatory regions in genes. This accumulation of mutations could contribute to neurodevelopmental disorders.

The human brain undergoes intricate developmental processes, meticulously guided by genetic blueprints. However, DNA damage can occur during these stages, potentially leading to irreversible mutations in nerve cells if not properly repaired. While the occurrence of such mutations has been recognized, the precise mechanisms governing their suppression remained elusive.

This study demonstrates that Polβ is essential in preventing a specific type of mutation known as insertion-deletion (indel) mutations near CpG sites, regions of the genome with high gene regulatory activity. These sites undergo dynamic changes in methylation, a chemical modification of DNA, during brain development. 

The researchers found that Polβ repairs the DNA damage associated with demethylation at these sites, preventing the accumulation of indel mutations. In the absence of Polβ, indel mutations near CpG sites increased approximately ninefold.

This research highlights a previously unknown role of Polβ in safeguarding the integrity of the genome during brain development. The findings suggest that deficiencies in Polβ could contribute to neurodevelopmental disorders arising from accumulated mutations.

This research provides a new molecular basis for understanding the origin of brain developmental disorders and may contribute to preventative techniques in the future.

“Our study is the first in the world to demonstrate the crucial role of Polβ in preventing mutations in developing nerve cells,” says Dr. Noriyuki Sugo, the lead author of the study. 

“We believe this finding offers a new perspective on the causes of neurodevelopmental disorders and opens up exciting avenues for neuroscience, cancer, and aging research.”  The team plans to further investigate the link between Polβ dysfunction and specific neurodevelopmental conditions.

About this genetics and neurology research news

Author: Saori Obayashi
Source: Osaka University
Contact: Saori Obayashi – Osaka University
Image: The image is credited to Neuroscience News

Original Research: Open access.
“DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons” by Noriyuki Sugo et al. PNAS

Abstract

DNA polymerase β suppresses somatic indels at CpG dinucleotides in developing cortical neurons

Somatic mutations in cortical neurons have been implicated in psychiatric disorders. While endogenous DNA damage and repair errors are potential contributors to these mutations during development, the underlying mutagenic mechanism remains unclear.

Here, we investigated somatic mutations in immature cortical neurons using mouse somatic cell nuclear transfer-derived embryonic stem cells and whole-genome sequencing. Insertions and deletions (indels) were commonly observed in both repeat and nonrepeat sequences in wild-type cells.

The loss of DNA polymerase β (Polβ), an enzyme involved in gap-filling during base excision repair and Ten-Eleven Translocation (TET)-mediated active DNA demethylation, in neural progenitor cells increased indel frequency by ~ninefold at cytosine-phosphate-guanine (CpG) dinucleotides and raised the frequency of structural variants by ~fivefold.

These mutations were enriched in neuronal genes, leading to frameshift mutations, amino acid insertions/deletions, and the gain and loss of CpG sites in regulatory regions.

Our findings suggest that Polβ preferentially repairs DNA lesions generated at CpG sites by TET-mediated active demethylation, thereby suppressing the mutagenesis that accompanies neuronal gene activation during cortical development.

FastUKB is an innovative tool specifically developed to streamline and enhance research workflows utilizing the UK Biobank, effectively addressing key limitations of existing platforms such as the UK Biobank Research Analysis Platform (RAP). One of its most notable features is its breakthrough bulk data extraction functionality, which transforms traditionally complex coding tasks into intuitive click operations. This is made possible through a user-friendly interface equipped with dropdown menus and a hierarchical variable tree structure, allowing researchers to effortlessly navigate and select the data they need. Unlike RAP, which restricts users to selecting only 30 variables at a time-a significant hindrance to analytical efficiency-FastUKB enables the extraction of an unlimited number of variables in a single operation. What’s more, it supports data extraction across multiple entities, including participant data (encompassing basic demographic information and clinical phenotypes), proteomics data from olink_instance, genomics data, neuroimaging and cardiac imaging data, metabolomics data, and physical activity monitoring data from activity_monitor, among others. When compared to existing tools like ukbREST and ukbtools, FastUKB stands out by offering broader batch extraction capabilities, automated field matching, and a much lower technical barrier, making it accessible to a wider range of researchers.​

Beyond data extraction, FastUKB functions as a comprehensive intelligent data processing and analysis hub, providing end-to-end support throughout the research process, from data cleaning to advanced statistical analysis. Its built-in medical-specific quality control module is designed to handle the unique challenges of UK Biobank data, automatically identifying and addressing missing values marked by special encodings such as -1, -3, and -7, and detecting outliers based on medical expertise to flag physiologically unreasonable values. Additionally, it converts UK Biobank’s unique coding system into standard classifications familiar to researchers and cross-validates the logical consistency between related variables to ensure the reliability of the analytical foundation. FastUKB also simplifies the often time-consuming task of generating baseline characteristic tables that meet the standards of top-tier medical journals. By allowing users to select variables and grouping methods, the tool automatically chooses appropriate statistical methods based on data type and distribution, performs relevant statistical tests to calculate between-group P-values, and generates the baseline table seamlessly. Furthermore, it offers a wide range of advanced statistical analysis tools, including linear regression, logistic regression, Cox proportional hazards models, subgroup analysis, interaction analysis, polygenic risk scoring, and sensitivity analysis-all accessible through simple parameter settings, eliminating the need for complex coding.​

Another key advantage of FastUKB is its custom variable upload and smart matching system, which significantly enhances the tool’s flexibility and applicability. Researchers can upload custom ID lists in CSV, XLSX, or TXT formats, and the system will intelligently match and extract data from these specific samples, facilitating precise sample selection for various epidemiological study designs such as cohort and case-control studies. For instance, in case-control studies, users can upload matched control group IDs, and the system can even automatically identify the most suitable matched samples within the UK Biobank based on specified variables like age, gender, and socioeconomic status. This system also supports the upload of custom variables for integration with UK Biobank raw data, including external data from other platforms, derived variables such as disease risk scores, and ensures clear data version control to distinguish between original and user-uploaded data.​

FastUKB has already proven its value in practical applications. In a study exploring the relationship between sleep patterns, genetic risk, and incident rheumatoid arthritis, the tool efficiently extracted sleep behavior indicators from 375,133 participants. Similarly, in a study investigating plasma metabolite profiles linked to the EAT-Lancet diet and inflammatory bowel disease, it facilitated the processing of nearly 900 metabolites, allowing researchers to focus on scientific questions rather than technical details. While currently tailored to the UK Biobank’s data structure and variable encoding system, FastUKB’s modular architecture is designed for scalability, with future development potentially extending its framework to accommodate other large-scale biomedical datasets like FinnGen or All of Us. By lowering the barrier to accessing and analyzing large biomedical datasets, FastUKB democratizes research, accelerates the research cycle, improves research quality, and ultimately contributes to advancing medical knowledge and translating findings into clinical practice.

The American Geriatrics Society (AGS) has released a landmark update to its list of alternatives to medications listed in the 2023 AGS Beers Criteria^® – the most widely adopted guidelines to help clinicians identify potentially inappropriate medications for older adults. This new effort delivers not only a comprehensive suite of safer pharmacologic options, but also a strong emphasis on effective non-pharmacologic treatments for common conditions impacting frail and aging populations.

The AGS panel is comprised of 19 national experts from 14 states, including Noll Campbell, PharmD, M.S., of the Regenstrief Institute and Purdue University College of Pharmacy. Dr. Campbell is the only expert from Indiana. The panel is a multidisciplinary AGS panel of physicians, pharmacists, nurses, psychologists and physical therapists that systematically reviewed and curated alternatives for some of the most challenging prescribing scenarios faced in geriatric practice.

The AGS Beers Criteria^® identifies medications that are more likely to harm than help older adults due to side effects such as sedation, falls, delirium and interactions with other conditions. Recommendations are structured for rapid use in clinical practice, emphasizing clear tables referenced by symptom or diagnosis and supplemented by links to reliable resources for both health professionals and the public.

In practice, we see the risks of potentially inappropriate medications play out in the emergency rooms, clinics, nursing homes or when families are struggling at home. Our aim with this document is to provide support beyond saying ‘don’t prescribe,’ by offering clinicians, patients and families with a list of credible, actionable alternatives – whether it’s a safer medicine or a proven lifestyle approach.”

Dr. Noll Campbell, PharmD, M.S., of the Regenstrief Institute and Purdue University College of Pharmacy

A novel feature is the inclusion of patient and caregiver-friendly materials, from decision aids and handouts on deprescribing to support for making lifestyle changes – reflecting a modern, team-based and patient-centered approach to medication safety for older adults. All of these resources are generated and hosted by the American Geriatrics Society.

Rigorous, interprofessional approach

Panelists were assigned to eight topic-specific workgroups covering insomnia and anxiety; allergy and pruritus (itchy skin); cardiovascular and anticoagulation therapies; pain; delirium and dementia; diabetes; gastrointestinal syndromes; and genitourinary syndromes.

Each group sought and reviewed high-quality guidelines, best-practice documents and systematic reviews most applicable to common geriatric scenarios. These resources were then distilled into tables of alternatives for 21 common conditions. The panel prioritized U.S.-based guidance but included international sources when more recent or rigorous. Notably, selections focused on both medications and non-pharmacologic alternatives – such as cognitive behavioral therapy for insomnia, exercise and physical therapy for Parkinson’s disease, lifestyle changes for constipation and heartburn, and behavioral or dietary interventions for urinary symptoms.

Core principles for safer prescribing

To guide clinicians, the panel offers five key principles.

• Stopping a potentially inappropriate drug is not the ultimate goal; the priority is to help patients feel better and reduce the risk of harm.
• Non-drug (behavioral and lifestyle) strategies should often be first line.
• Always seek the underlying cause of symptoms before prescribing.
• Avoiding a risky drug is important, but clinical judgment and individualization remain critical.
• Use the many available resources for patients, caregivers and clinicians to support implementation and deprescribing.

Balancing real-world practice, research gaps and patient and caregiver needs

The panel acknowledges that guidelines and systematic reviews often lack specificity for the oldest or most complex patients, and that real-life symptoms (e.g., insomnia, involuntary weight loss) are not always tied to a single clear diagnosis. As described in the article’s discussion, recommendations remain flexible, encouraging clinicians to tailor approaches according to each individual’s clinical status, functional goals and life circumstances.

“We recognize that simply removing a medication may not be enough, especially if symptoms return or worsen,” said Dr. Campbell. “Our intent is to provide practical, prioritized alternatives that can be started or considered right away, so that care is both safer and responsive to what matters most to older adults and their caregivers. We want clinicians to have real tools, not just warnings.”

Authors are from the following states: Alabama, Arkansas, California, Colorado, Connecticut, Illinois, Indiana, Iowa, Maine, Michigan, Missouri, New York, Texas and Utah.

New research indicates that caffeine consumption is associated with subsequent increases in positive affect, and this association is strongest within the first 2.5 hours after awakening (i.e., in the morning).

“Caffeine is a central nervous system stimulant that is used by approximately 80% of the world’s population and consumed in a wide variety of forms, including beverages like coffee, tea, soda (e.g., coke), and energy drinks, but also in food items such as chocolate,” said Bielefeld University researcher Justin Hachenberger and his colleagues.

“Positive expectations related to caffeine consumption include reduced tiredness and fatigue, enhanced cognitive and physical performance, and a positive shift in mood.”

“While there is a large body of evidence for such beneficial effects coming from experimental studies, there is a lack of studies investigating associations of caffeine particularly with mood or affective states in naturalistic, real-world settings.”

The study involved 236 young adults from Germany over a period of up to four weeks.

The participants completed short questionnaires on their smartphones seven times a day, indicating their current mood and whether they had consumed a caffeinated drink in the preceding 90 minutes.

Accordingly, the study focused on caffeine consumption in everyday life, not just in artificial laboratory settings.

The researchers also investigated whether coffee has different effects on different individuals.

“We were somewhat surprised to find no differences between individuals with varying levels of caffeine consumption or differing degrees of depressive symptoms, anxiety, or sleep problems,” Dr. Hachenberger said.

“The links between caffeine intake and positive or negative emotions were fairly consistent across all groups.”

“We expected that people with higher levels of anxiety would experience negative mood changes, such as increased nervousness, after consuming caffeine.”

“However, people who react to caffeine in a bad way may avoid it and that the study did not include people who completely abstain from caffeine.”

The scientists explain the mood-boosting effect of caffeine on morning mood with its ability to block adenosine receptors, which promotes wakefulness and makes people feel more energetic.

“Caffeine works by blocking adenosine receptors, which can increase dopamine activity in key brain regions — an effect that studies have linked to improved mood and greater alertness,” said University of Warwick’s Professor Anu Realo.

“Yet, it remains unclear whether these effects are related to a reduction in withdrawal symptoms after a night’s sleep.”

“Even people with moderate caffeine consumption can experience mild withdrawal symptoms that disappear with the first cup of coffee or tea in the morning.”

The study appears in the journal Scientific Reports.

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J. Hachenberger et al. 2025. The association of caffeine consumption with positive affect but not with negative affect changes across the day. Sci Rep 15, 28536; doi: 10.1038/s41598-025-14317-0