A Genome-Wide Association Study for Regulators of Micronucleus Formation in Mice.

In mammals the regulation of genomic instability plays a key role in tumor suppression and also controls genome plasticity, which is important for recombination during the processes of immunity and meiosis. Most studies to identify regulators of genomic instability have been performed in cells in culture or in systems that report on gross rearrangements of the genome, yet subtle differences in the level of genomic instability can contribute to whole organism phenotypes such as tumor predisposition. Here we performed a genome-wide association study in a population of 1379 outbred Crl:CFW(SW)-US_P08 mice to dissect the genetic landscape of micronucleus formation, a biomarker of chromosomal breaks, whole chromosome loss, and extranuclear DNA. Variation in micronucleus levels is a complex trait with a genome-wide heritability of 53.1%. We identify seven loci influencing micronucleus formation (false discovery rate <5%), and define candidate genes at each locus. Intriguingly at several loci we find evidence for sexual dimorphism in micronucleus formation, with a locus on chromosome 11 being specific to males.This work was supported by Cancer Research UK and the Wellcome Trust.This is the final version of the article. It first appeared from the Genetics Society of America via http://dx.doi.org/10.1534/g3.116.03076

Integrative Copy Number Analysis of Uveal Melanoma Reveals Novel Candidate Genes Involved in Tumorigenesis Including a Tumor Suppressor Role for PHF10/BAF45a

Uveal melanoma is a primary malignancy of the eye with oncogenic mutations in , and additional mutations in (usually associated with LOH of Chr 3), , or . There are other characteristic chromosomal alterations, but their significance is not clear. To investigate genes driving chromosomal alterations, we integrated copy number, transcriptome, and mutation data from three cohorts and followed up key findings. We observed significant enrichment of transcripts on chromosomes 1p, 3, 6, 8, and 16q and identified seven shared focal copy number alterations (FCNAs) on Chr 1p36, 2q37, 3, 6q25, 6q27, and 8q24. Integrated analyses revealed clusters of genes in focal copy number regions whose expression was associated with metastasis and worse overall survival. This included genes from Chr 1p36, 3p21, and 8q24.3. At Chr 6q27, we identified two tumors with homozygous deletion of and one with a frameshift mutation with concomitant loss of the wild-type allele. Downregulation of in uveal melanoma cell lines and tumors altered a number of biological pathways including development and adhesion. These findings provide support for a role for as a novel tumor suppressor at Chr 6q27. Integration of copy number, transcriptome, and mutation data revealed novel candidate genes playing a role in uveal melanoma pathogenesis and a potential tumor suppressor role for

Barriers and facilitators to recognize and discuss depression and anxiety experienced by adults with vision impairment or blindness: a qualitative study

Background: Depression and anxiety are highly prevalent, but often unrecognized in adults with vision impairment (VI) or blindness. The purpose of this study was to explore visually impaired and blind adults’ views on facilitators and barriers in recognizing and discussing mental health problems. Methods: Semi-structured interviews, based on the Integrated Model for Change, were conducted with 16 visually impaired or blind adults receiving support from three Dutch low vision service organizations. Interview data was analyzed using the framework approach. Results: Participants perceived their focus on practical support with regard to their VI, lack of mental health literacy, and misattribution of symptoms of depression or anxiety as barriers for recognizing mental health problems. With regard to discussing mental health problems, they perceived difficulties in acknowledging their VI and mental health problems due to feelings of vulnerability and inequality. Participants mentioned that their social support system and healthcare providers (could) facilitate them in recognizing and discussing mental health problems. However, participants thought that healthcare providers currently often lacked the knowledge, skills and attitude to recognize and discuss this topic with their clients. Conclusion: Our findings suggest that visually impaired and blind adults may experience several barriers to recognize, acknowledge and discuss mental health. Healthcare providers and social support systems seem essential for them in reducing these barriers. However, there might be a mismatch between the needs of visually impaired and blind adults and healthcare providers’ knowledge, skills and attitude. Training healthcare providers may improve detection of depression and anxiety in adults with VI or blindness, and enhance clinician-patient communication on mental health

Experiences with traumatic events, consequences and care among people with visual impairment and post-traumatic stress disorder: a qualitative study from The Netherlands

OBJECTIVE: Having a visual impairment is known to be associated with an increased vulnerability to (potentially) traumatic events. Little is known about how people with visual impairment experience and process such events. This qualitative study aimed to provide more insight into experiences with traumatic events, consequences of traumatic events and post-traumatic stress disorder (PTSD)-related care among people with visual impairment and PTSD. METHODS: Eighteen persons with visual impairment and (a history of) PTSD were interviewed. Among them were 14 women and 4 men aged between 23 and 66 years. Recruitment of participants was done through health professionals from two low-vision service centres and a patient association for people with eye diseases and visual impairment in The Netherlands. Interviews focused on experiences with (1) traumatic events, (2) consequences of traumatic events and (3) PTSD-related care. Thematic content analysis of interview data was performed using ATLAS.ti. The COnsolidated criteria for REporting Qualitative research (COREQ) checklist was used to check for completeness and transparency of the study. Data were collected between 2018 and 2020. RESULTS: The most commonly reported traumatic events were sexual and physical abuse. Many participants experienced that their impairment had negatively affected their acceptance by others, independence and self-esteem, increasing their vulnerability for traumatic events. Additionally, having a visual impairment negatively impacted participants' ability to respond to situations and aggravated post-traumatic stress reactions. Existing treatments seem suitable for people with visual impairment when accommodated to the impairment. CONCLUSIONS: Having a visual impairment may affect traumatic events and post-traumatic stress reactions, particularly by contributing to low self-esteem, problems in social interactions and a lack of visual information. Insights from this study provide starting points for adapting pretraumatic and post-traumatic care to the needs of people with visual impairment

Perspectives on Implementing the Patient Health Questionnaire-4 in Low-Vision Service Organizations to Screen for Depression and Anxiety

Purpose: To describe the process of implementing a screening questionnaire for depression and anxiety, the Patient Health Questionnaire-4 (PHQ-4), in low-vision service (LVS) organizations. Methods: This study consisted of three parts: (1) a usability study combined with semistructured interviews, in which clients (n = 10) of LVS organizations expressed their preference for using the PHQ-4; (2) a feasibility study, in which the PHQ-4 was implemented on a small scale and its use was evaluated, involving health care providers (n = 6) and clients (n = 9); and (3) semistructured interviews to identify barriers and facilitators for implementing the PHQ-4 according to health care providers (n = 6) and managers (n = 4) of LVS organizations. Results were integrated into themes and linked to constructs of the Consolidated Framework for Implementation Research (CFIR). Results: Six themes were derived from the substudies: (1) quality of the intervention, (2) applicability for clients of LVS organizations, (3) attitude and needs of clients, (4) attitude of health care providers, (5) support within LVS organizations, and (6) embedment in current practice. Results could be linked to 12 CFIR constructs. The constructs "relative advantage," "patient needs and resources," and "available resources" emerged most prominently in our themes as either barrier or facilitator. Conclusions: The PHQ-4 seems an appropriate screening instrument for use in LVS organizations because of its quality and adaptable use. It might provide opportunities to timely detect depression and anxiety, but challenges in implementing the PHQ-4 should be considered. Translational Relevance: Barriers and facilitators for implementing the PHQ-4 may also apply to implementing other questionnaires in LVS organizations

Shotgun proteomics aids discovery of novel protein-coding genes, alternative splicing, and “resurrected” pseudogenes in the mouse genome

Recent advances in proteomic mass spectrometry (MS) offer the chance to marry high-throughput peptide sequencing to transcript models, allowing the validation, refinement, and identification of new protein-coding loci. We present a novel pipeline that integrates highly sensitive and statistically robust peptide spectrum matching with genome-wide protein-coding predictions to perform large-scale gene validation and discovery in the mouse genome for the first time. In searching an excess of 10 million spectra, we have been able to validate 32%, 17%, and 7% of all protein-coding genes, exons, and splice boundaries, respectively. Moreover, we present strong evidence for the identification of multiple alternatively spliced translations from 53 genes and have uncovered 10 entirely novel protein-coding genes, which are not covered in any mouse annotation data sources. One such novel protein-coding gene is a fusion protein that spans the Ins2 and Igf2 loci to produce a transcript encoding the insulin II and the insulin-like growth factor 2–derived peptides. We also report nine processed pseudogenes that have unique peptide hits, demonstrating, for the first time, that they are not just transcribed but are translated and are therefore resurrected into new coding loci. This work not only highlights an important utility for MS data in genome annotation but also provides unique insights into the gene structure and propagation in the mouse genome. All these data have been subsequently used to improve the publicly available mouse annotation available in both the Vega and Ensembl genome browsers (http://vega.sanger.ac.uk)