Teasing out the Effects of Natural Stressors at Chemically Contaminated Sites.

Aquatic ecosystems are often impacted by a multitude of stressors, many of which are introduced by a combination of anthropogenic activities such as agricultural development, urbanization, damming, and industrial discharge. Determining the primary stressors responsible for ecological impairments at a site can be complex and challenging; however, it is crucial for making informed management decisions. Improper diagnosis of an impaired system can lead to misguided attempts at remediation, which can be both time consuming and costly. We focused on the development, implementation, and evaluation of methodologies that, in combination, allowed us to identify the primary stressors. These included a four-phase, weight-of-evidence (WOE) assessment including in situ Toxicity Identification and Evaluation (iTIE) testing, physicochemical and macrobenthos characterization, reciprocal sediment transplants, and laboratory and in situ toxicity testing. The contaminants of concern (COCs) at the site were elevated levels of ammonia, chloride, pH, and total dissolved solids in groundwater upwellings into a high-quality waterway. Reciprocal transplants of site sediments and nearby reference sediments and traditional benthic sampling showed impaired benthic indices and multiple stations around a contaminated industrial settling basin. Impaired stations had elevated COCs in groundwaters but exhibited a steep vertical concentration gradient, with concentrations decreasing near the sediment-surface water interface. We describe Phase 4 of the study, which focused on teasing out the role of dissolved oxygen sags in benthic macroinvertebrate responses. Extensive submerged and emergent macrophytes, algae, and cyanobacteria co-occurred at the impaired sites and increased throughout the summer. Laboratory testing suggested that ammonia and pH were possibly toxic at the sites, based on groundwater concentrations. The in situ toxicity testing, however, showed toxicity occurring even at stations with low levels of COCs concurrently with large diurnal fluxes in dissolved oxygen (DO). A final phase using a type of iTIE approach utilized limnocorrals with and without aeration and with in situ toxicity measures using Hyalella azteca. The Phase 4 assessment revealed that low DO levels were primarily responsible for impaired benthic communities, and COC upwellings were diluted at the sediment-water interface to nontoxic levels. These findings will allow for improved management decisions for more efficient and effective restoration activities. Environ Toxicol Chem 2024;00:1-13. © 2024 SETAC.

BAI1 localizes AMPA receptors at the cochlear afferent post-synaptic density and is essential for hearing.

Type I spiral ganglion neurons (SGNs) convey sound information to the central auditory pathway by forming synapses with inner hair cells (IHCs) in the mammalian cochlea. The molecular mechanisms regulating the formation of the post-synaptic density (PSD) in the SGN afferent terminals are still unclear. Here, we demonstrate that brain-specific angiogenesis inhibitor 1 (BAI1) is required for the clustering of AMPA receptors GluR2-4 (glutamate receptors 2-4) at the PSD. Adult Bai1-deficient mice have functional IHCs but fail to transmit information to the SGNs, leading to highly raised hearing thresholds. Despite the almost complete absence of AMPA receptor subunits, the SGN fibers innervating the IHCs do not degenerate. Furthermore, we show that AMPA receptors are still expressed in the cochlea of Bai1-deficient mice, highlighting a role for BAI1 in trafficking or anchoring GluR2-4 to the PSDs. These findings identify molecular and functional mechanisms required for sound encoding at cochlear ribbon synapses.

Absence of Embigin accelerates hearing loss and causes sub-viability, brain and heart defects in C57BL/6N mice due to interaction with Cdh23ahl.

Mouse studies continue to help elaborate upon the genetic landscape of mammalian disease and the underlying molecular mechanisms. Here, we have investigated an Embigintm1b allele maintained on a standard C57BL/6N background and on a co-isogenic C57BL/6N background in which the Cdh23ahl allele has been "repaired." The hypomorphic Cdh23ahl allele is present in several commonly used inbred mouse strains, predisposing them to progressive hearing loss, starting in high-frequency regions. Absence of the neural cell adhesion molecule Embigin on the standard C57BL/6N background leads to accelerated hearing loss and causes sub-viability, brain and cardiac defects. Contrastingly, Embigintm1b/tm1b mice maintained on the co-isogenic "repaired" C57BL/6N background exhibit normal hearing and viability. Thus Embigin genetically interacts with Cdh23. Importantly, our study is the first to demonstrate an effect of the common Cdh23ahl allele outside of the auditory system, which has important ramifications for genetic studies involving inbred strains carrying this allele.

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: A randomized controlled trial.

AIM: The aim was to determine whether specialist-led habit training using Habit Training with Biofeedback (HTBF) is more effective than specialist-led habit training alone (HT) for chronic constipation and whether outcomes of interventions are improved by stratification to HTBF or HT based on diagnosis (functional defaecation disorder vs. no functional defaecation disorder) by radio-physiological investigations (INVEST). METHOD: This was a parallel three-arm randomized single-blinded controlled trial, permitting two randomized comparisons: HTBF versus HT alone; INVEST- versus no-INVEST-guided intervention. The inclusion criteria were age 18-70 years; attending specialist hospitals in England; self-reported constipation for >6 months; refractory to basic treatment. The main exclusions were secondary constipation and previous experience of the trial interventions. The primary outcome was the mean change in Patient Assessment of Constipation Quality of Life score at 6 months on intention to treat. The secondary outcomes were validated disease-specific and psychological questionnaires and cost-effectiveness (based on EQ-5D-5L). RESULTS: In all, 182 patients were randomized 3:3:2 (target 384): HT n = 68; HTBF n = 68; INVEST-guided treatment n = 46. All interventions had similar reductions (improvement) in the primary outcome at 6 months (approximately -0.8 points of a 4-point scale) with no statistically significant difference between HT and HTBF (-0.03 points; 95% CI -0.33 to 0.27; P = 0.85) or INVEST versus no-INVEST (0.22; -0.11 to 0.55; P = 0.19). Secondary outcomes showed a benefit for all interventions with no evidence of greater cost-effectiveness of HTBF or INVEST compared with HT. CONCLUSION: The results of the study at 6 months were inconclusive. However, with the caveat of under-recruitment and further attrition at 6 months, a simple, cheaper approach to intervention may be as clinically effective and more cost-effective than more complex and invasive approaches.

Development of an international glossary for clinical guidelines collaboration.

OBJECTIVES: Clinical practice guidelines (CPGs) are often created through collaboration among organizations. The use of inconsistent terminology may cause poor communication and delays. This study aimed to develop a glossary of terms related to collaboration in guideline development. STUDY DESIGN AND SETTING: A literature review of collaborative guidelines was performed to develop an initial list of terms related to guideline collaboration. The list of terms was presented to the members of the Guideline International Network Guidelines Collaboration Working Group, who provided presumptive definitions for each term and proposed additional terms to be included. The revised list was subsequently reviewed by an international, multidisciplinary panel of expert stakeholders. Recommendations received during this pre-Delphi review were implemented to augment an initial draft glossary. The glossary was then critically evaluated and refined through two rounds of Delphi surveys and a virtual consensus meeting with all panel members as Delphi participants. RESULTS: Forty-nine experts participated in the pre-Delphi survey, and 44 participated in the two-round Delphi process. Consensus was reached for 37 terms and definitions. CONCLUSION: Uptake and utilization of this guideline collaboration glossary by key organizations and stakeholder groups may facilitate collaboration among guideline-producing organizations by improving communication, minimizing conflicts, and increasing guideline development efficiency.

Evaluation of Meloidogyne Incognita and Rotylenchulus Reniformis Nematode-resistant Cotton Cultivars with Supplemental Corteva Agriscience Nematicides.

Meloidogyne incognita- and Rotylenchulus reniformis-resistant new cotton cultivars have recently become available, giving growers a new option in nematode management. The objectives of this study were: (i) to determine the yield potential of the new cultivars PHY 360 W3FE (M. incognita-resistant) and PHY 332 W3FE (R. reniformis-resistant) in nematode-infested fields and (ii) to evaluate the effects of combining the nematicides Reklemel (fluazaindolizine), Vydate C-LV (oxamyl), and the seed treatment BIOST Nematicide 100 (heat killed Burkholderia rinojenses and its non-living spent fermentation media) with resistant cotton cultivars on nematode population levels and lint yield. Field experiments in 2020 and 2021 indicated M. incognita population levels were 73% lower on PHY 360 W3FE (R) and 80% lower for R. reniformis on the PHY 332 W3FE (R) at 40 days after planting. Nematode eggs per gram of root were further reduced an average of 86% after the addition of Reklemel and Vydate C-LV when averaging both cultivars over the two years. Tests with BIOST Nematicide 100 + Reklemel + Vydate C-LV (0.56 + 2.5 L/ha) in both M. incognita and R. reniformis fields produced higher lint yields. Overall, planting PHY 360 W3FE (R) and PHY 332 W3FE (R) improved yields an average of 364 kg/ha while limiting nematode population increases. The addition of the nematicides further increased yields 152 kg/ha of the nematode-resistant cultivars.

Improved fistula plug outcome depends on the type of plug: a single-centre retrospective study.

AIM: Fistula-in-ano is a common condition that is potentially difficult to treat. In recent years 'sphincter-sparing' procedures have increased in popularity due to the lower rates of reported complications, such as incontinence. One such treatment is the fistula plug, which has seen varied success compared with other techniques. There are currently several plugs on the market and it is possible that difference in outcomes could be linked to the type of plug used. The aim of this study was to compare healing and complication rates between two fistula plugs in a single tertiary referral centre in the UK. METHOD: We conducted a single-centre retrospective analysis of all patients over the age of 18 years who underwent elective fistula plug insertion, with two different fistula plugs over a 13-year period. RESULTS: A total of 113 patients underwent fistula plug insertion (plug A n = 90; plug B n = 23). Plug B had been on the market for the final 4 years of the study period, hence the differing patient numbers. There was no difference in patient demographics, fistula type or aetiology of the fistula between the two plugs. Plug B had a significantly higher fistula healing rate compared with plug A (56.5% vs. 12.2%; p < 0.005). A quarter of all patients experienced a complication, 93% being those who had fistula plug A inserted. The most common complication was extrusion of the plug within 72 h of insertion. CONCLUSION: This study demonstrated significantly different outcomes according to the type of fistula plug used. Whilst current randomized controlled trials have not found a significant difference in healing rates when comparing one type of fistula plug to other treatment modalities, this study suggests that plug type may influence efficacy.

Genome-wide screening reveals the genetic basis of mammalian embryonic eye development.

BACKGROUND: Microphthalmia, anophthalmia, and coloboma (MAC) spectrum disease encompasses a group of eye malformations which play a role in childhood visual impairment. Although the predominant cause of eye malformations is known to be heritable in nature, with 80% of cases displaying loss-of-function mutations in the ocular developmental genes OTX2 or SOX2, the genetic abnormalities underlying the remaining cases of MAC are incompletely understood. This study intended to identify the novel genes and pathways required for early eye development. Additionally, pathways involved in eye formation during embryogenesis are also incompletely understood. This study aims to identify the novel genes and pathways required for early eye development through systematic forward screening of the mammalian genome. RESULTS: Query of the International Mouse Phenotyping Consortium (IMPC) database (data release 17.0, August 01, 2022) identified 74 unique knockout lines (genes) with genetically associated eye defects in mouse embryos. The vast majority of eye abnormalities were small or absent eyes, findings most relevant to MAC spectrum disease in humans. A literature search showed that 27 of the 74 lines had previously published knockout mouse models, of which only 15 had ocular defects identified in the original publications. These 12 previously published gene knockouts with no reported ocular abnormalities and the 47 unpublished knockouts with ocular abnormalities identified by the IMPC represent 59 genes not previously associated with early eye development in mice. Of these 59, we identified 19 genes with a reported human eye phenotype. Overall, mining of the IMPC data yielded 40 previously unimplicated genes linked to mammalian eye development. Bioinformatic analysis showed that several of the IMPC genes colocalized to several protein anabolic and pluripotency pathways in early eye development. Of note, our analysis suggests that the serine-glycine pathway producing glycine, a mitochondrial one-carbon donator to folate one-carbon metabolism (FOCM), is essential for eye formation. CONCLUSIONS: Using genome-wide phenotype screening of single-gene knockout mouse lines, STRING analysis, and bioinformatic methods, this study identified genes heretofore unassociated with MAC phenotypes providing models to research novel molecular and cellular mechanisms involved in eye development. These findings have the potential to hasten the diagnosis and treatment of this congenital blinding disease.

Patient perceptions of facilitators and barriers to reducing hazardous alcohol use among people living with HIV in East Africa.

BACKGROUND: Hazardous alcohol use among people living with HIV is associated with poor outcomes and increased morbidity and mortality. Understanding the hazardous drinking experiences of people living with HIV is needed to reduce their alcohol use. METHODS: We conducted 60 interviews among people living with HIV in East Africa with hazardous drinking histories. Interviews and Alcohol Use Disorder Identification Test (AUDIT) scores were conducted 41 - 60 months after their baseline assessment of alcohol use to identify facilitators and barriers to reduced alcohol use over time. RESULTS: People living with HIV who stopped or reduced hazardous drinking were primarily motivated by their HIV condition and desire for longevity. Facilitators of reduced drinking included health care workers' recommendations to reduce drinking (despite little counseling and no referrals) and social support. In those continuing to drink at hazardous levels, barriers to reduced drinking were stress, social environment, alcohol accessibility and alcohol dependency. CONCLUSIONS: Interventions that capacity-build professional and lay health care workers with the skills and resources to decrease problematic alcohol use, along with alcohol cessation in peer support structures, should be explored.

Analysis of genome-wide knockout mouse database identifies candidate ciliopathy genes.

We searched a database of single-gene knockout (KO) mice produced by the International Mouse Phenotyping Consortium (IMPC) to identify candidate ciliopathy genes. We first screened for phenotypes in mouse lines with both ocular and renal or reproductive trait abnormalities. The STRING protein interaction tool was used to identify interactions between known cilia gene products and those encoded by the genes in individual knockout mouse strains in order to generate a list of "candidate ciliopathy genes." From this list, 32 genes encoded proteins predicted to interact with known ciliopathy proteins. Of these, 25 had no previously described roles in ciliary pathobiology. Histological and morphological evidence of phenotypes found in ciliopathies in knockout mouse lines are presented as examples (genes Abi2, Wdr62, Ap4e1, Dync1li1, and Prkab1). Phenotyping data and descriptions generated on IMPC mouse line are useful for mechanistic studies, target discovery, rare disease diagnosis, and preclinical therapeutic development trials. Here we demonstrate the effective use of the IMPC phenotype data to uncover genes with no previous role in ciliary biology, which may be clinically relevant for identification of novel disease genes implicated in ciliopathies.

Multivariate phenotype analysis enables genome-wide inference of mammalian gene function.

The function of the majority of genes in the human and mouse genomes is unknown. Investigating and illuminating this dark genome is a major challenge for the biomedical sciences. The International Mouse Phenotyping Consortium (IMPC) is addressing this through the generation and broad-based phenotyping of a knockout (KO) mouse line for every protein-coding gene, producing a multidimensional data set that underlies a genome-wide annotation map from genes to phenotypes. Here, we develop a multivariate (MV) statistical approach and apply it to IMPC data comprising 148 phenotypes measured across 4,548 KO lines. There are 4,256 (1.4% of 302,997 observed data measurements) hits called by the univariate (UV) model analysing each phenotype separately, compared to 31,843 (10.5%) hits in the observed data results of the MV model, corresponding to an estimated 7.5-fold increase in power of the MV model relative to the UV model. One key property of the data set is its 55.0% rate of missingness, resulting from quality control filters and incomplete measurement of some KO lines. This raises the question of whether it is possible to infer perturbations at phenotype-gene pairs at which data are not available, i.e., to infer some in vivo effects using statistical analysis rather than experimentation. We demonstrate that, even at missing phenotypes, the MV model can detect perturbations with power comparable to the single-phenotype analysis, thereby filling in the complete gene-phenotype map with good sensitivity. A factor analysis of the MV model's fitted covariance structure identifies 20 clusters of phenotypes, with each cluster tending to be perturbed collectively. These factors cumulatively explain 75% of the KO-induced variation in the data and facilitate biological interpretation of perturbations. We also demonstrate that the MV approach strengthens the correspondence between IMPC phenotypes and existing gene annotation databases. Analysis of a subset of KO lines measured in replicate across multiple laboratories confirms that the MV model increases power with high replicability.

Site-Level Comprehensiveness of Care Is Associated with Individual Clinical Retention Among Adults Living with HIV in International Epidemiology Databases to Evaluate AIDS, a Global HIV Cohort Collaboration, 2000-2016.

Retention in care (RIC) reduces HIV transmission and associated morbidity and mortality. We examined whether delivery of comprehensive services influenced individual RIC within the International epidemiology Databases to Evaluate AIDS (IeDEA) network. We collected site data through IeDEA assessments 1.0 (2000-2009) and 2.0 (2010-2016). Each site received a comprehensiveness score for service availability (1 = present, 0 = absent), with tallies ranging from 0 to 7. We obtained individual-level cohort data for adults with at least one visit from 2000 to 2016 at sites responding to either assessment. Person-time was recorded annually, with RIC defined as completing two visits at least 90 days apart in each calendar year. Multivariable modified Poisson regression clustered by site yielded risk ratios and predicted probabilities for individual RIC by comprehensiveness. Among 347,060 individuals in care at 122 sites with 1,619,558 person-years of follow-up, 69.8% of person-time was retained in care, varying by region from 53.8% (Asia-Pacific) to 82.7% (East Africa); RIC improved by about 2% per year from 2000 to 2016 (p = 0.012). Every site provided CD4+ count testing, and >90% of individuals received care at sites that provided combination antiretroviral therapy adherence measures, prevention of mother-to-child transmission, tuberculosis screening, HIV-related prevention, and community tracing services. In adjusted models, individuals at sites with more comprehensive services had higher probabilities of RIC (0.71, 0.74, and 0.83 for scores 5, 6, and 7, respectively; p = 0.019). Within IeDEA, greater site-level comprehensiveness of services was associated with improved individual RIC. Much work remains in exploring this relationship, which may inform HIV clinical practice and health systems planning.

Human-specific gene CT47 blocks PRMT5 degradation to lead to meiosis arrest.

Exploring the functions of human-specific genes (HSGs) is challenging due to the lack of a tractable genetic model system. Testosterone is essential for maintaining human spermatogenesis and fertility, but the underlying mechanism is unclear. Here, we identified Cancer/Testis Antigen gene family 47 (CT47) as an essential regulator of human-specific spermatogenesis by stabilizing arginine methyltransferase 5 (PRMT5). A humanized mouse model revealed that CT47 functions to arrest spermatogenesis by interacting with and regulating CT47/PRMT5 accumulation in the nucleus during the leptotene/zygotene-to-pachytene transition of meiosis. We demonstrate that testosterone induces nuclear depletion of CT47/PRMT5 and rescues leptotene-arrested spermatocyte progression in humanized testes. Loss of CT47 in human embryonic stem cells (hESCs) by CRISPR/Cas9 led to an increase in haploid cells but blocked the testosterone-induced increase in haploid cells when hESCs were differentiated into haploid spermatogenic cells. Moreover, CT47 levels were decreased in nonobstructive azoospermia. Together, these results established CT47 as a crucial regulator of human spermatogenesis by preventing meiosis initiation before the testosterone surge.

AAV-mediated rescue of Eps8 expression in vivo restores hair-cell function in a mouse model of recessive deafness.

The transduction of acoustic information by hair cells depends upon mechanosensitive stereociliary bundles that project from their apical surface. Mutations or absence of the stereociliary protein EPS8 cause deafness in humans and mice, respectively. Eps8 knockout mice (Eps8 -/- ) have hair cells with immature stereocilia and fail to become sensory receptors. Here, we show that exogenous delivery of Eps8 using Anc80L65 in P1-P2 Eps8 -/- mice in vivo rescued the hair bundle structure of apical-coil hair cells. Rescued hair bundles correctly localize EPS8, WHIRLIN, MYO15, and BAIAP2L2, and generate normal mechanoelectrical transducer currents. Inner hair cells with normal-looking stereocilia re-expressed adult-like basolateral ion channels (BK and KCNQ4) and have normal exocytosis. The number of hair cells undergoing full recovery was not sufficient to rescue hearing in Eps8 -/- mice. Adeno-associated virus (AAV)-transduction of P3 apical-coil and P1-P2 basal-coil hair cells does not rescue hair cells, nor does Anc80L65-Eps8 delivery in adult Eps8 -/- mice. We propose that AAV-induced gene-base therapy is an efficient strategy to recover the complex hair-cell defects in Eps8 -/- mice. However, this therapeutic approach may need to be performed in utero since, at postnatal ages, Eps8 -/- hair cells appear to have matured or accumulated damage beyond the point of repair.

Identifying genetic determinants of inflammatory pain in mice using a large-scale gene-targeted screen.

ABSTRACT: Identifying the genetic determinants of pain is a scientific imperative given the magnitude of the global health burden that pain causes. Here, we report a genetic screen for nociception, performed under the auspices of the International Mouse Phenotyping Consortium. A biased set of 110 single-gene knockout mouse strains was screened for 1 or more nociception and hypersensitivity assays, including chemical nociception (formalin) and mechanical and thermal nociception (von Frey filaments and Hargreaves tests, respectively), with or without an inflammatory agent (complete Freund's adjuvant). We identified 13 single-gene knockout strains with altered nocifensive behavior in 1 or more assays. All these novel mouse models are openly available to the scientific community to study gene function. Two of the 13 genes (Gria1 and Htr3a) have been previously reported with nociception-related phenotypes in genetically engineered mouse strains and represent useful benchmarking standards. One of the 13 genes (Cnrip1) is known from human studies to play a role in pain modulation and the knockout mouse reported herein can be used to explore this function further. The remaining 10 genes (Abhd13, Alg6, BC048562, Cgnl1, Cp, Mmp16, Oxa1l, Tecpr2, Trim14, and Trim2) reveal novel pathways involved in nociception and may provide new knowledge to better understand genetic mechanisms of inflammatory pain and to serve as models for therapeutic target validation and drug development.

Neuroplastin genetically interacts with Cadherin 23 and the encoded isoform Np55 is sufficient for cochlear hair cell function and hearing.

Mammalian hearing involves the mechanoelectrical transduction (MET) of sound-induced fluid waves in the cochlea. Essential to this process are the specialised sensory cochlear cells, the inner (IHCs) and outer hair cells (OHCs). While genetic hearing loss is highly heterogeneous, understanding the requirement of each gene will lead to a better understanding of the molecular basis of hearing and also to therapeutic opportunities for deafness. The Neuroplastin (Nptn) gene, which encodes two protein isoforms Np55 and Np65, is required for hearing, and homozygous loss-of-function mutations that affect both isoforms lead to profound deafness in mice. Here we have utilised several distinct mouse models to elaborate upon the spatial, temporal, and functional requirement of Nptn for hearing. While we demonstrate that both Np55 and Np65 are present in cochlear cells, characterisation of a Np65-specific mouse knockout shows normal hearing thresholds indicating that Np65 is functionally redundant for hearing. In contrast, we find that Nptn-knockout mice have significantly reduced maximal MET currents and MET channel open probabilities in mature OHCs, with both OHCs and IHCs also failing to develop fully mature basolateral currents. Furthermore, comparing the hearing thresholds and IHC synapse structure of Nptn-knockout mice with those of mice that lack Nptn only in IHCs and OHCs shows that the majority of the auditory deficit is explained by hair cell dysfunction, with abnormal afferent synapses contributing only a small proportion of the hearing loss. Finally, we show that continued expression of Neuroplastin in OHCs of adult mice is required for membrane localisation of Plasma Membrane Ca2+ ATPase 2 (PMCA2), which is essential for hearing function. Moreover, Nptn haploinsufficiency phenocopies Atp2b2 (encodes PMCA2) mutations, with heterozygous Nptn-knockout mice exhibiting hearing loss through genetic interaction with the Cdh23ahl allele. Together, our findings provide further insight to the functional requirement of Neuroplastin for mammalian hearing.

INFRAFRONTIER quality principles in systemic phenotyping.

Improving reproducibility and replicability in preclinical research is a widely discussed and pertinent topic, especially regarding ethical responsibility in animal research. INFRAFRONTIER, the European Research Infrastructure for the generation, phenotyping, archiving, and distribution of model mammalian genomes, is addressing this issue by developing internal quality principles for its different service areas, that provides a quality framework for its operational activities. This article introduces the INFRAFRONTIER Quality Principles in Systemic Phenotyping of genetically altered mouse models. A total of 11 key principles are included, ranging from general requirements for compliance with guidelines on animal testing, to the need for well-trained personnel and more specific standards such as the exchange of reference lines. Recently established requirements such as the provision of FAIR (Findable, Accessible, Interoperable, Reusable) data are also addressed. For each quality principle, we have outlined the specific context, requirements, further recommendations, and key references.

Advances in mouse genetics for the study of human disease.

The mouse is the pre-eminent model organism for studies of mammalian gene function and has provided an extraordinarily rich range of insights into basic genetic mechanisms and biological systems. Over several decades, the characterization of mouse mutants has illuminated the relationship between gene and phenotype, providing transformational insights into the genetic bases of disease. However, if we are to deliver the promise of genomic and precision medicine, we must develop a comprehensive catalogue of mammalian gene function that uncovers the dark genome and elucidates pleiotropy. Advances in large-scale mouse mutagenesis programmes allied to high-throughput mouse phenomics are now addressing this challenge and systematically revealing novel gene function and multi-morbidities. Alongside the development of these pan-genomic mutational resources, mouse genetics is employing a range of diversity resources to delineate gene-gene and gene-environment interactions and to explore genetic context. Critically, mouse genetics is a powerful tool for assessing the functional impact of human genetic variation and determining the causal relationship between variant and disease. Together these approaches provide unique opportunities to dissect in vivo mechanisms and systems to understand pathophysiology and disease. Moreover, the provision and utility of mouse models of disease has flourished and engages cumulatively at numerous points across the translational spectrum from basic mechanistic studies to pre-clinical studies, target discovery and therapeutic development.