2021 assessment of the status of the West Coast Demersal Scalefish Resource

A recovery program for the West Coast Demersal Scalefish Resource was introduced between late 2007 and early 2010, based on the maintenance of retained catches of demersal species (overall suite and each indicator species) by both the commercial and recreational sectors below 50% of the catches reported in 2005/06 (original catch recovery benchmarks)

Probiotic modulation of symbiotic gut microbial–host metabolic interactions in a humanized microbiome mouse model

The transgenomic metabolic effects of exposure to either Lactobacillus paracasei or Lactobacillus rhamnosus probiotics have been measured and mapped in humanized extended genome mice (germ-free mice colonized with human baby flora). Statistical analysis of the compartmental fluctuations in diverse metabolic compartments, including biofluids, tissue and cecal short-chain fatty acids (SCFAs) in relation to microbial population modulation generated a novel top-down systems biology view of the host response to probiotic intervention. Probiotic exposure exerted microbiome modification and resulted in altered hepatic lipid metabolism coupled with lowered plasma lipoprotein levels and apparent stimulated glycolysis. Probiotic treatments also altered a diverse range of pathways outcomes, including amino-acid metabolism, methylamines and SCFAs. The novel application of hierarchical-principal component analysis allowed visualization of multicompartmental transgenomic metabolic interactions that could also be resolved at the compartment and pathway level. These integrated system investigations demonstrate the potential of metabolic profiling as a top-down systems biology driver for investigating the mechanistic basis of probiotic action and the therapeutic surveillance of the gut microbial activity related to dietary supplementation of probiotics

Genetic epidemiology of motor neuron disease-associated variants in the Scottish population

Genetic understanding of motor neuron disease (MND) has evolved greatly in the past 10 years, including the recent identification of association between MND and variants in TBK1 and NEK1. Our aim was to determine the frequency of pathogenic variants in known MND genes and to assess whether variants in TBK1 and NEK1 contribute to the burden of MND in the Scottish population. SOD1, TARDBP, OPTN, TBK1, and NEK1 were sequenced in 441 cases and 400 controls. In addition to 44 cases known to carry a C9orf72 hexanucleotide repeat expansion, we identified 31 cases and 2 controls that carried a loss-of-function or pathogenic variant. Loss-of-function variants were found in TBK1 in 3 cases and no controls and, separately, in NEK1 in 3 cases and no controls. This study provides an accurate description of the genetic epidemiology of MND in Scotland and provides support for the contribution of both TBK1 and NEK1 to MND susceptibility in the Scottish population

Distribution and medical impact of loss-of-function variants in the Finnish founder population.

Exome sequencing studies in complex diseases are challenged by the allelic heterogeneity, large number and modest effect sizes of associated variants on disease risk and the presence of large numbers of neutral variants, even in phenotypically relevant genes. Isolated populations with recent bottlenecks offer advantages for studying rare variants in complex diseases as they have deleterious variants that are present at higher frequencies as well as a substantial reduction in rare neutral variation. To explore the potential of the Finnish founder population for studying low-frequency (0.5-5%) variants in complex diseases, we compared exome sequence data on 3,000 Finns to the same number of non-Finnish Europeans and discovered that, despite having fewer variable sites overall, the average Finn has more low-frequency loss-of-function variants and complete gene knockouts. We then used several well-characterized Finnish population cohorts to study the phenotypic effects of 83 enriched loss-of-function variants across 60 phenotypes in 36,262 Finns. Using a deep set of quantitative traits collected on these cohorts, we show 5 associations (p<5×10⁻⁸) including splice variants in LPA that lowered plasma lipoprotein(a) levels (P = 1.5×10⁻¹¹⁷). Through accessing the national medical records of these participants, we evaluate the LPA finding via Mendelian randomization and confirm that these splice variants confer protection from cardiovascular disease (OR = 0.84, P = 3×10⁻⁴), demonstrating for the first time the correlation between very low levels of LPA in humans with potential therapeutic implications for cardiovascular diseases. More generally, this study articulates substantial advantages for studying the role of rare variation in complex phenotypes in founder populations like the Finns and by combining a unique population genetic history with data from large population cohorts and centralized research access to National Health Registers

The clinical and genetic spectrum of autosomal-recessive TOR1A-related disorders.

In the field of rare diseases, progress in molecular diagnostics led to the recognition that variants linked to autosomal-dominant neurodegenerative diseases of later onset can, in the context of biallelic inheritance, cause devastating neurodevelopmental disorders and infantile or childhood-onset neurodegeneration. TOR1A-associated arthrogryposis multiplex congenita 5 (AMC5) is a rare neurodevelopmental disorder arising from biallelic variants in TOR1A, a gene that in the heterozygous state is associated to torsion dystonia-1 (DYT1 or DYT-TOR1A), an early-onset dystonia with reduced penetrance. While 15 individuals with TOR1A-AMC5 have been reported (less than 10 in detail), a systematic investigation of the full disease-associated spectrum has not been conducted. Here, we assess the clinical, radiological and molecular characteristics of 57 individuals from 40 families with biallelic variants in TOR1A. Median age at last follow-up was 3 years (0-24 years). Most individuals presented with severe congenital flexion contractures (95%) and variable developmental delay (79%). Motor symptoms were reported in 79% and included lower limb spasticity and pyramidal signs, as well as gait disturbances. Facial dysmorphism was an integral part of the phenotype, with key features being a broad/full nasal tip, narrowing of the forehead and full cheeks. Analysis of disease-associated manifestations delineated a phenotypic spectrum ranging from normal cognition and mild gait disturbance to congenital arthrogryposis, global developmental delay, intellectual disability, absent speech and inability to walk. In a subset, the presentation was consistent with fetal akinesia deformation sequence with severe intrauterine abnormalities. Survival was 71% with higher mortality in males. Death occurred at a median age of 1.2 months (1 week - 9 years) due to respiratory failure, cardiac arrest, or sepsis. Analysis of brain MRI studies identified non-specific neuroimaging features, including a hypoplastic corpus callosum (72%), foci of signal abnormality in the subcortical and periventricular white matter (55%), diffuse white matter volume loss (45%), mega cisterna magna (36%) and arachnoid cysts (27%). The molecular spectrum included 22 distinct variants, defining a mutational hotspot in the C-terminal domain of the Torsin-1A protein. Genotype-phenotype analysis revealed an association of missense variants in the 3-helix bundle domain to an attenuated phenotype, while missense variants near the Walker A/B motif as well as biallelic truncating variants were linked to early death. In summary, this systematic cross-sectional analysis of a large cohort of individuals with biallelic TOR1A variants across a wide age-range delineates the clinical and genetic spectrum of TOR1A-related autosomal-recessive disease and highlights potential predictors for disease severity and survival

Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease

Inherited retinal disease is a common cause of visual impairment and represents a highly heterogeneous group of conditions. Here, we present findings from a cohort of 722 individuals with inherited retinal disease, who have had whole-genome sequencing (n = 605), whole-exome sequencing (n = 72), or both (n = 45) performed, as part of the NIHR-BioResource Rare Diseases research study. We identified pathogenic variants (single-nucleotide variants, indels, or structural variants) for 404/722 (56%) individuals. Whole-genome sequencing gives unprecedented power to detect three categories of pathogenic variants in particular: structural variants, variants in GC-rich regions, which have significantly improved coverage compared to whole-exome sequencing, and variants in non-coding regulatory regions. In addition to previously reported pathogenic regulatory variants, we have identified a previously unreported pathogenic intronic variant in $\textit{CHM}$ in two males with choroideremia. We have also identified 19 genes not previously known to be associated with inherited retinal disease, which harbor biallelic predicted protein-truncating variants in unsolved cases. Whole-genome sequencing is an increasingly important comprehensive method with which to investigate the genetic causes of inherited retinal disease.This work was supported by The National Institute for Health Research England (NIHR) for the NIHR BioResource – Rare Diseases project (grant number RG65966). The Moorfields Eye Hospital cohort of patients and clinical and imaging data were ascertained and collected with the support of grants from the National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital, National Health Service Foundation Trust, and UCL Institute of Ophthalmology, Moorfields Eye Hospital Special Trustees, Moorfields Eye Charity, the Foundation Fighting Blindness (USA), and Retinitis Pigmentosa Fighting Blindness. M.M. is a recipient of an FFB Career Development Award. E.M. is supported by UCLH/UCL NIHR Biomedical Research Centre. F.L.R. and D.G. are supported by Cambridge NIHR Biomedical Research Centre

An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge

There is tremendous potential for genome sequencing to improve clinical diagnosis and care once it becomes routinely accessible, but this will require formalizing research methods into clinical best practices in the areas of sequence data generation, analysis, interpretation and reporting. The CLARITY Challenge was designed to spur convergence in methods for diagnosing genetic disease starting from clinical case history and genome sequencing data. DNA samples were obtained from three families with heritable genetic disorders and genomic sequence data were donated by sequencing platform vendors. The challenge was to analyze and interpret these data with the goals of identifying disease-causing variants and reporting the findings in a clinically useful format. Participating contestant groups were solicited broadly, and an independent panel of judges evaluated their performance. RESULTS: A total of 30 international groups were engaged. The entries reveal a general convergence of practices on most elements of the analysis and interpretation process. However, even given this commonality of approach, only two groups identified the consensus candidate variants in all disease cases, demonstrating a need for consistent fine-tuning of the generally accepted methods. There was greater diversity of the final clinical report content and in the patient consenting process, demonstrating that these areas require additional exploration and standardization. CONCLUSIONS: The CLARITY Challenge provides a comprehensive assessment of current practices for using genome sequencing to diagnose and report genetic diseases. There is remarkable convergence in bioinformatic techniques, but medical interpretation and reporting are areas that require further development by many groups

Bi-allelic Loss-of-Function CACNA1B Mutations in Progressive Epilepsy-Dyskinesia.

The occurrence of non-epileptic hyperkinetic movements in the context of developmental epileptic encephalopathies is an increasingly recognized phenomenon. Identification of causative mutations provides an important insight into common pathogenic mechanisms that cause both seizures and abnormal motor control. We report bi-allelic loss-of-function CACNA1B variants in six children from three unrelated families whose affected members present with a complex and progressive neurological syndrome. All affected individuals presented with epileptic encephalopathy, severe neurodevelopmental delay (often with regression), and a hyperkinetic movement disorder. Additional neurological features included postnatal microcephaly and hypotonia. Five children died in childhood or adolescence (mean age of death: 9 years), mainly as a result of secondary respiratory complications. CACNA1B encodes the pore-forming subunit of the pre-synaptic neuronal voltage-gated calcium channel Cav2.2/N-type, crucial for SNARE-mediated neurotransmission, particularly in the early postnatal period. Bi-allelic loss-of-function variants in CACNA1B are predicted to cause disruption of Ca2+ influx, leading to impaired synaptic neurotransmission. The resultant effect on neuronal function is likely to be important in the development of involuntary movements and epilepsy. Overall, our findings provide further evidence for the key role of Cav2.2 in normal human neurodevelopment.MAK is funded by an NIHR Research Professorship and receives funding from the Wellcome Trust, Great Ormond Street Children's Hospital Charity, and Rosetrees Trust. E.M. received funding from the Rosetrees Trust (CD-A53) and Great Ormond Street Hospital Children's Charity. K.G. received funding from Temple Street Foundation. A.M. is funded by Great Ormond Street Hospital, the National Institute for Health Research (NIHR), and Biomedical Research Centre. F.L.R. and D.G. are funded by Cambridge Biomedical Research Centre. K.C. and A.S.J. are funded by NIHR Bioresource for Rare Diseases. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant number WT098051). We acknowledge support from the UK Department of Health via the NIHR comprehensive Biomedical Research Centre award to Guy's and St. Thomas' National Health Service (NHS) Foundation Trust in partnership with King's College London. This research was also supported by the NIHR Great Ormond Street Hospital Biomedical Research Centre. J.H.C. is in receipt of an NIHR Senior Investigator Award. The research team acknowledges the support of the NIHR through the Comprehensive Clinical Research Network. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR, Department of Health, or Wellcome Trust. E.R.M. acknowledges support from NIHR Cambridge Biomedical Research Centre, an NIHR Senior Investigator Award, and the University of Cambridge has received salary support in respect of E.R.M. from the NHS in the East of England through the Clinical Academic Reserve. I.E.S. is supported by the National Health and Medical Research Council of Australia (Program Grant and Practitioner Fellowship)

Comparisons between the biological characteristics of three co-occuring and reef-dwelling labrid species at two different latitudes

The first aim of this PhD thesis was to obtain sound quantitative biological data for three abundant and co-occurring reef-dwelling labrid species, i.e. the Western King Wrasse Coris auricularis, the Brown-spotted Wrasse Notolabrus parilus and the Southern Maori Wrasse Ophthalmolepis lineolatus, in the Jurien Bay Marine Park (JBMP) and in the waters off Perth, 250 km to the south. These data were acquired to undertake the following. 1. Determine whether the maximum body size and age and the instantaneous growth rate of each of these species are consistent with the Metabolic Theory of Ecology (MTE). 2. Test the hypothesis that each species is a protogynous hermaphrodite and that the size and age at maturity and sex change of each species have a similar relationship to its maximum size and age. 3. Test the hypothesis that the food resources in temperate Western Australia are partitioned among each of the three species at both of the above locations and that the species compositions of the prey of each labrid species differs between locations as a result of the differences that are likely to be present in the relative abundances of prey at these two different latitudes. The specific aims associated with the different aspects of the biology and, where appropriate, hypotheses concerning those aspects, are given in the respective chapters. The implications of the Metabolic Theory of Ecology (MTE) that certain variables for a species follow predictable trends with latitude, i.e. with temperature, was explored using data for three reef-dwelling species of labrid. The maximum length, mass and age of C. auricularis, N. parilus and O. lineolatus, when expressed as the average of the top 10 % of the values for those variables, were significantly greater (P generally < 0.001) in the waters off Perth at c. 32°S than in those of the Jurien Bay Marine Park at c. 30°S. While these latitudinal trends conform to the predictions of the MTE, the instantaneous growth rates of each species during the earlier part of life were similar at both latitudes. The greater rate of growth of each species throughout the remaining and majority of life at the higher latitude suggests either that less energy is required for basal metabolism and/or physical activity in the cooler environment, or that these species are enzymatically better adapted to the lower temperature. In terms of interspecific comparisons, the rank order of maximum length, mass and growth (in terms of both length and mass at age) of these species is the same at both latitudes, but the precise order does vary slightly among these variables. This indicates that the three species respond to the differences between the temperature and other environmental variables at the two latitudes in a similar relative manner. The growth of O. lineolatus was least in both latitudes, irrespective of whether size was expressed in terms of length or mass. The growth of C. auricularis was greater, however, than N. parilus when using length, but either less or the same when employing mass, reflecting a greater body mass at length of the latter species. This difference is relevant as it would appear more appropriate to use mass as the indicator variable when considering predictions based on metabolic rate as this is related to temperature in ectotherms. Growth curves fitted to both the lengths and masses at age for the males of each species lay above and largely parallel to those for their females at all ages, indicating that sex change is size dependent. The rate of instantaneous growth at a given mass for each species, which began to diverge as mass increased, was consistently greater for the cooler than warmer environment (latitude), a trend that does not conform to the predictions of the MTE. Examination of the histological characteristics of the gonads of a wide size and age range of C. auricularis, N. parilus and O. lineolatus from both the JBMP and waters off Perth, combined with the pattern of distribution of the lengths and ages of each sex, demonstrated that each of these three labrid species are protogynous hermaphrodites. The presence of two and young small C. auricularis with gonads consisting of both immature ovarian and testicular components suggests that this species, at least, may exhibit an early juvenile bisexual stage. All individuals of C. auricularis, N. parilus and O. lineolatus with lengths less than 186, 162 and 223 mm, respectively, and ages less than 3.1, 3.0 and 4.7 years, respectively, were females, whereas the largest and oldest individuals of each species were males. The lengths and ages of the other bisexual individuals of C. auricularis and those of N. parilus and O. lineolatus all fell within the respective length and age ranges at which both females and males of those species were found. The oocytes of these bisexuals were all at the previtellogenic stage, whereas the testicular component always contained spermatocytes and sometimes advanced spermatids. These characteristics suggest that these individuals are changing from female to male. While the spawning periods of each of C. auricularis, N. parilus and O. lineolatus in the two locations were similar, they differed markedly among those three species. This would reduce the potential for competition for food and space resources by the larvae and juveniles of these species. In the case of each species, a greater amount of energy was invested in gonadal development in the waters off Perth than in the JBMP, thereby parallelling the greater investment of energy in somatic growth in those waters. Thus, in the context of gonadal and somatic growth, each species is apparently better adapted to exploiting the environmental conditions found in the cooler temperatures at the higher latitude, i.e. waters off Perth, than to the warmer temperatures found at the lower latitude. Coris auricularis and O. lineolatus matured at a smaller length and younger age in the cooler waters off Perth than in the warmer environment of the JBMP, which is the converse of the pattern typically exhibited by ectothermic species. While N. parilus also matured at a younger age in the waters off Perth than in the JBMP, the difference was small and, in contrast to the other two species, maturation occurred at a greater length in the cooler environment. This study confirmed that the dietary compositions of C. auricularis, N. parilus and O. lineolatus differed significantly with latitude (i.e. between JBMP at c. 30°S and c. 32°S off Perth), changed with increasing body size and almost invariably differed among those species in the more offshore reefs in each location in which they cooccurred. Latitudinal differences in the dietary compositions of each species in exposed reefs typically reflected greater contributions by large crustaceans, bivalve molluscs, echinoids and annelids to the diets in the waters off Perth than in the JBMP, whereas the reverse was true for gastropods and small crustaceans. The diet of each species exhibited similar, but not identical, quantitative changes with increasing body size, with the contributions of small crustaceans declining and those of large crustaceans and echinoids increasing, while that of gastropods underwent little change. Within the JBMP, the dietary compositions of both C. auricularis and N. parilus were similar in exposed and sheltered reefs and the same was true for N. parilus in the sheltered reefs and interspersed areas of seagrass. The latter similarity demonstrated that, in both of those divergent habitat types, N. parilus feeds on prey associated with either the sand or the macrophytes that cover and lie between the reefs. Although the main dietary components of each species were the same, i.e. gastropods, small crustaceans (mainly amphipods and isopods), large crustaceans (particularly penaeids and brachyuran crabs) and echinoids, their contributions varied among those species, which accounts for the significant interspecific differences in diet. Coris auricularis had the most distinct diet, due mainly to ingesting greater volumes of small crustaceans, e.g. amphipods and isopods, and lesser volumes of large crustaceans, e.g. brachyuran crabs, which was associated with a relatively narrower mouth and smaller teeth and the absence of prominent canines at the rear of the jaw. The above intra and interspecific differences in dietary composition would reduce, on the south-west coast of Australia, the potential for competition for food among and within these three abundant labrids, each of which belongs to different genera within the Julidine clade

Advancing precision in histocompatibility and immunogenetics: a comprehensive review of the UCLA exchange program.

Precise typing of human leukocyte antigens (HLA) is crucial for clinical hematopoietic stem cell and solid organ transplantations, transfusion medicine, HLA-related disease association, and drug hypersensitivity analysis. The UCLA Cell Exchange program has played a vital role in providing educational and proficiency testing surveys to HLA laboratories worldwide for the past 5 decades. This article highlights the significant contribution of the UCLA Cell and DNA Exchange Programs in advancing HLA antibody testing, genotyping, crossmatches, and, more recently, virtual crossmatches. Additionally, we discuss future directions of the UCLA Cell Exchange program to support histocompatibility testing to adapt to the fast-evolving field of immunotherapy, tolerance and xenotransplantation