Evidence for 28 genetic disorders discovered by combining healthcare and research data

De novo mutations in protein-coding genes are a well-established cause of developmental disorders. However, genes known to be associated with developmental disorders account for only a minority of the observed excess of such de novo mutations. Here, to identify previously undescribed genes associated with developmental disorders, we integrate healthcare and research exome-sequence data from 31,058 parent–offspring trios of individuals with developmental disorders, and develop a simulation-based statistical test to identify gene-specific enrichment of de novo mutations. We identified 285 genes that were significantly associated with developmental disorders, including 28 that had not previously been robustly associated with developmental disorders. Although we detected more genes associated with developmental disorders, much of the excess of de novo mutations in protein-coding genes remains unaccounted for. Modelling suggests that more than 1,000 genes associated with developmental disorders have not yet been described, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of genes associated with developmental disorders

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Developing a toolkit for the assessment and monitoring of musculoskeletal ageing

The complexities and heterogeneity of the ageing process have slowed the development of consensus on appropriate biomarkers of healthy ageing. The Medical Research Council–Arthritis Research UK Centre for Integrated research into Musculoskeletal Ageing (CIMA) is a collaboration between researchers and clinicians at the Universities of Liverpool, Sheffield and Newcastle. One of CIMA’s objectives is to ‘Identify and share optimal techniques and approaches to monitor age-related changes in all musculoskeletal tissues, and to provide an integrated assessment of musculoskeletal function’—in other words to develop a toolkit for assessing musculoskeletal ageing. This toolkit is envisaged as an instrument that can be used to characterise and quantify musculoskeletal function during ‘normal’ ageing, lend itself to use in large-scale, internationally important cohorts, and provide a set of biomarker outcome measures for epidemiological and intervention studies designed to enhance healthy musculoskeletal ageing. Such potential biomarkers include: biochemical measurements in biofluids or tissue samples, in vivo measurements of body composition, imaging of structural and physical properties, and functional tests. This review assesses candidate biomarkers of musculoskeletal ageing under these four headings, details their biological bases, strengths and limitations, and makes practical recommendations for their use. In addition, we identify gaps in the evidence base and priorities for further research on biomarkers of musculoskeletal ageing

UKRI MRC National Musculoskeletal Ageing Network: strategic prioritisation to increase healthy lifespan and minimise physical frailty

The UKRI Medical Research Council National Musculoskeletal Ageing Network (Director: Professor Cyrus Cooper and Deputy-Director: Professor Nicholas Harvey) brings together, over a 2-year period, key UKRI MRC investments in musculoskeletal research: the MRC Lifecourse Epidemiology Centre, MRC-Versus Arthritis Centre for Integrated Research in Musculoskeletal Ageing (CIMA), MRC-Versus Arthritis Centre for Musculoskeletal Ageing Research (CMAR), MRC Epidemiology Unit, MRC Integrative Epidemiology Unit, and MRC Unit for Lifelong Health and Ageing. Together, these span the Universities of Southampton, Sheffield, Liverpool, Newcastle, Nottingham, Birmingham, Oxford, Bristol, Cambridge, and UCL, with further links to associated NIHR Biomedical Research Centres. This multidisciplinary collaboration will underpin a step change in musculoskeletal ageing research capacity and strategy (principally across the diseases osteoporosis, osteoarthritis, sarcopenia, and rheumatoid arthritis) by identifying key tractable research priorities; developing an integrated multidisciplinary and diversified technology partnership to address the identified research gaps; providing a platform to disseminate best practice; supporting early and mid-career researchers to build research capacity and develop technical expertise to ensure longevity to current UKRI investments; prosecuting an ongoing programme of innovative studies from discovery science to clinical impact.In this editorial, we briefly set out perspectives on the current landscape and identify research priorities fundamental to achieving healthy musculoskeletal ageing, as articulated and agreed at a scoping workshop of the Network held at the Academy of Medical Sciences, London, UK, on June 17, 2022