Peter Donnelly

Background: Multimorbidity (MM), the presence of 2 or more long-term conditions, and problem alcohol use are both significant global concerns associated with poor health outcomes and substantial socioeconomic consequences, but their relationship remains under-explored. This study estimates the prevalence of MM among people with alcohol-specific conditions (ASC, conditions entirely caused by alcohol consumption) and compares it to those without ASC.Methods: We searched six databases from inception until February 2026 for studies that included a measurement of MM prevalence in individuals with ASC. Pooled absolute prevalence of MM in people with ASC was calculated from studies with cross-sectional data. Prevalence odds ratio of MM between those with ASC and those without was calculated using a random-effects meta-analysis from studies with a control group. Sensitivity and meta-regression analyses examined covariate effects.Findings: From 34,727 citations 364 full-texts were reviewed, and 86 studies featuring 1,885,987 people with ASC were included. The absolute prevalence of MM in those with ASC was 38% (95% CI 33-44, k=86), with substantial heterogeneity across studies (I2 99.99%). The odds ratio of MM between those with and without ASC at a threshold of at least two long-term conditions was 2.63 times greater (95% CI 2.03-3.53, k=14, p<0.0001). Comparative prevalence was higher in younger populations with ASC compared to without (<45 years old, OR 3.41, 95%CI 2·17–5·36) than in older populations (≥45 years old, OR 1.83, 95% CI 1·36–2·46).Interpretation: This meta-analysis demonstrates that MM is common and disproportionately prevalent among people with ASC. The odds of MM prevalence in individuals with ASC, compared to those without, are particularly elevated in younger cohorts. These findings highlight a substantial disease burden and lend support to targeted screening, earlier intervention, and more integrated addiction, mental and physical healthcare, with important implications for service design, policy, and future research.

Mammalian meiotic recombination proceeds via repair of hundreds of programmed DNA double-strand breaks, which requires choreographed binding of RPA, DMC1, and RAD51 to single-stranded DNA substrates. High-resolution in vivo binding maps of these proteins provide insights into the underlying molecular mechanisms. When assayed in F₁-hybrid mice, these maps can distinguish the broken chromosome from the chromosome used as template for repair, revealing more mechanistic detail and enabling the structure of the recombination intermediates to be inferred. By applying CRISPR-Cas9 mutagenesis directly on F₁-hybrid embryos, we have extended this approach to explore the molecular detail of recombination when a key component is knocked out. As a proof of concept, we have generated hybrid biallelic knockouts ofDmc1and built maps of meiotic binding of RAD51 and RPA in them. DMC1 is essential for meiotic recombination, and comparison of these maps with those from wild-type mice is informative about the structure and timing of critical recombination intermediates. We observe redistribution of RAD51 binding and complete abrogation of D-loop recombination intermediates at a molecular level inDmc1mutants. These data provide insight on the configuration of RPA in D-loop intermediates and suggest that stable strand exchange proceeds via multiple rounds of strand invasion with template switching in mouse. Our methodology provides a high-throughput approach for characterization of gene function in meiotic recombination at low animal cost.

We present and assess the UK Biobank (UKB) Polygenic Risk Score (PRS) Release, a set of PRSs for 28 diseases and 25 quantitative traits being made available on the individuals in UKB. We also release a benchmarking software tool to enable like-for-like performance evaluation for different PRSs for the same disease or trait. Extensive benchmarking shows the PRSs in the UKB Release to outperform a broad set of 81 published PRSs. For many of the diseases and traits we also validate the PRS algorithms in other cohorts. The availability of PRSs for 53 traits on the same set of individuals also allows a systematic assessment of their properties, and the increased power of these PRSs increases the evidence for their potential clinical benefit.

Egg-laying mammals (monotremes) are the only extant mammalian outgroup to therians (marsupial and eutherian animals) and provide key insights into mammalian evolution^1,2. Here we generate and analyse reference genomes of the platypus (Ornithorhynchus anatinus) and echidna (Tachyglossus aculeatus), which represent the only two extant monotreme lineages. The nearly complete platypus genome assembly has anchored almost the entire genome onto chromosomes, markedly improving the genome continuity and gene annotation. Together with our echidna sequence, the genomes of the two species allow us to detect the ancestral and lineage-specific genomic changes that shape both monotreme and mammalian evolution. We provide evidence that the monotreme sex chromosome complex originated from an ancestral chromosome ring configuration. The formation of such a unique chromosome complex may have been facilitated by the unusually extensive interactions between the multi-X and multi-Y chromosomes that are shared by the autosomal homologues in humans. Further comparative genomic analyses unravel marked differences between monotremes and therians in haptoglobin genes, lactation genes and chemosensory receptor genes for smell and taste that underlie the ecological adaptation of monotremes.

During meiosis, homologous chromosomes pair (synapse) and recombine, enabling balanced segregation and generating genetic diversity. In many vertebrates, recombination initiates with double-strand breaks (DSBs) within hotspots where PRDM9 binds, and deposits H3K4me3 and H3K36me3. However, no protein(s) recognising this unique combination of histone marks have yet been identified. We identified Zcwpw1 , which possesses H3K4me3 and H3K36me3 recognition domains, as highly co-expressed with Prdm9 . Here, we show that ZCWPW1 has co-evolved with PRDM9 and, in human cells, is strongly and specifically recruited to PRDM9 binding sites, with higher affinity than sites possessing H3K4me3 alone. Surprisingly, ZCWPW1 also recognizes CpG dinucleotides, including within many Alu transposons. Male Zcwpw1 homozygous knockout mice show completely normal DSB positioning, but persistent DMC1 foci at many hotspots, particularly those more strongly bound by PRDM9, severe DSB repair and synapsis defects, and downstream sterility. Our findings suggest a model where ZCWPW1 recognition of PRDM9-bound sites on either the homologous, or broken, chromosome is critical for synapsis, and hence fertility. Graphical Abstract Legend: In humans and other species, recombination is initiated by double strand breaks at sites bound by PRDM9. Upon binding, PRDM9 deposits the histone marks H3K4me3 and H3K36me, but the functional importance of these marks has remained unknown. Here, we show that PRDM9 recruits ZCWPW1, a reader of both these marks, to its binding sites genome-wide. ZCWPW1 does not help position the breaks themselves, but is essential for their downstream repair and chromosome pairing, and ultimately meiotic success and fertility in mice.

Whole-genome sequencing (WGS) is becoming widely used in clinical medicine in diagnostic contexts and to inform treatment choice. Here we evaluate the potential of the Oxford Nanopore Technologies (ONT) MinION long-read sequencer for routine WGS by sequencing the reference sample NA12878 and the genome of an individual with ataxia-pancytopenia syndrome and severe immune dysregulation. We develop and apply a novel reference panel-free analytical method to infer and then exploit phase information which improves single-nucleotide variant (SNV) calling performance from otherwise modest levels. In the clinical sample, we identify and directly phase two non-synonymous de novo variants in SAMD9L, (OMIM #159550) inferring that they lie on the same paternal haplotype. Whilst consensus SNV-calling error rates from ONT data remain substantially higher than those from short-read methods, we demonstrate the substantial benefits of analytical innovation. Ongoing improvements to base-calling and SNV-calling methodology must continue for nanopore sequencing to establish itself as a primary method for clinical WGS.

Sequencing and the single sperm: During meiosis, homologous chromosomes undergo doublestrand breaks in DNA that can cross over, shuffling genetic material. However, not every double-strand break resolves in a crossover event. Hinch et al. wanted to determine the rules governing DNA recombination. They developed a method to sequence individual mouse sperm and applied it to mice carrying two different alleles of a protein involved in mammalian crossovers. A high-resolution genetic map revealed the relationships between the distribution of crossovers, proteins involved in recombination, and specific factors determining whether a double-strand break becomes a crossover. Science , this issue p. eaau8861

The Iberian Peninsula is linguistically diverse and has a complex demographic history, including a centuries-long period of Muslim rule. Here, we study the fine-scale genetic structure of its population, and the genetic impacts of historical events, leveraging powerful, haplotype-based statistical methods to analyse 1413 individuals from across Spain. We detect extensive fine-scale population structure at extremely fine scales (below 10 Km) in some regions, including Galicia. We identify a major east-west axis of genetic differentiation, and evidence of historical north to south population movement. We find regionally varying fractions of north-west African ancestry (0–11%) in modern-day Iberians, related to an admixture event involving European-like and north-west African-like source populations. We date this event to 860–1120 CE, implying greater genetic impacts in the early half of Muslim rule in Iberia. Together, our results indicate clear genetic impacts of population movements associated with both the Muslim conquest and the subsequent Reconquista.