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Humans deploy a number of specific behaviours for forming social bonds, one of which is laughter. However, two questions have not yet been investigated with respect to laughter: (1) Does laughter increase the sense of bonding to those with whom we laugh? and (2) Does laughter facilitate prosocial generosity? Using changes in pain threshold as a proxy for endorphin upregulation in the brain and a standard economic game (the Dictator Game) as an assay of prosociality, we show that laughter does trigger the endorphin system and, through that, seems to enhance social bonding, but it does not reliably influence donations to others. This suggests that social bonding and prosociality may operate via different mechanisms, or on different time scales, and relate to different functional objectives.

Diffuse gliomas are the commonest malignant primary brain tumour in adults. Herein, we present analysis of the genomic landscape of adult glioma, by whole genome sequencing of 403 tumours (256 glioblastoma, 89 astrocytoma, 58 oligodendroglioma; 338 primary, 65 recurrence). We identify an extended catalogue of recurrent coding and non-coding genetic mutations that represents a source for future studies and provides a high-resolution map of structural variants, copy number changes and global genome features including telomere length, mutational signatures and extrachromosomal DNA. Finally, we relate these to clinical outcome. As well as identifying drug targets for treatment of glioma our findings offer the prospect of improving treatment allocation with established targeted therapies. The genomic landscape of diffuse gliomas remains to be characterised. Here, the authors perform whole genome sequencing of 403 tumours and identify recurrent coding and non-coding genetic mutations, their associations with clinical outcomes and potential therapeutic targets.

Background Single base substitution (SBS) mutations, particularly C > T and T > C, are increased owing to unrepaired DNA replication errors in mismatch repair-deficient (MMRd) cancers. Excess CpG > TpG mutations have been reported in MMRd cancers defective in mismatch detection (dMutSα), but not in mismatch correction (dMutLα). Somatic CpG > TpG mutations conventionally result from unrepaired spontaneous deamination of 5’-methylcytosine throughout the cell cycle, causing T:G mismatches and signature SBS1. It has been proposed that MutSα detects those mismatches, prior to error correction by base excision repair (BER). However, other evidence appears inconsistent with that hypothesis: for example, MutSα is specifically expressed in S/G 2 phases of the cell cycle, and defects in replicative DNA polymerase proofreading specifically cause excess CpG > TpG mutations in signature SBS10b. Methods We analysed mutation spectra and COSMIC mutation signatures in whole-genome sequencing data from 1803 colorectal cancers (164 dMutLα, 20 dMutSα) and 596 endometrial cancers (103 dMutLα, 9 dMutSα) from the UK 100,000 Genomes Project. We mapped each C > T mutation to its genomic features, including normal DNA methylation state, replication timing, transcription strand, and replication strand, to investigate the mechanism(s) by which these mutations arise. Results We confirmed that dMutSα tumours specifically had higher CpG > TpG burdens than dMutLα tumours. We could fully reconstitute the observed dMutSα CpG > TpG mutation spectrum by adding CpG > TpG mutations in proportion to their SBS1 activity to the dMutLα spectrum. However, other evidence indicated that the SBS1 excess in dMutSα cancers did not come from 5’-methylcytosine deamination alone: non-CpG C > T mutations were also increased in dMutSα cancers; and, in contrast to tumours deficient in BER, CpG > TpG mutations were biased to the leading DNA replication strand, at similar levels in dMutSα and dMutLα cancers, suggesting an origin in DNA replication. Other substitution mutations usually corrected by BER were not increased in dMutSα tumours. Conclusions There is a CpG > TpG and SBS1 excess specific to dMutSα MMRd tumours, consistent with previous reports, and we find a general increase in somatic C > T mutations. Contrary to some other studies, the similar leading replication strand bias in both dMutSα and dMutLα tumours indicates that at least some of the excess CpG > TpG mutations arise via DNA replication errors, and not primarily via the replication-independent deamination of 5’-methylcytosine.

Colorectal carcinoma (CRC) is a common cause of mortality 1 , but a comprehensive description of its genomic landscape is lacking 2 – 9 . Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome. We extend the molecular pathways involved in CRC development, define four new common subgroups of microsatellite-stable CRC based on genomic features and show that these groups have independent prognostic associations. We also characterize several rare molecular CRC subgroups, some with potential clinical relevance, including cancers with both microsatellite and chromosomal instability. We demonstrate a spectrum of mutational profiles across the colorectum, which reflect aetiological differences. These include the role of Escherichia coli pks+ colibactin in rectal cancers 10 and the importance of the SBS93 signature 11 – 13 , which suggests that diet or smoking is a risk factor. Immune-escape driver mutations 14 are near-ubiquitous in hypermutant tumours and occur in about half of microsatellite-stable CRCs, often in the form of HLA copy number changes. Many driver mutations are actionable, including those associated with rare subgroups (for example, BRCA1 and IDH1 ), highlighting the role of whole-genome sequencing in optimizing patient care. Whole-genome sequencing of more than 2,000 colorectal carcinoma samples provides a highly detailed view of the genomic landscape of this cancer and identifies new driver mutations.

Peptides generated by proteasome-catalyzed splicing of noncontiguous amino acid sequences have been shown to constitute a source of nontemplated human leukocyte antigen class I (HLA-I) epitopes, but their role in pathogen-specific immunity remains unknown. CD8⁺ T cells are key mediators of HIV type 1 (HIV-1) control, and identification of novel epitopes to enhance targeting of infected cells is a priority for prophylactic and therapeutic strategies. To explore the contribution of proteasome-catalyzed peptide splicing (PCPS) to HIV-1 epitope generation, we developed a broadly applicable mass spectrometry-based discovery workflow that we employed to identify spliced HLA-I–bound peptides on HIV-infected cells. We demonstrate that HIV-1–derived spliced peptides comprise a relatively minor component of the HLA-I–bound viral immunopeptidome. Although spliced HIV-1 peptides may elicit CD8⁺ T cell responses relatively infrequently during infection, CD8⁺ T cells primed by partially overlapping contiguous epitopes in HIV-infected individuals were able to cross-recognize spliced viral peptides, suggesting a potential role for PCPS in restricting HIV-1 escape pathways. Vaccine-mediated priming of responses to spliced HIV-1 epitopes could thus provide a novel means of exploiting epitope targets typically underutilized during natural infection.

Although laughter forms an important part of human non-verbal communication, it has received rather less attention than it deserves in both the experimental and the observational literatures. Relaxed social (Duchenne) laughter is associated with feelings of wellbeing and heightened affect, a proximate explanation for which might be the release of endorphins. We tested this hypothesis in a series of six experimental studies in both the laboratory (watching videos) and naturalistic contexts (watching stage performances), using change in pain threshold as an assay for endorphin release. The results show that pain thresholds are significantly higher after laughter than in the control condition. This pain-tolerance effect is due to laughter itself and not simply due to a change in positive affect. We suggest that laughter, through an endorphin-mediated opiate effect, may play a crucial role in social bonding.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing for a detailed description of the somatic mutational landscape of ccRCC. We identify candidate driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for therapeutic interventions. Genomic characterisation identified patients with divergent clinical outcome; higher number of structural copy number alterations associated with poorer prognosis, whereas VHL mutations were independently associated with a better prognosis. The observations that higher T-cell infiltration is associated with better overall survival and that genetically predicted immune evasion is not common supports the rationale for immunotherapy. These findings should inform personalised surveillance and treatment strategies for ccRCC patients. The genomic landscape of clear cell renal cell carcinoma (ccRCC) remains to be comprehensively characterised. Here, whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project was used to identify potential drivers and clinical correlations to inform the development of therapies.

Testicular germ cell tumours (TGCT), which comprise seminoma and non-seminoma subtypes, are the most common cancers in young men. In this study, we present a comprehensive whole genome sequencing analysis of adult TGCTs. Leveraging samples from participants recruited via the UK National Health Service and data from the Genomics England 100,000 Genomes Project, our results provide an extended description of genomic elements underlying TGCT pathogenesis. This catalogue offers a comprehensive, high-resolution map of copy number alterations, structural variation, and key global genome features, including mutational signatures and analysis of extrachromosomal DNA amplification. This study establishes correlations between genomic alterations and histological diversification, revealing divergent evolutionary trajectories among TGCT subtypes. By reconstructing the chronological order of driver events, we identify a subgroup of adult TGCTs undergoing relatively late whole genome duplication. Additionally, we present evidence that human leukocyte antigen loss is a more prevalent mechanism of immune disruption in seminomas. Collectively, our findings provide valuable insights into the developmental and immune modulatory processes implicated in TGCT pathogenesis and progression. Testicular germ cell tumours (TGCT) are the most common cancers in young men. Here, the authors analyse the genomic landscape of TGCT using data from the Genomics England 100,000 Genomes Project, revealing divergent evolutionary trajectories and the prevalence of human leukocyte antigen loss.

This thesis uses genealogical trees to identify, date, and quantify patterns of admixture between Neandertals and individual modern human populations, using a combination of high quality data and parametric methodology. Previous methods on this subject have either approximated features of trees, or inferred them indirectly. Here, genealogical trees are used directly to understand the admixture process between humans and Neandertals by extending a recently developed method named CEPHi: Coalescent Estimation of Population History. CEPHi uses recombinationally cold regions of the human genome to build genealogical trees specifying the relationships between individuals in two input populations (one Neandertal, one human), including estimated population size histories, split times, and coalescence and mutation times. Using CEPHi, a Neandertal-human population split time of ~712,000 years in the past is estimated, as well as uncovering loci introduced by Neandertal-human admixture, revealing distinct bimodal distributions of estimated coalescence times between non-African and Neandertal haplotypes. A Neandertal population history is inferred, from the time of their split with humans up to ~50,000 years ago (the fossil age), showing this archaic species to have suffered a bottleneck at this time, consistent with leaving Africa, followed by a further reduction to extinction. Contrasting African-Neandertal and Eurasian-Neandertal analyses are used to define admixture using genealogical trees, and test our procedures in CEPHi via coalescent-based simulations. This region-level definition of admixture is used to specify sets of introgressed coldspots across 13 modern human populations. These sets are compared between pairs of populations, revealing information about the possible timing of interactions between Neandertals and modern humans, and sharing of admixture events between human groups, especially with respect to the split time between European and Asian populations. Online sets of introgressed regions for each of the four continents in our dataset are provided: African, American, Asian, and European. Finally, in order to investigate the variation in time of contact between Neandertals and individual human populations, a novel method is described and implemented which dates admixture between individual human populations and Neandertals, using information from genealogical trees. Dates of admixture are estimated as ~50-60,000 years in the past in European populations, and ~80-90,000 years in the past in Asian populations, suggestive of potentially somewhat distinct histories between European and Asian populations. This method can be applied to date any set of introgressed regions, including those shared between particular populations, enabling a clearer picture of the joint evolutionary history of modern humans, Neandertals, and other archaic species.