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Colorectal carcinoma (CRC) is a common cause of mortality1, but a comprehensive description of its genomic landscape is lacking2–9. 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 Escherichiacolipks+colibactin in rectal cancers10and the importance of the SBS93 signature11–13, which suggests that diet or smoking is a risk factor. Immune-escape driver mutations14are 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, BRCA1and IDH1), highlighting the role of whole-genome sequencing in optimizing patient care.

As hippocampal neurons respond to diverse types of information1, a subset assembles into microcircuits representing a memory2. Those neurons typically undergo energy-intensive molecular adaptations, occasionally resulting in transient DNA damage3–5. Here we found discrete clusters of excitatory hippocampal CA1 neurons with persistent double-stranded DNA (dsDNA) breaks, nuclear envelope ruptures and perinuclear release of histone and dsDNA fragments hours after learning. Following these early events, some neurons acquired an inflammatory phenotype involving activation of TLR9 signalling and accumulation of centrosomal DNA damage repair complexes6. Neuron-specific knockdown of Tlr9impaired memory while blunting contextual fear conditioning-induced changes of gene expression in specific clusters of excitatory CA1 neurons. Notably, TLR9 had an essential role in centrosome function, including DNA damage repair, ciliogenesis and build-up of perineuronal nets. We demonstrate a novel cascade of learning-induced molecular events in discrete neuronal clusters undergoing dsDNA damage and TLR9-mediated repair, resulting in their recruitment to memory circuits. With compromised TLR9 function, this fundamental memory mechanism becomes a gateway to genomic instability and cognitive impairments implicated in accelerated senescence, psychiatric disorders and neurodegenerative disorders. Maintaining the integrity of TLR9 inflammatory signalling thus emerges as a promising preventive strategy for neurocognitive deficits.

Here the Human Pangenome Reference Consortium presents a first draft of the human pangenome reference. The pangenome contains 47 phased, diploid assemblies from a cohort of genetically diverse individuals1. These assemblies cover more than 99% of the expected sequence in each genome and are more than 99% accurate at the structural and base pair levels. Based on alignments of the assemblies, we generate a draft pangenome that captures known variants and haplotypes and reveals new alleles at structurally complex loci. We also add 119 million base pairs of euchromatic polymorphic sequences and 1,115 gene duplications relative to the existing reference GRCh38. Roughly 90 million of the additional base pairs are derived from structural variation. Using our draft pangenome to analyse short-read data reduced small variant discovery errors by 34% and increased the number of structural variants detected per haplotype by 104% compared with GRCh38-based workflows, which enabled the typing of the vast majority of structural variant alleles per sample.

Various species of the intestinal microbiota have been associated with the development of colorectal cancer1,2, but it has not been demonstrated that bacteria have a direct role in the occurrence of oncogenic mutations. Escherichia colican carry the pathogenicity island pks, which encodes a set of enzymes that synthesize colibactin3. This compound is believed to alkylate DNA on adenine residues4,5and induces double-strand breaks in cultured cells3. Here we expose human intestinal organoids to genotoxic pks+E. coliby repeated luminal injection over five months. Whole-genome sequencing of clonal organoids before and after this exposure revealed a distinct mutational signature that was absent from organoids injected with isogenic pks-mutant bacteria. The same mutational signature was detected in a subset of 5,876 human cancer genomes from two independent cohorts, predominantly in colorectal cancer. Our study describes a distinct mutational signature in colorectal cancer and implies that the underlying mutational process results directly from past exposure to bacteria carrying the colibactin-producing pkspathogenicity island.

Forest edges influence more than half of the world’s forests and contribute to worldwide declines in biodiversity and ecosystem functions. However, predicting these declines is challenging in heterogeneous fragmented landscapes. Here we assembled a global dataset on species responses to fragmentation and developed a statistical approach for quantifying edge impacts in heterogeneous landscapes to quantify edge-determined changes in abundance of 1,673 vertebrate species. We show that the abundances of 85% of species are affected, either positively or negatively, by forest edges. Species that live in the centre of the forest (forest core), that were more likely to be listed as threatened by the International Union for Conservation of Nature (IUCN), reached peak abundances only at sites farther than 200–400 m from sharp high-contrast forest edges. Smaller-bodied amphibians, larger reptiles and medium-sized non-volant mammals experienced a larger reduction in suitable habitat than other forest-core species. Our results highlight the pervasive ability of forest edges to restructure ecological communities on a global scale.

WE have obtained preparations of peripheral nerve tissue in culture which provide either Schwann cell populations, essentially free of connective tissue cells such as fibroblasts, or outgrowing neurites from sensory (or autonomic) ganglia entirely free of ensheathing Schwann cells or connective tissue elements. Thus, these two major elements of peripheral nerve can be studied and characterised separately or in recombination. We report here that the ‘bare’ sensory ganglion neurite provides a potent stimulus for thymidine incorporation and mitosis in Schwann cells.

THE biosynthesis of methyl mercury from mercuric ion, by microorganisms which live in sediments polluted with mercury, is of special significance to the bio-accumulation of mercury1–3. Although the mechanism of methyl mercury biosynthesis is understood to a large extent at the molecular level4–6, very little is known about the mechanisms of molecular interaction in both the bio-accumulation and the neurotoxicity of this compound. It is clear that ingestion by humans of food contaminated by methyl mercury leads to the synthesis of methyl mercury chloride in the stomach, and this, being very non-polar, is easily transported into the blood stream7. The distribution of methyl mercury in animals is characteristically different from that of inorganic mercury, in that alkyl mercury compounds have a tendency to partition into the lipids, or hydrophobic regions of the cell8.

Recovery from demyelinating events in the adult central nervous system (CNS) may depend in some situations on the generation, by cell division, of new oligodendrocytes (ODCs)1. Adult ODCs, identified by morphological criteria, have been shown to divide in vivo in response to induced demyelination or to physical trauma2,3, although the factors that elicit this response are unknown. Adult ODCs do not proliferate in vitro under normal conditions (ref. 4 and P.M.W., unpublished observations). Encouraged by observations that axons provide a mitogenic stimulus for Schwann cells5,6and support the proliferation of embryonic ODC progenitors7, we have studied the response of adult ODCs, identified by immunocytological criteria, to axons of dorsal root ganglion neurones in culture. We have now found that adult ODCs proliferate in vitro when neurones are present but not when neurones are absent, suggesting that neurones can elicit ODC division under the conditions prevailing in our culture system.

Methylglyoxal preferentially sensitizes anoxic bacterial and mammalian cells to the lethal effects of ionizing radiation. The radio-protective effect of anoxia on mammalian cells is effectively abolished in the presence of methylglyoxal, whereas sensitization of oxygenated mammalian cells is slight.

SEVERAL compounds have now been described as adrenergic β-receptor antagonists including dichloroisoprenaline1pronethalol (‘Alderlin’)2, propranolol (‘Inderal’)3, MJ 1999 (ref. 4), and INPEA5. Propranolol is about ten times more active than the other compounds in blocking the inotropic and chronotropic actions of catecholamines6. Studies with pronethalol and propranolol have shown that adrenergic β-receptor antagonists are valuable in the treatment of various clinical disorders7–11. The use of pronethalol was restricted when it was shown to be a potential carcinogenic agent in mice12; propranolol is devoid of this action13. This communication describes some of the pharmacological properties of a new adrenergic β-receptor antagonist 1-isopropylamino-3-(3-tolyloxy)-2-propanol hydrochloride (‘I.C.I. 45,763’), selected from a series of phenoxypropanolamines synthesized by Crowther Smith and Wood14.

FOR decades, the closeness of the 11.1-yr cycle of solar activity and the 11.86-yr period of Jupiter has been noted, along with some speculation that the planets may have a causal effect on triggering solar activity. Two studies1,2have presented a planetary function which stays in phase for hundreds of years, and both of them considered the influence of the planets with large values of mass/(distance to Sun)3or (mi/di3), namely Jupiter, Venus, Earth, and Mercury, although Mercury effects were not evaluated quantitatively in either case because of the assumption that they would represent a short term perturbation. Okal and Anderson3indicate that Mercury effects can be important and that the magnitude of the tides of the Sun do not have the same power spectrum as the solar activity. Although this paper does not consider Mercury, it presents a more general model than just a tidal concept; tides are likely to be less important than torque effects on the oblate spinning Sun, for example. The study reported in ref. 3 was limited to an evaluation of the maximum tidal potential. Lack of correlation of this function with solar activity is not equivalent to reducing the credibility of all planetary hypotheses of solar activity.

Ammonia is toxic to all vertebrates. It can be converted to the less toxic urea, but this is a metabolically expensive process1found only in terrestrial vertebrates that cannot readily excrete ammonia and marine fish that use urea as an osmotic filler. Freshwater fish mostly excrete ammonia2,3with only a small quantity of urea4,5. It seems the ornithine cycle for urea production has been sup-pressed in all freshwater teleosts6except for some airbreathers which, when exposed to air, increase urea synthesis via the cycle7. Here we show that the tilapia fish Oreochromls alcalicus grahami, the only fish living in Lake Magadi, an alkaline soda lake (pH = 9.6–10) in the Kenyan Rift Valley, excretes exclusively urea and has ornithine–urea cycle enzymes in its liver. A closely related species that lives in water at pH7.1 lacks these enzymes and excretes mainly ammonia with small amounts of urea produced via uricolysis4. It dies within 60 min when placed in water from Lake Magadi. We suggest that urea production via the ornithine-urea cycle permits O. a. grahami to survive the very alkaline conditions in Lake Magadi.

THERE have been incidences of extensive alkyl-mercury poisoning in Japan and Sweden. In Japan a large number of people belonging to the fishing population around Minamata Bay were seriously affected by what is now called Minamata disease. This incident was traced back to pollution of the bay with the mercury containing effluent of a large chemical plant. When methyl thiomethyl-mercury was isolated from shellfish in the area of the bay it was suggested that mercury could be alkylated by “plankton and other marine life”2. It was discovered later that the spent catalyst of an acetaldehyde reactor, which caused the pollution, contained approximately 1 per cent methyl mercury; and the biological methylation of mercury was thought to be insignificant.

CELLULASES classified as Cxattack soluble derivatives of cellulose, such as carboxymethylcellulose or hydroxyethylcellulose, and also substrates such as alkali or acid swollen cellulose. Highly ordered cellulose as in the cotton fibre is, however, not attacked. The attack on native cellulose is a two-step process and the first of these steps probably involves an enzyme (so-called C1) which attacks the native cellulose in some unknown fashion to produce a reactive cellulose1.

DR. D. V. AGER has recently reported the views of the British Mesozoic Committee on the conclusions of the colloquium held at Luxembourg in 1962 on the stages of the Mesozoic of the Mediterranean countries1. This present communication is intended to show that not all British geologists interested in the subject accept these conclusions.

KAUFMAN1has reported that 5-iodo-2′-deoxy-uridine (IUDR or IDU), the deoxyribonucleoside of 5-iodouracil, is effective in controlling herpes simplex keratitis in rabbit and human eyes. IUDR2, 5-iodo-2′-deoxycytidine (ICDR), that is, the deoxyribonucleoside of 5-iodocytosine3, as well as their 3′,5′-diacetyl derivatives, were synthesized with the view of examination of them as potential chemotherapeutic agents in cancer. Both IUDR and ICDR have been shown to inhibit the biosynthesis of deoxyribonucleic acid (DNA) and, in addition, to be incorporated as IUDR 5′-phosphate into DNA, in place of thymidine 5′-phosphate4–6. This communication confirms the efficacy of IUDR in the treatment of an infection of rabbit eyes with a DNA-virus, namely, herpes simplex, and describes a similar anti-viral activity for ICDR and 3′,5′-diacetyl-5-iodo-2′-deoxyuridine (Ac2IUDR); in addition, a preliminary test of 3′,5′-diacetyl-5-iodo-2′-deoxyuridine (Ac2IUDR); has indicated that this derivative is also active.