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Although cancer initiation and progression are generally associated with the accumulation of somatic mutations1,2, substantial epigenomic alterations underlie many aspects of tumorigenesis and cancer susceptibility3–6, suggesting that genetic mechanisms might not be the only drivers of malignant transformation7. However, whether purely non-genetic mechanisms are sufficient to initiate tumorigenesis irrespective of mutations has been unknown. Here, we show that a transient perturbation of transcriptional silencing mediated by Polycomb group proteins is sufficient to induce an irreversible switch to a cancer cell fate in Drosophila. This is linked to the irreversible derepression of genes that can drive tumorigenesis, including members of the JAK–STAT signalling pathway and zfh1, the fly homologue of the ZEB1oncogene, whose aberrant activation is required for Polycomb perturbation-induced tumorigenesis. These data show that a reversible depletion of Polycomb proteins can induce cancer in the absence of driver mutations, suggesting that tumours can emerge through epigenetic dysregulation leading to inheritance of altered cell fates.

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTXand OTX2. CBFA2T2is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES+KI67+unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB.

Here we describe the LifeTime Initiative, which aims to track, understand and target human cells during the onset and progression of complex diseases, and to analyse their response to therapy at single-cell resolution. This mission will be implemented through the development, integration and application of single-cell multi-omics and imaging, artificial intelligence and patient-derived experimental disease models during the progression from health to disease. The analysis of large molecular and clinical datasets will identify molecular mechanisms, create predictive computational models of disease progression, and reveal new drug targets and therapies. The timely detection and interception of disease embedded in an ethical and patient-centred vision will be achieved through interactions across academia, hospitals, patient associations, health data management systems and industry. The application of this strategy to key medical challenges in cancer, neurological and neuropsychiatric disorders, and infectious, chronic inflammatory and cardiovascular diseases at the single-cell level will usher in cell-based interceptive medicine in Europe over the next decade.

In cancer, recurrent somatic single-nucleotide variants—which are rare in most paediatric cancers—are confined largely to protein-coding genes1–3. Here we report highly recurrent hotspot mutations (r.3A>G) of U1 spliceosomal small nuclear RNAs (snRNAs) in about 50% of Sonic hedgehog (SHH) medulloblastomas. These mutations were not present across other subgroups of medulloblastoma, and we identified these hotspot mutations in U1 snRNA in only <0.1% of 2,442 cancers, across 36 other tumour types. The mutations occur in 97% of adults (subtype SHHδ) and 25% of adolescents (subtype SHHα) with SHH medulloblastoma, but are largely absent from SHH medulloblastoma in infants. The U1 snRNA mutations occur in the 5′ splice-site binding region, and snRNA-mutant tumours have significantly disrupted RNA splicing and an excess of 5′ cryptic splicing events. Alternative splicing mediated by mutant U1 snRNA inactivates tumour-suppressor genes (PTCH1) and activates oncogenes (GLI2and CCND2), and represents a target for therapy. These U1 snRNA mutations provide an example of highly recurrent and tissue-specific mutations of a non-protein-coding gene in cancer.

Study of the origin and development of cerebellar tumours has been hampered by the complexity and heterogeneity of cerebellar cells that change over the course of development. Here we use single-cell transcriptomics to study more than 60,000 cells from the developing mouse cerebellum and show that different molecular subgroups of childhood cerebellar tumours mirror the transcription of cells from distinct, temporally restricted cerebellar lineages. The Sonic Hedgehog medulloblastoma subgroup transcriptionally mirrors the granule cell hierarchy as expected, while group 3 medulloblastoma resembles Nestin+stem cells, group 4 medulloblastoma resembles unipolar brush cells, and PFA/PFB ependymoma and cerebellar pilocytic astrocytoma resemble the prenatal gliogenic progenitor cells. Furthermore, single-cell transcriptomics of human childhood cerebellar tumours demonstrates that many bulk tumours contain a mixed population of cells with divergent differentiation. Our data highlight cerebellar tumours as a disorder of early brain development and provide a proximate explanation for the peak incidence of cerebellar tumours in early childhood. Sequencing data from the developing cerebellum are compared with bulk sequencing data from paediatric tumours, providing insights into their potential origins and suggesting that many cerebellar tumours have their origins early in utero.

Epigenetic research has accelerated rapidly in the twenty-first century, generating justified excitement and hope, but also a degree of hype. Here we review how the field has evolved over the last few decades and reflect on some of the recent advances that are changing our understanding of biology. We discuss the interplay between epigenetics and DNA sequence variation as well as the implications of epigenetics for cellular memory and plasticity. We consider the effects of the environment and both intergenerational and transgenerational epigenetic inheritance on biology, disease and evolution. Finally, we present some new frontiers in epigenetics with implications for human health. The authors review recent advances and current debates in epigenetics, including how epigenetic mechanisms interact with genetic variation, ageing, disease and the environment.

Human glioblastomas harbour a subpopulation of glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare ‘outlier’ clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant glioblastoma stem cells. Finally, we show that functionally distinct glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for glioblastoma-targeted therapy.

Schizophrenia is a severe mental illness with a typically chronic course affecting nearly 1% of the human population. It is generally accepted that genetic factors have an important pathogenic role in a substantial portion of schizophrenia cases; however, despite decades of family studies, there is no agreed-upon mode of inheritance1–6. The discovery of genetic aetiologic factors and resolution of the inheritance pattern(s) will undoubtably emerge from genetic linkage studies. With these objectives in mind, we undertook a linkage project, starting in 1985, in a previously well-documented kindred from north Sweden. Multipoint linkage analyses were used to screen the proximal long arm of chromosome 5 using restriction fragment length polymorphism (RFLP) markers at five loci and the distal long arm using RFLPs at two loci, one of which was the locus for the glucocorticoid receptor. We found strong evidence against linkage between schizophrenia and the seven loci. These results, together with the positive evidence7for linkage of schizophrenia with markers in the proximal long arm of chromosome 5 lead us to conclude that the genetic factors underlying schizophrenia are heterogeneous.

A Correction to this paper has been published: https://doi.org/10.1038/s41586-021-03287-8.

Migration is an important factor in the biological evolution of human populations, and surnames provide one of the simplest records of identification. The distribution of surnames can supply quantitative information on the structure of human populations1–3. Surnames considered as alleles of a gene transmitted only by the male line can be assumed to be neutral markers4and therefore satisfy the expectations of the neutral theory of evolution5, which is entirely described by random genetic drift, mutation and migration. As data on surnames are easier to collect than those from genes, the information yield is potentially increased, but the validity of the conclusions must be tested in actual samples. The purpose of this report is to compare the estimates of migration rates in Italy, as inferred by the surname distribution found in the telephone directories and other sources, with the corresponding estimates from official demographic sources. Our findings show that in these samples the ratio of surnames to individuals makes it possible to calculate reliable estimates of migration rates.

CYSTIC FIBROSIS (CF) is an autosomal recessive genetic disorder with a frequency of about 1/1,600 among newborn infants of European descent. In spite of extensive investigation its primary molecular abnormality remains unknown. It has been observed that most CF patients lack an α2macroglobulin–protease complex1and that binding of trypsin and other proteases to α2macroglobulin (α2M) is lower in plasma of CF patients than in that of normal controls2. We therefore decided to study the interaction of trypsin with plasma proteins of CF patients. Here we report that trypsin-binding IgG (TbIgG) is present in 80% of CF patients and in 30% of their mothers, but not in 97% of normal controls or in other relatives of CF patients. Experimental evidence supports the antibody nature of TbIgG, which is presumably produced against the porcine trypsin ingested by CF patients as pancreatic extracts for substitutive enzyme therapy.

IT seems of interest to analyse if, in a given species, there is any relationship between the volume of the cell-nuclei and their deoxyribonucleic acid (DNA)-content. Except within the same tissue, H. H. Swift1denies the existence of such a relationship. Recent findings by G. Marinone2in cells of different nature in hæmatopoietic organs are in agreement with this view. C. Leuchtenberger and F. Schrader3, however, conclude that even in the same organ—the liver of the white rat—no direct relationship exists between the nuclear volume and the DNA-content.

THE discovery of recombination in Escherichia coli1,2has given to bacterial genetics a much wider scope than it had before. Three years after its first publication, however, the results obtained by Leder-berg with the strain known as K 12 still stand alone, no other bacterial strain having been found to show a similar behaviour. This is partly due to the fact that demonstration of recombination is a slow business, owing to the work required for the preparation of suitable substrains. In fact, the only method known so far is still the original one of mixing substrains having different growth requirements on a minimal medium where neither parental strain can grow, but on which cells possessing some of the synthetic capacities of one strain and some of the other will be able to form colonies. As such colonies, called by Lederberg ‘prototrophs’, usually appear at a very low rate, care must be taken that recombination is not simulated by back-mutation in either parental strain.

DRUG resistance in bacteria has been investigated genetically in several cases, since Demerec began with penicillin resistance in Staphylococcus aureus1. The proposal to distinguish two classes of drug resistance—those in which the top level of resistance can be obtained in a single step, and those in which it can be acquired only gradually—has clearly a practical importance; its theoretical meaning has not been entirely elucidated, since genetical analysis has several limitations in bacteria. In fact, while mutational patterns are open to investigation in most cases, crossings can only be regularly undertaken, as in Lederberg and Tatum's original discovery2, in a few strains of E. coli. In one of these, E. coli K-12, some work on the genetics of drug resistance has been carried out, the most extensive investigation relating to streptomycin. Full resistance in E. coli is developed in a single step3,4.

THE deoxyribonucleic acid content of the interphasic nuclei is, for a given species, approximately the same in the different tissues and double that of the spermatic nuclei of the same species. However, it is known that certain organs contain different classes of nuclei with an amount of deoxyribonucleic acid that is a simple multiple of the basic value. This constancy of deoxyribonucleic acid content is considered by some to be absolute1; others claim on the contrary that the ‘theoretical diploid value’ is only an equilibrium value, from which the mean content varies more or less widely, as a function of the physiological2or mitotic activity3of the cells. The influence of mitotic activity upon the deoxyribonucleic acid content of the nuclei of the tubuli in a kidney showing compensatory hypertrophy after extirpation of the kidney on the other side has been studied by us.

IN the course of experiments on the bactericidal action of X-rays on the R and S phases of Escherichia coli, it was found that the survival-rate in three stocks (76, 111, Ida), irradiated twenty-four hours after seeding, was different1; one of them (stock Ida) was more resistant to the radiation as compared with the other two stocks. No significant differences were found between S and R phases of the same strains. According to the hit-theory of biological effects of radiation the survival-rate is a measure of the target volume, which has been assumed to represent the bacterial ‘nucleus’2,3. If in the case of bacteria the so-called nucleoplasmic ratio of plants and animals holds true, and if, on the other side, the target volume obtained from X-ray experiments really represents the size of the bacterial ‘nucleus’, one would expect the size of the bacterial cells to be correlated to the target volumes. A biometric analysis of twenty-four hours old bacteria, carried on the projected images of photomicrographs of bacteria stained with Henrici's Congo Red method4, has shown that E. coli with a larger target volume are larger than the ones with smaller target volume. The variability curves obtained for the three stocks were almost normal, and the differences found between their means were statistically significant. It is suggested that such correlation might indicate the presence of polyploidy among different stocks of the same bacterial species, as it has previously been found in other organisms. A detailed description of such experiments will be published elsewhere.