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The advantage of genomic monitoring over cytogenetics for clinical assessment of leukemia is illustrated by a case of pediatric acute lymphoblastic leukemia in which a lesion underlying lethal end-stage myeloid disease could be detected by whole-genome sequencing years before the risk manifested cytogenetically.

In this Tool of the Trade article, Tim Coorens describes the development of SComatic, an algorithm enabling the detection of somatic mutations in single-cell RNA- or ATAC-sequencing data, and its use to study lineage relations and mutational signatures.

It remains unclear why some paediatric tumours appear to have such a low mutation burden. Here, the authors shed light on this paradox by analysing Wilms tumours using high resolution and high depth sequencing approaches, finding that - due to an unusual clonal architecture - standard methods significantly underestimate the mutation burden at the cellular level.

Coorens et. al. perform whole-genome sequencing and phylogenetic analyses in a child patient with leukemia that underwent lineage switch following therapy, finding that the AML arose from a pre-existing clone, rather than the most recent ALL relapse.

The Somatic Mosaicism across Human Tissues Network aims to create a reference catalogue of somatic mosaicism across different tissues and cells within individuals.

The expansion of clones with distinct SERPINA1 somatic mutants in the livers of alpha-1 antitrypsin deficiency (A1AT) patients is consistent with convergent evolution. These variants interfere with the auto-polymerization and intra-ER accumulation of the Z-A1AT protein, thus highlighting potentially targetable domains.

The genomic features of precursor conditions of multiple myeloma provide multiple biological insights into disease origins and evolution, together with opportunities to identify those at highest risk of progression.

Lightbody et al. present SWIFT-seq, a single-cell RNA sequencing approach to profile circulating tumor cells from patients with multiple myeloma and its precursor conditions and leverage it to derive clinical and biological insights into the disease.

Whole-gene sequencing of microdissected gastric glands from individuals with and without gastric cancer reveals distinct patterns of somatic mutations and provides insights into influences on the somatic evolution of the gastric epithelium.

Single cell analysis of early human embryos identifies key changes in pluripotency, the requirement of FGF signalling for embryo survival, and defines a putative anterior-like region of hypoblast cells, providing insights into how early human development is regulated.

Somatic mutations obtained from laser microdissected biopsies of human tissues are used to reconstruct the developmental phylogenies of these tissues back to the zygote.

The authors report the mutational landscape of 29 cell types from microdissected biopsies from 19 organs and explore the mechanisms underlying mutation rates in normal tissues.

Malignant rhabdoid tumours (MRT) have been suggested to originate in the ectoderm-derived neural crest. Here, the authors analyse MRTs using phylogenetics, scRNA-seq, and patient-derived organoids; they find evidence for an MRT origin in the neural crest lineage and suggest differentiation treatment with HDAC/mTOR inhibitors.

Phylogenies of human placental cells based on whole-genome sequencing of bulk samples and microdissections reveal extensive mutagenesis in placental tissue, and suggest that mosaicism is a typical part of normal placental development.

Persistent DNA lesions can occur throughout the human lifespan and can remain in the genome of affected cells for several years and generate a substantial proportion of the mutational burden.

Healthy tissues from individuals with germline mutations in POLE or POLD1 show increased mutational burden, suggesting that normal cells are capable of tolerating high mutation rates.

Whole-genome sequencing of normal human endometrial glands shows that most are clonal cell populations and frequently carry cancer driver mutations that occur early in life, and that parity has a protective effect.

The molecular characterisation of germ cell tumours (GCT) is necessary to understand their development and histological diversification. Here, the authors use whole-genome and transcriptome sequencing of GCTs across distinct histologies to reveal their somatic evolution and clonal diversification, as well as identify several putative biomarkers for treatment stratification.

Using single-cell and multi-omics data of fetal blood, a high-resolution molecular map of dysregulated haematopoiesis in Down syndrome is provided.

Phylogenetic trees from whole-genome sequencing datasets with the pipeline Sequoia are reconstructed to define the evolutionary history of clonally expanding cells and to clarify how somatic mutations shape normal cell behavior.

Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of NOTCH1 rearrangements.

Whole-genome sequencing of healthy human epithelial crypts from the small intestines of 39 individuals highlights APOBEC enzymes as a common contributor to the overall mutational burden in this tissue.

Single-cell transcriptomic and phylogenetic analyses reveal new insights into the developmental origin and potential therapeutic targets for a particularly aggressive form of B-cell acute lymphoblastic leukemia in infants.

It is unclear whether somatic mutation rates are elevated in Lynch Syndrome (LS), which is the most common cause of hereditary colorectal cancer. Here, the authors use whole-genome sequencing and organoid cultures to show that normal tissues in LS patients are genomically stable, while ancestor cells of neoplastic tissues undergo multiple cycles of clonal evolution.

Whole-genome sequencing is used to analyse the landscape of somatic mutation in intestinal crypts from 16 mammalian species, revealing that rates of somatic mutation inversely scale with the lifespan of the animal across species.

Inherited mutations in MUTYH have been shown to predispose patients to colorectal cancers. Here, the authors show that MUTYH mutations lead to an increased somatic base substitution mutation rate in normal intestinal epithelial cells, which is the likely cause for the increased cancer risk.

Whole-genome sequencing analysis of somatic mutations in liver samples from patients with chronic liver disease identifies driver mutations in metabolism-related genes such as FOXO1, and shows that these variants frequently exhibit convergent evolution.

Whole-genome sequencing of haematopoietic colonies from human fetuses reveals the somatic mutations acquired by individual progenitors, which are used as barcodes to construct a phylogenetic tree of blood development.

Histologically normal tissues of individuals with a germline NF1 mutation exhibited multiple second NF1 hits, unrelated to their tumors, that conferred a selective advantage.

Haematopoiesis has high clonal diversity up to about 65 years of age, after which diversity drops precipitously owing to positive selection acting on a handful of clones that expand exponentially throughout adulthood.

A study of 21,879 families with rare genetic diseases identifies 12 with 2- to 7-fold excess of germline mutations, most of which are due to DNA repair defects or exposure to mutagenic chemotherapy, although most individuals with a hypermutated genome will not have a genetic disease.

In this Review, the authors compare the characteristics and detection methods of germline and somatic variants. Furthermore, they outline how the interplay between the two types of genetic variation can affect human health.

Transcriptomic analysis may provide information about the differentiation state and cell of origin of a cancer. Here, the authors assess mRNA signals in 1300 childhood and adult renal tumors and report a fetal origin of childhood tumors and no dedifferentiation of adult tumors.

NanoSeq is used to detect mutations in single DNA molecules and analyses show that mutational processes that are independent of cell division are important contributors to somatic mutagenesis.

Whole-genome sequencing of normal bronchial epithelium from 16 individuals shows that tobacco smoking increases genomic heterogeneity, mutational burden and driver mutations, whereas stopping smoking promotes replenishment of the epithelium with near-normal cells.

Genome sequencing of hundreds of normal colonic crypts from 42 individuals sheds light on mutational processes and driver mutations in normal colorectal epithelial cells.

The developmental Genotype-Tissue Expression (dGTEx) projects will catalogue and integrate gene expression, regulation and genetics data across 120 human donors from birth to adulthood with developmentally matched non-human primates, including 126 rhesus macaques and 72 common marmosets.

This protocol describes a workflow that combines laser-capture microdissection with low-input genome sequencing, while circumventing the use of whole-genome amplification, for accurate detection of somatic mutations in non-neoplastic tissues.