News & Views in 2023

The spatial biology revolution promises deep insights into tissue organization, but deriving this knowledge from diverse, complex data remains a major obstacle. Data-driven discovery of the multicellular organization of tissues is now achieved by transforming multimodal spatial imaging data using deep learning.

A new study combining experimental treatments of human blood cells from thousands of individuals with flow-cytometry-based phenotyping and then genome-wide association analyses identifies genetic loci associated with non-resting cell states. Integrating the results with disease association signals yields insights into the underlying biology.

New research reports that paused RNA polymerase II (RNAPII) enhances the targeting and activity of BAF chromatin remodelers. These findings suggest a new paradigm for understanding how the collaborative action of chromatin remodelers and the transcriptional machinery govern cell-type-specific chromatin accessibility.

CX-5461 (also known as pidnarulex), currently in phase 1/2 trials, induces selective killing of homologous-recombination-deficient or BRCA1- or BRCA2-mutated tumors in preclinical models. New work confirms these findings but shows it to be a remarkably potent mutagen that induces extensive genetic changes in cultured human cells with or without BRCA1/2 mutations, raising substantial safety issues.

Long segments of the genome that are shared ‘identical by descent’ (IBD) demonstrate recent relatedness between individuals. A new computational method robustly identifies shared IBD segments in human ancient DNA data, providing insights into the mobility and demography of prehistoric human societies.

Deep learning shows promise for predicting gene expression levels from DNA sequences. However, recent studies show that current state-of-the-art models struggle to accurately characterize expression variation from personal genomes, limiting their usefulness in personalized medicine.

Variants in the HLA region on chromosome 6 are strongly associated with many immune-related diseases. A method to construct personalized HLA genomes from single-cell RNA sequencing data, coupled with single-cell HLA expression quantitative trait loci modeling, identifies how genetic variants influence HLA gene expression across cell states.

The pancreas is an essential organ present in all vertebrates, and human pancreatic agenesis is an extremely rare disorder of largely unknown genetic determinants. A study now demonstrates that a primate-specific regulatory network controlled by the KRAB zinc-finger protein ZNF808 is essential for pancreas development.

Brain somatic mosaicism is linked to several neurological disorders and is thought to arise post-zygotically. A study suggests that pre-zygotic aneuploidy followed by post-zygotic partial reversion leads to a recurrent form of brain mosaicism-related epilepsy.

The mechanisms of many disease-associated variants are uncertain because of limited power to detect their modest effects on gene expression. This study finds that natural selection leads to preferential detection of disease-associated versus expression-associated variants.

DNA mismatch repair deficiency (MMRd) is associated with elevated tumor mutational burden (TMB) and exceptional immunotherapy responses, yet some patients experience no clinical benefit. Recent work proposes that high intra-tumoral heterogeneity can offset immunogenicity in sporadic MMRd, suggesting a potential mechanism of immunotherapy failure.

Many precision cancer therapies function by inhibiting oncogenic signaling pathways. A new study describes the counterintuitive finding that forced hyperactivation of the same pathways can also enable selective tumor targeting.

Transformation of a myeloproliferative neoplasm to a secondary acute myeloid leukemia is rare but devastating. Single-cell, multi-omic characterization of hematopoietic stem and progenitor cells now shows the role of inflammation in transformation driven by mutations in TP53, with effects on the mutant clone but also non-mutant counterparts.

The symmetric inheritance of histone modifications by the nascent chromatin fibers during DNA replication is essential for proper developmental progression. Two new studies using mouse embryonic stem cells further illuminate the role of histone inheritance in early cell fate decisions.

In this issue of Nature Genetics, Lara-Astiaso et al. systematically characterized the functional roles of several chromatin factors in hematopoiesis by combining functional CRISPR screens with single-cell transcriptomics and chromatin accessibility profiling, revealing lineage biases and relationships with important transcription factors.

A novel pipeline that expands the utility of the protein language model ESM1b has provided variant effect predictions for more than 40,000 protein isoforms. This strategy outperformed several state-of-the-art methods over multiple benchmarks.

Identifying genetic risk factors for binge-eating disorder (BED) is vital to understand its etiology and develop effective prevention and intervention strategies. To overcome under-reporting of clinical BED diagnosis, a new study uses machine learning to identify genetic variants associated with quantitative BED risk scores and finds evidence for a pathological role of heme metabolism.

Incidence of keratinocyte skin cancer varies markedly between populations living in different areas of the world. A detailed analysis of somatic mutations in the normal skin of individuals from the UK and Singapore reveals different patterns of clonal mutational landscapes that could contribute to differential risk.

The three-dimensional organization of mammalian chromosomes can regulate transcription. Whether transcription itself influences genome structure has remained a source of debate. Using sensitive genome-wide readouts, two recent studies describe the involvement of transcription on genome architecture by different mechanisms.

Identifying the ways that a study sample is not representative is essential for maximizing the generalizability of findings to the population. A new method proposes discerning non-representativeness in large-scale genetic studies by comparing the genotypes of closely related participants.