Reviews & Analysis

PD-1 pathway blockade in combination with chemotherapy has emerged as a treatment paradigm for patients with resectable lung cancer, but insights into predictive biomarkers and mechanisms of immune responses are lacking. A study uses spatial transcriptomic methods to identify patterns within the tumor microenvironment associated with response.

Existing functional genomics datasets are European-centric. The Asian Immune Diversity Atlas incorporated single-cell RNA-sequencing data from approximately 1 million peripheral blood mononuclear cells from around 500 donors of diverse Asian ancestries. Mapping of splicing quantitative trait loci revealed context-specific regulation of alternative splicing, as well as cell-type and ancestry-specific genetic effects on complex diseases.

The SCHEMATIC resource combines CRISPR pairwise gene knockout experiments across tumor cell types with large-scale drug sensitivity assays to identify a core network of highly penetrant, synthetic lethal genetic interactions that can help to match individuals with cancer to targeted therapies.

Using reported parental disease history to decipher the genetics of Alzheimer’s disease may be promising, but this approach is also susceptible to complex selection and information bias that can mislead researchers if not accounted for.

A novel method for analyzing single-cell genomics enables direct inference of cell cycle and proliferation status, highlighting the diversity of proliferation rates in clonal cancer. This approach opens a new avenue for high-resolution exploration of the role of proliferation in cancer evolution at the single-cell level.

Advancements in single-cell analysis technologies are enabling exploration of the intricacies of the human brain at unprecedented resolution. However, most research thus far has focused on the adult brain. Here, these tools are applied to reveal cell-type-specific gene-expression dynamics as the brain grows from childhood to adulthood.

Chromosomal instability plays a crucial part in tumor progression, shaping cancer cell phenotypes and driving treatment resistance. We harnessed two single-cell multiomics methods to characterize the heterogeneity of acute myeloid leukemia with complex karyotype (CK-AML). Our data link genetic, non-genetic and functional heterogeneity and reveal intriguing therapeutic sensitivities.

PopV is an ensemble method for cell type labeling in single-cell genomics. A Cell Ontology-inspired voting procedure across different algorithms highlights low confidence annotations, thereby guiding human-in-the loop components of the annotation process.

Using single-cell whole-genome sequencing, we reveal the landscape of copy number alterations in normal breast tissue from both BRCA carriers and wild-type individuals.

Perez, Goronzy et al. present ChIP-DIP, which enables multiplex genomic mapping of hundreds of epitopes from a single sample. The authors apply ChIP-DIP to localize modified histones, transcription factors and other chromatin-interacting proteins at scale, in both cell lines and primary cells.

Alzheimer’s disease is a complex, heterogeneous disorder with multiple genetic subtypes. Spatial and single-cell gene expression analyses of these subtypes have provided new insights into general and subtype-specific cellular and molecular mechanisms of Alzheimer’s disease.

The two-hit hypothesis suggests that a second mutation is necessary for cancer development in cells with a defective tumor-suppressor gene, such as BRCA1. However, a study now shows that the loss of just one Brca1 allele in mice can pre-program cells for cancer-promoting changes, indicating cancer may progress earlier than previously thought.

NKX3.1-expressing intermediate Basal-B cells represent a transient basal stem cell state during prostate regeneration, inflammation and cancer initiation. Remarkably, activation of JAK/STAT signaling is essential in regulating expansion and differentiation of Basal-B-like cells during prostate inflammation, identifying this signaling pathway as a potential therapeutic target in prostatitis associated with increased Basal-B signature.

Structural variations (SVs) impact gene expression, genome stability and disease susceptibility. This Review discusses recent advances in genome-engineering tools that enable precise SV generation and highlights the challenges that remain.

The calcium-dependent protein kinase ZmCPK39 is identified as a key immune component in maize infected with foliar pathogens. Its expression is lower in resistant maize lines than in susceptible lines, leading to stabilization of the transcription factor ZmDi19, elevated expression of the anti-microbial protein ZmPR10 and enhanced resistance to multiple foliar diseases.

This review describes evidence of multiple Denisovan populations, each with varying relatedness to Altai Denisovans, that introgressed into modern humans and highlights how introgression influenced human adaptation to a range of environments.

DNA variants arising in the genome of cancer cells are a major cause of therapy failure, but for most variants, their effects on drug response are unknown. Base-editing screens provide a systematic approach to uncover the functions of cancer variants at scale, which might help to inform the use of precision cancer therapies.

Distinguishing ordinary diabetes from its monogenic forms has been one of the challenges in optimally managing the disease. Using high-quality imputation of rare variants and large databases, a study now defines the gray zone between the two and lays down a blueprint for objectively evaluating the related variants.

This Perspective discusses approaches to generate ultimate genotypes, combining the best chromosome segments in livestock and crop populations, to increase key production, sustainability and welfare traits, compared with the current best individuals.

C-to-T mutations in CpG dinucleotides are widespread in cancers and are also observed in normal cells. By developing and using a technique to quantify DNA polymerase errors (polymerase error rate sequencing, PER-seq), we reveal that C-to-T mutations in CpG dinucleotides constitute part of the error signature of both wild-type and mutant cancer-associated DNA polymerase ε.