Kinase fusion proteins (KFPs) are an emerging class of diverse intracellular plant immune receptors with critical roles in immunity in wheat (Triticum aestivum) and other members of the Triticeae. These proteins contain at least one kinase domain fused to one or more additional domains, possibly including another kinase domain. Many KFP kinase domains are predicted to possess an atypical structural motif, the extended β-finger, indicating that KFPs may operate through shared mechanisms in plant immunity despite their structural diversity. Recent research has demonstrated that KFP SR62TK from Aegilops sharonensis and RWT4 (allelic to PM24) from wheat serve as primary receptors that initiate immune signaling by recruiting a nucleotide-binding leucine-rich repeat (NLR) protein similar to sensor and helper NLR pairs. This study consolidates the current understanding of KFPs, emphasizing their structural and functional diversity, evolutionary significance and potential for engineering durable disease resistance in crops.

Therapeutic advances have improved cancer outcomes, but early-stage detection remains the single most important determinant of favorable prognoses across many cancer types. Cancer genomics has yielded detailed maps of somatic mutation and methylation patterns characteristic of different cancers, enabling the development of assays to detect mutation-bearing tumor-derived DNA in tissue biopsies, blood and other body fluids at the earliest stages of disease. In parallel, it has also become clear that small clones bearing cancer-associated mutations arise commonly in histologically normal tissues, a phenomenon that becomes universal in proliferative tissues with age but leads to cancer in only a small minority of individuals. This review article outlines established strategies for early cancer detection and highlights emerging insights into the genetics of precancerous mutant clones that have led to the recent development of prognostic frameworks for identifying high-risk individuals, making it increasingly possible to intercept evolving cancer at a premalignant or early malignant stage, when interventions are most effective.

The high prevalence (>5%) of autoimmune hypothyroidism (AIHT) provides a unique opportunity to dissect genetic contributions to systemic and organ-specific autoimmunity. Here we performed a genome-wide association meta-analysis of 81,718 AIHT cases in FinnGen and the UK Biobank, identifying 418 independent signals (P < 5 × 10-8). At 48 of these loci, a protein-coding variant is, or is highly correlated (r2 > 0.95) with, the lead variant, including Finnish-enriched coding variants in LAG3, ZAP70 and TG. We demonstrated that ZAP70:T155M reduces T cell activation and broadly compare large-scale scans of nonthyroid autoimmunity and thyroid-stimulating hormone levels with a Bayesian classifier to assign loci into distinct groupings, estimating that 38% are involved in general autoimmunity whereas 20% are thyroid specific. We further identified substantial antagonistic pleiotropy, with 10% of AIHT loci showing a consistent protective effect against skin cancer. The AIHT results, including numerous genes encoding checkpoint proteins, support the causal role of natural immune variation influencing cancer outcomes.

How chromatin conformation relates to chromatin state remains a central challenge in genome regulation. Here we present Pico-C, a low-input Micro-C approach that enables high-resolution, temporally resolved three-dimensional genome mapping during early Drosophila embryogenesis. Contrary to a prevailing view of a disorganized genome before zygotic genome activation (ZGA), we uncover a dynamic and ordered emergence of chromatin loops during pre-ZGA nuclear cycles. Spatial autocorrelation analysis points to context-dependent regulatory influences on chromatin. Notably, inhibition of transcriptional elongation has site-specific effects, retaining some early loops while weakening insulation at active promoters, suggesting distinct regulatory dependencies. Machine learning models trained on sequence features identify orthogonal, motif-specific contributions to architecture. Co-depletion of the pioneer factors Zelda and GAF leads to factor-specific perturbations in chromatin architecture, further highlighting a modular regulatory logic in genome establishment. Together, our findings reveal that early genome organization is orchestrated by an interplay of overlapping yet separable regulatory inputs.

KRAB zinc-finger proteins (KZFPs) are the most abundant family of DNA-binding proteins in humans and primarily induce the epigenetic silencing of transposable elements. While KZFPs use this ability to control the transposition potential of transposable elements, they can also act as epigenetic switches that gate transposable element-derived cis-regulatory modules in a cell context-specific manner. In this way, they participate in the domestication of mobile elements, expanding their ability to establish complex gene regulatory networks. In this Perspective, we discuss emerging evidence that mutations in KZFP genes can explain human disorders and that there is a need to understand the effect of mutations in their transposable element targets. We argue that increased focus on this large yet historically understudied family will greatly contribute to addressing gaps in our understanding of cell lineage specification during development, human phenotypes and related pathologies.

Tomato (Solanum lycopersicum), one of the world's most valuable vegetable crops, has suffered from diminished genetic diversity and stress resistance. Wild tomatoes serve as an invaluable genetic reservoir, yet their potential for stress resilience remains largely unexploited in tomato breeding. Here we report a genus-wide super-pangenome across 16 tomato species by integrating 20 telomere-to-telomere genomes and 27 published chromosome-scale genomes. Genus-wide population analysis demonstrates broad genetic diversity with limited gene flows among principal clades. Pan-centromere analysis reveals a diverse landscape and dynamic evolution of the mysterious tomato centromeres involving rapid diversification, satellite emergence and repositioning. A comprehensive catalog of structural variants uncovers extensive rearrangements, especially from wild tomatoes, and discovers key molecular markers associated with salinity resistance. Structural-variant-based genome-wide association studies identified a leucine-rich repeat receptor gene SlGMAK conferring gray mold resistance. Our telomere-to-telomere super-pangenome will accelerate exploiting the untapped potential of wild relatives to improve modern tomatoes for stress resilience.