Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset f...Atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions (aFTLD-U) is neuropathologically characterized by aggregation of the FET family of proteins and clinically manifests as sporadic young-onset frontotemporal dementia. Here we describe a major risk locus on chr15q14 identified through a genome-wide association study in 59 pathologically confirmed aFTLD-U cases and 3,153 controls (lead single nucleotide polymorphism rs549846383, P = 5.85 × 10, odds ratio 26.7). When combined with data from 28 additional aFTLD-U cases, 3,712 controls and 3,215 individuals with other neurodegenerative diseases and by leveraging in-house and public long-read genome sequencing data from 1,715 individuals, we identified a tandem repeat expansion on the associated haplotypes in an intron of GOLGA8A. We found variation in repeat length, motif length, and motif sequence, with long CT-dimer expansions strongly associated with aFTLD-U. Although the functional consequence of this repeat remains unknown, its presence in nearly 60% of aFTLD-U cases points to a fundamental role in disease pathogenesis.
Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN...Therapy-related myeloid neoplasm (tMN) is a fatal consequence of exposure to cytotoxic therapy administered in the treatment of cancer. Individuals with pre-existing TP53 clonal hematopoiesis (CH) are at high risk of tMN, with avoidance of therapy being the only strategy to reduce tMN risk. Here, in four randomized clinical trials, we show that the CDK4/6 inhibitor trilaciclib, given in conjunction with a variety of chemotherapeutic regimens and across diverse populations of patients with cancer, mitigates chemotherapy-related expansion of CH clones with mutations in DNA damage response genes, including TP53. This finding was also observed in a syngeneic mouse model of TP53-mutant CH, demonstrating that CDK4/6 inhibition blocks platinum-induced TP53 competitive repopulation through promoting hematopoietic stem and progenitor quiescence and decreasing the stemness advantage of TP53-mutant clones. This represents a proof of concept for a potential pharmacologic strategy to block chemotherapy-induced expansion of preleukemic TP53-mutant clones.
The transcriptional interference model suggests that RNA polymerases elongating through overlapping transcription units mutually inhibit transcription and disrupt associated cis-regulatory elements. As a longstanding fun...The transcriptional interference model suggests that RNA polymerases elongating through overlapping transcription units mutually inhibit transcription and disrupt associated cis-regulatory elements. As a longstanding fundamental concept of gene regulation, the idea of reciprocal inhibition between sense and antisense transcription has been supported by a significant body of research. However, despite the model's biophysical plausibility and historical significance, evidence from large-scale transcriptome studies raises questions about its universal applicability. In particular, the new data indicate that a measurable influence of transcriptional interference is absent from the majority of loci with overlapping transcription. Here we highlight key aspects of overlapping transcription and propose potential solutions to this emerging puzzle. Gaining a better understanding of the molecular mechanisms that render loci sensitive or resistant to interference could lead to groundbreaking insights into the biology of gene regulation.
Zhang H, Windhorst A, Bornhofen E
… +18 more, Tulpova Z, Novak P, Macas J, Simkova H, Nadzieja M, Kim JM, Cram D, Cao Y, Konkin DJF, Sass O, Welna G, Himmelbach A, Mascher M, Link W, Kwon SJ, Yang TJ, Andersen SU, Jayakodi M
Winter faba beans exhibit significant yield advantages over spring cultivars and hold promise for enhancing local protein production and agricultural sustainability. However, the threat of winter kill limits wider cultiv...Winter faba beans exhibit significant yield advantages over spring cultivars and hold promise for enhancing local protein production and agricultural sustainability. However, the threat of winter kill limits wider cultivation, and the genetics of faba bean winter hardiness remain unresolved. Here we develop a greatly improved faba bean reference genome and combine this with resequencing and phenotyping of winter and spring accessions to identify genetic determinants of winter hardiness. Genome-wide association analysis of frost tolerance traits identifies a major winter hardiness locus, the most strongly associated variant of which explains the vast majority of phenotypic variation and accurately differentiates between winter and spring types. Furthermore, we identify additional signals within the winter faba bean gene pool that could lead to further improvement of winter hardiness. Our work provides improved genomic resources and resolves the genetics of a key agronomic trait in a global protein crop to facilitate future breeding efforts.
Population-level structural variant (SV) profiling is crucial in the era of pangenomes. However, identifying SVs from genome assemblies and pangenome graphs remains a substantial challenge. Here we present Swave, a seque...Population-level structural variant (SV) profiling is crucial in the era of pangenomes. However, identifying SVs from genome assemblies and pangenome graphs remains a substantial challenge. Here we present Swave, a sequence-to-image, deep learning-based method that accurately resolves both simple and complex SVs, along with their population characteristics, from assembly-derived pangenome graphs. Swave introduces 'projection waves' to summarize the dotplot images that capture mapping patterns between reference and SV-indicating alleles in the pangenome. Then, a recurrent neural network distinguishes true SV signals from background noise introduced by genomic repeats. Swave demonstrates superior performance in both SV-type classification and genotyping compared with existing methods. When applied to healthy cohorts and rare-disease cohorts, Swave reveals complex and polymorphic SV patterns across human populations and identifies potentially pathogenic SVs. These advancements will facilitate the creation of comprehensive population-level SV catalogs, deepening our understanding of SVs in genetic diversity and disease associations.
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...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 SR62 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 so...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-a...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). At 48 of these loci, a protein-coding variant is, or is highly correlated (r > 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.
Dossa K, Arnau G, Malédon E
… +18 more, Nudol E, Gravillon MC, Perrot C, Laurent L, Sergeant S, Uneau Y, Umber M, Casi D, Irep JL, Hammouya D, Andypain S, Hubert O, Chilin-Charles Y, Louisor J, Hery M, Fouks B, Cornet D, Chaïr H
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-dimensi...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 transpo...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.
Li J, Wang J, Ibarra IL
… +23 more, Cheng X, Luecken MD, Lu J, Monavarfeshani A, Yan W, Zheng Y, Zuo Z, Colborn SLZ, Cortez BS, Owen LA, Wick B, Bao X, Choi J, Haeussler M, Tran NM, Shekhar K, Sanes JR, Stout JT, Chen S, Li Y, DeAngelis MM, Theis FJ, Chen R
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 pot...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.
Boivin M, Yu J, Eura N
… +22 more, Schmitt L, Pietri D, Grandgirard E, Goetz-Reiner P, Plassard D, Nahy C, Maglott A, Morlet B, Gao C, Lefebvre E, Philipps M, Eberling P, Pichot A, Rossolillo P, Thibault C, Oulad-Abdelghani M, Nishino I, Yang K, Wang N, Wang Z, Deng J, Charlet-Berguerand N
A total of 3-6% human genome is composed of microsatellite sequences, which are short DNA elements composed of two to six nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leadin...A total of 3-6% human genome is composed of microsatellite sequences, which are short DNA elements composed of two to six nucleotide motifs repeated in tandem. Expansion of a subset of these microsatellites is the leading cause of >60 diseases. However, most of these mutations are located in sequences annotated as noncoding, which raises questions about their pathogenicity. Here we found that GGC repeat expansions causing oculopharyngodistal myopathy with or without oculopharyngeal myopathy leukoencephalopathy are located within previously unrecognized open reading frames (ORFs), resulting in their translation into new polyglycine-containing proteins. Antibodies developed against these proteins stain the p62-positive inclusions typical of these diseases. Moreover, expression of these polyglycine proteins causes locomotor and skeletal muscle alterations associated with neurodegeneration in cell, fly and mouse models. Finally, we identified a compound, the cationic porphyrin TMPyP4, targeting the expression of these polyglycine proteins, raising hope to develop a therapy for these disorders. Overall, this work highlights the complexity and richness of the human genome and the importance of mutations in yet-unrecognized small ORFs.
Marzban S, Stiehl T, Xie Z
… +13 more, Andersen M, Snyder J, Gudmand-Høyer J, Ottesen JT, Mon Père NV, Werner B, Huang W, DeZern AE, Sekeres MA, Walter MJ, Padron E, Gillis N, West J
Clonal hematopoiesis (CH) results from the acquisition and expansion of somatic mutations in hematopoietic stem and progenitor cells and is associated with age-related clinical sequelae, including an increased risk for c...Clonal hematopoiesis (CH) results from the acquisition and expansion of somatic mutations in hematopoietic stem and progenitor cells and is associated with age-related clinical sequelae, including an increased risk for cardiovascular disease, myeloid neoplasms and complications related to cancer therapy. Chemotherapy and radiation can accelerate CH expansion and further elevate the risk of adverse events, including cardiotoxicity and therapy-related myeloid neoplasms. Although CH is increasingly recognized as a clinically relevant precursor state and predictive biomarker, the long-term dynamics of CH expansion in humans remain poorly understood. Longitudinal data are often collected but not integrated with mathematical prediction. Mathematical modeling is essential for characterizing CH evolution, estimating clone fitness, inferring stem cell pool dynamics and enabling patient-level predictions. This study summarizes the current evidence on CH dynamics in humans, compares mathematical models used to predict CH progression, assesses the validity of model assumptions and discusses the implications for clinical management of individuals with these precursor conditions.