{"title":"Adaptation: by giant leaps or many tiny steps?","authors":"William R. Milligan, Guy Sella","doi":"10.1038/s41576-026-00978-8","DOIUrl":"10.1038/s41576-026-00978-8","url":null,"abstract":"Despite more than a century of research, we still lack a general understanding of the genetic basis of adaptation. We argue that reframing this question around the genetic and ecological properties of the traits under selection may chart a way forward. In this Comment, the authors argue that understanding the genetic basis of adaptation requires considering the genetic architecture and ecological properties of traits under selection. They propose a framework that predicts when evolution proceeds by many small changes or few large-effect variants, and when its genetic basis should be predictable across populations and species.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 7","pages":"505-506"},"PeriodicalIF":51.4,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Pleiotropic effects of cis-regulatory mutations","authors":"Patricia J. Wittkopp","doi":"10.1038/s41576-026-00981-z","DOIUrl":"10.1038/s41576-026-00981-z","url":null,"abstract":"The pleiotropic effects of cis-regulatory mutations are generally assumed to be limited by the modularity of enhancers. However, the discovery of cis-regulatory sequences that affect multiple tissues, multiple genes or genome structure suggests that they may be subject to greater evolutionary constraint than often considered. In this Comment, Patricia Wittkopp revisits assumptions that cis-regulatory mutations are weakly pleiotropic, ultimately calling for more data to assess the extent to which they are less pleiotropic and deleterious than trans-regulatory mutations.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 7","pages":"503-504"},"PeriodicalIF":51.4,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055634","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Transposable elements as catalysts of evolutionary innovation","authors":"Cedric Feschotte","doi":"10.1038/s41576-026-00980-0","DOIUrl":"10.1038/s41576-026-00980-0","url":null,"abstract":"Long understudied for dogmatic and technical reasons, transposable elements are now recognized as major drivers of evolutionary innovation. They contribute both as prolific sources of cis-regulatory elements that rewire gene networks and as donors of protein domains that give rise to new host genes. In this Comment, Cedric Feschotte highlights evidence from diverse lineages showing that transposable elements are key drivers of evolutionary innovation, repeatedly introducing regulatory and coding sequences that reconfigure genome function.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 7","pages":"501-502"},"PeriodicalIF":51.4,"publicationDate":"2026-05-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148055649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Written in blood: DNA methylation in liquid biopsy","authors":"Aniruddha Chatterjee, Euan J. Rodger","doi":"10.1038/s41576-026-00977-9","DOIUrl":"10.1038/s41576-026-00977-9","url":null,"abstract":"In this Journal Club, Chatterjee and Rodger highlight two studies by Guo et al. and Shen et al. that demonstrated how genome-wide DNA methylation profiling enables sensitive detection and classification of tumour-derived cell-free DNA, advancing epigenetic approaches in liquid biopsy for cancer diagnostics.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 9","pages":"668-668"},"PeriodicalIF":51.4,"publicationDate":"2026-05-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147988477","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Single-cell trimodal profiling with scHiCAR","authors":"Yueyuan Xu \u0000 (, ), Xiaolin Wei \u0000 (, )","doi":"10.1038/s41576-026-00970-2","DOIUrl":"10.1038/s41576-026-00970-2","url":null,"abstract":"In this Tools of the Trade article, Yueyuan Xu and Xiaolin Wei discuss scHiCAR (single-cell Hi-C with assay for transposase-accessible chromatin and RNA sequencing), a trimodal single-cell method for simultaneously profiling gene expression, chromatin accessibility and 3D genome organization.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 9","pages":"663-664"},"PeriodicalIF":51.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Guillaume P. Ramstein, Jingjing Zhai, Edward S. Buckler, Maud I. Tenaillon, Jean-Luc Jannink
{"title":"Translating functional molecular knowledge into crop-breeding success","authors":"Guillaume P. Ramstein, Jingjing Zhai, Edward S. Buckler, Maud I. Tenaillon, Jean-Luc Jannink","doi":"10.1038/s41576-026-00968-w","DOIUrl":"10.1038/s41576-026-00968-w","url":null,"abstract":"Historical plant breeding, which optimizes phenotypes through selective crossing guided by phenotypic evaluation and molecular markers, is limited by evolutionary constraints that hinder rapid crop improvement. A new paradigm, precision breeding, circumvents these limitations by targeting genetic variants through functional molecular knowledge. To generate this knowledge at scale, sequence-based deep learning leverages high-quality genome sequence data to predict variant effects at base-pair resolution. When linked to agronomically important traits, these predictions enable breeders to prioritize variants for precision selection or editing. Although it is still in the early stages of development, we foresee three key applications for this approach: introgressing genes from distant breeding pools, purging deleterious mutations and designing new plant ideotypes. Looking ahead, refined computational models will facilitate targeted editing and the systematic redesign of complex physiological processes to address emerging breeding goals under shifting environmental conditions. In this Perspective, Ramstein and colleagues discuss the use of emerging machine learning tools for function-informed prioritization of variants for plant breeding; they outline future applications in which precision breeding strategies have the potential to be most effective.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 10","pages":"797-812"},"PeriodicalIF":51.4,"publicationDate":"2026-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147982404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The long reach of the Red Queen","authors":"Mia T. Levine","doi":"10.1038/s41576-026-00976-w","DOIUrl":"10.1038/s41576-026-00976-w","url":null,"abstract":"Selfish genetic elements antagonize subunits of essential multi-protein complexes. Research now suggests that intermolecular compensatory evolution among these subunits preserves the integrity and function of these vital but vulnerable complexes. Red Queen dynamics describe a mode of evolution in which interacting biological entities continually adapt and counteradapt. This Comment discusses the pervasiveness of these dynamics within genomes, which can involve selfish genetic elements, and highlights building evidence that they can even drive compensatory coevolution among subunits of essential protein complexes.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 7","pages":"507-508"},"PeriodicalIF":51.4,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147974344","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The discovery of gene imprinting","authors":"Mary Gehring","doi":"10.1038/s41576-026-00973-z","DOIUrl":"10.1038/s41576-026-00973-z","url":null,"abstract":"In this Journal Club, Mary Gehring recalls a 1970 paper from Jerry Kermicle, which used elegant maize genetics to show that alleles behave differently depending on parental origin, laying the conceptual foundation for gene imprinting.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 9","pages":"667-667"},"PeriodicalIF":51.4,"publicationDate":"2026-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147974308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Computational approaches for multimodal lineage tracing","authors":"Kun Wang, Xionglei He, Zheng Hu","doi":"10.1038/s41576-026-00969-9","DOIUrl":"10.1038/s41576-026-00969-9","url":null,"abstract":"Understanding how cells commit to distinct fates over time is fundamental to elucidating the principles and mechanisms that govern organismal development, tissue regeneration and disease progression. Multimodal lineage tracing, which couples heritable lineage information with single-cell multi-omics, has revolutionized our ability to chart cellular dynamics and fate decisions at unprecedented resolution. However, the resulting datasets are inherently complex and heterogeneous, calling for sophisticated computational frameworks capable of transforming raw measurements into coherent biological insights. Here we comprehensively survey recent methodological advances that substantially expand the computational toolkit for analysing lineage-resolved, single-cell multi-omic data, enabling more accurate lineage reconstruction, trajectory inference, ancestral state estimation and identification of molecular programmes driving cell-state transitions. Emerging high-resolution lineage-tracing technologies and deep learning-based analytical models promise to further unlock the full potential of multimodal lineage tracing, offering an increasingly complete and quantitative view of cellular evolution in both health and disease. Multimodal lineage tracing links heritable ancestry with single-cell molecular states to reveal how cell fates emerge during development, regeneration and disease. In this Review, the authors survey key computational challenges and methods for phylogenetic inference, fate mapping and gene programme discovery.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 10","pages":"779-796"},"PeriodicalIF":51.4,"publicationDate":"2026-05-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147974289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Time matters: circadian genetics and the molecular logic of human health and disease","authors":"Tia Tyrsett Kuo, Jiarui Wang, Steve A. Kay","doi":"10.1038/s41576-026-00962-2","DOIUrl":"10.1038/s41576-026-00962-2","url":null,"abstract":"Time is an essential but often underappreciated determinant of human physiology and disease. The circadian clock, a genetic timing system, orchestrates transcriptional and signalling networks across tissues to maintain homeostasis. Recent discoveries have refined our understanding of this system, from a linear transcription–translation feedback loop to a distributed, dynamically coupled network that integrates environmental cues and physiological processes. Genetic variation in core circadian genes and circadian misalignment are now recognized as key modifiers of disease risk, progression and therapeutic response. As precision medicine begins to embrace temporal biology, defining how the circadian clock operates in health and disease has become increasingly important. This Review synthesizes recent advances in circadian genetics and molecular mechanisms, emphasizing their physiological, pathological and therapeutic implications, and outlines future priorities: resolving the composition of the molecular clock, developing disease-specific models, and expanding the chemical toolbox to modulate and interrogate circadian pathways. The circadian clock controls transcriptional and signalling networks across tissues to maintain homeostasis, with pathological consequences to its disruption. Kuo et al. review our understanding of circadian genetic and molecular mechanisms in health and disease, as well as emerging opportunities to probe and therapeutically target circadian regulation.","PeriodicalId":19067,"journal":{"name":"Nature Reviews Genetics","volume":"27 10","pages":"744-761"},"PeriodicalIF":51.4,"publicationDate":"2026-05-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147942330","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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