Pub Date : 2025-12-19DOI: 10.1016/j.gde.2025.102416
Elias T Friman, Wendy A Bickmore
Transcriptional regulation involves the binding of thousands of transcription factors (TFs) to hundreds of thousands of enhancers and promoters. How do the collective activities of these proteins and cis-regulatory elements achieve precise and dynamic gene regulation? At an individual enhancer, TFs can interact to affect each other’s binding and the recruitment of different co-factors, resulting in cooperative outputs. More recently, new types of cooperative behaviour between enhancers have been discovered. In this review, we consider whether some of the same principles could contribute to both TF and enhancer cooperativity, focusing specifically on positive cooperativity (or synergy) and the role of 3D chromatin organisation.
{"title":"Enhancer cooperativity in the folded genome","authors":"Elias T Friman, Wendy A Bickmore","doi":"10.1016/j.gde.2025.102416","DOIUrl":"10.1016/j.gde.2025.102416","url":null,"abstract":"<div><div>Transcriptional regulation involves the binding of thousands of transcription factors (TFs) to hundreds of thousands of enhancers and promoters. How do the collective activities of these proteins and cis-regulatory elements achieve precise and dynamic gene regulation? At an individual enhancer, TFs can interact to affect each other’s binding and the recruitment of different co-factors, resulting in cooperative outputs. More recently, new types of cooperative behaviour between enhancers have been discovered. In this review, we consider whether some of the same principles could contribute to both TF and enhancer cooperativity, focusing specifically on positive cooperativity (or synergy) and the role of 3D chromatin organisation.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102416"},"PeriodicalIF":3.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145792128","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-12-19DOI: 10.1016/j.gde.2025.102415
Erin N Gilbertson , Steven K Reilly
Understanding the genetic basis of phenotypic differences across species has been a longstanding goal of evolutionary biology since Darwin. While a recent proliferation of mammalian genomes has provided an unprecedented inventory of sequence differences between species, the vast majority are in noncoding loci, where it remains challenging to link genetic changes to function. Cis-regulatory elements (CREs) control gene expression via combinatorial, redundant, and context-dependent interactions that are both evolutionarily amenable to change but render their gene regulatory logic difficult to decipher. Recent advances in comparative genomics, functional profiling across species, and high-throughput perturbation assays have begun to catalog cross-species differences in gene expression and CRE function. In parallel, machine learning approaches trained on these data are beginning to predict cis-regulatory activity differences from DNA sequences alone. Here, we highlight recent advances in both experimental and computational strategies to study gene regulatory evolution.
{"title":"Integrating machine learning and functional genomics to study cross-species gene regulatory evolution","authors":"Erin N Gilbertson , Steven K Reilly","doi":"10.1016/j.gde.2025.102415","DOIUrl":"10.1016/j.gde.2025.102415","url":null,"abstract":"<div><div>Understanding the genetic basis of phenotypic differences across species has been a longstanding goal of evolutionary biology since Darwin. While a recent proliferation of mammalian genomes has provided an unprecedented inventory of sequence differences between species, the vast majority are in noncoding loci, where it remains challenging to link genetic changes to function. Cis-regulatory elements (CREs) control gene expression via combinatorial, redundant, and context-dependent interactions that are both evolutionarily amenable to change but render their gene regulatory logic difficult to decipher. Recent advances in comparative genomics, functional profiling across species, and high-throughput perturbation assays have begun to catalog cross-species differences in gene expression and CRE function. In parallel, machine learning approaches trained on these data are beginning to predict cis-regulatory activity differences from DNA sequences alone. Here, we highlight recent advances in both experimental and computational strategies to study gene regulatory evolution.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"96 ","pages":"Article 102415"},"PeriodicalIF":3.6,"publicationDate":"2025-12-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145771942","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-15DOI: 10.1016/j.gde.2025.102414
Olga Rosspopoff , Didier Trono , Cédric Feschotte
Transposable elements (TEs) are abundant and dynamic components of eukaryotic genomes, subject to regulation by equally adaptive regulatory systems. A coevolution of TEs and zinc finger genes can be documented throughout metazoan evolution. In humans, TEs account for half of the genome, and nearly all TE subfamilies are preferentially bound by at least one of the approximately 400 KRAB zinc finger proteins (ZFPs). The majority of human KRAB-ZFPs appear to tame the cis-regulatory activities of TEs, thereby facilitating their integration within gene regulatory networks. In turn, throughout vertebrate evolution, TE protein domains have fused repeatedly with ZFPs to give rise to new classes of regulatory proteins. Thus, the TE–ZFP interplay has been a powerful catalyst of biological innovation.
{"title":"Mix-and-match between transposable elements and zinc finger proteins fuels genic and regulatory innovation","authors":"Olga Rosspopoff , Didier Trono , Cédric Feschotte","doi":"10.1016/j.gde.2025.102414","DOIUrl":"10.1016/j.gde.2025.102414","url":null,"abstract":"<div><div>Transposable elements (TEs) are abundant and dynamic components of eukaryotic genomes, subject to regulation by equally adaptive regulatory systems. A coevolution of TEs and zinc finger genes can be documented throughout metazoan evolution. In humans, TEs account for half of the genome, and nearly all TE subfamilies are preferentially bound by at least one of the approximately 400 KRAB zinc finger proteins (ZFPs). The majority of human KRAB-ZFPs appear to tame the <em>cis</em>-regulatory activities of TEs, thereby facilitating their integration within gene regulatory networks. In turn, throughout vertebrate evolution, TE protein domains have fused repeatedly with ZFPs to give rise to new classes of regulatory proteins. Thus, the TE–ZFP interplay has been a powerful catalyst of biological innovation.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"95 ","pages":"Article 102414"},"PeriodicalIF":3.6,"publicationDate":"2025-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145527962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-11DOI: 10.1016/j.gde.2025.102412
Ricardo Muñiz-Trejo , Jaeda EJ Patton , Santiago Herrera-Álvarez , Joseph W Thornton
New methods are revealing the character of epistatic interactions within proteins and their impacts on evolution. Variation in biochemical phenotypes across protein sequences is determined primarily by the context-independent effects of amino acids and global nonlinearities imposed by biophysical mechanisms. Specific epistasis — primarily pairwise interactions — plays a subsidiary role, but collectively has a major impact on evolution. Every substitution in an evolving protein changes the effects of many potential mutations at epistatically coupled sites. As homologs diverge from common ancestors, the constraints that determine the accessibility of subsequent mutations gradually drift apart. Opportunities for adaptation and functional innovation also change over time, because each substitution epistatically modifies the effects of mutations on existing and new protein phenotypes. Over moderate evolutionary timescales, the outcomes of protein evolution — both their sequences and biochemical properties — thus become strongly contingent on the substitutions that happen to occur in each lineage. This interplay between random chance and each proteins’ epistatic architecture helps explain widely observed lineage-specific patterns of conservation and variation that are not expected under the dominant schools of thought in molecular evolution.
{"title":"Epistatic drift in protein evolution","authors":"Ricardo Muñiz-Trejo , Jaeda EJ Patton , Santiago Herrera-Álvarez , Joseph W Thornton","doi":"10.1016/j.gde.2025.102412","DOIUrl":"10.1016/j.gde.2025.102412","url":null,"abstract":"<div><div>New methods are revealing the character of epistatic interactions within proteins and their impacts on evolution. Variation in biochemical phenotypes across protein sequences is determined primarily by the context-independent effects of amino acids and global nonlinearities imposed by biophysical mechanisms. Specific epistasis — primarily pairwise interactions — plays a subsidiary role, but collectively has a major impact on evolution. Every substitution in an evolving protein changes the effects of many potential mutations at epistatically coupled sites. As homologs diverge from common ancestors, the constraints that determine the accessibility of subsequent mutations gradually drift apart. Opportunities for adaptation and functional innovation also change over time, because each substitution epistatically modifies the effects of mutations on existing and new protein phenotypes. Over moderate evolutionary timescales, the outcomes of protein evolution — both their sequences and biochemical properties — thus become strongly contingent on the substitutions that happen to occur in each lineage. This interplay between random chance and each proteins’ epistatic architecture helps explain widely observed lineage-specific patterns of conservation and variation that are not expected under the dominant schools of thought in molecular evolution.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"95 ","pages":"Article 102412"},"PeriodicalIF":3.6,"publicationDate":"2025-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145507846","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-11-06DOI: 10.1016/j.gde.2025.102413
Gayani Senevirathne , Terence D Capellini
Modern humans exhibit marked musculoskeletal changes when compared to those of our African ape relatives, such as chimpanzees, bonobos, and gorillas. These changes reflect adaptive shifts during hominin evolution in spine, pelvis, knee, and foot morphology toward obligate bipedalism, shoulder, elbow, and hand morphology for propulsive throwing and precision object manipulation, and brain size expansion and craniofacial morphology for enhanced cognition related to complex culture and language. The molecular basis for these traits remains unknown, in part owing to the experimental difficulties in connecting DNA base-pairs to phenotypes. Here, we discuss recent methodological advances in the life sciences that help to connect genotype to phenotype and pave the way for understanding the molecular basis for human skeletal evolution. In this context, we also discuss the importance of recent findings in how adaptive evolution shapes modern disease risk.
{"title":"New methodological approaches and insights gained toward understanding the evolved human skeleton","authors":"Gayani Senevirathne , Terence D Capellini","doi":"10.1016/j.gde.2025.102413","DOIUrl":"10.1016/j.gde.2025.102413","url":null,"abstract":"<div><div>Modern humans exhibit marked musculoskeletal changes when compared to those of our African ape relatives, such as chimpanzees, bonobos, and gorillas. These changes reflect adaptive shifts during hominin evolution in spine, pelvis, knee, and foot morphology toward obligate bipedalism, shoulder, elbow, and hand morphology for propulsive throwing and precision object manipulation, and brain size expansion and craniofacial morphology for enhanced cognition related to complex culture and language. The molecular basis for these traits remains unknown, in part owing to the experimental difficulties in connecting DNA base-pairs to phenotypes. Here, we discuss recent methodological advances in the life sciences that help to connect genotype to phenotype and pave the way for understanding the molecular basis for human skeletal evolution. In this context, we also discuss the importance of recent findings in how adaptive evolution shapes modern disease risk.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"95 ","pages":"Article 102413"},"PeriodicalIF":3.6,"publicationDate":"2025-11-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145472530","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-10-29DOI: 10.1016/j.gde.2025.102411
Alexander E Downie , Jenny Tung
Immune genes show remarkably consistent evidence of selection, modification, and diversification across the tree of life. Parasites are a key force in this process, but many questions remain about the genetic and phenotypic targets of parasite-mediated selection and how these connect to each other. Ecological immunology — the study of immune variation in natural settings — can complement genetic inference by providing an organismal perspective on immune evolution, including how immune adaptation may be explained or constrained by host life history and ecological context. In this review, we outline key questions in immune evolution where ecological immunology offers insights for evolutionary geneticists, and we explore the value of evolutionary genetic approaches for testing fundamental assumptions in ecological immunology.
{"title":"Evolutionary genetics meets ecological immunology: insights into the evolution of immune systems","authors":"Alexander E Downie , Jenny Tung","doi":"10.1016/j.gde.2025.102411","DOIUrl":"10.1016/j.gde.2025.102411","url":null,"abstract":"<div><div>Immune genes show remarkably consistent evidence of selection, modification, and diversification across the tree of life. Parasites are a key force in this process, but many questions remain about the genetic and phenotypic targets of parasite-mediated selection and how these connect to each other. Ecological immunology — the study of immune variation in natural settings — can complement genetic inference by providing an organismal perspective on immune evolution, including how immune adaptation may be explained or constrained by host life history and ecological context. In this review, we outline key questions in immune evolution where ecological immunology offers insights for evolutionary geneticists, and we explore the value of evolutionary genetic approaches for testing fundamental assumptions in ecological immunology.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"95 ","pages":"Article 102411"},"PeriodicalIF":3.6,"publicationDate":"2025-10-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145410717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The gastrointestinal (GI) tract evolved in response to dietary changes and pathogen exposures that varied throughout history. As a major interface between the host and environment, the GI epithelia have evolved specialized barrier and immune functions while optimizing nutrient processing and absorption. Recent technological breakthroughs in modeling human biology in vitro and comparative single-cell genomics are providing novel insights into the genetic, cellular, and ontogenic basis of human evolution. In this review, we provide a broad overview of human-specific gut changes and how GI organoids and single-cell technologies can offer a mechanistic understanding of the specific features of human GI tract physiology.
{"title":"Human gut evolution: insights from stem cell models and single-cell genomics","authors":"Rubén López-Sandoval , Stefano Secchia , Joep Beumer , Jarrett Gray Camp","doi":"10.1016/j.gde.2025.102398","DOIUrl":"10.1016/j.gde.2025.102398","url":null,"abstract":"<div><div>The gastrointestinal (GI) tract evolved in response to dietary changes and pathogen exposures that varied throughout history. As a major interface between the host and environment, the GI epithelia have evolved specialized barrier and immune functions while optimizing nutrient processing and absorption. Recent technological breakthroughs in modeling human biology <em>in vitro</em> and comparative single-cell genomics are providing novel insights into the genetic, cellular, and ontogenic basis of human evolution. In this review, we provide a broad overview of human-specific gut changes and how GI organoids and single-cell technologies can offer a mechanistic understanding of the specific features of human GI tract physiology.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"95 ","pages":"Article 102398"},"PeriodicalIF":3.6,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145151709","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-09-03DOI: 10.1016/j.gde.2025.102397
Andres Bendesky
Recent advances in single-cell genomics are propelling a flurry of discoveries about the cellular composition of the brain and other organs across species. These discoveries, coupled with experimental manipulations, have begun to reveal how variation between species in the proportion of cell types, including the outright disappearance of some cell types and the emergence of new ones, contributes to the evolution of behavior. This review highlights these emerging findings in the context of more traditional approaches to study the evolution of behavior and discusses important outstanding questions in this field.
{"title":"Behavioral evolution by diverging cell type composition","authors":"Andres Bendesky","doi":"10.1016/j.gde.2025.102397","DOIUrl":"10.1016/j.gde.2025.102397","url":null,"abstract":"<div><div>Recent advances in single-cell genomics are propelling a flurry of discoveries about the cellular composition of the brain and other organs across species. These discoveries, coupled with experimental manipulations, have begun to reveal how variation between species in the proportion of cell types, including the outright disappearance of some cell types and the emergence of new ones, contributes to the evolution of behavior. This review highlights these emerging findings in the context of more traditional approaches to study the evolution of behavior and discusses important outstanding questions in this field.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"95 ","pages":"Article 102397"},"PeriodicalIF":3.6,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144932407","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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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