{"title":"Linking phenotype to genotype using comprehensive genomic comparisons","authors":"Leon Hilgers , Michael Hiller","doi":"10.1016/j.gde.2025.102384","DOIUrl":"10.1016/j.gde.2025.102384","url":null,"abstract":"<div><div>Comparative genomics is a powerful approach to illuminate the genetic basis of phenotypic diversity across macro-evolutionary timescales. Recent advances in sequencing, genome assembly, annotation, and comparative methods promoted large-scale analyses that unveiled genomic determinants contributing to differences in cognition, metabolism, and body plans as well as phenotypes with biomedical relevance, such as cancer resistance, longevity, and viral tolerance. These studies highlight joint contributions of multiple molecular mechanisms and indicate an underappreciated role for gene and enhancer losses driving phenotypic change. However, challenges remain, including comprehensive phenotype databases and genome annotations, improved approaches for identifying lineage-specific adaptations, and functional tests. Here, we review recent progress, highlight major discoveries, and discuss future directions for linking phenotype to genotype using comparative genomics.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"94 ","pages":"Article 102384"},"PeriodicalIF":3.7,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144696870","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}
{"title":"Dynamic three-dimensional epigenomic reorganization for the development of undifferentiated spermatogonia in mice","authors":"Masahiro Nagano , Mitinori Saitou","doi":"10.1016/j.gde.2025.102383","DOIUrl":"10.1016/j.gde.2025.102383","url":null,"abstract":"<div><div>Germ cells are unique in their ability to acquire totipotency. Toward this end, they reorganize their three-dimensional (3D) epigenome during their development, including epigenetic reprogramming in primordial germ cells that differentiate mitotic prospermatogonia and ensuing unique epigenetic programming for generating undifferentiated spermatogonia/spermatogonial stem cells (SSCs). Advances in low-input epigenomic and 3D genomic techniques, along with complementary in-depth characterization of scalable <em>in vitro</em> reconstitution systems for germ cell development, that is, <em>in vitro</em> gametogenesis, have elucidated a number of fundamental events during these processes, including insulation augmentation in highly open chromatin following epigenetic reprogramming in mitotic prospermatogonia and insulation erasure and further euchromatization accompanied by chromosomal radial repositioning in undifferentiated spermatogonia/SSCs. These 3D epigenomic organizations likely serve as a foundation for generating fully functional gametes. Elucidating the mechanisms underlying 3D epigenomic reorganization during germ cell development will be instrumental not only for understanding the basis for totipotency but also for further advancing <em>in vitro</em> gametogenesis.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"94 ","pages":"Article 102383"},"PeriodicalIF":3.7,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144680499","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}
{"title":"Evolution and ecology of commensal gut protists: recent advances","authors":"Abigail Lind","doi":"10.1016/j.gde.2025.102382","DOIUrl":"10.1016/j.gde.2025.102382","url":null,"abstract":"<div><div>The microbial community colonizing the animal gut includes all domains of life, including eukaryotic microbes. Historically viewed as pathogens, increasing evidence has revealed that many protists are commensal members of the microbiome with diverse ecological functions. This review synthesizes recent advances in our understanding of the ecology and evolution of these organisms, with a focus on phylogenetic diversity, microbial interactions, and genomic signatures of adaptation. New technologies such as single-cell genomics and transcriptomics, long-read sequencing technologies, and co-culture strategies have made these new findings possible, but much remains to be investigated. Further work is needed to understand how these diverse organisms contribute to the gut environment and evolve to colonize animal hosts.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"94 ","pages":"Article 102382"},"PeriodicalIF":3.7,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144654706","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}
{"title":"Why and how paternal mitochondrial DNA gets cut out of the inheritance","authors":"Mayu Shimomura, Thomas R Hurd","doi":"10.1016/j.gde.2025.102381","DOIUrl":"10.1016/j.gde.2025.102381","url":null,"abstract":"<div><div>Mitochondrial DNA (mtDNA) is inherited maternally across animals, yet the evolutionary rationale behind this unusual mode of inheritance remains a longstanding mystery. Understanding the processes that prevent the transmission of paternal mtDNA and thus ensure maternal-only inheritance is crucial to uncovering the evolutionary significance of this widespread phenomenon. Historically, research has focused on mechanisms that act within eggs to destroy sperm mitochondria via autophagy and the ubiquitin-proteasome degradation system. However, recent discoveries across multiple animal species, including humans, reveal a surprising twist: paternal mtDNA is actively degraded within mitochondria independently of and prior to the complete breakdown of the organelle itself, often even prior to fertilization. Only a few studies have begun to illuminate the molecular machinery responsible for this early mtDNA elimination. In this review, we explore the emerging landscape of paternal mtDNA elimination mechanisms across species, highlighting newly discovered pathways, evolutionary implications, and open questions that are furthering our understanding of mitochondrial inheritance.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"94 ","pages":"Article 102381"},"PeriodicalIF":3.7,"publicationDate":"2025-07-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144633892","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}
{"title":"Transcription-Export complex in neurodevelopmental disorders","authors":"Rudrarup Bhattacharjee , Shreya Agarwala , Danielle Mazurkiewicz , Jozef Gecz , Raman Kumar","doi":"10.1016/j.gde.2025.102380","DOIUrl":"10.1016/j.gde.2025.102380","url":null,"abstract":"<div><div>The genomic information is insulated in the nucleus of all eukaryotic cells. Error-free transcription needs to be followed by an efficient export of the messenger RNAs (mRNA) to facilitate the regulated synthesis of proteins for carrying out cellular functions. The functionally conserved <u>Tr</u>anscription-<u>Ex</u>port (TREX) complex is a key player in mediating mRNA export from the nucleus to the cytoplasm, along with RNA processing steps including 3′-end processing, 5′ capping, transcriptional regulation, R-loop resolution, and splicing. TREX, a multifunctional complex, has important roles in stress response, mitotic progression, embryonic stem cell self-renewal and differentiation, and maintaining genome stability. Most of these processes are essential for the appropriate development and function of the brain. Consistent with this notion, partial loss of function variants in the TREX components THOC2, THOC6, and DDX39B were implicated in neurodevelopmental disorders. Furthermore, a growing body of evidence also highlighted the involvement of defective nucleocytoplasmic RNA transport in the development of neurodegenerative diseases. Overall, the TREX complex is emerging as a crucial player in neurological diseases, making it a critical target for both diagnosis and therapeutic intervention.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"94 ","pages":"Article 102380"},"PeriodicalIF":3.7,"publicationDate":"2025-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144597101","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}
{"title":"Centromere regulation in the germline and early embryo","authors":"Marta Grzonka , Ben E Black , Michael A Lampson","doi":"10.1016/j.gde.2025.102379","DOIUrl":"10.1016/j.gde.2025.102379","url":null,"abstract":"<div><div>Centromeres are essential for genome inheritance, serving as sites for kinetochore assembly and for final sister chromatid cohesion to ensure accurate chromosome segregation during cell division. These roles must persist through radical physical changes to chromosomes and other biological challenges presented by specialized processes in the germlines of both sexes and during early embryonic development. Centromeres in most organisms are epigenetically defined by the presence of a histone H3 variant, CENP-A. Therefore, to maintain centromeres, CENP-A nucleosomes must be inherited across generations through the germline. However, unique aspects of gametogenesis, including asymmetric meiosis and prolonged cell cycle arrest in the female germline and extensive chromatin reorganization in the male germline, introduce additional layers of complexity to the process of centromere inheritance. Here, we review the implications of these processes for centromere regulation during gametogenesis and early embryonic development, drawing on findings from mouse and fruit fly models.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"94 ","pages":"Article 102379"},"PeriodicalIF":3.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587669","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}
{"title":"Exploring the origin of the development: totipotent stem cells","authors":"Shiyu Li , Hui Shen , Bing Peng , Peng Du","doi":"10.1016/j.gde.2025.102377","DOIUrl":"10.1016/j.gde.2025.102377","url":null,"abstract":"<div><div>As the origin of the development, a fertilized egg owns the ability to generate a whole new organism, including both embryonic and extraembryonic tissues, representing the highest developmental potency, totipotency. For more than 40 years, pluripotent stem cells, with differentiation potential weaker than that of totipotent cells, have been easily derived from inner cell mass and maintained <em>in vitro</em>. Until now, capturing totipotent stem cells is still challenging. Recently, the stable culture of mouse and human totipotent blastomere–like cells was achieved for the first time using spliceosomal repression. Subsequently, other methods, particularly epigenetic manipulation, have also succeeded in culturing mouse totipotent stem cells. These advancements provide an excellent system for studying early embryonic development and offer new possibilities for regenerative medicine. However, the <em>in vitro</em> culture of totipotent stem cells has only been recently realized, and much further exploration is needed in this field. This review aims to compare different totipotent stem cells and discuss their potential applications in regenerative medicine and disease modeling.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"94 ","pages":"Article 102377"},"PeriodicalIF":3.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144587668","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}
Raphaëlle Dubruille , Béatrice Horard , Benjamin Loppin
{"title":"A haystack in the needle: packaging sperm DNA in insects","authors":"Raphaëlle Dubruille , Béatrice Horard , Benjamin Loppin","doi":"10.1016/j.gde.2025.102378","DOIUrl":"10.1016/j.gde.2025.102378","url":null,"abstract":"<div><div>The global replacement of nucleosomes with nonhistone chromosomal proteins during sperm differentiation is a widespread phenomenon in sexually reproducing animals. In mammals, for instance, sperm chromatin is essentially packaged with protamines, a type of sperm nuclear basic proteins (SNBPs). In contrast to vertebrates, where many taxa retain variable levels of histones in their sperm chromatin, insects seem to systematically eliminate histones during spermiogenesis. This diversity of sperm packaging across metazoa raises questions about the functional significance of the histone-to-protamine transition that occurs during spermiogenesis. Recent studies in Drosophila and other insects have shed light on the function of SNBPs in packaging ultracompact sperm DNA and preparing paternal chromosomes for their integration into the diploid zygote.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102378"},"PeriodicalIF":3.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144570296","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}
{"title":"Mitochondrial curation for the next generation","authors":"Gregory C. Gundberg , Jeremy Nance","doi":"10.1016/j.gde.2025.102376","DOIUrl":"10.1016/j.gde.2025.102376","url":null,"abstract":"<div><div>The mitochondrial genome (mtDNA) can accumulate deleterious mutations that lead to disease. Animals have evolved strategies to eliminate mtDNA mutations in the maternal germ line, increasing the likelihood that their progeny inherit healthy mitochondria. Here, we provide an overview of mitochondrial quality control in the germ line, focusing on recent findings in mammals, <em>Drosophila</em>, and <em>C. elegans</em>. We discuss three strategies for quality control: elimination of sperm mtDNA, which prevents transmission of paternal mtDNA to progeny; the genetic bottleneck, which reduces the effective number of mtDNAs in germ cells, potentially exposing mutations to selection; and purifying selection, which selects for healthier mtDNAs. Finally, we discuss outstanding questions in the field and technical advances needed to address them.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102376"},"PeriodicalIF":3.7,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144563535","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}
{"title":"The HNRNPs and neurodevelopmental disorders","authors":"Madelyn A Gillentine","doi":"10.1016/j.gde.2025.102371","DOIUrl":"10.1016/j.gde.2025.102371","url":null,"abstract":"<div><div>The <em>HNRNP</em> gene family has long been investigated in neurodegenerative disorders and cancer. Over the last several years, multiple members of the gene family have been associated with neurodevelopmental disorders. To date, there are nine well-established HNRNP-related neurodevelopmental disorders (HNRNP-RNDDs), at least three that are actively being characterized, and several candidate genes with a small number of patients. Here, we review the over 1000 individuals in the literature and patient databases and describe the overall phenotypic spectra of the HNRNP-RNDDs. Furthermore, we discuss recent advances in understanding the pathomechanisms of the HNRNP-RNDDs and how that will impact future therapeutic development.</div></div>","PeriodicalId":50606,"journal":{"name":"Current Opinion in Genetics & Development","volume":"93 ","pages":"Article 102371"},"PeriodicalIF":3.7,"publicationDate":"2025-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144517124","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}