Pub Date : 2024-04-23DOI: 10.1093/genetics/iyae045
Vitoria K. Paolillo, Matthew E. Ochs, E. Lundquist
Neurogenesis involves the precisely coordinated action of genetic programs controlling large-scale neuronal fate specification down to terminal events of neuronal differentiation. The Q neuroblasts in Caenorhabditis elegans, QL on the left and QR on the right, divide, differentiate, and migrate in a similar pattern to produce three neurons each. However, QL on the left migrates posteriorly, and QR on the right migrates anteriorly. The MAB-5/Hox transcription factor is necessary and sufficient for posterior Q lineage migration and is normally expressed only in the QL lineage. To define genes controlled by MAB-5 in the Q cells, fluorescence-activated cell sorting was utilized to isolate populations of Q cells at a time in early L1 larvae when MAB-5 first becomes active. Sorted Q cells from wild-type, mab-5 loss-of-function (lof), and mab-5 gain-of-function (gof) mutants were subject to RNA-seq and differential expression analysis. Genes enriched in Q cells included those involved in cell division, DNA replication, and DNA repair, consist with the neuroblast stem cell identity of the Q cells at this stage. Genes affected by mab-5 included those involved in neurogenesis, neural development, and interaction with the extracellular matrix. cwn-1, which encodes a Wnt signaling molecule, showed a paired response to mab-5 in the Q cells: cwn-1 expression was reduced in mab-5(lof) and increased in mab-5(gof), suggesting that MAB-5 is required for cwn-1 expression in Q cells. MAB-5 is required to prevent anterior migration of the Q lineage while it transcriptionally reprograms the Q lineage for posterior migration. Functional genetic analysis revealed that CWN-1 is required downstream of MAB-5 to inhibit anterior migration of the QL lineage, likely in parallel to EGL-20/Wnt in a noncanonical Wnt pathway. In sum, work here describes a Q cell transcriptome, and a set of genes regulated by MAB-5 in the QL lineage. One of these genes, cwn-1, acts downstream of mab-5 in QL migration, indicating that this gene set includes other genes utilized by MAB-5 to facilitate posterior neuroblast migration.
{"title":"MAB-5/Hox regulates the Q neuroblast transcriptome, including cwn-1/Wnt, to mediate posterior migration in Caenorhabditis elegans.","authors":"Vitoria K. Paolillo, Matthew E. Ochs, E. Lundquist","doi":"10.1093/genetics/iyae045","DOIUrl":"https://doi.org/10.1093/genetics/iyae045","url":null,"abstract":"Neurogenesis involves the precisely coordinated action of genetic programs controlling large-scale neuronal fate specification down to terminal events of neuronal differentiation. The Q neuroblasts in Caenorhabditis elegans, QL on the left and QR on the right, divide, differentiate, and migrate in a similar pattern to produce three neurons each. However, QL on the left migrates posteriorly, and QR on the right migrates anteriorly. The MAB-5/Hox transcription factor is necessary and sufficient for posterior Q lineage migration and is normally expressed only in the QL lineage. To define genes controlled by MAB-5 in the Q cells, fluorescence-activated cell sorting was utilized to isolate populations of Q cells at a time in early L1 larvae when MAB-5 first becomes active. Sorted Q cells from wild-type, mab-5 loss-of-function (lof), and mab-5 gain-of-function (gof) mutants were subject to RNA-seq and differential expression analysis. Genes enriched in Q cells included those involved in cell division, DNA replication, and DNA repair, consist with the neuroblast stem cell identity of the Q cells at this stage. Genes affected by mab-5 included those involved in neurogenesis, neural development, and interaction with the extracellular matrix. cwn-1, which encodes a Wnt signaling molecule, showed a paired response to mab-5 in the Q cells: cwn-1 expression was reduced in mab-5(lof) and increased in mab-5(gof), suggesting that MAB-5 is required for cwn-1 expression in Q cells. MAB-5 is required to prevent anterior migration of the Q lineage while it transcriptionally reprograms the Q lineage for posterior migration. Functional genetic analysis revealed that CWN-1 is required downstream of MAB-5 to inhibit anterior migration of the QL lineage, likely in parallel to EGL-20/Wnt in a noncanonical Wnt pathway. In sum, work here describes a Q cell transcriptome, and a set of genes regulated by MAB-5 in the QL lineage. One of these genes, cwn-1, acts downstream of mab-5 in QL migration, indicating that this gene set includes other genes utilized by MAB-5 to facilitate posterior neuroblast migration.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"130 39","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140669243","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-18DOI: 10.1093/genetics/iyae055
Yang Ping Kuo, Oana Carja
Spatially-resolved datasets are revolutionizing knowledge in molecular biology, yet are under-utilized for questions in evolutionary biology. To gain insight from these large-scale datasets of spatial organization, we need mathematical representations and modeling techniques that can both capture their complexity, but also allow for mathematical tractability. Evolutionary graph theory utilizes the mathematical representation of networks as a proxy for heterogeneous population structure and has started to reshape our understanding of how spatial structure can direct evolutionary dynamics. However, previous results are derived for the case of a single new mutation appearing in the population and the role of network structure in shaping fitness landscape crossing is still poorly understood. Here we study how network structured populations cross fitness landscapes and show that even a simple extension to a two-mutational landscape can exhibit complex evolutionary dynamics that cannot be predicted using previous single-mutation results. We show how our results can be intuitively understood through the lens of how the two main evolutionary properties of a network, the amplification and acceleration factors, change the expected fate of the intermediate mutant in the population and further discuss how to link these models to spatially-resolved datasets of cellular organization.
{"title":"Evolutionary graph theory beyond single mutation dynamics: on how network structured populations cross fitness landscapes.","authors":"Yang Ping Kuo, Oana Carja","doi":"10.1093/genetics/iyae055","DOIUrl":"https://doi.org/10.1093/genetics/iyae055","url":null,"abstract":"Spatially-resolved datasets are revolutionizing knowledge in molecular biology, yet are under-utilized for questions in evolutionary biology. To gain insight from these large-scale datasets of spatial organization, we need mathematical representations and modeling techniques that can both capture their complexity, but also allow for mathematical tractability. Evolutionary graph theory utilizes the mathematical representation of networks as a proxy for heterogeneous population structure and has started to reshape our understanding of how spatial structure can direct evolutionary dynamics. However, previous results are derived for the case of a single new mutation appearing in the population and the role of network structure in shaping fitness landscape crossing is still poorly understood. Here we study how network structured populations cross fitness landscapes and show that even a simple extension to a two-mutational landscape can exhibit complex evolutionary dynamics that cannot be predicted using previous single-mutation results. We show how our results can be intuitively understood through the lens of how the two main evolutionary properties of a network, the amplification and acceleration factors, change the expected fate of the intermediate mutant in the population and further discuss how to link these models to spatially-resolved datasets of cellular organization.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"50 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140623548","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-16DOI: 10.1093/genetics/iyae058
Felipe Nieto-Panqueva, Miriam Vázquez-Acevedo, Patrice P Hamel, Diego González-Halphen
Mitochondrial genes can be naturally or artificially relocalized in the nuclear genome in a process known as allotopic expression, such is the case of the mitochondrial cox2 gene, encoding subunit II of cytochrome c oxidase (CcO). In yeast, cox2 can be allotopically expressed and is able to restore respiratory growth of a cox2-null mutant if the Cox2 subunit carries the W56R substitution within the first transmembrane stretch. However, the COX2W56R strain exhibits reduced growth rates and lower steady-state CcO levels when compared to wild-type yeast. Here, we investigated the impact of overexpressing selected candidate genes predicted to enhance internalization of the allotopic Cox2W56R precursor into mitochondria. The overproduction of Cox20, Oxa1, and Pse1 facilitated Cox2W56R precursor internalization, improving the respiratory growth of the COX2W56R strain. Overproducing TIM22 components had a limited effect on Cox2W56R import, while overproducing TIM23-related components showed a negative effect. We further explored the role of the Mgr2 subunit within the TIM23 translocator in the import process by deleting and overexpressing the MGR2 gene. Our findings indicate that Mgr2 is instrumental in modulating the TIM23 translocon to correctly sort Cox2W56R. We propose a biogenesis pathway followed by the allotopically produced Cox2 subunit based on the participation of the two different structural/functional forms of the TIM23 translocon, TIM23MOTOR and TIM23SORT, that must follow a concerted and sequential mode of action to insert Cox2W56R into the inner mitochondrial membrane in the correct Nout-Cout topology.
{"title":"Identification of factors limiting the allotopic production of the Cox2 subunit of yeast cytochrome c oxidase.","authors":"Felipe Nieto-Panqueva, Miriam Vázquez-Acevedo, Patrice P Hamel, Diego González-Halphen","doi":"10.1093/genetics/iyae058","DOIUrl":"https://doi.org/10.1093/genetics/iyae058","url":null,"abstract":"Mitochondrial genes can be naturally or artificially relocalized in the nuclear genome in a process known as allotopic expression, such is the case of the mitochondrial cox2 gene, encoding subunit II of cytochrome c oxidase (CcO). In yeast, cox2 can be allotopically expressed and is able to restore respiratory growth of a cox2-null mutant if the Cox2 subunit carries the W56R substitution within the first transmembrane stretch. However, the COX2W56R strain exhibits reduced growth rates and lower steady-state CcO levels when compared to wild-type yeast. Here, we investigated the impact of overexpressing selected candidate genes predicted to enhance internalization of the allotopic Cox2W56R precursor into mitochondria. The overproduction of Cox20, Oxa1, and Pse1 facilitated Cox2W56R precursor internalization, improving the respiratory growth of the COX2W56R strain. Overproducing TIM22 components had a limited effect on Cox2W56R import, while overproducing TIM23-related components showed a negative effect. We further explored the role of the Mgr2 subunit within the TIM23 translocator in the import process by deleting and overexpressing the MGR2 gene. Our findings indicate that Mgr2 is instrumental in modulating the TIM23 translocon to correctly sort Cox2W56R. We propose a biogenesis pathway followed by the allotopically produced Cox2 subunit based on the participation of the two different structural/functional forms of the TIM23 translocon, TIM23MOTOR and TIM23SORT, that must follow a concerted and sequential mode of action to insert Cox2W56R into the inner mitochondrial membrane in the correct Nout-Cout topology.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"104 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140612309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-16DOI: 10.1093/genetics/iyae038
Kari D Hagen, Christopher J S Hart, Shane G McInally, Scott C Dawson
Giardia is a prevalent single-celled microaerophilic intestinal parasite causing diarrheal disease and significantly impacting global health. Double diploid (essentially tetraploid) Giardia trophozoites have presented a formidable challenge to the development of molecular genetic tools to interrogate gene function. High sequence divergence and the high percentage of hypothetical proteins lacking homology to proteins in other eukaryotes have limited our understanding of Giardia protein function, slowing drug target validation and development. For more than 25 years, Giardia A and B assemblages have been readily amenable to transfection with plasmids or linear DNA templates. Here, we highlight the utility and power of genetic approaches developed to assess protein function in Giardia, with particular emphasis on the more recent clustered regularly interspaced palindromic repeats/Cas9-based methods for knockdowns and knockouts. Robust and reliable molecular genetic approaches are fundamental toward the interrogation of Giardia protein function and evaluation of druggable targets. New genetic approaches tailored for the double diploid Giardia are imperative for understanding Giardia's unique biology and pathogenesis.
贾第虫（Giardia）是一种流行的单细胞嗜微气肠寄生虫，可引起腹泻病，对全球健康产生重大影响。贾第虫滋养体的双二倍体（本质上是四倍体）对开发分子遗传工具以研究基因功能提出了严峻的挑战。高度的序列差异和与其他真核生物蛋白质缺乏同源性的假定蛋白质的高比例限制了我们对贾第鞭毛虫蛋白质功能的了解，减缓了药物靶点的验证和开发。25 年多来，贾第虫 A 型和 B 型集合体很容易被质粒或线性 DNA 模板转染。在此，我们将重点介绍为评估贾第虫蛋白质功能而开发的遗传方法的实用性和强大功能，尤其是最近基于聚类规则间隔回文重复序列/Cas9的基因敲除和基因敲除方法。稳健可靠的分子遗传方法是研究贾第虫蛋白质功能和评估药物靶点的基础。为双二倍体贾第虫量身定制的新遗传方法对于了解贾第虫独特的生物学和致病机理至关重要。
{"title":"Harnessing the power of new genetic tools to illuminate Giardia biology and pathogenesis.","authors":"Kari D Hagen, Christopher J S Hart, Shane G McInally, Scott C Dawson","doi":"10.1093/genetics/iyae038","DOIUrl":"https://doi.org/10.1093/genetics/iyae038","url":null,"abstract":"Giardia is a prevalent single-celled microaerophilic intestinal parasite causing diarrheal disease and significantly impacting global health. Double diploid (essentially tetraploid) Giardia trophozoites have presented a formidable challenge to the development of molecular genetic tools to interrogate gene function. High sequence divergence and the high percentage of hypothetical proteins lacking homology to proteins in other eukaryotes have limited our understanding of Giardia protein function, slowing drug target validation and development. For more than 25 years, Giardia A and B assemblages have been readily amenable to transfection with plasmids or linear DNA templates. Here, we highlight the utility and power of genetic approaches developed to assess protein function in Giardia, with particular emphasis on the more recent clustered regularly interspaced palindromic repeats/Cas9-based methods for knockdowns and knockouts. Robust and reliable molecular genetic approaches are fundamental toward the interrogation of Giardia protein function and evaluation of druggable targets. New genetic approaches tailored for the double diploid Giardia are imperative for understanding Giardia's unique biology and pathogenesis.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"13 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140612369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-12DOI: 10.1093/genetics/iyae057
Erick I Rios, Davi Gonçalves, Kevin A Morano, Jill L Johnson
Hsp90 is an abundant and essential molecular chaperone that mediates the folding and activation of client proteins in a nucleotide-dependent cycle. Hsp90 inhibition directly or indirectly impacts the function of 10-15% of all proteins due to degradation of client proteins or indirect downstream effects. Due to its role in chaperoning oncogenic proteins, Hsp90 is an important drug target. However, compounds that occupy the ATP-binding pocket and broadly inhibit function have not achieved widespread use due to negative effects. More selective inhibitors are needed; however, it is unclear how to achieve selective inhibition. We conducted a quantitative proteomic analysis of soluble proteins in yeast strains expressing wild-type Hsp90 or mutants that disrupt different steps in the client folding pathway. Out of 2,482 proteins in our sample set (approximately 38% of yeast proteins), we observed statistically significant changes in abundance of 350 (14%) of those proteins (log2 fold change ≥1.5). Of these, 257/350 (∼73%) with the strongest differences in abundance were previously connected to Hsp90 function. Principal component analysis of the entire dataset revealed that the effects of the mutants could be separated into three primary clusters. As evidence that Hsp90 mutants affect different pools of clients, simultaneous co-expression of two mutants in different clusters restored wild-type growth. Our data suggests that the ability of Hsp90 to sample a wide range of conformations allows the chaperone to mediate folding of a broad array of clients and that disruption of conformational flexibility results in client defects dependent on those states.
{"title":"Quantitative proteomic analysis reveals unique Hsp90 cycle-dependent client interactions.","authors":"Erick I Rios, Davi Gonçalves, Kevin A Morano, Jill L Johnson","doi":"10.1093/genetics/iyae057","DOIUrl":"https://doi.org/10.1093/genetics/iyae057","url":null,"abstract":"Hsp90 is an abundant and essential molecular chaperone that mediates the folding and activation of client proteins in a nucleotide-dependent cycle. Hsp90 inhibition directly or indirectly impacts the function of 10-15% of all proteins due to degradation of client proteins or indirect downstream effects. Due to its role in chaperoning oncogenic proteins, Hsp90 is an important drug target. However, compounds that occupy the ATP-binding pocket and broadly inhibit function have not achieved widespread use due to negative effects. More selective inhibitors are needed; however, it is unclear how to achieve selective inhibition. We conducted a quantitative proteomic analysis of soluble proteins in yeast strains expressing wild-type Hsp90 or mutants that disrupt different steps in the client folding pathway. Out of 2,482 proteins in our sample set (approximately 38% of yeast proteins), we observed statistically significant changes in abundance of 350 (14%) of those proteins (log2 fold change ≥1.5). Of these, 257/350 (∼73%) with the strongest differences in abundance were previously connected to Hsp90 function. Principal component analysis of the entire dataset revealed that the effects of the mutants could be separated into three primary clusters. As evidence that Hsp90 mutants affect different pools of clients, simultaneous co-expression of two mutants in different clusters restored wild-type growth. Our data suggests that the ability of Hsp90 to sample a wide range of conformations allows the chaperone to mediate folding of a broad array of clients and that disruption of conformational flexibility results in client defects dependent on those states.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"162 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140584210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-06DOI: 10.1093/genetics/iyae053
Cody J Drozd, Tamjid A Chowdhury, Christopher C Quinn
In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. In C. elegans, the UNC-16 ortholog of the MAPK8IP3 protein can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.
{"title":"UNC-16 interacts with LRK-1 and WDFY-3 to regulate the termination of axon growth.","authors":"Cody J Drozd, Tamjid A Chowdhury, Christopher C Quinn","doi":"10.1093/genetics/iyae053","DOIUrl":"https://doi.org/10.1093/genetics/iyae053","url":null,"abstract":"In humans, MAPK8IP3 (also known as JIP3) is a neurodevelopmental disorder-associated gene. In C. elegans, the UNC-16 ortholog of the MAPK8IP3 protein can regulate the termination of axon growth. However, its role in this process is not well understood. Here, we report that UNC-16 promotes axon termination through a process that includes the LRK-1(LRRK-1/LRRK-2) kinase and the WDFY-3 (WDFY3/Alfy) selective autophagy protein. Genetic analysis suggests that UNC-16 promotes axon termination through an interaction between its RH1 domain and the dynein complex. Loss of unc-16 function causes accumulation of late endosomes specifically in the distal axon. Moreover, we observe synergistic interactions between loss of unc-16 function and disruptors of endolysosomal function, indicating that the endolysosomal system promotes axon termination. We also find that the axon termination defects caused by loss of UNC-16 function require the function of a genetic pathway that includes lrk-1 and wdfy-3, two genes that have been implicated in autophagy. These observations suggest a model where UNC-16 promotes axon termination by interacting with the endolysosomal system to regulate a pathway that includes LRK-1 and WDFY-3.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"50 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140583979","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Complex chromosomal rearrangements (CCRs) are often observed in clinical samples from patients with cancer and congenital diseases but are difficult to induce experimentally. Here, we report the first success in establishing animal models for CCRs. Mutation in Recql5, a crucial member of the DNA helicase RecQ family involved in DNA replication, transcription, and repair, enabled CRISPR/Cas9-mediated CCRs, establishing a mouse model containing triple fusion genes and megabase-sized inversions. Some of these structural features of individual chromosomal rearrangements use template switching and microhomology-mediated break-induced replication mechanisms and are reminiscent of the newly described phenomenon "chromoanasynthesis." These data show that Recql5-mutant mice could be a powerful tool to analyze the pathogenesis of CCRs (particularly chromoanasynthesis) whose underlying mechanisms are poorly understood. The Recql5 mutants generated in this study are to be deposited at key animal research facilities, thereby making them accessible for future research on CCRs.
{"title":"A Recql5 mutant facilitates complex CRISPR/Cas9-mediated-chromosomal engineering in mouse zygotes.","authors":"Satoru Iwata, Miki Nagahara, Risako Ido, Takashi Iwamoto","doi":"10.1093/genetics/iyae054","DOIUrl":"https://doi.org/10.1093/genetics/iyae054","url":null,"abstract":"Complex chromosomal rearrangements (CCRs) are often observed in clinical samples from patients with cancer and congenital diseases but are difficult to induce experimentally. Here, we report the first success in establishing animal models for CCRs. Mutation in Recql5, a crucial member of the DNA helicase RecQ family involved in DNA replication, transcription, and repair, enabled CRISPR/Cas9-mediated CCRs, establishing a mouse model containing triple fusion genes and megabase-sized inversions. Some of these structural features of individual chromosomal rearrangements use template switching and microhomology-mediated break-induced replication mechanisms and are reminiscent of the newly described phenomenon \"chromoanasynthesis.\" These data show that Recql5-mutant mice could be a powerful tool to analyze the pathogenesis of CCRs (particularly chromoanasynthesis) whose underlying mechanisms are poorly understood. The Recql5 mutants generated in this study are to be deposited at key animal research facilities, thereby making them accessible for future research on CCRs.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"121 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140584421","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Transposable elements (TEs) are DNA sequences capable of moving within genomes and significantly influence genomic evolution. The nematode Caenorhabditis inopinata exhibits a much higher TE copy number than its sister species, C. elegans. In this study, we identified a novel autonomous TE belonging to the hAT superfamily from a spontaneous TE-insertion mutant in C. inopinata and named this transposon Ci-hAT1. Further bioinformatic analyses uncovered three additional autonomous hAT elements-Ci-hAT2, Ci-hAT3, and Ci-hAT4-along with over 1,000 copies of two non-autonomous miniature inverted-repeat transposable elements (MITEs), mCi-hAT1 and mCi-hAT4, likely derived from Ci-hAT1 and Ci-hAT4 through internal deletion. We tracked at least three sequential transpositions of Ci-hAT1 over several years. However, the transposition rates of the other three autonomous hAT elements were lower, suggesting varying activity levels. Notably, the distribution patterns of the two MITE families differed significantly: mCi-hAT1 was primarily located in the chromosome arms, a pattern observed in the TEs of other Caenorhabditis species, whereas mCi-hAT4 was more evenly distributed across chromosomes. Additionally, interspecific transcriptome analysis indicated that C. inopinata genes with upstream or intronic these MITE insertions tend to be more highly expressed than their orthologous genes in C. elegans. These findings highlight the significant role of de-silenced TEs in driving the evolution of genomes and transcriptomes, leading to species-specific genetic diversity.
可转座元件（Transposable elements，TE）是能够在基因组内移动的 DNA 序列，对基因组进化有重大影响。线虫 Caenorhabditis inopinata 的可转座元件拷贝数远远高于其姊妹物种 C. elegans。在这项研究中，我们从C. inopinata的一个自发TE插入突变体中发现了一个属于hAT超家族的新型自主TE，并将其命名为Ci-hAT1转座子。进一步的生物信息学分析发现了另外三个自主的 hAT 元件--Ci-hAT2、Ci-hAT3 和 Ci-hAT4，以及超过 1,000 个拷贝的两个非自主的微型倒转重复转座元件（MITE）--mCi-hAT1 和 mCi-hAT4，它们很可能是通过内部缺失从 Ci-hAT1 和 Ci-hAT4 衍生而来的。几年来，我们跟踪了至少三次 Ci-hAT1 的连续转座。然而，其他三个自主 hAT 元件的转座率较低，这表明它们的活动水平各不相同。值得注意的是，这两个 MITE 家族的分布模式存在显著差异：mCi-hAT1 主要位于染色体臂，这也是在其他 Caenorhabditis 物种的 TEs 中观察到的模式，而 mCi-hAT4 则更均匀地分布在染色体上。此外，种间转录组分析表明，具有上游或内含这些 MITE 插入物的 C. inopinata 基因往往比其在 elegans 中的同源基因表达得更高。这些发现凸显了去沉默的 TE 在推动基因组和转录组进化中的重要作用，从而导致物种特有的遗传多样性。
{"title":"The impact of differential transposition activities of autonomous and non-autonomous hAT transposable elements on genome architecture and gene expression in Caenorhabditis inopinata.","authors":"Ryuhei Hatanaka, Katsunori Tamagawa, Nami Haruta, Asako Sugimoto","doi":"10.1093/genetics/iyae052","DOIUrl":"https://doi.org/10.1093/genetics/iyae052","url":null,"abstract":"Transposable elements (TEs) are DNA sequences capable of moving within genomes and significantly influence genomic evolution. The nematode Caenorhabditis inopinata exhibits a much higher TE copy number than its sister species, C. elegans. In this study, we identified a novel autonomous TE belonging to the hAT superfamily from a spontaneous TE-insertion mutant in C. inopinata and named this transposon Ci-hAT1. Further bioinformatic analyses uncovered three additional autonomous hAT elements-Ci-hAT2, Ci-hAT3, and Ci-hAT4-along with over 1,000 copies of two non-autonomous miniature inverted-repeat transposable elements (MITEs), mCi-hAT1 and mCi-hAT4, likely derived from Ci-hAT1 and Ci-hAT4 through internal deletion. We tracked at least three sequential transpositions of Ci-hAT1 over several years. However, the transposition rates of the other three autonomous hAT elements were lower, suggesting varying activity levels. Notably, the distribution patterns of the two MITE families differed significantly: mCi-hAT1 was primarily located in the chromosome arms, a pattern observed in the TEs of other Caenorhabditis species, whereas mCi-hAT4 was more evenly distributed across chromosomes. Additionally, interspecific transcriptome analysis indicated that C. inopinata genes with upstream or intronic these MITE insertions tend to be more highly expressed than their orthologous genes in C. elegans. These findings highlight the significant role of de-silenced TEs in driving the evolution of genomes and transcriptomes, leading to species-specific genetic diversity.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"22 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140584203","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-05DOI: 10.1093/genetics/iyae036
Ethalinda K Cannon, John L Portwood, Rita K Hayford, Olivia C Haley, Jack M Gardiner, Carson M Andorf, Margaret R Woodhouse
Pan-genomes, encompassing the entirety of genetic sequences found in a collection of genomes within a clade, are more useful than single reference genomes for studying species diversity. This is especially true for a species like Zea mays, which has a particularly diverse and complex genome. Presenting pan-genome data, analyses, and visualization is challenging, especially for a diverse species, but more so when pan-genomic data is linked to extensive gene model and gene data, including classical gene information, markers, insertions, expression and proteomic data, and protein structures as is the case at MaizeGDB. Here, we describe MaizeGDB's expansion to include the genic subset of the Zea pan-genome in a pan-gene data center featuring the maize genomes hosted at MaizeGDB, and the outgroup teosinte Zea genomes from the Pan-Andropoganeae project. The new data center offers a variety of browsing and visualization tools, including sequence alignment visualization, gene trees and other tools, to explore pan-genes in Zea that were calculated by the pipeline Pandagma. Combined, these data will help maize researchers study the complexity and diversity of Zea, and to use the comparative functions to validate pan-gene relationships for a selected gene model.
{"title":"Enhanced pan-genomic resources at the maize genetics and genomics database.","authors":"Ethalinda K Cannon, John L Portwood, Rita K Hayford, Olivia C Haley, Jack M Gardiner, Carson M Andorf, Margaret R Woodhouse","doi":"10.1093/genetics/iyae036","DOIUrl":"https://doi.org/10.1093/genetics/iyae036","url":null,"abstract":"Pan-genomes, encompassing the entirety of genetic sequences found in a collection of genomes within a clade, are more useful than single reference genomes for studying species diversity. This is especially true for a species like Zea mays, which has a particularly diverse and complex genome. Presenting pan-genome data, analyses, and visualization is challenging, especially for a diverse species, but more so when pan-genomic data is linked to extensive gene model and gene data, including classical gene information, markers, insertions, expression and proteomic data, and protein structures as is the case at MaizeGDB. Here, we describe MaizeGDB's expansion to include the genic subset of the Zea pan-genome in a pan-gene data center featuring the maize genomes hosted at MaizeGDB, and the outgroup teosinte Zea genomes from the Pan-Andropoganeae project. The new data center offers a variety of browsing and visualization tools, including sequence alignment visualization, gene trees and other tools, to explore pan-genes in Zea that were calculated by the pipeline Pandagma. Combined, these data will help maize researchers study the complexity and diversity of Zea, and to use the comparative functions to validate pan-gene relationships for a selected gene model.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"14 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140584404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-04DOI: 10.1093/genetics/iyae050
Paul W Sternberg, Kimberly Van Auken, Qinghua Wang, Adam Wright, Karen Yook, Magdalena Zarowiecki, Valerio Arnaboldi, Andrés Becerra, Stephanie Brown, Scott Cain, Juancarlos Chan, Wen J Chen, Jaehyoung Cho, Paul Davis, Stavros Diamantakis, Sarah Dyer, Dionysis Grigoriadis, Christian A Grove, Todd Harris, Kevin Howe, Ranjana Kishore, Raymond Lee, Ian Longden, Manuel Luypaert, Hans-Michael Muller, Paulo Nuin, Mark Quinton-Tulloch, Daniela Raciti, Tim Schedl, Gary Schindelman, Lincoln Stein
WormBase has been the major repository and knowledgebase of information about the genome and genetics of C. elegans and other nematodes of experimental interest for over two decades. We have three goals: to keep current with the fast-paced C. elegans research, to provide better integration with other resources, and to be sustainable. Here we discuss the current state of WormBase as well as progress and plans for moving core WormBase infrastructure to the Alliance of Genome Resources (the Alliance). As an Alliance member, WormBase will continue to interact with the C. elegans community, develop new features as needed, and curate key information from the literature and large-scale projects.
二十多年来，WormBase 一直是有关秀丽隐杆线虫和其他具有实验意义的线虫基因组和遗传学的主要信息库和知识库。我们有三个目标：跟上快节奏的秀丽隐杆线虫研究、更好地整合其他资源以及可持续发展。在此，我们将讨论 WormBase 的现状，以及将 WormBase 核心基础设施转移到基因组资源联盟（Alliance of Genome Resources，简称联盟）的进展和计划。作为联盟成员，WormBase 将继续与文氏虫社区互动，根据需要开发新功能，并从文献和大型项目中收集关键信息。
{"title":"WormBase 2024: status and transitioning to Alliance infrastructure.","authors":"Paul W Sternberg, Kimberly Van Auken, Qinghua Wang, Adam Wright, Karen Yook, Magdalena Zarowiecki, Valerio Arnaboldi, Andrés Becerra, Stephanie Brown, Scott Cain, Juancarlos Chan, Wen J Chen, Jaehyoung Cho, Paul Davis, Stavros Diamantakis, Sarah Dyer, Dionysis Grigoriadis, Christian A Grove, Todd Harris, Kevin Howe, Ranjana Kishore, Raymond Lee, Ian Longden, Manuel Luypaert, Hans-Michael Muller, Paulo Nuin, Mark Quinton-Tulloch, Daniela Raciti, Tim Schedl, Gary Schindelman, Lincoln Stein","doi":"10.1093/genetics/iyae050","DOIUrl":"https://doi.org/10.1093/genetics/iyae050","url":null,"abstract":"WormBase has been the major repository and knowledgebase of information about the genome and genetics of C. elegans and other nematodes of experimental interest for over two decades. We have three goals: to keep current with the fast-paced C. elegans research, to provide better integration with other resources, and to be sustainable. Here we discuss the current state of WormBase as well as progress and plans for moving core WormBase infrastructure to the Alliance of Genome Resources (the Alliance). As an Alliance member, WormBase will continue to interact with the C. elegans community, develop new features as needed, and curate key information from the literature and large-scale projects.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"51 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140584214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"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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