Genetics最新文献_第4页

Adapting and optimizing GCaMP8f for use in Caenorhabditis elegans. 调整和优化 GCaMP8f，使其用于秀丽隐杆线虫。

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae125

Jun Liu, Elsa Bonnard, Monika Scholz

{"title":"Adapting and optimizing GCaMP8f for use in Caenorhabditis elegans.","authors":"Jun Liu, Elsa Bonnard, Monika Scholz","doi":"10.1093/genetics/iyae125","DOIUrl":"10.1093/genetics/iyae125","url":null,"abstract":"Improved genetically encoded calcium indicators (GECIs) are essential for capturing intracellular dynamics of both muscle and neurons. A novel set of GECIs with ultrafast kinetics and high sensitivity was recently reported by Zhang et al. (2023). While these indicators, called jGCaMP8, were demonstrated to work in Drosophila and mice, data for Caenorhabditis elegans were not reported. Here, we present an optimized construct for C. elegans and use this to generate several strains expressing GCaMP8f (fast variant of the indicator). Utilizing the myo-2 promoter, we compare pharyngeal muscle activity measured with GCaMP7f and GCaMP8f and find that GCaMP8f is brighter upon binding to calcium, shows faster kinetics, and is not disruptive to the intrinsic contraction dynamics of the pharynx. Additionally, we validate its application for detecting neuronal activity in touch receptor neurons which reveals robust calcium transients even at small stimulus amplitudes. As such, we establish GCaMP8f as a potent tool for C. elegans research which is capable of extracting fast calcium dynamics at very low magnifications across multiple cell types.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Neurogenesis in Caenorhabditis elegans. 秀丽隐杆线虫的神经发生

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae116

Richard J Poole, Nuria Flames, Luisa Cochella

{"title":"Neurogenesis in Caenorhabditis elegans.","authors":"Richard J Poole, Nuria Flames, Luisa Cochella","doi":"10.1093/genetics/iyae116","DOIUrl":"10.1093/genetics/iyae116","url":null,"abstract":"Animals rely on their nervous systems to process sensory inputs, integrate these with internal signals, and produce behavioral outputs. This is enabled by the highly specialized morphologies and functions of neurons. Neuronal cells share multiple structural and physiological features, but they also come in a large diversity of types or classes that give the nervous system its broad range of functions and plasticity. This diversity, first recognized over a century ago, spurred classification efforts based on morphology, function, and molecular criteria. Caenorhabditis elegans, with its precisely mapped nervous system at the anatomical level, an extensive molecular description of most of its neurons, and its genetic amenability, has been a prime model for understanding how neurons develop and diversify at a mechanistic level. Here, we review the gene regulatory mechanisms driving neurogenesis and the diversification of neuron classes and subclasses in C. elegans. We discuss our current understanding of the specification of neuronal progenitors and their differentiation in terms of the transcription factors involved and ensuing changes in gene expression and chromatin landscape. The central theme that has emerged is that the identity of a neuron is defined by modules of gene batteries that are under control of parallel yet interconnected regulatory mechanisms. We focus on how, to achieve these terminal identities, cells integrate information along their developmental lineages. Moreover, we discuss how neurons are diversified postembryonically in a time-, genetic sex-, and activity-dependent manner. Finally, we discuss how the understanding of neuronal development can provide insights into the evolution of neuronal diversity.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457946/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Tdh3 and Rom2 are functional modulators of a conserved condensate-resident RNA-binding protein, Scd6, in Saccharomyces cerevisiae. Tdh3和Rom2是酿酒酵母中一种保守的凝结常驻RNA结合蛋白Scd6的功能调节剂。

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae127

Chitra Togra, Riya Dhage, Purusharth I Rajyaguru

{"title":"Tdh3 and Rom2 are functional modulators of a conserved condensate-resident RNA-binding protein, Scd6, in Saccharomyces cerevisiae.","authors":"Chitra Togra, Riya Dhage, Purusharth I Rajyaguru","doi":"10.1093/genetics/iyae127","DOIUrl":"10.1093/genetics/iyae127","url":null,"abstract":"Arginine-glycine-glycine motif proteins play a crucial role in determining mRNA fate. Suppressor of clathrin deficiency 6 (Scd6) is a conserved arginine-glycine-glycine motif containing ribonucleoprotein (RNP) condensate-resident, translation repressor, and decapping activator protein in Saccharomyces cerevisiae. Identifying protein factors that can modulate Scd6 function is critical to understanding the regulation of mRNA fate by Scd6. In this study, using an approach that combined mRNA tethering assay with flow cytometry, we screened 50 genes for their role in modulating the translation repression activity of Scd6. We identified 8 conserved modulators with human homologs. Of these, we further characterized in detail guanine nucleotide exchange factor Rho1 multicopy suppressor 2 (Rom2) and glycolytic enzyme triose phosphate dehydrogenase 3 (Tdh3), which, respectively, impede and promote translation repression activity of Scd6. Our study reveals that Rom2 negatively regulates the arginine methylation of Scd6 and antagonizes its localization to P-bodies. Tdh3, on the other hand, promotes Scd6 interaction with Hmt1, thereby promoting the arginine methylation of Scd6 and enhanced eIF4G1 interaction, which is known to promote its repression activity. Identifying these novel modulators provides exciting new insights into the role of a metabolic enzyme of the glycolytic pathway and guanine nucleotide exchange factor implicated in the cell wall integrity pathway in regulating Scd6 function and, thereby, cytoplasmic mRNA fate.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141876447","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}

引用次数: 0

Direct inference of the distribution of fitness effects of spontaneous mutations from recombinant inbred Caenorhabditis elegans mutation accumulation lines. 从重组近交系秀丽隐杆线虫突变积累品系中直接推断自发突变的适应效应分布。

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae136

Timothy A Crombie, Moein Rajaei, Ayush Shekhar Saxena, Lindsay M Johnson, Sayran Saber, Robyn E Tanny, José Miguel Ponciano, Erik C Andersen, Juannan Zhou, Charles F Baer

{"title":"Direct inference of the distribution of fitness effects of spontaneous mutations from recombinant inbred Caenorhabditis elegans mutation accumulation lines.","authors":"Timothy A Crombie, Moein Rajaei, Ayush Shekhar Saxena, Lindsay M Johnson, Sayran Saber, Robyn E Tanny, José Miguel Ponciano, Erik C Andersen, Juannan Zhou, Charles F Baer","doi":"10.1093/genetics/iyae136","DOIUrl":"10.1093/genetics/iyae136","url":null,"abstract":"The distribution of fitness effects of new mutations plays a central role in evolutionary biology. Estimates of the distribution of fitness effect from experimental mutation accumulation lines are compromised by the complete linkage disequilibrium between mutations in different lines. To reduce the linkage disequilibrium, we constructed 2 sets of recombinant inbred lines from a cross of 2 Caenorhabditis elegans mutation accumulation lines. One set of lines (\"RIAILs\") was intercrossed for 10 generations prior to 10 generations of selfing; the second set of lines (\"RILs\") omitted the intercrossing. Residual linkage disequilibrium in the RIAILs is much less than in the RILs, which affects the inferred distribution of fitness effect when the sets of lines are analyzed separately. The best-fit model estimated from all lines (RIAILs + RILs) infers a large fraction of mutations with positive effects (∼40%); models that constrain mutations to have negative effects fit much worse. The conclusion is the same using only the RILs. For the RIAILs, however, models that constrain mutations to have negative effects fit nearly as well as models that allow positive effects. When mutations in high linkage disequilibrium are pooled into haplotypes, the inferred distribution of fitness effect becomes increasingly negative-skewed and leptokurtic. We conclude that the conventional wisdom-most mutations have effects near 0, a handful of mutations have effects that are substantially negative, and mutations with positive effects are very rare-is likely correct, and that unless it can be shown otherwise, estimates of the distribution of fitness effect that infer a substantial fraction of mutations with positive effects are likely confounded by linkage disequilibrium.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976947","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}

引用次数: 0

The geometry of admixture in population genetics: the blessing of dimensionality. 人口遗传学中的掺杂几何：维度之福。

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae134

José-Angel Oteo, Gonzalo Oteo-García

{"title":"The geometry of admixture in population genetics: the blessing of dimensionality.","authors":"José-Angel Oteo, Gonzalo Oteo-García","doi":"10.1093/genetics/iyae134","DOIUrl":"10.1093/genetics/iyae134","url":null,"abstract":"We present a geometry-based interpretation of the f-statistics framework, commonly used in population genetics to estimate phylogenetic relationships from genomic data. The focus is on the determination of the mixing coefficients in population admixture events subject to post-admixture drift. The interpretation takes advantage of the high dimension of the dataset and analyzes the problem as a dimensional reduction issue. We show that it is possible to think of the f-statistics technique as an implicit transformation of the genomic data from a phase space into a subspace where the mapped data structure is more similar to the ancestral admixture configuration. The 2-way mixing coefficient is, as a matter of fact, carried out implicitly in this subspace. In addition, we propose the admixture test to be evaluated in the subspace because the comparison with the conventional one provides an important assessment of the admixture model. The overarching geometric framework provides slightly more general formulas than the f-formalism by using a different rationale as a starting point. Explicitly addressed are 2- and 3-way admixtures. The mixture proportions are provided by suitable linear fits, in 2 or 3 dimensions, that can be easily visualized. The difficulties encountered with introgression and gene flow are also addressed. The developments and findings are illustrated with numerical simulations and real-world cases.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141976948","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}

引用次数: 0

Candida albicans PPR proteins are required for the expression of respiratory Complex I subunits. 白念珠菌 PPR 蛋白是呼吸复合体 I 亚基表达所必需的。

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae124

Joanna Maria Wenda, Katarzyna Drzewicka, Patrycja Mulica, Emmanuel Tetaud, Jean Paul di Rago, Paweł Golik, Karolina Łabędzka-Dmoch

{"title":"Candida albicans PPR proteins are required for the expression of respiratory Complex I subunits.","authors":"Joanna Maria Wenda, Katarzyna Drzewicka, Patrycja Mulica, Emmanuel Tetaud, Jean Paul di Rago, Paweł Golik, Karolina Łabędzka-Dmoch","doi":"10.1093/genetics/iyae124","DOIUrl":"10.1093/genetics/iyae124","url":null,"abstract":"Pentatricopeptide repeat (PPR) proteins bind RNA and are present in mitochondria and chloroplasts of Eukaryota. In fungi, they are responsible for controlling mitochondrial genome expression, mainly on the posttranscriptional level. Candida albicans is a human opportunistic pathogen with a facultative anaerobic metabolism which, unlike the model yeast Saccharomyces cerevisiae, possesses mitochondrially encoded respiratory Complex I (CI) subunits and does not tolerate loss of mtDNA. We characterized the function of 4 PPR proteins of C. albicans that lack orthologs in S. cerevisiae and found that they are required for the expression of mitochondrially encoded CI subunits. We demonstrated that these proteins localize to mitochondria and are essential to maintain the respiratory capacity of cells. Deletion of genes encoding these PPR proteins results in changes in steady-state levels of mitochondrial RNAs and proteins. We demonstrated that C. albicans cells lacking CaPpr4, CaPpr11, and CaPpr13 proteins show no CI assembly, whereas the lack of CaPpr7p results in a decreased CI activity. CaPpr13p is required to maintain the bicistronic NAD4L-NAD5 mRNA, whereas the other 3 PPR proteins are likely involved in translation-related assembly of mitochondrially encoded CI subunits. In addition, we show that CaAep3p, which is an ortholog of ScAep3p, performs the evolutionary conserved function of controlling expression of the ATP8-ATP6 mRNA. We also show that C. albicans cells lacking PPR proteins express a higher level of the inducible alternative oxidase (AOX2) which likely rescues respiratory defects and compensates for oxidative stress.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141789601","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}

引用次数: 0

Transcriptomic analysis of meiotic genes during the mitosis-to-meiosis transition in Drosophila females. 雌果蝇有丝分裂至减数分裂过渡期减数分裂基因的转录组分析

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae130

Ana Maria Vallés, Thomas Rubin, Nicolas Macaisne, Laurine Dal Toe, Anahi Molla-Herman, Christophe Antoniewski, Jean-René Huynh

{"title":"Transcriptomic analysis of meiotic genes during the mitosis-to-meiosis transition in Drosophila females.","authors":"Ana Maria Vallés, Thomas Rubin, Nicolas Macaisne, Laurine Dal Toe, Anahi Molla-Herman, Christophe Antoniewski, Jean-René Huynh","doi":"10.1093/genetics/iyae130","DOIUrl":"10.1093/genetics/iyae130","url":null,"abstract":"Germline cells produce gametes, which are specialized cells essential for sexual reproduction. Germline cells first amplify through several rounds of mitosis before switching to the meiotic program, which requires specific sets of proteins for DNA recombination, chromosome pairing, and segregation. Surprisingly, we previously found that some proteins of the synaptonemal complex, a prophase I meiotic structure, are already expressed and required in the mitotic region of Drosophila females. Here, to assess if additional meiotic genes were expressed earlier than expected, we isolated mitotic and meiotic cell populations to compare their RNA content. Our transcriptomic analysis reveals that all known meiosis I genes are already expressed in the mitotic region; however, only some of them are translated. As a case study, we focused on mei-W68, the Drosophila homolog of Spo11, to assess its expression at both the mRNA and protein levels and used different mutant alleles to assay for a premeiotic function. We could not detect any functional role for Mei-W68 during homologous chromosome pairing in dividing germ cells. Our study paves the way for further functional analysis of meiotic genes expressed in the mitotic region.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142120917","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}

引用次数: 0

The emerging H3K9me3 chromatin landscape during zebrafish embryogenesis. 斑马鱼胚胎发育过程中新出现的 H3K9me3 染色质景观

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae138

Katherine L Duval, Ashley R Artis, Mary G Goll

{"title":"The emerging H3K9me3 chromatin landscape during zebrafish embryogenesis.","authors":"Katherine L Duval, Ashley R Artis, Mary G Goll","doi":"10.1093/genetics/iyae138","DOIUrl":"10.1093/genetics/iyae138","url":null,"abstract":"The structural organization of eukaryotic genomes is contingent upon the fractionation of DNA into transcriptionally permissive euchromatin and repressive heterochromatin. However, we have a limited understanding of how these distinct states are first established during animal embryogenesis. Histone 3 lysine 9 trimethylation (H3K9me3) is critical to heterochromatin formation, and bulk establishment of this mark is thought to help drive large-scale remodeling of an initially naive chromatin state during animal embryogenesis. However, a detailed understanding of this process is lacking. Here, we leverage CUT&RUN to define the emerging H3K9me3 landscape of the zebrafish embryo with high sensitivity and temporal resolution. Despite the prevalence of DNA transposons in the zebrafish genome, we found that LTR transposons are preferentially targeted for embryonic H3K9me3 deposition, with different families exhibiting distinct establishment timelines. High signal-to-noise ratios afforded by CUT&RUN revealed new, emerging sites of low-amplitude H3K9me3 that initiated before the major wave of zygotic genome activation (ZGA). Early sites of establishment predominated at specific subsets of transposons and were particularly enriched for transposon sequences with maternal piRNAs and pericentromeric localization. Notably, the number of H3K9me3 enriched sites increased linearly across blastula development, while quantitative comparison revealed a >10-fold genome-wide increase in H3K9me3 signal at established sites over just 30 min at the onset of major ZGA. Continued maturation of the H3K9me3 landscape was observed beyond the initial wave of bulk establishment.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes. PACS1/PACS2综合征模型中的PACS-1变体蛋白定位异常。

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae118

Dana T Byrd, Ziyuan Christina Han, Christopher A Piggott, Yishi Jin

{"title":"PACS-1 variant protein is aberrantly localized in Caenorhabditis elegans model of PACS1/PACS2 syndromes.","authors":"Dana T Byrd, Ziyuan Christina Han, Christopher A Piggott, Yishi Jin","doi":"10.1093/genetics/iyae118","DOIUrl":"10.1093/genetics/iyae118","url":null,"abstract":"PACS (phosphofurin acidic cluster sorting) proteins are known for their roles in sorting cargo proteins to organelles and can physically interact with WD40 repeat-containing protein WDR37. PACS1, PACS2, and WDR37 variants are associated with multisystemic syndromes and neurodevelopmental disorders characterized by intellectual disability, seizures, developmental delays, craniofacial abnormalities, and autism spectrum disorder. However, the functional effects of syndromic variants at the cellular level remain unknown. Here, we report the expression pattern of Caenorhabditis elegans orthologs of PACS and WDR37 and their interaction. We show that cePACS-1 and ceWDR-37 colocalize to somatic cytoplasm of many types of cells and are mutually required for expression, supporting a conclusion that the intermolecular dependence of PACS1/PACS2/PACS-1 and WDR37/WDR-37 is evolutionarily conserved. We further show that editing in PACS1 and PACS2 variants in cePACS-1 changes protein localization in multiple cell types, including neurons. Moreover, expression of human PACS1 can functionally complement C. elegans PACS-1 in neurons, demonstrating conserved functions of the PACS-WDR37 axis in an invertebrate model system. Our findings reveal effects of human variants and suggest potential strategies to identify regulatory network components that may contribute to understanding molecular underpinnings of PACS/WDR37 syndromes.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141731527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vivo dissection of the mouse tyrosine catabolic pathway with CRISPR-Cas9 identifies modifier genes affecting hereditary tyrosinemia type 1. 利用 CRISPR-Cas9 对小鼠酪氨酸代谢途径进行体内剖析，发现影响遗传性酪氨酸血症 1 型的修饰基因。

IF 3.3 3区生物学

Genetics Pub Date : 2024-10-07 DOI: 10.1093/genetics/iyae139

Jean-François Rivest, Sophie Carter, Claudia Goupil, Pénélope Antérieux, Denis Cyr, Roth-Visal Ung, Dorothée Dal Soglio, Fabrice Mac-Way, Paula J Waters, Massimiliano Paganelli, Yannick Doyon

{"title":"In vivo dissection of the mouse tyrosine catabolic pathway with CRISPR-Cas9 identifies modifier genes affecting hereditary tyrosinemia type 1.","authors":"Jean-François Rivest, Sophie Carter, Claudia Goupil, Pénélope Antérieux, Denis Cyr, Roth-Visal Ung, Dorothée Dal Soglio, Fabrice Mac-Way, Paula J Waters, Massimiliano Paganelli, Yannick Doyon","doi":"10.1093/genetics/iyae139","DOIUrl":"10.1093/genetics/iyae139","url":null,"abstract":"Hereditary tyrosinemia type 1 is an autosomal recessive disorder caused by mutations (pathogenic variants) in fumarylacetoacetate hydrolase, an enzyme involved in tyrosine degradation. Its loss results in the accumulation of toxic metabolites that mainly affect the liver and kidneys and can lead to severe liver disease and liver cancer. Tyrosinemia type 1 has a global prevalence of approximately 1 in 100,000 births but can reach up to 1 in 1,500 births in some regions of Québec, Canada. Mutating functionally related \"modifier' genes (i.e. genes that, when mutated, affect the phenotypic impacts of mutations in other genes) is an emerging strategy for treating human genetic diseases. In vivo somatic genome editing in animal models of these diseases is a powerful means to identify modifier genes and fuel treatment development. In this study, we demonstrate that mutating additional enzymes in the tyrosine catabolic pathway through liver-specific genome editing can relieve or worsen the phenotypic severity of a murine model of tyrosinemia type 1. Neonatal gene delivery using recombinant adeno-associated viral vectors expressing Staphylococcus aureus Cas9 under the control of a liver-specific promoter led to efficient gene disruption and metabolic rewiring of the pathway, with systemic effects that were distinct from the phenotypes observed in whole-body knockout models. Our work illustrates the value of using in vivo genome editing in model organisms to study the direct effects of combining pathological mutations with modifier gene mutations in isogenic settings.","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11457941/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142044231","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0