Genetics最新文献_第10页

Double-strand breaks induce short-scale DNA replication and damage amplification in the fully grown mouse oocytes. 在完全发育的小鼠卵母细胞中，双链断裂诱导短尺度DNA复制和损伤扩增。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab054

Jun-Yu Ma, Xie Feng, Feng-Yun Xie, Sen Li, Lei-Ning Chen, Shi-Ming Luo, Shen Yin, Xiang-Hong Ou

{"title":"Double-strand breaks induce short-scale DNA replication and damage amplification in the fully grown mouse oocytes.","authors":"Jun-Yu Ma, Xie Feng, Feng-Yun Xie, Sen Li, Lei-Ning Chen, Shi-Ming Luo, Shen Yin, Xiang-Hong Ou","doi":"10.1093/genetics/iyab054","DOIUrl":"10.1093/genetics/iyab054","url":null,"abstract":"Break-induced replication (BIR) is essential for the repair of DNA double-strand breaks (DSBs) with single ends. DSBs-induced microhomology-mediated BIR (mmBIR) and template-switching can increase the risk of complex genome rearrangement. In addition, DSBs can also induce the multi-invasion-mediated DSB amplification. The mmBIR-induced genomic rearrangement has been identified in cancer cells and patients with rare diseases. However, when and how mmBIR is initiated have not been fully and deeply studied. Furthermore, it is not well understood about the conditions for initiation of multi-invasion-mediated DSB amplification. In the G2 phase oocyte of mouse, we identified a type of short-scale BIR (ssBIR) using the DNA replication indicator 5-ethynyl-2'-deoxyuridine (EdU). These ssBIRs could only be induced in the fully grown oocytes but not the growing oocytes. If the DSB oocytes were treated with Rad51 or Chek1/2 inhibitors, both EdU signals and DSB marker γH2A.X foci would decrease. In addition, the DNA polymerase inhibitor Aphidicolin could inhibit the ssBIR and another inhibitor ddATP could reduce the number of γH2A.X foci in the DSB oocytes. In conclusion, our results showed that DNA DSBs in the fully grown oocytes can initiate ssBIR and be amplified by Rad51 or DNA replication.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"218 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/genetics/iyab054","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25540151","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: 3

Erratum to: The genetic architecture of human complex phenotypes is modulated by linkage disequilibrium and heterozygosity. 人类复杂表型的遗传结构是由连锁不平衡和杂合性调节的。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab064

Dominic Holland, Oleksandr Frei, Rahul Desikan, Chun-Chieh Fan, Alexey A Shadrin, Olav B Smeland, Ole A Andreassen, Anders M Dale

引用次数: 0

The fitness costs and benefits of trisomy of each Candida albicans chromosome. 每条白色念珠菌染色体三体的适应度成本和收益。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab056

Feng Yang, Robert T Todd, Anna Selmecki, Yuan-Ying Jiang, Yong-Bing Cao, Judith Berman

{"title":"The fitness costs and benefits of trisomy of each Candida albicans chromosome.","authors":"Feng Yang, Robert T Todd, Anna Selmecki, Yuan-Ying Jiang, Yong-Bing Cao, Judith Berman","doi":"10.1093/genetics/iyab056","DOIUrl":"https://doi.org/10.1093/genetics/iyab056","url":null,"abstract":"Candida albicans is a prevalent human fungal pathogen. Rapid genomic change, due to aneuploidy, is a common mechanism that facilitates survival from multiple types of stresses including the few classes of available antifungal drugs. The stress survival of aneuploids occurs despite the fitness costs attributed to most aneuploids growing under idealized lab conditions. Systematic study of the aneuploid state in C. albicans has been hindered by the lack of a comprehensive collection of aneuploid strains. Here, we describe a collection of diploid C. albicans aneuploid strains, each carrying one extra copy of each chromosome, all from the same genetic background. We tested the fitness of this collection under several physiological conditions including shifts in pH, low glucose, oxidative stress, temperature, high osmolarity, membrane stress, and cell wall stress. We found that most aneuploids, under most conditions, were less fit than their euploid parent, yet there were specific conditions under which specific aneuploid isolates provided a fitness benefit relative to the euploid parent strain. Importantly, this fitness benefit was attributable to the change in the copy number of specific chromosomes. Thus, C. albicans can tolerate aneuploidy of each chromosome and some aneuploids confer improved growth under conditions that the yeast encounters in its host niches.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"218 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/genetics/iyab056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25586602","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

Gene body methylation is under selection in Arabidopsis thaliana. 拟南芥基因体甲基化处于选择过程中。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab061

Aline Muyle, Jeffrey Ross-Ibarra, Danelle K Seymour, Brandon S Gaut

{"title":"Gene body methylation is under selection in Arabidopsis thaliana.","authors":"Aline Muyle, Jeffrey Ross-Ibarra, Danelle K Seymour, Brandon S Gaut","doi":"10.1093/genetics/iyab061","DOIUrl":"https://doi.org/10.1093/genetics/iyab061","url":null,"abstract":"Abstract In plants, mammals and insects, some genes are methylated in the CG dinucleotide context, a phenomenon called gene body methylation (gbM). It has been controversial whether this phenomenon has any functional role. Here, we took advantage of the availability of 876 leaf methylomes in Arabidopsis thaliana to characterize the population frequency of methylation at the gene level and to estimate the site-frequency spectrum of allelic states. Using a population genetics model specifically designed for epigenetic data, we found that genes with ancestral gbM are under significant selection to remain methylated. Conversely, ancestrally unmethylated genes were under selection to remain unmethylated. Repeating the analyses at the level of individual cytosines confirmed these results. Estimated selection coefficients were small, on the order of 4 Nes = 1.4, which is similar to the magnitude of selection acting on codon usage. We also estimated that A. thaliana is losing gbM threefold more rapidly than gaining it, which could be due to a recent reduction in the efficacy of selection after a switch to selfing. Finally, we investigated the potential function of gbM through its link with gene expression. Across genes with polymorphic methylation states, the expression of gene body methylated alleles was consistently and significantly higher than unmethylated alleles. Although it is difficult to disentangle genetic from epigenetic effects, our work suggests that gbM has a small but measurable effect on fitness, perhaps due to its association to a phenotype-like gene expression.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"218 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225343/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38892857","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: 13

Steroid hormone pathways coordinate developmental diapause and olfactory remodeling in Pristionchus pacificus. 类固醇激素通路协调太平洋竖蛾发育滞育和嗅觉重塑。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab071

Heather R Carstensen, Reinard M Villalon, Navonil Banerjee, Elissa A Hallem, Ray L Hong

{"title":"Steroid hormone pathways coordinate developmental diapause and olfactory remodeling in Pristionchus pacificus.","authors":"Heather R Carstensen, Reinard M Villalon, Navonil Banerjee, Elissa A Hallem, Ray L Hong","doi":"10.1093/genetics/iyab071","DOIUrl":"https://doi.org/10.1093/genetics/iyab071","url":null,"abstract":"Developmental and behavioral plasticity allow animals to prioritize alternative genetic programs during fluctuating environments. Behavioral remodeling may be acute in animals that interact with host organisms, since reproductive adults and the developmentally arrested larvae often have different ethological needs for chemical stimuli. To understand the genes that coordinate the development and host-seeking behavior, we used the entomophilic nematode Pristionchus pacificus to characterize dauer-constitutive mutants (Daf-c) that inappropriately enter developmental diapause to become dauer larvae. We found two Daf-c loci with dauer-constitutive and cuticle exsheathment phenotypes that can be rescued by the feeding of Δ7-dafachronic acid, and that are dependent on the conserved canonical steroid hormone receptor Ppa-DAF-12. Specifically at one locus, deletions in the sole hydroxysteroid dehydrogenase (HSD) in P. pacificus resulted in Daf-c phenotypes. Ppa-hsd-2 is expressed in the canal-associated neurons (CANs) and excretory cells whose homologous cells in Caenorhabditis elegans are not known to be involved in the dauer decision. While in wildtype only dauer larvae are attracted to host odors, hsd-2 mutant adults show enhanced attraction to the host beetle pheromone, along with ectopic activation of a marker for putative olfactory neurons, Ppa-odr-3. Surprisingly, this enhanced odor attraction acts independently of the Δ7-DA/DAF-12 module, suggesting that Ppa-HSD-2 may be responsible for several steroid hormone products involved in coordinating the dauer decision and host-seeking behavior in P. pacificus.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"218 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/genetics/iyab071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38961426","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: 6

Compensation for the absence of the catalytically active half of DNA polymerase ε in yeast by positively selected mutations in CDC28. CDC28正选择突变补偿酵母中DNA聚合酶ε催化活性的缺失。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab060

Elena I Stepchenkova, Anna S Zhuk, Jian Cui, Elena R Tarakhovskaya, Stephanie R Barbari, Polina V Shcherbakova, Dmitrii E Polev, Roman Fedorov, Eugenia Poliakov, Igor B Rogozin, Artem G Lada, Youri I Pavlov

{"title":"Compensation for the absence of the catalytically active half of DNA polymerase ε in yeast by positively selected mutations in CDC28.","authors":"Elena I Stepchenkova, Anna S Zhuk, Jian Cui, Elena R Tarakhovskaya, Stephanie R Barbari, Polina V Shcherbakova, Dmitrii E Polev, Roman Fedorov, Eugenia Poliakov, Igor B Rogozin, Artem G Lada, Youri I Pavlov","doi":"10.1093/genetics/iyab060","DOIUrl":"https://doi.org/10.1093/genetics/iyab060","url":null,"abstract":"Current eukaryotic replication models postulate that leading and lagging DNA strands are replicated predominantly by dedicated DNA polymerases. The catalytic subunit of the leading strand DNA polymerase ε, Pol2, consists of two halves made of two different ancestral B-family DNA polymerases. Counterintuitively, the catalytically active N-terminal half is dispensable, while the inactive C-terminal part is required for viability. Despite extensive studies of yeast Saccharomyces cerevisiae strains lacking the active N-terminal half, it is still unclear how these strains survive and recover. We designed a robust method for constructing mutants with only the C-terminal part of Pol2. Strains without the active polymerase part show severe growth defects, sensitivity to replication inhibitors, chromosomal instability, and elevated spontaneous mutagenesis. Intriguingly, the slow-growing mutant strains rapidly accumulate fast-growing clones. Analysis of genomic DNA sequences of these clones revealed that the adaptation to the loss of the catalytic N-terminal part of Pol2 occurs by a positive selection of mutants with improved growth. Elevated mutation rates help generate sufficient numbers of these variants. Single nucleotide changes in the cell cycle-dependent kinase gene, CDC28, improve the growth of strains lacking the N-terminal part of Pol2, and rescue their sensitivity to replication inhibitors and, in parallel, lower mutation rates. Our study predicts that changes in mammalian homologs of cyclin-dependent kinases may contribute to cellular responses to the leading strand polymerase defects.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"218 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/genetics/iyab060","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25581408","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

An evolutionary genomic approach reveals both conserved and species-specific genetic elements related to human disease in closely related Aspergillus fungi. 进化基因组方法揭示了在密切相关的曲霉真菌中与人类疾病相关的保守和物种特异性遗传元素。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab066

Matthew E Mead, Jacob L Steenwyk, Lilian P Silva, Patrícia A de Castro, Nauman Saeed, Falk Hillmann, Gustavo H Goldman, Antonis Rokas

{"title":"An evolutionary genomic approach reveals both conserved and species-specific genetic elements related to human disease in closely related Aspergillus fungi.","authors":"Matthew E Mead, Jacob L Steenwyk, Lilian P Silva, Patrícia A de Castro, Nauman Saeed, Falk Hillmann, Gustavo H Goldman, Antonis Rokas","doi":"10.1093/genetics/iyab066","DOIUrl":"https://doi.org/10.1093/genetics/iyab066","url":null,"abstract":"Aspergillosis is an important opportunistic human disease caused by filamentous fungi in the genus Aspergillus. Roughly 70% of infections are caused by Aspergillus fumigatus, with the rest stemming from approximately a dozen other Aspergillus species. Several of these pathogens are closely related to A. fumigatus and belong in the same taxonomic section, section Fumigati. Pathogenic species are frequently most closely related to nonpathogenic ones, suggesting Aspergillus pathogenicity evolved multiple times independently. To understand the repeated evolution of Aspergillus pathogenicity, we performed comparative genomic analyses on 18 strains from 13 species, including 8 species in section Fumigati, which aimed to identify genes, both ones previously connected to virulence as well as ones never before implicated, whose evolution differs between pathogens and nonpathogens. We found that most genes were present in all species, including approximately half of those previously connected to virulence, but a few genes were section- or species-specific. Evolutionary rate analyses identified over 1700 genes whose evolutionary rate differed between pathogens and nonpathogens and dozens of genes whose rates differed between specific pathogens and the rest of the taxa. Functional testing of deletion mutants of 17 transcription factor-encoding genes whose evolution differed between pathogens and nonpathogens identified eight genes that affect either fungal survival in a model of phagocytic killing, host survival in an animal model of fungal disease, or both. These results suggest that the evolution of pathogenicity in Aspergillus involved both conserved and species-specific genetic elements, illustrating how an evolutionary genomic approach informs the study of fungal disease.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"218 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/genetics/iyab066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38944938","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: 7

Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae. 多重突变率评估：确定酿酒酵母中 Msh2 变体的致病性。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab058

Anja R Ollodart, Chiann-Ling C Yeh, Aaron W Miller, Brian H Shirts, Adam S Gordon, Maitreya J Dunham

{"title":"Multiplexing mutation rate assessment: determining pathogenicity of Msh2 variants in Saccharomyces cerevisiae.","authors":"Anja R Ollodart, Chiann-Ling C Yeh, Aaron W Miller, Brian H Shirts, Adam S Gordon, Maitreya J Dunham","doi":"10.1093/genetics/iyab058","DOIUrl":"10.1093/genetics/iyab058","url":null,"abstract":"Despite the fundamental importance of mutation rate as a driving force in evolution and disease risk, common methods to assay mutation rate are time-consuming and tedious. Established methods such as fluctuation tests and mutation accumulation experiments are low-throughput and often require significant optimization to ensure accuracy. We established a new method to determine the mutation rate of many strains simultaneously by tracking mutation events in a chemostat continuous culture device and applying deep sequencing to link mutations to alleles of a DNA-repair gene. We applied this method to assay the mutation rate of hundreds of Saccharomyces cerevisiae strains carrying mutations in the gene encoding Msh2, a DNA repair enzyme in the mismatch repair pathway. Loss-of-function mutations in MSH2 are associated with hereditary nonpolyposis colorectal cancer, an inherited disorder that increases risk for many different cancers. However, the vast majority of MSH2 variants found in human populations have insufficient evidence to be classified as either pathogenic or benign. We first benchmarked our method against Luria-Delbrück fluctuation tests using a collection of published MSH2 missense variants. Our pooled screen successfully identified previously characterized nonfunctional alleles as high mutators. We then created an additional 185 human missense variants in the yeast ortholog, including both characterized and uncharacterized alleles curated from ClinVar and other clinical testing data. In a set of alleles of known pathogenicity, our assay recapitulated ClinVar's classification; we then estimated pathogenicity for 157 variants classified as uncertain or conflicting reports of significance. This method is capable of studying the mutation rate of many microbial species and can be applied to problems ranging from the generation of high-fidelity polymerases to measuring the frequency of antibiotic resistance emergence.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"218 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225350/pdf/iyab058.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"25603736","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

Detecting sex-linked genes using genotyped individuals sampled in natural populations. 利用在自然种群中采样的基因分型个体检测性连锁基因。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab053

Jos Käfer, Nicolas Lartillot, Gabriel A B Marais, Franck Picard

引用次数: 0

Studying models of balancing selection using phase-type theory. 利用相型理论研究平衡选择模型。

IF 3.3 3区生物学

Genetics Pub Date : 2021-06-24 DOI: 10.1093/genetics/iyab055

Kai Zeng, Brian Charlesworth, Asger Hobolth

{"title":"Studying models of balancing selection using phase-type theory.","authors":"Kai Zeng, Brian Charlesworth, Asger Hobolth","doi":"10.1093/genetics/iyab055","DOIUrl":"https://doi.org/10.1093/genetics/iyab055","url":null,"abstract":"Balancing selection (BLS) is the evolutionary force that maintains high levels of genetic variability in many important genes. To further our understanding of its evolutionary significance, we analyze models with BLS acting on a biallelic locus: an equilibrium model with long-term BLS, a model with long-term BLS and recent changes in population size, and a model of recent BLS. Using phase-type theory, a mathematical tool for analyzing continuous time Markov chains with an absorbing state, we examine how BLS affects polymorphism patterns in linked neutral regions, as summarized by nucleotide diversity, the expected number of segregating sites, the site frequency spectrum, and the level of linkage disequilibrium (LD). Long-term BLS affects polymorphism patterns in a relatively small genomic neighborhood, and such selection targets are easier to detect when the equilibrium frequencies of the selected variants are close to 50%, or when there has been a population size reduction. For a new mutation subject to BLS, its initial increase in frequency in the population causes linked neutral regions to have reduced diversity, an excess of both high and low frequency derived variants, and elevated LD with the selected locus. These patterns are similar to those produced by selective sweeps, but the effects of recent BLS are weaker. Nonetheless, compared to selective sweeps, nonequilibrium polymorphism and LD patterns persist for a much longer period under recent BLS, which may increase the chance of detecting such selection targets. An R package for analyzing these models, among others (e.g., isolation with migration), is available.","PeriodicalId":12706,"journal":{"name":"Genetics","volume":"218 2","pages":""},"PeriodicalIF":3.3,"publicationDate":"2021-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1093/genetics/iyab055","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38887531","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