Pub Date : 2024-09-24DOI: 10.1093/genetics/iyae155
Gaston I Jofre, Andrius J Dagilis, Victoria E Sepúlveda, Tayte Anspach, Ashutosh Singh, Anuradha Chowdhary, Daniel R Matute
Blastomyces is an emerging primary fungal pathogen that affects patients worldwide. The evolutionary processes that have resulted in the current diversity in the genus remain largely unexplored. We used whole genome sequences from 99 Blastomyces isolates, including two sequenced in this study using long-read technologies, to infer the phylogenetic relationships between Blastomyces species. We find that five different methods infer five different phylogenetic trees. Additionally, we find gene tree discordance along the genome with differences in the relative phylogenetic placement of several species of Blastomyces, which we hypothesize is caused by introgression. Our results suggest the urgent need to systematically collect Blastomyces samples around the world and study the evolutionary processes that govern intra- and interspecific variation in these medically important fungi.
{"title":"Admixture in the fungal pathogen Blastomyces.","authors":"Gaston I Jofre, Andrius J Dagilis, Victoria E Sepúlveda, Tayte Anspach, Ashutosh Singh, Anuradha Chowdhary, Daniel R Matute","doi":"10.1093/genetics/iyae155","DOIUrl":"https://doi.org/10.1093/genetics/iyae155","url":null,"abstract":"<p><p>Blastomyces is an emerging primary fungal pathogen that affects patients worldwide. The evolutionary processes that have resulted in the current diversity in the genus remain largely unexplored. We used whole genome sequences from 99 Blastomyces isolates, including two sequenced in this study using long-read technologies, to infer the phylogenetic relationships between Blastomyces species. We find that five different methods infer five different phylogenetic trees. Additionally, we find gene tree discordance along the genome with differences in the relative phylogenetic placement of several species of Blastomyces, which we hypothesize is caused by introgression. Our results suggest the urgent need to systematically collect Blastomyces samples around the world and study the evolutionary processes that govern intra- and interspecific variation in these medically important fungi.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308850","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 : 2024-09-18DOI: 10.1093/genetics/iyae144
Gözde Atağ, Shamam Waldman, Shai Carmi, Mehmet Somel
Patterson's f-statistics are among the most heavily utilized tools for analyzing genome-wide allele frequency data for demographic inference. Beyond studying admixture, f3- and f4-statistics are also used for clustering populations to identify groups with similar histories. However, previous studies have noted an unexpected behavior of f-statistics: multiple populations from a certain region systematically show higher genetic affinity to a more distant population than to their neighbors, a pattern that is mismatched with alternative measures of genetic similarity. We call this counter-intuitive pattern "sister repulsion". We first present a novel instance of sister repulsion, where genomes from Bronze Age East Anatolian sites show higher affinity toward Bronze Age Greece rather than each other. This is observed both using f3- and f4-statistics, contrasts with archaeological/historical expectation, and also contradicts genetic affinity patterns captured using principal components analysis or multidimensional scaling on genetic distances. We then propose a simple demographic model to explain this pattern, where sister populations receive gene flow from a genetically distant source. We calculate f3- and f4-statistics using simulated genetic data with varying population genetic parameters, confirming that low-level gene flow from an external source into populations from 1 region can create sister repulsion in f-statistics. Unidirectional gene flow between the studied regions (without an external source) can likewise create repulsion. Meanwhile, similar to our empirical observations, multidimensional scaling analyses of genetic distances still cluster sister populations together. Overall, our results highlight the impact of low-level admixture events when inferring demographic history using f-statistics.
Patterson 的 f 统计量是用于分析全基因组等位基因频率数据以进行人口推断的最常用工具之一。除了研究混杂外,f3 和 f4 统计量还用于聚类,以确定具有相似历史的群体。然而,以往的研究注意到了 f 统计量的一种意想不到的行为:来自某一地区的多个种群系统性地表现出与较远种群的遗传亲和性高于与邻近种群的遗传亲和性,这种模式与遗传相似性的其他衡量标准不匹配。我们称这种反直觉模式为 "姊妹排斥"。我们首先介绍了姊妹排斥的一个新实例,即青铜时代东安纳托利亚遗址的基因组与青铜时代希腊的亲和力更高,而不是相互亲和力更高。这是用 f3- 和 f4 统计法观察到的,与考古学/历史学的预期相反,也与用主成分分析或遗传距离多维缩放捕捉到的遗传亲和模式相矛盾。随后,我们提出了一个简单的人口统计模型来解释这种模式,即姐妹种群接受来自遗传上遥远来源的基因流。我们利用不同种群遗传参数的模拟遗传数据计算了f3-和f4-统计量,证实了来自外部的低水平基因流进入来自一个地区的种群会在f-统计量中产生姊妹排斥。研究区域之间的单向基因流动(无外部来源)同样会产生排斥。同时,与我们的经验观察相似,遗传距离的多维比例分析仍然会将姊妹种群聚集在一起。总之,我们的研究结果凸显了利用 f 统计量推断人口历史时低水平混杂事件的影响。
{"title":"An explanation for the sister repulsion phenomenon in Patterson's f-statistics.","authors":"Gözde Atağ, Shamam Waldman, Shai Carmi, Mehmet Somel","doi":"10.1093/genetics/iyae144","DOIUrl":"https://doi.org/10.1093/genetics/iyae144","url":null,"abstract":"<p><p>Patterson's f-statistics are among the most heavily utilized tools for analyzing genome-wide allele frequency data for demographic inference. Beyond studying admixture, f3- and f4-statistics are also used for clustering populations to identify groups with similar histories. However, previous studies have noted an unexpected behavior of f-statistics: multiple populations from a certain region systematically show higher genetic affinity to a more distant population than to their neighbors, a pattern that is mismatched with alternative measures of genetic similarity. We call this counter-intuitive pattern \"sister repulsion\". We first present a novel instance of sister repulsion, where genomes from Bronze Age East Anatolian sites show higher affinity toward Bronze Age Greece rather than each other. This is observed both using f3- and f4-statistics, contrasts with archaeological/historical expectation, and also contradicts genetic affinity patterns captured using principal components analysis or multidimensional scaling on genetic distances. We then propose a simple demographic model to explain this pattern, where sister populations receive gene flow from a genetically distant source. We calculate f3- and f4-statistics using simulated genetic data with varying population genetic parameters, confirming that low-level gene flow from an external source into populations from 1 region can create sister repulsion in f-statistics. Unidirectional gene flow between the studied regions (without an external source) can likewise create repulsion. Meanwhile, similar to our empirical observations, multidimensional scaling analyses of genetic distances still cluster sister populations together. Overall, our results highlight the impact of low-level admixture events when inferring demographic history using f-statistics.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299277","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 : 2024-09-17DOI: 10.1093/genetics/iyae152
Robert A Townley, Kennedy S Stacy, Fatemeh Cheraghi, Claire C de la Cova
Raf protein kinases act as Ras-GTP sensing components of the ERK signal transduction pathway in animal cells, influencing cell proliferation, differentiation, and survival. In humans, somatic and germline mutations in the genes BRAF and RAF1 are associated with malignancies and developmental disorders. Recent studies shed light on the structure of activated Raf, a heterotetramer consisting of Raf and 14-3-3 dimers, and raised the possibility that a Raf C-terminal distal tail segment (DTS) regulates activation. We investigated the role of the DTS using the Caenorhabditis elegans Raf ortholog lin-45. Truncations removing the DTS strongly enhanced lin-45(S312A), a weak gain-of-function allele equivalent to RAF1 mutations found in patients with Noonan Syndrome. We genetically defined three elements of the LIN-45 DTS, which we termed the active site binding sequence (ASBS), the KTP motif, and the aromatic cluster. In the context of lin-45(S312A), mutation of each of these elements enhanced activity. We used AlphaFold to predict DTS protein interactions for LIN-45, fly Raf, and human BRAF, within the activated heterotetramer complex. We propose distinct functions for the LIN-45 DTS elements: i) the ASBS binds the kinase active site as an inhibitor, ii) phosphorylation of the KTP motif modulates DTS-kinase domain interaction, and iii) the aromatic cluster anchors the DTS in an inhibitory conformation. Human RASopathy-associated variants in BRAF affect residues of the DTS, consistent with these predictions. This work establishes that the Raf/LIN-45 DTS negatively regulates signaling in C. elegans and provides a model for its function in other Raf proteins.
{"title":"The Raf/LIN-45 C-terminal distal tail segment negatively regulates signaling in Caenorhabditis elegans.","authors":"Robert A Townley, Kennedy S Stacy, Fatemeh Cheraghi, Claire C de la Cova","doi":"10.1093/genetics/iyae152","DOIUrl":"10.1093/genetics/iyae152","url":null,"abstract":"<p><p>Raf protein kinases act as Ras-GTP sensing components of the ERK signal transduction pathway in animal cells, influencing cell proliferation, differentiation, and survival. In humans, somatic and germline mutations in the genes BRAF and RAF1 are associated with malignancies and developmental disorders. Recent studies shed light on the structure of activated Raf, a heterotetramer consisting of Raf and 14-3-3 dimers, and raised the possibility that a Raf C-terminal distal tail segment (DTS) regulates activation. We investigated the role of the DTS using the Caenorhabditis elegans Raf ortholog lin-45. Truncations removing the DTS strongly enhanced lin-45(S312A), a weak gain-of-function allele equivalent to RAF1 mutations found in patients with Noonan Syndrome. We genetically defined three elements of the LIN-45 DTS, which we termed the active site binding sequence (ASBS), the KTP motif, and the aromatic cluster. In the context of lin-45(S312A), mutation of each of these elements enhanced activity. We used AlphaFold to predict DTS protein interactions for LIN-45, fly Raf, and human BRAF, within the activated heterotetramer complex. We propose distinct functions for the LIN-45 DTS elements: i) the ASBS binds the kinase active site as an inhibitor, ii) phosphorylation of the KTP motif modulates DTS-kinase domain interaction, and iii) the aromatic cluster anchors the DTS in an inhibitory conformation. Human RASopathy-associated variants in BRAF affect residues of the DTS, consistent with these predictions. This work establishes that the Raf/LIN-45 DTS negatively regulates signaling in C. elegans and provides a model for its function in other Raf proteins.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299279","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 : 2024-09-12DOI: 10.1093/genetics/iyae150
Yue Yao, Ziqing Yin, Fernando R Rosas Bringas, Jonathan Boudeman, Daniele Novarina, Michael Chang
Multiple pathways are known to suppress the formation of gross chromosomal rearrangements (GCRs), which can cause human diseases including cancer. In contrast, much less is known about pathways that promote their formation. The spindle assembly checkpoint (SAC), which ensures the proper separation of chromosomes during mitosis, has been reported to promote GCR, possibly by delaying mitosis to allow GCR-inducing DNA repair to occur. Here we show that this conclusion is the result of an experimental artifact arising from the synthetic lethality caused by disruption of the SAC and loss of the CIN8 gene, which is often lost in the genetic assay used to select for GCRs. After correcting for this artifact, we find no role of the SAC in promoting GCR.
{"title":"Revisiting the role of the spindle assembly checkpoint in the formation of gross chromosomal rearrangements in Saccharomyces cerevisiae.","authors":"Yue Yao, Ziqing Yin, Fernando R Rosas Bringas, Jonathan Boudeman, Daniele Novarina, Michael Chang","doi":"10.1093/genetics/iyae150","DOIUrl":"https://doi.org/10.1093/genetics/iyae150","url":null,"abstract":"<p><p>Multiple pathways are known to suppress the formation of gross chromosomal rearrangements (GCRs), which can cause human diseases including cancer. In contrast, much less is known about pathways that promote their formation. The spindle assembly checkpoint (SAC), which ensures the proper separation of chromosomes during mitosis, has been reported to promote GCR, possibly by delaying mitosis to allow GCR-inducing DNA repair to occur. Here we show that this conclusion is the result of an experimental artifact arising from the synthetic lethality caused by disruption of the SAC and loss of the CIN8 gene, which is often lost in the genetic assay used to select for GCRs. After correcting for this artifact, we find no role of the SAC in promoting GCR.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299278","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 : 2024-09-06DOI: 10.1093/genetics/iyae129
Kai J Jürgens, Maik Drechsler, Achim Paululat
Scanning electron microscopy is the method of choice to visualize the surface structures of animals, fungi, plants, or inorganic objects at the highest resolution and often with impressive appeal. Numerous scanning electron microscope (SEM) images exist of Drosophila melanogaster, one of the most important model organisms in genetics and developmental biology, which have been taken partly for esthetics and often to solve scientific questions. Our work presents a collection of images comprising many prominent anatomical details of D. melanogaster in excellent quality to create a research and teaching resource for all Drosophilists.
{"title":"An anatomical atlas of Drosophila melanogaster-the wild-type.","authors":"Kai J Jürgens, Maik Drechsler, Achim Paululat","doi":"10.1093/genetics/iyae129","DOIUrl":"https://doi.org/10.1093/genetics/iyae129","url":null,"abstract":"<p><p>Scanning electron microscopy is the method of choice to visualize the surface structures of animals, fungi, plants, or inorganic objects at the highest resolution and often with impressive appeal. Numerous scanning electron microscope (SEM) images exist of Drosophila melanogaster, one of the most important model organisms in genetics and developmental biology, which have been taken partly for esthetics and often to solve scientific questions. Our work presents a collection of images comprising many prominent anatomical details of D. melanogaster in excellent quality to create a research and teaching resource for all Drosophilists.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141563","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 : 2024-09-06DOI: 10.1093/genetics/iyae122
Matthew D Vandermeulen, Michael C Lorenz, Paul J Cullen
Eukaryotic organisms are composed of different cell types with defined shapes and functions. Specific cell types are produced by the process of cell differentiation, which is regulated by signal transduction pathways. Signaling pathways regulate cell differentiation by sensing cues and controlling the expression of target genes whose products generate cell types with specific attributes. In studying how cells differentiate, fungi have proved valuable models because of their ease of genetic manipulation and striking cell morphologies. Many fungal species undergo filamentous growth-a specialized growth pattern where cells produce elongated tube-like projections. Filamentous growth promotes expansion into new environments, including invasion into plant and animal hosts by fungal pathogens. The same signaling pathways that regulate filamentous growth in fungi also control cell differentiation throughout eukaryotes and include highly conserved mitogen-activated protein kinase (MAPK) pathways, which is the focus of this review. In many fungal species, mucin-type sensors regulate MAPK pathways to control filamentous growth in response to diverse stimuli. Once activated, MAPK pathways reorganize cell polarity, induce changes in cell adhesion, and promote the secretion of degradative enzymes that mediate access to new environments. However, MAPK pathway regulation is complicated because related pathways can share components with each other yet induce unique responses (i.e. signal specificity). In addition, MAPK pathways function in highly integrated networks with other regulatory pathways (i.e. signal integration). Here, we discuss signal specificity and integration in several yeast models (mainly Saccharomyces cerevisiae and Candida albicans) by focusing on the filamentation MAPK pathway. Because of the strong evolutionary ties between species, a deeper understanding of the regulation of filamentous growth in established models and increasingly diverse fungal species can reveal fundamentally new mechanisms underlying eukaryotic cell differentiation.
{"title":"Conserved signaling modules regulate filamentous growth in fungi: a model for eukaryotic cell differentiation.","authors":"Matthew D Vandermeulen, Michael C Lorenz, Paul J Cullen","doi":"10.1093/genetics/iyae122","DOIUrl":"https://doi.org/10.1093/genetics/iyae122","url":null,"abstract":"<p><p>Eukaryotic organisms are composed of different cell types with defined shapes and functions. Specific cell types are produced by the process of cell differentiation, which is regulated by signal transduction pathways. Signaling pathways regulate cell differentiation by sensing cues and controlling the expression of target genes whose products generate cell types with specific attributes. In studying how cells differentiate, fungi have proved valuable models because of their ease of genetic manipulation and striking cell morphologies. Many fungal species undergo filamentous growth-a specialized growth pattern where cells produce elongated tube-like projections. Filamentous growth promotes expansion into new environments, including invasion into plant and animal hosts by fungal pathogens. The same signaling pathways that regulate filamentous growth in fungi also control cell differentiation throughout eukaryotes and include highly conserved mitogen-activated protein kinase (MAPK) pathways, which is the focus of this review. In many fungal species, mucin-type sensors regulate MAPK pathways to control filamentous growth in response to diverse stimuli. Once activated, MAPK pathways reorganize cell polarity, induce changes in cell adhesion, and promote the secretion of degradative enzymes that mediate access to new environments. However, MAPK pathway regulation is complicated because related pathways can share components with each other yet induce unique responses (i.e. signal specificity). In addition, MAPK pathways function in highly integrated networks with other regulatory pathways (i.e. signal integration). Here, we discuss signal specificity and integration in several yeast models (mainly Saccharomyces cerevisiae and Candida albicans) by focusing on the filamentation MAPK pathway. Because of the strong evolutionary ties between species, a deeper understanding of the regulation of filamentous growth in established models and increasingly diverse fungal species can reveal fundamentally new mechanisms underlying eukaryotic cell differentiation.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142141564","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 : 2024-09-06DOI: 10.1093/genetics/iyae146
Andrew P Morgan, Bret A Payseur
Meiotic recombination is required for faithful chromosome segregation in most sexually reproducing organisms and shapes the distribution of genetic variation in populations. Both the overall rate and the spatial distribution of crossovers vary within and between species. Adjacent crossovers on the same chromosome tend to be spaced more evenly than expected at random, a phenomenon known as crossover interference. Although interference has been observed in many taxa, the factors that influence the strength of interference are not well understood. We used house mice (Mus musculus), a well-established model system for understanding recombination, to study the effects of genetics and age on recombination rate and interference in the male germline. We analyzed crossover positions in 503 progeny from reciprocal F1 hybrids between inbred strains representing the three major subspecies of house mice. Consistent with previous studies, autosomal alleles from M. m. musculus tend to increase recombination rate, while inheriting a M. m. musculus X chromosome decreases recombination rate. Old males transmit an average of 0.6 more crossovers per meiosis (5.0%) than young males, though the effect varies across genetic backgrounds. We show that the strength of crossover interference depends on genotype, providing a rare demonstration that interference evolves over short timescales. Differences between reciprocal F1s suggest that X-linked factors modulate the strength of interference. Our findings motivate additional comparisons of interference among recently diverged species and further examination of the role of paternal age in determining the number and positioning of crossovers.
在大多数有性生殖的生物中,减数分裂重组是染色体忠实分离的必要条件,并决定了种群中遗传变异的分布。在物种内部和物种之间,交叉的总体比率和空间分布都各不相同。同一染色体上相邻交叉点的间隔往往比预期的要均匀,这种现象被称为交叉干扰。虽然在许多类群中都观察到了干扰现象,但对影响干扰强度的因素却不甚了解。我们利用家鼠(Mus musculus)这一了解重组的成熟模型系统,研究了遗传和年龄对雄性生殖系重组率和干扰的影响。我们分析了代表三个主要家鼠亚种的近交系互交 F1 杂交产生的 503 个后代的交叉位置。与之前的研究一致,来自家鼠的常染色体等位基因往往会增加重组率,而遗传家鼠X染色体则会降低重组率。与年轻雄性相比,老年雄性在每次减数分裂中平均多传递 0.6 个交叉基因(5.0%),但这一效应在不同的遗传背景下有所不同。我们的研究表明,交叉干扰的强度取决于基因型,这罕见地证明了干扰会在短时间内演变。互交 F1 之间的差异表明,X 连锁因素会调节干扰的强度。我们的发现促使我们对最近分化的物种之间的干扰进行更多的比较,并进一步研究父系年龄在决定交叉的数量和定位方面的作用。
{"title":"Genetic background affects the strength of crossover interference in house mice.","authors":"Andrew P Morgan, Bret A Payseur","doi":"10.1093/genetics/iyae146","DOIUrl":"10.1093/genetics/iyae146","url":null,"abstract":"<p><p>Meiotic recombination is required for faithful chromosome segregation in most sexually reproducing organisms and shapes the distribution of genetic variation in populations. Both the overall rate and the spatial distribution of crossovers vary within and between species. Adjacent crossovers on the same chromosome tend to be spaced more evenly than expected at random, a phenomenon known as crossover interference. Although interference has been observed in many taxa, the factors that influence the strength of interference are not well understood. We used house mice (Mus musculus), a well-established model system for understanding recombination, to study the effects of genetics and age on recombination rate and interference in the male germline. We analyzed crossover positions in 503 progeny from reciprocal F1 hybrids between inbred strains representing the three major subspecies of house mice. Consistent with previous studies, autosomal alleles from M. m. musculus tend to increase recombination rate, while inheriting a M. m. musculus X chromosome decreases recombination rate. Old males transmit an average of 0.6 more crossovers per meiosis (5.0%) than young males, though the effect varies across genetic backgrounds. We show that the strength of crossover interference depends on genotype, providing a rare demonstration that interference evolves over short timescales. Differences between reciprocal F1s suggest that X-linked factors modulate the strength of interference. Our findings motivate additional comparisons of interference among recently diverged species and further examination of the role of paternal age in determining the number and positioning of crossovers.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142143446","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 : 2024-09-04DOI: 10.1093/genetics/iyae123
{"title":"Correction to: Fixation times of de novo and standing beneficial variants in subdivided populations.","authors":"","doi":"10.1093/genetics/iyae123","DOIUrl":"10.1093/genetics/iyae123","url":null,"abstract":"","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141861309","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 : 2024-09-04DOI: 10.1093/genetics/iyae115
Thomas P Conway, Lucia Simonicova, W Scott Moye-Rowley
Azole resistance in the pathogenic yeast Candida glabrata is a serious clinical complication and increasing in frequency. The majority of resistant organisms have been found to contain a substitution mutation in the Zn2Cys6 zinc cluster-containing transcription factor Pdr1. These mutations typically lead to this factor driving high, constitutive expression of target genes like the ATP-binding cassette transporter-encoding gene CDR1. Overexpression of Cdr1 is required for the observed elevated fluconazole resistance exhibited by strains containing one of these hyperactive PDR1 alleles. While the identity of hyperactive PDR1 alleles has been extensively documented, the mechanisms underlying how these gain-of-function (GOF) forms of Pdr1 lead to elevated target gene transcription are not well understood. We have used a tandem affinity purification-tagged form of Pdr1 to identify coactivator proteins that biochemically purify with the wild-type and 2 different GOF forms of Pdr1. Three coactivator proteins were found to associate with Pdr1: the SWI/SNF complex Snf2 chromatin remodeling protein and 2 different components of the SAGA complex, Spt7 and Ngg1. We found that deletion mutants lacking either SNF2 or SPT7 exhibited growth defects, even in the absence of fluconazole challenge. To overcome these issues, we employed a conditional degradation system to acutely deplete these coactivators and determined that loss of either coactivator complex, SWI/SNF or SAGA, caused defects in Pdr1-dependent transcription. A double degron strain that could be depleted for both SWI/SNF and SAGA exhibited a profound defect in PDR1 autoregulation, revealing that these complexes work together to ensure high-level Pdr1-dependent gene transcription.
{"title":"Overlapping coactivator function is required for transcriptional activation by the Candida glabrata Pdr1 transcription factor.","authors":"Thomas P Conway, Lucia Simonicova, W Scott Moye-Rowley","doi":"10.1093/genetics/iyae115","DOIUrl":"10.1093/genetics/iyae115","url":null,"abstract":"<p><p>Azole resistance in the pathogenic yeast Candida glabrata is a serious clinical complication and increasing in frequency. The majority of resistant organisms have been found to contain a substitution mutation in the Zn2Cys6 zinc cluster-containing transcription factor Pdr1. These mutations typically lead to this factor driving high, constitutive expression of target genes like the ATP-binding cassette transporter-encoding gene CDR1. Overexpression of Cdr1 is required for the observed elevated fluconazole resistance exhibited by strains containing one of these hyperactive PDR1 alleles. While the identity of hyperactive PDR1 alleles has been extensively documented, the mechanisms underlying how these gain-of-function (GOF) forms of Pdr1 lead to elevated target gene transcription are not well understood. We have used a tandem affinity purification-tagged form of Pdr1 to identify coactivator proteins that biochemically purify with the wild-type and 2 different GOF forms of Pdr1. Three coactivator proteins were found to associate with Pdr1: the SWI/SNF complex Snf2 chromatin remodeling protein and 2 different components of the SAGA complex, Spt7 and Ngg1. We found that deletion mutants lacking either SNF2 or SPT7 exhibited growth defects, even in the absence of fluconazole challenge. To overcome these issues, we employed a conditional degradation system to acutely deplete these coactivators and determined that loss of either coactivator complex, SWI/SNF or SAGA, caused defects in Pdr1-dependent transcription. A double degron strain that could be depleted for both SWI/SNF and SAGA exhibited a profound defect in PDR1 autoregulation, revealing that these complexes work together to ensure high-level Pdr1-dependent gene transcription.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141727968","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 : 2024-09-04DOI: 10.1093/genetics/iyae098
Jia Wen, Quan Sun, Le Huang, Lingbo Zhou, Margaret F Doyle, Lynette Ekunwe, Peter Durda, Nels C Olson, Alexander P Reiner, Yun Li, Laura M Raffield
Most gene expression and alternative splicing quantitative trait loci (eQTL/sQTL) studies have been biased toward European ancestry individuals. Here, we performed eQTL and sQTL analyses using TOPMed whole-genome sequencing-derived genotype data and RNA-sequencing data from stored peripheral blood mononuclear cells in 1,012 African American participants from the Jackson Heart Study (JHS). At a false discovery rate of 5%, we identified 17,630 unique eQTL credible sets covering 16,538 unique genes; and 24,525 unique sQTL credible sets covering 9,605 unique genes, with lead QTL at P < 5e-8. About 24% of independent eQTLs and independent sQTLs with a minor allele frequency > 1% in JHS were rare (minor allele frequency < 0.1%), and therefore unlikely to be detected, in European ancestry individuals. Finally, we created an open database, which is freely available online, allowing fast query and bulk download of our QTL results.
{"title":"Gene expression and splicing QTL analysis of blood cells in African American participants from the Jackson Heart Study.","authors":"Jia Wen, Quan Sun, Le Huang, Lingbo Zhou, Margaret F Doyle, Lynette Ekunwe, Peter Durda, Nels C Olson, Alexander P Reiner, Yun Li, Laura M Raffield","doi":"10.1093/genetics/iyae098","DOIUrl":"10.1093/genetics/iyae098","url":null,"abstract":"<p><p>Most gene expression and alternative splicing quantitative trait loci (eQTL/sQTL) studies have been biased toward European ancestry individuals. Here, we performed eQTL and sQTL analyses using TOPMed whole-genome sequencing-derived genotype data and RNA-sequencing data from stored peripheral blood mononuclear cells in 1,012 African American participants from the Jackson Heart Study (JHS). At a false discovery rate of 5%, we identified 17,630 unique eQTL credible sets covering 16,538 unique genes; and 24,525 unique sQTL credible sets covering 9,605 unique genes, with lead QTL at P < 5e-8. About 24% of independent eQTLs and independent sQTLs with a minor allele frequency > 1% in JHS were rare (minor allele frequency < 0.1%), and therefore unlikely to be detected, in European ancestry individuals. Finally, we created an open database, which is freely available online, allowing fast query and bulk download of our QTL results.</p>","PeriodicalId":48925,"journal":{"name":"Genetics","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11373511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141761974","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}