bioRxiv - Genetics最新文献_第8页

Stimulation of locus coeruleus inputs to the frontal cortex in mice induces cell type-specific expression of the Apoe gene 刺激小鼠额叶皮层的神经节输入可诱导细胞特异性表达载脂蛋白基因

bioRxiv - Genetics Pub Date : 2024-07-23 DOI: 10.1101/2024.07.22.604695

Genevieve E Craig, Lizbeth Ramos, Samuel R Essig, Nicholas J Eagles, Andrew E Jaffe, Keri Martinowich, Henry L Hallock

{"title":"Stimulation of locus coeruleus inputs to the frontal cortex in mice induces cell type-specific expression of the Apoe gene","authors":"Genevieve E Craig, Lizbeth Ramos, Samuel R Essig, Nicholas J Eagles, Andrew E Jaffe, Keri Martinowich, Henry L Hallock","doi":"10.1101/2024.07.22.604695","DOIUrl":"https://doi.org/10.1101/2024.07.22.604695","url":null,"abstract":"Deficits in attention are common across a range of neuropsychiatric disorders. A multitude of brain regions, including the frontal cortex (FC) and locus coeruleus (LC), have been implicated in attention. Regulators of these brain regions at the molecular level are not well understood, but might elucidate underlying mechanisms of disorders with attentional deficits. To probe this, we used chemogenetic stimulation of neurons in the LC with axonal projections to the FC, and subsequent bulk RNA-sequencing from the mouse FC. We found that stimulation of this circuit caused an increase in transcription of the Apoe gene. To investigate cell type-specific expression of Apoe in the FC, we used a dual-virus approach to express either the excitatory DREADD receptor hM3Dq in LC neurons with projections to the FC, or a control virus, and found that increases in Apoe expression in the FC following depolarization of LC inputs is enriched in GABAergic neurons in a sex-dependent manner. The results of these experiments yield insights into how Apoe expression affects function in cortical microcircuits that are important for attention-guided behavior, and point to interneuron-specific expression of Apoe as a potential target for the amelioration of attention symptoms in disorders such as attention-deficit hyperactivity disorder (ADHD), schizophrenia, and Alzheimers disease (AD).","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141785257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long shared haplotypes identify the Southern Urals as a primary source for the 10th century Hungarians 长期共享的单倍型将南乌拉尔确定为 10 世纪匈牙利人的主要来源地

bioRxiv - Genetics Pub Date : 2024-07-23 DOI: 10.1101/2024.07.21.599526

Balázs Gyuris, Leonid Vyazov, Attila Türk, Pavel Flegontov, Bea Szeifert, Péter Langó, Balázs Gusztáv Mende, Veronika Csáky, Andrey A. Chizhevskiy, Ilgizar R. Gazimzyanov, Aleksandr A. Khokhlov, Aleksandr G. Kolonskikh, Natalia P. Matveeva, Rida R. Ruslanova, Marina P. Rykun, Ayrat Sitdikov, Elizaveta V. Volkova, Sergei G. Botalov, Dmitriy G. Bugrov, Ivan V. Grudochko, Oleksii Komar, Alexander A. Krasnoperov, Olga E. Poshekhonova, Irina Chikunova, Flarit Sungatov, Dmitrii A. Stashenkov, Sergei Zubov, Alexander S. Zelenkov, Harald Ringbauer, Olivia Cheronet, Ron Pinhasi, Ali Akbari, Nadin Rohland, Swapan Mallick, David Reich, Anna Szécsényi-Nagy

{"title":"Long shared haplotypes identify the Southern Urals as a primary source for the 10th century Hungarians","authors":"Balázs Gyuris, Leonid Vyazov, Attila Türk, Pavel Flegontov, Bea Szeifert, Péter Langó, Balázs Gusztáv Mende, Veronika Csáky, Andrey A. Chizhevskiy, Ilgizar R. Gazimzyanov, Aleksandr A. Khokhlov, Aleksandr G. Kolonskikh, Natalia P. Matveeva, Rida R. Ruslanova, Marina P. Rykun, Ayrat Sitdikov, Elizaveta V. Volkova, Sergei G. Botalov, Dmitriy G. Bugrov, Ivan V. Grudochko, Oleksii Komar, Alexander A. Krasnoperov, Olga E. Poshekhonova, Irina Chikunova, Flarit Sungatov, Dmitrii A. Stashenkov, Sergei Zubov, Alexander S. Zelenkov, Harald Ringbauer, Olivia Cheronet, Ron Pinhasi, Ali Akbari, Nadin Rohland, Swapan Mallick, David Reich, Anna Szécsényi-Nagy","doi":"10.1101/2024.07.21.599526","DOIUrl":"https://doi.org/10.1101/2024.07.21.599526","url":null,"abstract":"During the Hungarian Conquest in the 10th century CE, the early medieval Magyars, a group of mounted warriors from Eastern Europe, settled in the Carpathian Basin. They likely introduced the Hungarian language to this new settlement area, during an event documented by both written sources and archaeological evidence. Previous archaeogenetic research identified the newcomers as migrants from the Eurasian steppe. However, genome-wide ancient DNA from putative source populations has not been available to test alternative theories of their precise source. We generated genome-wide ancient DNA data for 131 individuals from candidate archaeological contexts in the Circum-Uralic region in present-day Russia. Our results tightly link the Magyars to people of the Early Medieval Karayakupovo archaeological horizon on both the European and Asian sides of the southern Urals. Our analyes show that ancestors of the people of the Karayakupovo archaeological horizon were established in the Southern Urals by the Iron Age and that their descendants persisted locally in the Volga-Kama region until at least the 14th century.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141785255","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Population genetic structure of the aphid pest Myzus persicae in organic and conventional greenhouses 有机和传统温室中蚜虫害虫柿蚜的种群遗传结构

bioRxiv - Genetics Pub Date : 2024-07-23 DOI: 10.1101/2024.07.22.604537

Mariska M. Beekman, Joost van den Heuvel, S. Helena Donner, Jordy J. H. Litjens, Marcel Dicke, Bas J. Zwaan, Eveline C. Verhulst, Bart A. Pannebakker

{"title":"Population genetic structure of the aphid pest Myzus persicae in organic and conventional greenhouses","authors":"Mariska M. Beekman, Joost van den Heuvel, S. Helena Donner, Jordy J. H. Litjens, Marcel Dicke, Bas J. Zwaan, Eveline C. Verhulst, Bart A. Pannebakker","doi":"10.1101/2024.07.22.604537","DOIUrl":"https://doi.org/10.1101/2024.07.22.604537","url":null,"abstract":"Aphids display remarkable adaptability to pest control strategies and their parthenogenetic reproduction results in rapid numerical increase of higher-fitness clones. Consequently, a high prevalence of only a few clonal lines could indicate positive selection for these genotypes, potentially reflecting adaptation to pest control methods. Here, we investigated the clonal diversity and population genetic structure of the green peach aphid Myzus persicae using microsatellite markers, in both organic and conventionally managed Dutch sweet pepper greenhouses over four consecutive years. In total, 26 distinct multilocus genotypes (MLG) were detected, with higher clonal diversity in organic than in conventional greenhouses. Strikingly, a single MLG dominated conventional greenhouses in 2019, only to be completely replaced by a new dominant MLG by 2022. Whole-genome sequencing of 15 sampled lines — seven sharing the same MLG and eighth with unique MLGs — revealed that all aphids with the dominant MLG of 2019, collected from various locations and over multiple years, originated from a single parthenogenetic ancestor. Our findings indicate that the population genetic structure of M. persicae differs between organically and conventionally managed sweet pepper greenhouses. The presence of dominant MLGs in conventional crop systems may suggest positive selection or evolutionary forces such as a founder effect. Understanding the forces driving these differences in population genetic structure and their impact on the efficacy of biocontrol agents will further help us improve control strategies for M. persicae in greenhouse crops.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Reviving the Desired Gains Index: An optimal solution for parent selection in public plant breeding programs 恢复期望收益指数：公共植物育种计划中亲本选择的最佳解决方案

bioRxiv - Genetics Pub Date : 2024-07-23 DOI: 10.1101/2024.07.21.603926

Christian R Werner, Keith A Gardner, Daniel J Tolhurst

{"title":"Reviving the Desired Gains Index: An optimal solution for parent selection in public plant breeding programs","authors":"Christian R Werner, Keith A Gardner, Daniel J Tolhurst","doi":"10.1101/2024.07.21.603926","DOIUrl":"https://doi.org/10.1101/2024.07.21.603926","url":null,"abstract":"The Desired Gains Index is an optimal solution for parent selection in public plant breeding programs. It enables breeders to quantify their breeding objectives in terms of desired genetic gains (i.e., desired response to selection) and facilitates the efficient simultaneous improvement of multiple quantitative traits in a breeding population without the need for economic weights. We deliberately chose the term ″optimal″ here, which is typically associated with the profit-oriented selection indices commonly used in animal breeding, such as the Smith-Hazel Index. Our intention is to refute the perception that the Desired Gains Index is less efficient than the Smith-Hazel Index since both approaches maximise expected genetic gains in proportion to the breeding objective. To achieve this, we first review the relationship between the Desired Gains Index and the Smith-Hazel Index to show that desired gains are actually a form of economic weighting expressed as an improvement ratio for the traits under selection. We then present a general form of the Desired Gains Index to leverage best linear unbiased prediction (BLUP), which enables seamless integration of pedigree or genomic relationship information (e.g., genomic estimated breeding values) between the selection candidates and other related individuals. Finally, using stochastic simulation, we compare the performance of different parent selection strategies, including index selection for population improvement, independent culling, and selection of extreme genotypes. The objective of these demonstrations is to convey the potential impact and benefits of the Desired Gains Index to a broader audience without the need for a deep understanding of selection theory and the equations presented here.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"33 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772760","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In-utero rescue of neurological dysfunction in a mouse model of Wiedemann-Steiner syndrome 小鼠维德曼-施泰纳综合征模型神经功能障碍的胎儿期救治

bioRxiv - Genetics Pub Date : 2024-07-23 DOI: 10.1101/2024.07.19.604339

Tinna Reynisdottir, Kimberley Jade Anderson, Andrew Brinn, Katie Franklin, Juan Ouyang, Asbjorg Osk Snorradottir, Cathleen M Lutz, Aamir R Zuberi, Valerie Burke DeLeon, Hans Tomas Bjornsson

{"title":"In-utero rescue of neurological dysfunction in a mouse model of Wiedemann-Steiner syndrome","authors":"Tinna Reynisdottir, Kimberley Jade Anderson, Andrew Brinn, Katie Franklin, Juan Ouyang, Asbjorg Osk Snorradottir, Cathleen M Lutz, Aamir R Zuberi, Valerie Burke DeLeon, Hans Tomas Bjornsson","doi":"10.1101/2024.07.19.604339","DOIUrl":"https://doi.org/10.1101/2024.07.19.604339","url":null,"abstract":"Wiedemann-Steiner syndrome (WDSTS) is a rare genetic cause of intellectual disability primarily caused by heterozygous loss of function variants in the gene encoding the histone methyltransferase KMT2A. Prior studies have shown successful postnatal amelioration of disease phenotypes for Rett, Rubinstein-Taybi and Kabuki syndromes, related Mendelian disorders of the epigenetic machinery. To explore whether the neurological phenotype in WDSTS is treatable in-utero, we created a novel mouse model carrying a loss of function variant in between two loxP sites. Kmt2a+/LSL mice demonstrate core features of WDSTS including growth retardation, craniofacial abnormalities, and hypertrichosis as well as hippocampal memory defects. The neurological phenotypes show rescue upon restoration of KMT2A in-utero following breeding to a nestin-Cre. Together, our data provide a novel mouse model to explore the therapeutic window in WDSTS. Our work suggests that WDSTS has a window of opportunity extending at least until the mid-point of in-utero development, making WDSTS an ideal candidate for future therapeutic strategies.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"140 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141772759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Two dimensional sequence alignment shows that replication slippage may generate a significant proportion of all transversion substitutions. 二维序列比对显示，复制滑动可能会产生很大比例的所有转换置换。

bioRxiv - Genetics Pub Date : 2024-07-20 DOI: 10.1101/2024.07.17.603925

Albert J Erives

{"title":"Two dimensional sequence alignment shows that replication slippage may generate a significant proportion of all transversion substitutions.","authors":"Albert J Erives","doi":"10.1101/2024.07.17.603925","DOIUrl":"https://doi.org/10.1101/2024.07.17.603925","url":null,"abstract":"A new approach to DNA sequence alignment is introduced to expand the number of homology states between nucleotides. While standard gapped alignment (GA) operates under a two-state homology model of one-to-one and one-to-none (one-to-gap) relationships, a micro-paralogical gapped alignment (MPGA) approach adds one-to-many, many-to-many, and many-to-none relationships. This multi-state homology model is motivated by the DNA replication errors caused specifically by replication slippage (RS). RS produces short tandem repeats (TRs), constituting interrelated, micro-paralogous sequences. RS and TR-associated instability give rise to a major proportion of insertions and deletions, which require the insertion of gaps during multiple sequence alignment. While GA incurs the computational cost of determining optimal gap insertion, an unsolvable task with a two-state homology model, MPGA reduces the gap insertion task by reducing the overall number of gaps in 2D alignments. Two-dimensional self-alignment of a sequence occurs when tandem repeats are contracted into the same columns (dimension one) by occupying multiple rows (dimension two), an internal micro-paralogical dimension. A program called LINEUP is introduced to demonstrate the challenges and opportunities of 2D self-alignment of DNA sequences. It is then shown how 2D alignments can provide more precise measures of point mutation rates and transition-to-transversion ratios than 1D alignments. It is also shown how diversely-conserved protein-coding sequences have a distinctive signature of dinucleotide repeat depletion and trinucleotide enrichment relative to non-protein coding sequences and randomly shuffled, synthetic sequences. This trinucleotide enrichment occurs across all three reading frames. These results showcase significant new perspectives on basic mutational and evolutionary processes.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"62 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141740164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption 锰转运体 SLC30A10 和铁转运体 SLC40A1 和 SLC11A2 影响膳食中锰的吸收

bioRxiv - Genetics Pub Date : 2024-07-20 DOI: 10.1101/2024.07.17.603814

Milankumar Prajapati, Jared Z Zhang, Grace S Chong, Lauren Chiu, Courtney J Mercadante, Heather L Kowalski, Olga Antipova, Barry Lai, Martina Ralle, Brian P Jackson, Tracy Punshon, Shuling Guo, Mariam Aghajan, Thomas Benedict Bartnikas

{"title":"Manganese transporter SLC30A10 and iron transporters SLC40A1 and SLC11A2 impact dietary manganese absorption","authors":"Milankumar Prajapati, Jared Z Zhang, Grace S Chong, Lauren Chiu, Courtney J Mercadante, Heather L Kowalski, Olga Antipova, Barry Lai, Martina Ralle, Brian P Jackson, Tracy Punshon, Shuling Guo, Mariam Aghajan, Thomas Benedict Bartnikas","doi":"10.1101/2024.07.17.603814","DOIUrl":"https://doi.org/10.1101/2024.07.17.603814","url":null,"abstract":"SLC30A10 deficiency is a disease of severe manganese excess attributed to loss of SLC30A10-dependent manganese excretion via the gastrointestinal tract. Patients develop dystonia, cirrhosis, and polycythemia. They are treated with chelators but also respond to oral iron, suggesting that iron can outcompete manganese for absorption in this disease. Here we explore the latter observation. Intriguingly, manganese absorption is increased in Slc30a10-deficient mice despite manganese excess. Studies of multiple mouse models indicate that increased dietary manganese absorption reflects two processes: loss of manganese export from enterocytes into the gastrointestinal tract lumen by SLC30A10, and increased absorption of dietary manganese by iron transporters SLC11A2 (DMT1) and SLC40A1 (ferroportin). Our work demonstrates that aberrant absorption contributes prominently to SLC30A10 deficiency and expands our understanding of biological interactions between iron and manganese. Based on these results, we propose a reconsideration of the role of iron transporters in manganese homeostasis is warranted.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"28 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141740165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An essential role for RNA binding by Periphilin in silencing by the HUSH complex 在 HUSH 复合物的沉默过程中，Periphilin 与 RNA 的结合起着至关重要的作用

bioRxiv - Genetics Pub Date : 2024-07-19 DOI: 10.1101/2024.07.17.602677

Paul J Lehner, Niek Wit, Stuart Bloor

{"title":"An essential role for RNA binding by Periphilin in silencing by the HUSH complex","authors":"Paul J Lehner, Niek Wit, Stuart Bloor","doi":"10.1101/2024.07.17.602677","DOIUrl":"https://doi.org/10.1101/2024.07.17.602677","url":null,"abstract":"The human silencing hub (HUSH) complex is a transcription-dependent, epigenetic repressor complex that provides a genome-wide immunosurveillance system for the recognition and silencing of newly-integrated retroelements. The core HUSH complex of TASOR, MPP8 and Periphilin, represses these retroelements through SETDB1-mediated H3K9me3 deposition and MORC2-dependent chromatin compaction. HUSH-dependent silencing is RNA-mediated, yet no HUSH components contain any RNA-binding domain. Here we used an unbiased approach to identify which HUSH component was able to bind RNA and determine whether RNA-binding was essential for HUSH function. We identify Periphilin as the major RNA-binding component of the HUSH complex and show that Periphilin's N-terminal domain is essential for both RNA binding and HUSH function. Periphilin binding to RNA was independent of its interaction with TASOR or MPP8, as its N-terminal domain was sufficient for RNA targeting. The artificial tethering of Periphilin to a HUSH-insensitive, nascent transcript, enabled the HUSH-dependent silencing of the transcript. This tethering of Periphilin allowed the RNA-binding region of Periphilin to be removed such that only its C-terminal domain was required for oligomerisation and interaction with TASOR. We therefore show that Periphilin is the predominant RNA-binding protein of the HUSH complex and this RNA-binding is essential for HUSH activity.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"47 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141740166","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Cost-effective, High-throughput, Highly Accurate Genotyping Method for Outbred Populations 一种经济高效、高通量、高精确度的外交种群基因分型方法

bioRxiv - Genetics Pub Date : 2024-07-18 DOI: 10.1101/2024.07.17.603984

Denghui Chen, Apurva S Chitre, Khai-Minh H Nguyen, Katarina A Cohen, Beverly F Peng, Kendra S Ziegler, Faith Okamoto, Bonnie Lin, Benjamin B Johnson, Thiago M Sanches, Riyan Cheng, Oksana Polesskaya, Abraham A Palmer

{"title":"A Cost-effective, High-throughput, Highly Accurate Genotyping Method for Outbred Populations","authors":"Denghui Chen, Apurva S Chitre, Khai-Minh H Nguyen, Katarina A Cohen, Beverly F Peng, Kendra S Ziegler, Faith Okamoto, Bonnie Lin, Benjamin B Johnson, Thiago M Sanches, Riyan Cheng, Oksana Polesskaya, Abraham A Palmer","doi":"10.1101/2024.07.17.603984","DOIUrl":"https://doi.org/10.1101/2024.07.17.603984","url":null,"abstract":"Affordable sequencing and genotyping methods are essential for large scale genome-wide association studies. While genotyping microarrays and reference panels for imputation are available for human subjects, non-human model systems often lack such options. Our lab previously demonstrated an efficient and cost-effective method to genotype heterogeneous stock rats using double-digest genotyping-by-sequencing. However, low-coverage whole-genome sequencing offers an alternative method that has several advantages. Here, we describe a cost-effective, high-throughput, high-accuracy genotyping method for N/NIH heterogeneous stock rats that can use a combination of sequencing data previously generated by double-digest genotyping-by-sequencing and more recently generated by low-coverage whole-genome-sequencing data. Using double-digest genotyping-by-sequencing data from 5,745 heterogeneous stock rats (mean 0.21x coverage) and low-coverage whole-genome-sequencing data from 8,760 heterogeneous stock rats (mean 0.27x coverage), we can impute 7.32 million bi-allelic single-nucleotide polymorphisms with a concordance rate >99.76% compared to high-coverage (mean 33.26x coverage) whole-genome sequencing data for a subset of the same individuals. Our results demonstrate the feasibility of using sequencing data from double-digest genotyping-by-sequencing or low-coverage whole-genome-sequencing for accurate genotyping, and demonstrate techniques that may also be useful for other genetic studies in non-human subjects.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141740169","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Proteostasis modulates gene dosage evolution in antibiotic-resistant bacteria 蛋白稳态调节抗生素细菌的基因剂量进化

bioRxiv - Genetics Pub Date : 2024-07-17 DOI: 10.1101/2024.07.15.603526

Chinmaya Jena, Saillesh Chinnaraj, Soham Deolankar, Nishad Matange

{"title":"Proteostasis modulates gene dosage evolution in antibiotic-resistant bacteria","authors":"Chinmaya Jena, Saillesh Chinnaraj, Soham Deolankar, Nishad Matange","doi":"10.1101/2024.07.15.603526","DOIUrl":"https://doi.org/10.1101/2024.07.15.603526","url":null,"abstract":"Evolution of gene expression frequently drives antibiotic resistance in bacteria. We had previously (Patel and Matange, eLife, 2021) shown that in Escherichia coli, mutations at the mgrB locus were beneficial in trimethoprim and led to overexpression of dihydrofolate reductase (DHFR), encoded by the folA gene. Here, we show that DHFR levels are further enhanced by spontaneous duplication of a genomic segment encompassing folA and spanning hundreds of kilobases. This duplication was rare in wild type E. coli. However, its frequency was elevated in a lon-knockout strain, altering the mutational landscape early during trimethoprim adaptation. We then exploit this system to investigate the relationship between trimethoprim pressure and folA copy number. During long-term evolution, folA duplications were frequently reversed. Reversal was slower under antibiotic pressure, first requiring the acquisition of point mutations in DHFR or its promoter. Unexpectedly, despite resistance-conferring point mutations, some populations under high trimethoprim pressure maintained folA duplication to compensate for low abundance DHFR mutants. We find that evolution of gene dosage depends on expression demand, which is generated by antibiotic and exacerbated by proteolysis of drug-resistant mutants of DHFR. We propose a novel role for proteostasis as a determinant of copy number evolution in antibiotic-resistant bacteria.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141740170","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0