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Fast and Robust Strand Displacement Cascades via Systematic Design Strategies 快速和强大的链位移级联通过系统的设计策略
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2022-01-01 DOI: 10.4230/LIPIcs.DNA.28.1
T. Kennedy, Cadence Pearce, Chris Thachuk
A barrier to wider adoption of molecular computation is the difficulty of implementing arbitrary chemical reaction networks (CRNs) that are robust and replicate the kinetics of designed behavior. DNA Strand Displacement (DSD) cascades have been a favored technology for this purpose due to their potential to emulate arbitrary CRNs and known principles to tune their reaction rates. Progress on leakless cascades has demonstrated that DSDs can be arbitrarily robust to spurious “leak” reactions when incorporating systematic domain level redundancy. These improvements in robustness result in slower kinetics of designed reactions. Existing work has demonstrated the kinetic and thermodynamic effects of sequence mismatch introduction and elimination during displacement. We present a systematic, sequence modification strategy for optimizing the kinetics of leakless cascades without practical cost to their robustness. An in-depth case study explores the effects of this optimization when applied to a typical leakless translator cascade. Thermodynamic analysis of energy barriers and kinetic experimental data support that DSD cascades can be fast and robust.
分子计算广泛应用的一个障碍是实现任意化学反应网络(crn)的困难,这些网络是稳健的,可以复制设计行为的动力学。DNA链位移(DSD)级联由于其模拟任意crn的潜力和调节其反应速率的已知原理,因此一直是一种受欢迎的技术。无泄漏级联的进展表明,当纳入系统域级冗余时,dsd可以对虚假的“泄漏”反应具有任意鲁棒性。鲁棒性的这些改进导致设计反应的动力学变慢。现有的工作已经证明了置换过程中序列失配的引入和消除对动力学和热力学的影响。我们提出了一种系统的、序列修改策略来优化无泄漏级联的动力学,而不会对其鲁棒性造成实际损失。一个深入的案例研究探讨了这种优化在应用于典型的无泄漏翻译器级联时的效果。能量势垒的热力学分析和动力学实验数据支持了DSD级联的快速和鲁棒性。
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引用次数: 1
Whole-genome analysis reveals the contribution of non-coding de novo transposon insertions to autism spectrum disorder. 全基因组分析揭示了非编码从头转座子插入对自闭症谱系障碍的贡献。
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2021-11-27 DOI: 10.1186/s13100-021-00256-w
Rebeca Borges-Monroy, Chong Chu, Caroline Dias, Jaejoon Choi, Soohyun Lee, Yue Gao, Taehwan Shin, Peter J Park, Christopher A Walsh, Eunjung Alice Lee

Background: Retrotransposons have been implicated as causes of Mendelian disease, but their role in autism spectrum disorder (ASD) has not been systematically defined, because they are only called with adequate sensitivity from whole genome sequencing (WGS) data and a large enough cohort for this analysis has only recently become available.

Results: We analyzed WGS data from a cohort of 2288 ASD families from the Simons Simplex Collection by establishing a scalable computational pipeline for retrotransposon insertion detection. We report 86,154 polymorphic retrotransposon insertions-including > 60% not previously reported-and 158 de novo retrotransposition events. The overall burden of de novo events was similar between ASD individuals and unaffected siblings, with 1 de novo insertion per 29, 117, and 206 births for Alu, L1, and SVA respectively, and 1 de novo insertion per 21 births total. However, ASD cases showed more de novo L1 insertions than expected in ASD genes. Additionally, we observed exonic insertions in loss-of-function intolerant genes, including a likely pathogenic exonic insertion in CSDE1, only in ASD individuals.

Conclusions: These findings suggest a modest, but important, impact of intronic and exonic retrotransposon insertions in ASD, show the importance of WGS for their analysis, and highlight the utility of specific bioinformatic tools for high-throughput detection of retrotransposon insertions.

背景:逆转录转座子已被认为是孟德尔病的病因,但它们在自闭症谱系障碍(ASD)中的作用尚未被系统地定义,因为它们仅从全基因组测序(WGS)数据中获得足够的灵敏度,而且用于该分析的足够大的队列直到最近才可用。结果:通过建立可扩展的反转录转座子插入检测计算管道,我们分析了来自Simons Simplex Collection的2288个ASD家族的WGS数据。我们报告了86,154个多态性反转录转座子插入-包括> 60%以前未报道的-和158个新反转录转座子事件。新生事件的总体负担在ASD个体和未受影响的兄弟姐妹之间相似,Alu、L1和SVA分别每29例、117例和206例新生儿中有1例新生,每21例新生儿中有1例新生。然而,ASD病例在ASD基因中显示出比预期更多的L1新插入。此外,我们观察到功能丧失不耐受基因中的外显子插入,包括CSDE1中可能的致病性外显子插入,仅在ASD个体中存在。结论:这些发现表明,反转录转座子插入在ASD中具有适度但重要的影响,显示了WGS在分析反转录转座子插入中的重要性,并强调了高通量检测反转录转座子插入的特定生物信息学工具的实用性。
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引用次数: 14
Population analysis of retrotransposons in giraffe genomes supports RTE decline and widespread LINE1 activity in Giraffidae. 对长颈鹿基因组中逆转录转座子的种群分析表明,长颈鹿科动物中 RTE 的衰退和 LINE1 的广泛活动。
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2021-11-26 DOI: 10.1186/s13100-021-00254-y
Malte Petersen, Sven Winter, Raphael Coimbra, Menno J de Jong, Vladimir V Kapitonov, Maria A Nilsson

Background: The majority of structural variation in genomes is caused by insertions of transposable elements (TEs). In mammalian genomes, the main TE fraction is made up of autonomous and non-autonomous non-LTR retrotransposons commonly known as LINEs and SINEs (Long and Short Interspersed Nuclear Elements). Here we present one of the first population-level analysis of TE insertions in a non-model organism, the giraffe. Giraffes are ruminant artiodactyls, one of the few mammalian groups with genomes that are colonized by putatively active LINEs of two different clades of non-LTR retrotransposons, namely the LINE1 and RTE/BovB LINEs as well as their associated SINEs. We analyzed TE insertions of both types, and their associated SINEs in three giraffe genome assemblies, as well as across a population level sampling of 48 individuals covering all extant giraffe species.

Results: The comparative genome screen identified 139,525 recent LINE1 and RTE insertions in the sampled giraffe population. The analysis revealed a drastically reduced RTE activity in giraffes, whereas LINE1 is still actively propagating in the genomes of extant (sub)-species. In concert with the extremely low activity of the giraffe RTE, we also found that RTE-dependent SINEs, namely Bov-tA and Bov-A2, have been virtually immobile in the last 2 million years. Despite the high current activity of the giraffe LINE1, we did not find evidence for the presence of currently active LINE1-dependent SINEs. TE insertion heterozygosity rates differ among the different (sub)-species, likely due to divergent population histories.

Conclusions: The horizontally transferred RTE/BovB and its derived SINEs appear to be close to inactivation and subsequent extinction in the genomes of extant giraffe species. This is the first time that the decline of a TE family has been meticulously analyzed from a population genetics perspective. Our study shows how detailed information about past and present TE activity can be obtained by analyzing large-scale population-level genomic data sets.

背景:基因组中的大部分结构变异都是由插入的转座元件(TE)引起的。在哺乳动物基因组中,主要的转座元件由自主和非自主的非 LTR 反转座子组成,通常称为 LINE 和 SINE(长短穿插核元件)。在这里,我们首次对非模式生物--长颈鹿--的TE插入进行了种群水平的分析。长颈鹿是反刍动物中的半齿兽,是少数几个基因组被两个不同支系的非 LTR 反转座子(即 LINE1 和 RTE/BovB LINEs 及其相关的 SINEs)的假定活跃 LINEs 定殖的哺乳动物群体之一。我们分析了这两种类型的TE插入及其在三个长颈鹿基因组集合中的相关SINEs,以及涵盖所有现存长颈鹿物种的48个个体的种群水平取样:比较基因组筛选在长颈鹿种群中发现了 139,525 个最新的 LINE1 和 RTE 插入。分析结果表明,长颈鹿的 RTE 活性大大降低,而 LINE1 仍在现存(亚)物种的基因组中积极传播。由于长颈鹿 RTE 的活性极低,我们还发现依赖于 RTE 的 SINE(即 Bov-tA 和 Bov-A2)在过去的 200 万年中几乎没有移动。尽管长颈鹿 LINE1 的当前活性很高,但我们没有发现证据表明存在当前活跃的 LINE1 依赖性 SINEs。不同(亚)物种之间的TE插入杂合率不同,这可能是由于不同的种群历史造成的:结论:在现存长颈鹿物种的基因组中,横向转移的RTE/BovB及其衍生的SINEs似乎接近失活和消亡。这是首次从种群遗传学的角度对一个TE家族的衰落进行细致的分析。我们的研究表明,通过分析大规模种群级基因组数据集,可以获得有关过去和现在 TE 活动的详细信息。
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引用次数: 0
A comparative analysis of L1 retrotransposition activities in human genomes suggests an ongoing increase in L1 number despite an evolutionary trend towards lower activity. 人类基因组中L1逆转录活性的比较分析表明,尽管进化趋势趋向于低活性,但L1数量仍在持续增加。
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2021-11-15 DOI: 10.1186/s13100-021-00255-x
Sawsan Sami Wehbi, Heinrich Zu Dohna

Background: LINE-1 (Long Interspersed Nuclear Elements, L1) retrotransposons are the only autonomously active transposable elements in the human genome. The evolution of L1 retrotransposition rates and its implications for L1 dynamics are poorly understood. Retrotransposition rates are commonly measured in cell culture-based assays, but it is unclear how well these measurements provide insight into L1 population dynamics. This study applied comparative methods to estimate parameters for the evolution of retrotransposition rates, and infer L1 dynamics from these estimates.

Results: Our results show that the rates at which new L1s emerge in the human population correlate positively to cell-culture based retrotransposition activities, that there is an evolutionary trend towards lower retrotransposition activity, and that this evolutionary trend is not sufficient to counter-balance the increase in active L1s resulting from continuing retrotransposition.

Conclusions: Together, these findings support a model of the population-level L1 retrotransposition dynamics that is consistent with prior expectations and indicate the remaining gaps in the understanding of L1 dynamics in human genomes.

背景:LINE-1 (Long Interspersed Nuclear Elements, L1)逆转录转座子是人类基因组中唯一具有自主活性的转座子。L1逆转位率的演变及其对L1动力学的影响尚不清楚。逆转录转位率通常在基于细胞培养的检测中测量,但目前尚不清楚这些测量如何很好地提供对L1群体动态的洞察。本研究采用比较方法估计反转位率演变的参数,并从这些估计推断L1动态。结果:我们的研究结果表明,人类群体中新L1s的出现率与基于细胞培养的反转录转位活性呈正相关,存在一种降低反转录转位活性的进化趋势,并且这种进化趋势不足以抵消持续反转录转位导致的活跃L1s的增加。综上所述,这些发现支持了种群水平L1逆转录动力学模型,该模型与先前的预期一致,并指出了对人类基因组L1动力学理解的剩余空白。
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引用次数: 0
Chromosomal integration of Tn5253 occurs downstream of a conserved 11-bp sequence of the rbgA gene in Streptococcus pneumoniae and in all the other known hosts of this integrative conjugative element (ICE). 在肺炎链球菌和所有其他已知宿主中,Tn5253的染色体整合发生在rbgA基因保守的11bp序列的下游。
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2021-11-05 DOI: 10.1186/s13100-021-00253-z
Francesco Santoro, Valeria Fox, Alessandra Romeo, Elisa Lazzeri, Gianni Pozzi, Francesco Iannelli

Background: Tn5253, a composite Integrative Conjugative Element (ICE) of Streptococcus pneumoniae carrying tet(M) and cat resistance determinants, was found to (i) integrate at specific 83-bp integration site (attB), (ii) produce circular forms joined by a 84-bp sequence (attTn), and (iii) restore the chromosomal integration site. The purpose of this study is to functionally characterize the attB in S. pneumoniae strains with different genetic backgrounds and in other bacterial species, and to investigate the presence of Tn5253 attB site into bacterial genomes.

Results: Analysis of representative Tn5253-carryng transconjugants obtained in S. pneumoniae strains with different genetic backgrounds and in other bacterial species, namely Streptococcus agalactiae, Streptococcus gordonii, Streptococcus pyogenes, and Enterococcus faecalis showed that: (i) Tn5253 integrates in rbgA of S. pneumoniae and in orthologous rbgA genes of other bacterial species, (ii) integration occurs always downstream of a 11-bp sequence conserved among streptococcal and enterococcal hosts, (iii) length of the attB site corresponds to length of the duplication after Tn5253 integration, (iv) attB duplication restores rbgA CDS, (v) Tn5253 produced circular forms containing the attTn site at a concentration ranging between 2.0 × 10-5 to 1.2 × 10-2 copies per chromosome depending on bacterial species and strain, (vi) reconstitution of attB sites occurred at 3.7 × 10-5 to 1.7 × 10-2 copies per chromosome. A database search of complete microbial genomes using Tn5253 attB as a probe showed that (i) thirteen attB variants were present in the 85 complete pneumococcal genomes, (ii) in 75 pneumococcal genomes (88.3 %), the attB site was 83 or 84 nucleotides in length, while in 10 (11.7 %) it was 41 nucleotides, (iii) in other 19 bacterial species attB was located in orthologous rbgA genes and its size ranged between 17 and 84 nucleotides, (iv) the 11-bp sequence, which correspond to the last 11 nucleotides of attB sites, is conserved among the different bacterial species and can be considered the core of the Tn5253 integration site.

Conclusions: A functional characterization of the Tn5253 attB integration site combined with genome analysis contributed to elucidating the potential of Tn5253 horizontal gene transfer among different bacterial species.

背景:Tn5253是一种携带tet(M)和猫耐药性决定因子的肺炎链球菌整合共轭元件(ICE),被发现可以(i)在特定的83-bp整合位点(attB)整合,(ii)产生由84-bp序列连接的圆形(attn),以及(iii)恢复染色体整合位点。本研究的目的是对不同遗传背景的肺炎链球菌和其他细菌中attB的功能特征进行表征,并研究Tn5253 attB位点在细菌基因组中的存在。结果:对不同遗传背景的肺炎链球菌及其他细菌种无乳链球菌、哥donii链球菌、化脓性链球菌、粪肠球菌中具有代表性的携带tn5253的转偶联物进行分析,结果表明:(i) Tn5253整合到肺炎链球菌的rbgA和其他细菌物种的同源rbgA基因中,(ii)整合总是发生在链球菌和肠球菌宿主之间保守的11-bp序列的下游,(iii) attB位点的长度与Tn5253整合后的复制长度相对应,(iv) attB复制恢复rbgA CDS。(v)根据细菌种类和菌株的不同,Tn5253产生含有attn位点的环状结构,其浓度在每条染色体2.0 × 10-5至1.2 × 10-2个拷贝之间;(vi) attB位点的重构发生在每条染色体3.7 × 10-5至1.7 × 10-2个拷贝之间。以Tn5253为探针对完整微生物基因组进行数据库检索,结果显示:(1)85个完整肺炎球菌基因组中存在13个attB变体,(2)75个肺炎球菌基因组(88.3%)中,attB位点长度为83或84个核苷酸,10个(11.7%)为41个核苷酸,(3)在其他19种细菌中,attB位于同源rbgA基因中,大小在17至84个核苷酸之间,(4)11-bp序列。它对应于attB位点的最后11个核苷酸,在不同的细菌物种中是保守的,可以被认为是Tn5253整合位点的核心。结论:对Tn5253 attB整合位点的功能表征结合基因组分析有助于阐明Tn5253在不同细菌物种间水平基因转移的潜力。
{"title":"Chromosomal integration of Tn5253 occurs downstream of a conserved 11-bp sequence of the rbgA gene in Streptococcus pneumoniae and in all the other known hosts of this integrative conjugative element (ICE).","authors":"Francesco Santoro,&nbsp;Valeria Fox,&nbsp;Alessandra Romeo,&nbsp;Elisa Lazzeri,&nbsp;Gianni Pozzi,&nbsp;Francesco Iannelli","doi":"10.1186/s13100-021-00253-z","DOIUrl":"https://doi.org/10.1186/s13100-021-00253-z","url":null,"abstract":"<p><strong>Background: </strong>Tn5253, a composite Integrative Conjugative Element (ICE) of Streptococcus pneumoniae carrying tet(M) and cat resistance determinants, was found to (i) integrate at specific 83-bp integration site (attB), (ii) produce circular forms joined by a 84-bp sequence (attTn), and (iii) restore the chromosomal integration site. The purpose of this study is to functionally characterize the attB in S. pneumoniae strains with different genetic backgrounds and in other bacterial species, and to investigate the presence of Tn5253 attB site into bacterial genomes.</p><p><strong>Results: </strong>Analysis of representative Tn5253-carryng transconjugants obtained in S. pneumoniae strains with different genetic backgrounds and in other bacterial species, namely Streptococcus agalactiae, Streptococcus gordonii, Streptococcus pyogenes, and Enterococcus faecalis showed that: (i) Tn5253 integrates in rbgA of S. pneumoniae and in orthologous rbgA genes of other bacterial species, (ii) integration occurs always downstream of a 11-bp sequence conserved among streptococcal and enterococcal hosts, (iii) length of the attB site corresponds to length of the duplication after Tn5253 integration, (iv) attB duplication restores rbgA CDS, (v) Tn5253 produced circular forms containing the attTn site at a concentration ranging between 2.0 × 10<sup>-5</sup> to 1.2 × 10<sup>-2</sup> copies per chromosome depending on bacterial species and strain, (vi) reconstitution of attB sites occurred at 3.7 × 10<sup>-5</sup> to 1.7 × 10<sup>-2</sup> copies per chromosome. A database search of complete microbial genomes using Tn5253 attB as a probe showed that (i) thirteen attB variants were present in the 85 complete pneumococcal genomes, (ii) in 75 pneumococcal genomes (88.3 %), the attB site was 83 or 84 nucleotides in length, while in 10 (11.7 %) it was 41 nucleotides, (iii) in other 19 bacterial species attB was located in orthologous rbgA genes and its size ranged between 17 and 84 nucleotides, (iv) the 11-bp sequence, which correspond to the last 11 nucleotides of attB sites, is conserved among the different bacterial species and can be considered the core of the Tn5253 integration site.</p><p><strong>Conclusions: </strong>A functional characterization of the Tn5253 attB integration site combined with genome analysis contributed to elucidating the potential of Tn5253 horizontal gene transfer among different bacterial species.</p>","PeriodicalId":18854,"journal":{"name":"Mobile DNA","volume":null,"pages":null},"PeriodicalIF":4.9,"publicationDate":"2021-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8571831/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39593762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"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
Comparative genomic and transcriptomic analyses of transposable elements in polychaetous annelids highlight LTR retrotransposon diversity and evolution. 多毛环节动物转座因子的比较基因组学和转录组学分析突出了LTR反转录转座因子的多样性和进化。
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2021-10-29 DOI: 10.1186/s13100-021-00252-0
Jonathan Filée, Sarah Farhat, Dominique Higuet, Laure Teysset, Dominique Marie, Camille Thomas-Bulle, Stephane Hourdez, Didier Jollivet, Eric Bonnivard

Background: With the expansion of high throughput sequencing, we now have access to a larger number of genome-wide studies analyzing the Transposable elements (TEs) composition in a wide variety of organisms. However, genomic analyses often remain too limited in number and diversity of species investigated to study in depth the dynamics and evolutionary success of the different types of TEs among metazoans. Therefore, we chose to investigate the use of transcriptomes to describe the diversity of TEs in phylogenetically related species by conducting the first comparative analysis of TEs in two groups of polychaetes and evaluate the diversity of TEs that might impact genomic evolution as a result of their mobility.

Results: We present a detailed analysis of TEs distribution in transcriptomes extracted from 15 polychaetes depending on the number of reads used during assembly, and also compare these results with additional TE scans on associated low-coverage genomes. We then characterized the clades defined by 1021 LTR-retrotransposon families identified in 26 species. Clade richness was highly dependent on the considered superfamily. Copia elements appear rare and are equally distributed in only three clades, GalEa, Hydra and CoMol. Among the eight BEL/Pao clades identified in annelids, two small clades within the Sailor lineage are new for science. We characterized 17 Gypsy clades of which only 4 are new; the C-clade largely dominates with a quarter of the families. Finally, all species also expressed for the majority two distinct transcripts encoding PIWI proteins, known to be involved in control of TEs mobilities.

Conclusions: This study shows that the use of transcriptomes assembled from 40 million reads was sufficient to access to the diversity and proportion of the transposable elements compared to those obtained by low coverage sequencing. Among LTR-retrotransposons Gypsy elements were unequivocally dominant but results suggest that the number of Gypsy clades, although high, may be more limited than previously thought in metazoans. For BEL/Pao elements, the organization of clades within the Sailor lineage appears more difficult to establish clearly. The Copia elements remain rare and result from the evolutionary consistent success of the same three clades.

背景:随着高通量测序的扩展,我们现在可以获得更多的全基因组研究,分析各种生物中的转座因子(te)组成。然而,基因组分析在研究物种的数量和多样性方面往往过于有限,无法深入研究后生动物中不同类型te的动态和进化成功。因此,我们选择利用转录组来描述系统发育相关物种的TEs多样性,通过对两组多毛动物的TEs进行首次比较分析,并评估te的多样性,这些多样性可能由于它们的移动性而影响基因组进化。结果:我们详细分析了从15种多毛动物中提取的转录组中根据组装过程中使用的读取数的TE分布,并将这些结果与相关低覆盖率基因组的额外TE扫描进行了比较。然后,我们对26个物种的1021个ltr -反转录转座子家族进行了分类。进化支丰富度高度依赖于所考虑的超科。在GalEa、Hydra和CoMol三个分支中,Copia元素的分布较为均匀。在环节动物中发现的八个BEL/Pao分支中,水手谱系中的两个小分支是科学上的新分支。我们鉴定了17个吉普赛分支,其中只有4个是新的;c支系占主导地位,占四分之一的家庭。最后,所有物种在大多数情况下也表达了两种不同的编码PIWI蛋白的转录本,已知这两种转录本参与了te迁移的控制。结论:本研究表明,与低覆盖率测序相比,使用从4000万reads组装的转录组足以获得转座因子的多样性和比例。在ltr -反转录转座子中,吉普赛元素明确占主导地位,但结果表明,吉普赛分支的数量虽然很高,但可能比以前认为的在后生动物中更为有限。对于BEL/Pao元素,水手血统中的分支组织似乎更难以确定。Copia元素仍然很少见,是同一三个进化支系在进化上一致成功的结果。
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引用次数: 0
Differential regulation of transposable elements (TEs) during the murine submandibular gland development. 鼠颌下腺发育过程中转座因子(TEs)的差异调控。
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2021-10-22 DOI: 10.1186/s13100-021-00251-1
Braulio Valdebenito-Maturana, Francisca Torres, Mónica Carrasco, Juan Carlos Tapia

The submandibular gland (SG) is a relatively simple organ formed by three cell types: acinar, myoepithelial, and an intricate network of duct-forming epithelial cells, that together fulfills several physiological functions from assisting food digestion to acting as an immune barrier against pathogens. Successful SG organogenesis is the product of highly controlled and orchestrated genetic and transcriptional programs. Mounting evidence links Transposable Elements (TEs), originally thought to be selfish genetic elements, to different aspects of gene regulation in mammalian development and disease. To our knowledge, the role of TEs during murine SG organogenesis has not been studied. Using novel bioinformatic tools and publicly available RNA-Seq datasets, our results indicate that a significant number of genic and intergenic TEs are differentially expressed during the SG development. Furthermore, changes in expression of specific TEs correlated with that of genes involved in cellular division and differentiation, critical aspects for SG maturation. Altogether, we propose that TEs modulate gene networks that operate during SG development.

下颌骨腺(SG)是一个相对简单的器官,由三种细胞类型组成:腺泡细胞、肌上皮细胞和一个复杂的导管形成上皮细胞网络,它们共同完成从辅助食物消化到作为对抗病原体的免疫屏障的几种生理功能。成功的SG器官发生是高度控制和精心安排的遗传和转录程序的产物。转座因子(te)最初被认为是自私的遗传因子,但越来越多的证据表明,它与哺乳动物发育和疾病中基因调控的不同方面有关。据我们所知,TEs在小鼠SG器官发生中的作用尚未得到研究。利用新的生物信息学工具和公开的RNA-Seq数据集,我们的研究结果表明,在SG发育过程中,大量的基因和基因间te存在差异表达。此外,特异性te的表达变化与参与细胞分裂和分化的基因相关,而细胞分裂和分化是SG成熟的关键因素。总之,我们认为te调节在SG发育过程中运作的基因网络。
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引用次数: 7
Genomic approaches to trace the history of human brain evolution with an emerging opportunity for transposon profiling of ancient humans. 基因组方法追踪人类大脑进化的历史,为古代人类的转座子分析提供了新的机会。
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2021-10-18 DOI: 10.1186/s13100-021-00250-2
Yilan Wang, Boxun Zhao, Jaejoon Choi, Eunjung Alice Lee

Transposable elements (TEs) significantly contribute to shaping the diversity of the human genome, and lines of evidence suggest TEs as one of driving forces of human brain evolution. Existing computational approaches, including cross-species comparative genomics and population genetic modeling, can be adapted for the study of the role of TEs in evolution. In particular, diverse ancient and archaic human genome sequences are increasingly available, allowing reconstruction of past human migration events and holding the promise of identifying and tracking TEs among other evolutionarily important genetic variants at an unprecedented spatiotemporal resolution. However, highly degraded short DNA templates and other unique challenges presented by ancient human DNA call for major changes in current experimental and computational procedures to enable the identification of evolutionarily important TEs. Ancient human genomes are valuable resources for investigating TEs in the evolutionary context, and efforts to explore ancient human genomes will potentially provide a novel perspective on the genetic mechanism of human brain evolution and inspire a variety of technological and methodological advances. In this review, we summarize computational and experimental approaches that can be adapted to identify and validate evolutionarily important TEs, especially for human brain evolution. We also highlight strategies that leverage ancient genomic data and discuss unique challenges in ancient transposon genomics.

转座元件(TE)对塑造人类基因组的多样性有重要贡献,证据表明TE是人类大脑进化的驱动力之一。现有的计算方法,包括跨物种比较基因组学和群体遗传建模,可以用于研究TE在进化中的作用。特别是,多样化的古代和古代人类基因组序列越来越多,可以重建过去的人类迁徙事件,并有望以前所未有的时空分辨率识别和跟踪TE和其他进化上重要的遗传变异。然而,高度降解的短DNA模板和古代人类DNA带来的其他独特挑战要求对当前的实验和计算程序进行重大改变,以识别进化上重要的TE。古代人类基因组是在进化背景下研究TE的宝贵资源,探索古代人类基因组的努力将有可能为人类大脑进化的遗传机制提供一个新的视角,并激发各种技术和方法的进步。在这篇综述中,我们总结了计算和实验方法,这些方法可以用于识别和验证进化上重要的TE,特别是对于人脑进化。我们还强调了利用古代基因组数据的策略,并讨论了古代转座子基因组学中的独特挑战。
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引用次数: 2
Migrators within migrators: exploring transposable element dynamics in the monarch butterfly, Danaus plexippus 迁徙者中的迁徙者:探索帝王蝶的转座因子动力学
IF 4.9 2区 生物学 Q1 Biochemistry, Genetics and Molecular Biology Pub Date : 2021-09-28 DOI: 10.1101/2021.09.28.462135
Tobias Baril, Alex Hayward
Lepidoptera (butterflies and moths) are an important model system in ecology and evolution. A high-quality chromosomal genome assembly is available for the monarch butterfly (Danaus plexippus), but it lacks an in-depth transposable element (TE) annotation, presenting an opportunity to explore monarch TE dynamics and the impact of TEs on shaping the monarch genome. We find 6.21% of the monarch genome is comprised of TEs, a reduction of 6.85% compared to the original TE annotation performed on the draft genome assembly. Monarch TE content is low compared to two closely related species with available genomes, Danaus chrysippus (33.97% TE) and Danaus melanippus (11.87% TE). The biggest TE contributions to genome size in the monarch are LINEs and Penelope-like elements, and three newly identified families, r2-hero_dPle (LINE), penelope-1_dPle (Penelope-like), and hase2-1_dPle (SINE), collectively contribute 34.92% of total TE content. We find evidence of recent TE activity, with two novel Tc1 families rapidly expanding over recent timescales (tc1-1_dPle, tc1-2_dPle). LINE fragments show signatures of genomic deletions indicating a high rate of TE turnover. We investigate associations between TEs and wing colouration and immune genes and identify a three-fold increase in TE content around immune genes compared to other host genes. We provide a detailed TE annotation and analysis for the monarch genome, revealing a considerably smaller TE contribution to genome content compared to two closely related Danaus species with available genome assemblies. We identify highly successful novel DNA TE families rapidly expanding over recent timescales, and ongoing signatures of both TE expansion and removal highlight the dynamic nature of repeat content in the monarch genome. Our findings also suggest that insect immune genes are promising candidates for future interrogation of TE-mediated host adaptation.
鳞翅目(蝴蝶和飞蛾)是生态学和进化中重要的模式系统。高质量的黑脉金斑蝶(Danaus plexippus)染色体基因组组装是可用的,但它缺乏深入的转座元件(TE)注释,这为探索黑脉金斑蝶TE动力学和TE对形成黑脉金斑蝶基因组的影响提供了机会。我们发现6.21%的黑脉金斑蝶基因组由TE组成,与在基因组组装草图上进行的原始TE注释相比,减少了6.85%。黑脉金斑蝶(Danaus chrysippus)和黑脉金斑蝶(Danaus melanippus)的TE含量分别为33.97%和11.87%。TE对黑脉王基因组大小贡献最大的是LINEs和Penelope-like元件,其中新发现的r2-hero_dPle (LINE)、penelope-1_dPle (Penelope-like)和hase2-1_dPle (SINE)三个家族共贡献了34.92%的TE总含量。我们发现了最近TE活动的证据,两个新的Tc1家族在最近的时间尺度上迅速扩张(Tc1 - 1_dple, Tc1 - 2_dple)。LINE片段显示基因组缺失的特征,表明TE的高周转率。我们研究了TE与翅膀颜色和免疫基因之间的关系,并发现与其他宿主基因相比,免疫基因周围TE含量增加了三倍。我们对黑脉金斑蝶基因组进行了详细的TE注释和分析,发现与两种具有可用基因组片段的密切相关的Danaus物种相比,黑脉金斑蝶对基因组内容的贡献要小得多。我们发现了在最近的时间尺度上迅速扩展的非常成功的新DNA TE家族,并且TE扩展和去除的持续特征突出了帝王蝶基因组中重复内容的动态性质。我们的研究结果还表明,昆虫免疫基因是未来te介导的宿主适应研究的有希望的候选者。
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引用次数: 15
Unbiased proteomic mapping of the LINE-1 promoter using CRISPR Cas9. 利用 CRISPR Cas9 绘制 LINE-1 启动子的无偏蛋白质组图谱。
IF 4.7 2区 生物学 Q1 GENETICS & HEREDITY Pub Date : 2021-08-23 DOI: 10.1186/s13100-021-00249-9
Erica M Briggs, Paolo Mita, Xiaoji Sun, Susan Ha, Nikita Vasilyev, Zev R Leopold, Evgeny Nudler, Jef D Boeke, Susan K Logan

Background: The autonomous retroelement Long Interspersed Element-1 (LINE-1) mobilizes though a copy and paste mechanism using an RNA intermediate (retrotransposition). Throughout human evolution, around 500,000 LINE-1 sequences have accumulated in the genome. Most of these sequences belong to ancestral LINE-1 subfamilies, including L1PA2-L1PA7, and can no longer mobilize. Only a small fraction of LINE-1 sequences, approximately 80 to 100 copies belonging to the L1Hs subfamily, are complete and still capable of retrotransposition. While silenced in most cells, many questions remain regarding LINE-1 dysregulation in cancer cells.

Results: Here, we optimized CRISPR Cas9 gRNAs to specifically target the regulatory sequence of the L1Hs 5'UTR promoter. We identified three gRNAs that were more specific to L1Hs, with limited binding to older LINE-1 sequences (L1PA2-L1PA7). We also adapted the C-BERST method (dCas9-APEX2 Biotinylation at genomic Elements by Restricted Spatial Tagging) to identify LINE-1 transcriptional regulators in cancer cells. Our LINE-1 C-BERST screen revealed both known and novel LINE-1 transcriptional regulators, including CTCF, YY1 and DUSP1.

Conclusion: Our optimization and evaluation of gRNA specificity and application of the C-BERST method creates a tool for studying the regulatory mechanisms of LINE-1 in cancer. Further, we identified the dual specificity protein phosphatase, DUSP1, as a novel regulator of LINE-1 transcription.

背景:自主性逆转录因子长穿插元件-1(LINE-1)通过复制和粘贴机制,利用 RNA 中间体(逆转录)进行调动。在整个人类进化过程中,基因组中积累了约 500,000 个 LINE-1 序列。这些序列中的大部分属于祖先的 LINE-1 亚家族,包括 L1PA2-L1PA7,已经无法再移动。只有一小部分属于L1Hs亚家族的LINE-1序列(约80至100个拷贝)是完整的,仍能进行逆转录。虽然LINE-1在大多数细胞中处于沉默状态,但关于癌细胞中LINE-1的失调仍存在许多问题:在这里,我们对CRISPR Cas9 gRNA进行了优化,以特异性靶向L1Hs 5'UTR启动子的调控序列。我们发现了三种对L1Hs更具特异性的gRNA,它们与较早的LINE-1序列(L1PA2-L1PA7)的结合有限。我们还采用了C-BERST方法(dCas9-APEX2 Biotinylation at genomic Elements by Restricted Spatial Tagging)来鉴定癌细胞中的LINE-1转录调节因子。我们的LINE-1 C-BERST筛选发现了已知的和新的LINE-1转录调控因子,包括CTCF、YY1和DUSP1:结论:我们对 gRNA 特异性的优化和评估以及 C-BERST 方法的应用为研究 LINE-1 在癌症中的调控机制提供了一种工具。此外,我们还发现双重特异性蛋白磷酸酶 DUSP1 是 LINE-1 转录的新型调控因子。
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引用次数: 0
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Mobile DNA
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