Genome research最新文献

Chromosome-level subgenome-aware de novo assembly of Saccharomyces bayanus provides insight into genome divergence after hybridization 染色体级亚基因组感知的贝氏酵母从头组装有助于深入了解杂交后的基因组分化情况

IF 7 2区生物学

Genome research Pub Date : 2024-09-17 DOI: 10.1101/gr.279364.124

Cory Gardner, Junhao Chen, Christina Hadfield, Zhaolian Lu, David Debruin, Yu Zhan, Maureen Donlin, Tae-Hyuk Ahn, Zhenguo Lin

{"title":"Chromosome-level subgenome-aware de novo assembly of Saccharomyces bayanus provides insight into genome divergence after hybridization","authors":"Cory Gardner, Junhao Chen, Christina Hadfield, Zhaolian Lu, David Debruin, Yu Zhan, Maureen Donlin, Tae-Hyuk Ahn, Zhenguo Lin","doi":"10.1101/gr.279364.124","DOIUrl":"https://doi.org/10.1101/gr.279364.124","url":null,"abstract":"Interspecies hybridization is prevalent in various eukaryotic lineages and plays important roles in phenotypic diversification, adaptation, and speciation. To better understand the changes that occurred in the different subgenomes of a hybrid species and how they facilitate adaptation, we completed chromosome-level de novo assemblies of all chromosomes for a recently formed hybrid yeast, Saccharomyces bayanus strain CBS380, using Nanopore MinION long-read sequencing. We characterized the S. bayanus genome and compared it with its parent species, S. uvarum and S. eubayanus, and other S. bayanus genomes to better understand genome evolution after a relatively recent hybridization event. We observed multiple recombination events between the subgenomes in each chromosome, followed by loss of heterozygosity (LOH) in nine chromosome pairs. In addition to maintaining nearly all gene content and synteny from its parental genomes, S. bayanus has acquired many genes from other yeast species, primarily through the introgression of S. cerevisiae, such as those involved in the maltose metabolism. Finally, the patterns of recombination and LOH suggest an allotetraploid origin of S. bayanus. The gene acquisition and rapid LOH in the hybrid genome probably facilitated its adaptation to maltose brewing environments and mitigated the maladaptive effect of hybridization. This manuscript describes the first in-depth study using long-read sequencing technology of an S. bayanus hybrid genome which may serve as an excellent reference for future studies of this important yeast and other yeast strains.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Full-length RNA transcript sequencing traces brain isoform diversity in house mouse natural populations 全长 RNA 转录本测序追踪家鼠自然种群大脑同工酶的多样性

IF 7 2区生物学

Genome research Pub Date : 2024-09-17 DOI: 10.1101/gr.279166.124

Wenyu Zhang, Anja Guenther, Yuanxiao Gao, Kristian Ullrich, Bruno Huettel, Aftab Ahmad, Lei Duan, Kaizong Wei, Diethard Tautz

{"title":"Full-length RNA transcript sequencing traces brain isoform diversity in house mouse natural populations","authors":"Wenyu Zhang, Anja Guenther, Yuanxiao Gao, Kristian Ullrich, Bruno Huettel, Aftab Ahmad, Lei Duan, Kaizong Wei, Diethard Tautz","doi":"10.1101/gr.279166.124","DOIUrl":"https://doi.org/10.1101/gr.279166.124","url":null,"abstract":"The ability to generate multiple RNA transcript isoforms from the same gene is a general phenomenon in eukaryotes. However, the complexity and diversity of alternative isoforms in natural populations remain largely unexplored. Using a newly developed full-length transcripts enrichment protocol with 5' CAP selection, we sequenced full-length RNA transcripts of 48 individuals from outbred populations and subspecies of Mus musculus, and from the closely related sister species Mus spretus and Mus spicilegus as outgroups. The dataset represents the most extensive full-length high-quality isoform catalog at the population level to date. In total, we reliably identified 117,728 distinct isoforms, of which only 51% were previously annotated. We show that the population-specific distribution pattern of isoforms is phylogenetically informative and reflects the segregating SNP diversity between the populations. We find that ancient housekeeping genes are a major source of the overall isoform diversity, and that the generation of alternative first exons plays a major role in generating new isoforms. Given that our data allow us to distinguish between population-specific isoforms and isoforms that are conserved across multiple populations, it is possible to refine the annotation of the reference mouse genome to a set of about 40,000 isoforms that should be most relevant for comparative functional analysis across species.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142236238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-read RNA sequencing of archival tissues reveals novel genes and transcripts associated with clear cell renal cell carcinoma recurrence and immune evasion 档案组织的长读 RNA 测序揭示了与透明细胞肾细胞癌复发和免疫逃避相关的新基因和转录本

IF 7 2区生物学

Genome research Pub Date : 2024-09-16 DOI: 10.1101/gr.278801.123

Joshua Lee, Elizabeth A Snell, Joanne Brown, Charlotte Elizabeth Booth, Rosamonde E Banks, Daniel J Turner, Naveen Vasudev, Dimitris Lagos

{"title":"Long-read RNA sequencing of archival tissues reveals novel genes and transcripts associated with clear cell renal cell carcinoma recurrence and immune evasion","authors":"Joshua Lee, Elizabeth A Snell, Joanne Brown, Charlotte Elizabeth Booth, Rosamonde E Banks, Daniel J Turner, Naveen Vasudev, Dimitris Lagos","doi":"10.1101/gr.278801.123","DOIUrl":"https://doi.org/10.1101/gr.278801.123","url":null,"abstract":"The use of long-read direct RNA sequencing (DRS) and PCR cDNA sequencing (PCS) in clinical oncology remains limited, with no direct comparison between the two methods. We used DRS and PCS to study clear cell renal cell carcinoma (ccRCC), focussing on new transcript and gene discovery. Twelve primary ccRCC archival tumors, six from patients who went on to relapse, were analysed. Results were validated in an independent cohort of twenty patients by qRT-PCR and compared to DRS analysis of RCC4 cells. In archival clinical samples and due to long-term storage, average read length was lower (400-500nt) than that achieved through DRS of RCC4 cells (>1100nt). Still, deconvolution analysis showed a loss of immune infiltrate in primary tumors of patients who relapse as reported by others. Differentially expressed genes in patients who went on to relapse were determined with good overlap between DRS and PCS, identifying LINC04216 and the T cell exhaustion marker TOX as novel candidate recurrence-associated genes. Novel transcript analysis revealed over 10,000 candidate novel transcripts detected by both methods and in ccRCC cells in vitro, including a novel CD274 (PD-L1) transcript encoding for the soluble version of the protein with a longer 3' UTR and lower stability than the annotated transcript. Both methods identified 414 novel genes, also detected in RCC4 cells, including a novel noncoding gene over-expressed in patients who relapse. Overall, we showcase use of PCS and DRS in archival tumor samples to uncover unmapped features of cancer transcriptomes, linked to disease progression and immune evasion.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Measuring X inactivation skew for X-linked diseases with adaptive nanopore sequencing 利用自适应纳米孔测序技术测量 X 连锁疾病的 X 失活倾斜度

IF 7 2区生物学

Genome research Pub Date : 2024-09-16 DOI: 10.1101/gr.279396.124

Sena A Gocuk, James Lancaster, Shian Su, Jasleen K Jolly, Thomas L Edwards, Doron G Hickey, Matthew E Ritchie, Marnie E Blewitt, Lauren N Ayton, Quentin Gouil

{"title":"Measuring X inactivation skew for X-linked diseases with adaptive nanopore sequencing","authors":"Sena A Gocuk, James Lancaster, Shian Su, Jasleen K Jolly, Thomas L Edwards, Doron G Hickey, Matthew E Ritchie, Marnie E Blewitt, Lauren N Ayton, Quentin Gouil","doi":"10.1101/gr.279396.124","DOIUrl":"https://doi.org/10.1101/gr.279396.124","url":null,"abstract":"X-linked genetic disorders typically affect females less severely than males due to the presence of a second X Chromosome not carrying the deleterious variant. However, the phenotypic expression in females is highly variable, which may be explained by an allelic skew in X-Chromosome inactivation. Accurate measurement of X inactivation skew is crucial to understand and predict disease phenotype in carrier females, with prediction especially relevant for degenerative conditions. We propose a novel approach using nanopore sequencing to quantify skewed X inactivation accurately. By phasing sequence variants and methylation patterns, this single assay reveals the disease variant, X inactivation skew, its directionality, and is applicable to all patients and X-linked variants. Enrichment of X Chromosome reads through adaptive sampling enhances cost-efficiency. Our study includes a cohort of 16 X-linked variant carrier females affected by two X-linked inherited retinal diseases: choroideremia and RPGR-associated retinitis pigmentosa. As retinal DNA cannot be readily obtained, we instead determine the skew from peripheral samples (blood, saliva and buccal mucosa), and correlate it to phenotypic outcomes. This revealed a strong correlation between X inactivation skew and disease presentation, confirming the value in performing this assay and its potential as a way to prioritise patients for early intervention, such as gene therapy currently in clinical trials for these conditions. Our method of assessing skewed X inactivation is applicable to all long-read genomic datasets, providing insights into disease risk and severity and aiding in the development of individualised strategies for X-linked variant carrier females.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142235258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-read transcriptome sequencing of CLL and MDS patients uncovers molecular effects of SF3B1 mutations 对CLL和MDS患者进行长线程转录组测序，揭示SF3B1突变的分子效应

IF 7 2区生物学

Genome research Pub Date : 2024-09-13 DOI: 10.1101/gr.279327.124

Alicja Pacholewska, Matthias Lienhard, Mirko Brueggemann, Heike Haenel, Lorina Bilalli, Anja Koenigs, Felix Hess, Kerstin Becker, Karl Koehrer, Jesko Fabian Kaiser, Holger Gohlke, Norbert Gattermann, Michael Hallek, Carmen Diana Herling, Julian Koenig, Christina Grimm, Ralf Herwig, Kathi Zarnack, Michal R. Schweiger

{"title":"Long-read transcriptome sequencing of CLL and MDS patients uncovers molecular effects of SF3B1 mutations","authors":"Alicja Pacholewska, Matthias Lienhard, Mirko Brueggemann, Heike Haenel, Lorina Bilalli, Anja Koenigs, Felix Hess, Kerstin Becker, Karl Koehrer, Jesko Fabian Kaiser, Holger Gohlke, Norbert Gattermann, Michael Hallek, Carmen Diana Herling, Julian Koenig, Christina Grimm, Ralf Herwig, Kathi Zarnack, Michal R. Schweiger","doi":"10.1101/gr.279327.124","DOIUrl":"https://doi.org/10.1101/gr.279327.124","url":null,"abstract":"Mutations in splicing factor 3B subunit 1 (SF3B1) frequently occur in patients with chronic lymphocytic leukemia (CLL) and myelodysplastic syndromes (MDS). These mutations have different effects on the disease prognosis with beneficial effect in MDS and worse prognosis in CLL patients. A full-length transcriptome approach can expand our knowledge on SF3B1 mutation effects on RNA splicing and its contribution to patient survival and treatment options. We applied long-read transcriptome sequencing (LRTS) to 44 MDS and CLL patients, as well as two pairs of isogenic cell lines with and without SF3B1 mutations, and found >60% of novel isoforms. Splicing alterations were largely shared between cancer types and specifically affected the usage of introns and 3’ splice sites. Our data highlighted a constrained window at canonical 3’ splice sites in which dynamic splice site switches occurred in SF3B1-mutated patients. Using transcriptome-wide RNA binding maps and molecular dynamics simulations, we showed multimodal SF3B1 binding at 3’ splice sites and predicted reduced RNA binding at the second binding pocket of SF3B1K700E. Our work presents the hitherto most complete LRTS study of the SF3B1 mutation in CLL and MDS and provides a resource to study aberrant splicing in cancer. Moreover, we showed that different disease prognosis most likely results from the different cell types expanded during carcinogenesis rather than different mechanisms of action of the mutated SF3B1. These results have important implications for understanding the role of SF3B1 mutations in hematological malignancies and other related diseases.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231561","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhanced detection of RNA modifications and read mapping with high-accuracy nanopore RNA basecalling models 利用高精度纳米孔 RNA 基调用模型增强 RNA 修饰检测和读图能力

IF 7 2区生物学

Genome research Pub Date : 2024-09-13 DOI: 10.1101/gr.278849.123

Gregor Diensthuber, Leszek P Pryszcz, Laia Llovera, Morghan C Lucas, Anna Delgado-Tejedor, Sonia Cruciani, Jean-Yves Roignant, Oguzhan Begik, Eva Maria Novoa

{"title":"Enhanced detection of RNA modifications and read mapping with high-accuracy nanopore RNA basecalling models","authors":"Gregor Diensthuber, Leszek P Pryszcz, Laia Llovera, Morghan C Lucas, Anna Delgado-Tejedor, Sonia Cruciani, Jean-Yves Roignant, Oguzhan Begik, Eva Maria Novoa","doi":"10.1101/gr.278849.123","DOIUrl":"https://doi.org/10.1101/gr.278849.123","url":null,"abstract":"In recent years, nanopore direct RNA sequencing (DRS) became a valuable tool for studying the epitranscriptome, due to its ability to detect multiple modifications within the same full-length native RNA molecules. While RNA modifications can be identified in the form of systematic basecalling 'errors' in DRS datasets, N6-methyladenosine (m6A) modifications produce relatively low 'errors' compared to other RNA modifications, limiting the applicability of this approach to m6A sites that are modified at high stoichiometries. Here, we demonstrate that the use of alternative RNA basecalling models, trained with fully unmodified sequences, increases the 'error'signal of m6A, leading to enhanced detection and improved sensitivity even at low stoichiometries. Moreover, we find that high-accuracy alternative RNA basecalling models can show up to 97% median basecalling accuracy, outperforming currently available RNA basecalling models, which show 91% median basecalling accuracy. Notably, the use of high-accuracy basecalling models is accompanied by a significant increase in the number of mapped reads –especially in shorter RNA fractions– and increased basecalling error signatures at pseudouridine (Ψ) and N1-methylpseudouridine (m1Ψ) modified sites. Overall, our work demonstrates that alternative RNA basecalling models can be used to improve the detection of RNA modifications, read mappability, and basecalling accuracy in nanopore DRS datasets.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231560","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Long-read DNA and cDNA sequencing identify cancer-predisposing deep intronic variation in tumor-suppressor genes 长读DNA和cDNA测序确定肿瘤抑制基因中易致癌的深层内含子变异

IF 7 2区生物学

Genome research Pub Date : 2024-09-13 DOI: 10.1101/gr.279158.124

Suleyman Gulsuner, Amal AbuRayyan, Jessica B. Mandell, Ming K. Lee, Greta V. Bernier, Barbara M. Norquist, Sarah B. Pierce, Mary-Claire King, Tom Walsh

{"title":"Long-read DNA and cDNA sequencing identify cancer-predisposing deep intronic variation in tumor-suppressor genes","authors":"Suleyman Gulsuner, Amal AbuRayyan, Jessica B. Mandell, Ming K. Lee, Greta V. Bernier, Barbara M. Norquist, Sarah B. Pierce, Mary-Claire King, Tom Walsh","doi":"10.1101/gr.279158.124","DOIUrl":"https://doi.org/10.1101/gr.279158.124","url":null,"abstract":"The vast majority of deeply intronic genomic variants are benign, but some extremely rare or private deep intronic variants lead to exonification of intronic sequence with abnormal transcriptional consequences. Damaging variants of this class are likely underreported as causes of disease for several reasons: Most clinical DNA and RNA testing does not include full intronic sequences; many of these variants lie in complex repetitive regions that cannot be aligned from short-read whole-genome sequence; and, until recently, consequences of deep intronic variants were not accurately predicted by in silico tools. We evaluated the frequency and consequences of rare deep intronic variants for families severely affected with breast, ovarian, pancreatic, and/or metastatic prostate cancer, but with no causal variant identified by any previous genomic or cDNA-based approach. For 10 tumor-suppressor genes, we used multiplexed adaptive sampling long-read DNA sequencing and cDNA sequencing, based on patient-derived DNA and RNA, to systematically evaluate deep intronic variation. We identified all variants across the full genomic loci of targeted genes, applied the in silico tools SpliceAI and Pangolin to predict variants of functional consequence, and then carried out long-read cDNA sequencing to identify aberrant transcripts. For eight of the 120 (6%) previously unsolved families, rare deep intronic variants in BRCA1, PALB2, and ATM create intronic pseudoexons that are spliced into transcripts, leading to premature truncations. These results suggest that long-read DNA and cDNA sequencing can be integrated into variant discovery, with strategies for accurately characterizing pathogenic variants.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Comprehensive identification of genomic and environmental determinants of phenotypic plasticity in maize 全面鉴定玉米表型可塑性的基因组和环境决定因素

IF 7 2区生物学

Genome research Pub Date : 2024-09-13 DOI: 10.1101/gr.279027.124

Laura E. Tibbs-Cortes, Tingting Guo, Carson M. Andorf, Xianran Li, Jianming Yu

{"title":"Comprehensive identification of genomic and environmental determinants of phenotypic plasticity in maize","authors":"Laura E. Tibbs-Cortes, Tingting Guo, Carson M. Andorf, Xianran Li, Jianming Yu","doi":"10.1101/gr.279027.124","DOIUrl":"https://doi.org/10.1101/gr.279027.124","url":null,"abstract":"Maize phenotypes are plastic, determined by the complex interplay of genetics and environmental variables. Uncovering the genes responsible and understanding how their effects change across a large geographic region are challenging. In this study, we conducted systematic analysis to identify environmental indices that strongly influence 19 traits (including flowering time, plant architecture, and yield component traits) measured in the maize nested association mapping (NAM) population grown in 11 environments. Identified environmental indices based on day length, temperature, moisture, and combinations of these are biologically meaningful. Next, we leveraged a total of more than 20 million SNP and SV markers derived from recent de novo sequencing of the NAM founders for trait prediction and dissection. When combined with identified environmental indices, genomic prediction enables accurate performance predictions. Genome-wide association studies (GWASs) detected genetic loci associated with the plastic response to the identified environmental indices for all examined traits. By systematically uncovering the major environmental and genomic factors underlying phenotypic plasticity in a wide variety of traits and depositing our results as a track on the MaizeGDB genome browser, we provide a community resource as well as a comprehensive analytical framework to facilitate continuing complex trait dissection and prediction in maize and other crops. Our findings also provide a conceptual framework for the genetic architecture of phenotypic plasticity by accommodating two alternative models, regulatory gene model and allelic sensitivity model, as special cases of a continuum.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A novel approach for in vivo DNA footprinting using short double-stranded cell-free DNA from plasma 利用血浆中短双链无细胞 DNA 进行体内 DNA 追踪的新方法

IF 7 2区生物学

Genome research Pub Date : 2024-09-13 DOI: 10.1101/gr.279326.124

Jan Müller, Christina Hartwig, Mirko Sonntag, Lisa Bitzer, Christopher Adelmann, Yevhen Vainshtein, Karolina Glanz, Sebastian O. Decker, Thorsten Brenner, Georg F. Weber, Arndt von Haeseler, Kai Sohn

{"title":"A novel approach for in vivo DNA footprinting using short double-stranded cell-free DNA from plasma","authors":"Jan Müller, Christina Hartwig, Mirko Sonntag, Lisa Bitzer, Christopher Adelmann, Yevhen Vainshtein, Karolina Glanz, Sebastian O. Decker, Thorsten Brenner, Georg F. Weber, Arndt von Haeseler, Kai Sohn","doi":"10.1101/gr.279326.124","DOIUrl":"https://doi.org/10.1101/gr.279326.124","url":null,"abstract":"Here, we present a method for enrichment of double-stranded cfDNA with an average length of ∼40 bp from cfDNA for high-throughput DNA sequencing. This class of cfDNA is enriched at gene promoters and binding sites of transcription factors or structural DNA-binding proteins, so that a genome-wide DNA footprint is directly captured from liquid biopsies. In short double-stranded cfDNA from healthy individuals, we find significant enrichment of 203 transcription factor motifs. Additionally, short double-stranded cfDNA signals at specific genomic regions correlate negatively with DNA methylation, positively with H3K4me3 histone modifications and gene transcription. The diagnostic potential of short double-stranded cell-free DNA (cfDNA) in blood plasma has not yet been recognized. When comparing short double-stranded cfDNA from patient samples of pancreatic ductal adenocarcinoma with colorectal carcinoma or septic with postoperative controls, we identify 136 and 241 differentially enriched loci, respectively. Using these differentially enriched loci, the disease types can be clearly distinguished by principal component analysis, demonstrating the diagnostic potential of short double-stranded cfDNA signals as a new class of biomarkers for liquid biopsies.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142231563","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Evidence for compensatory evolution within pleiotropic regulatory elements 多效应调控元件补偿性进化的证据

IF 7 2区生物学

Genome research Pub Date : 2024-09-10 DOI: 10.1101/gr.279001.124

Zane Kliesmete, Peter Orchard, Victor Yan Kin Lee, Johanna Geuder, Simon M. Krauß, Mari Ohnuki, Jessica Jocher, Beate Vieth, Wolfgang Enard, Ines Hellmann

{"title":"Evidence for compensatory evolution within pleiotropic regulatory elements","authors":"Zane Kliesmete, Peter Orchard, Victor Yan Kin Lee, Johanna Geuder, Simon M. Krauß, Mari Ohnuki, Jessica Jocher, Beate Vieth, Wolfgang Enard, Ines Hellmann","doi":"10.1101/gr.279001.124","DOIUrl":"https://doi.org/10.1101/gr.279001.124","url":null,"abstract":"Pleiotropy, measured as expression breadth across tissues, is one of the best predictors for protein sequence and expression conservation. In this study, we investigated its effect on the evolution of cis-regulatory elements (CREs). To this end, we carefully reanalyzed the Epigenomics Roadmap data for nine fetal tissues, assigning a measure of pleiotropic degree to nearly half a million CREs. To assess the functional conservation of CREs, we generated ATAC-seq and RNA-seq data from humans and macaques. We found that more pleiotropic CREs exhibit greater conservation in accessibility, and the mRNA expression levels of the associated genes are more conserved. This trend of higher conservation for higher degrees of pleiotropy persists when analyzing the transcription factor binding repertoire. In contrast, simple DNA sequence conservation of orthologous sites between species tends to be even lower for pleiotropic CREs than for species-specific CREs. Combining various lines of evidence, we propose that the lack of sequence conservation in functionally conserved pleiotropic CREs is due to within-element compensatory evolution. In summary, our findings suggest that pleiotropy is also a good predictor for the functional conservation of CREs, even though this is not reflected in the sequence conservation of pleiotropic CREs.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":null,"pages":null},"PeriodicalIF":7.0,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142160429","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0