Genome research最新文献_第7页

Challenges in identifying mRNA transcript starts and ends from long-read sequencing data. 从长线程测序数据中识别 mRNA 转录本起点和终点的挑战。

IF 6.2 2区生物学

Genome research Pub Date : 2024-11-20 DOI: 10.1101/gr.279559.124

Ezequiel Calvo-Roitberg, Rachel F Daniels, Athma A Pai

{"title":"Challenges in identifying mRNA transcript starts and ends from long-read sequencing data.","authors":"Ezequiel Calvo-Roitberg, Rachel F Daniels, Athma A Pai","doi":"10.1101/gr.279559.124","DOIUrl":"10.1101/gr.279559.124","url":null,"abstract":"Long-read sequencing (LRS) technologies have the potential to revolutionize scientific discoveries in RNA biology through the comprehensive identification and quantification of full-length mRNA isoforms. Despite great promise, challenges remain in the widespread implementation of LRS technologies for RNA-based applications, including concerns about low coverage, high sequencing error, and robust computational pipelines. Although much focus has been placed on defining mRNA exon composition and structure with LRS data, less careful characterization has been done of the ability to assess the terminal ends of isoforms, specifically, transcription start and end sites. Such characterization is crucial for completely delineating full mRNA molecules and regulatory consequences. However, there are substantial inconsistencies in both start and end coordinates of LRS reads spanning a gene, such that LRS reads often fail to accurately recapitulate annotated or empirically derived terminal ends of mRNA molecules. Here, we describe the specific challenges of identifying and quantifying mRNA terminal ends with LRS technologies and how these issues influence biological interpretations of LRS data. We then review recent experimental and computational advances designed to alleviate these problems, with ideal use cases for each approach. Finally, we outline anticipated developments and necessary improvements for the characterization of terminal ends from LRS data.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"34 11","pages":"1719-1734"},"PeriodicalIF":6.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681504","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: 0

Understanding isoform expression by pairing long-read sequencing with single-cell and spatial transcriptomics. 通过将长线程测序与单细胞和空间转录组学配对，了解同工酶表达。

IF 6.2 2区生物学

Genome research Pub Date : 2024-11-20 DOI: 10.1101/gr.279640.124

Natan Belchikov, Justine Hsu, Xiang Jennie Li, Julien Jarroux, Wen Hu, Anoushka Joglekar, Hagen U Tilgner

{"title":"Understanding isoform expression by pairing long-read sequencing with single-cell and spatial transcriptomics.","authors":"Natan Belchikov, Justine Hsu, Xiang Jennie Li, Julien Jarroux, Wen Hu, Anoushka Joglekar, Hagen U Tilgner","doi":"10.1101/gr.279640.124","DOIUrl":"10.1101/gr.279640.124","url":null,"abstract":"RNA isoform diversity, produced via alternative splicing, and alternative usage of transcription start and poly(A) sites, results in varied transcripts being derived from the same gene. Distinct isoforms can play important biological roles, including by changing the sequences or expression levels of protein products. The first single-cell approaches to RNA sequencing-and later, spatial approaches-which are now widely used for the identification of differentially expressed genes, rely on short reads and offer the ability to transcriptomically compare different cell types but are limited in their ability to measure differential isoform expression. More recently, long-read sequencing methods have been combined with single-cell and spatial technologies in order to characterize isoform expression. In this review, we provide an overview of the emergence of single-cell and spatial long-read sequencing and discuss the challenges associated with the implementation of these technologies and interpretation of these data. We discuss the opportunities they offer for understanding the relationships between the distinct variable elements of transcript molecules and highlight some of the ways in which they have been used to characterize isoforms' roles in development and pathology. Single-nucleus long-read sequencing, a special case of the single-cell approach, is also discussed. We attempt to cover both the limitations of these technologies and their significant potential for expanding our still-limited understanding of the biological roles of RNA isoforms.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"34 11","pages":"1735-1746"},"PeriodicalIF":6.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610585/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681553","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: 0

DNA-m6A calling and integrated long-read epigenetic and genetic analysis with fibertools. 使用 fibertools 进行 DNA-m6A 调用和综合长读数表观遗传学和基因分析。

IF 6.2 2区生物学

Genome research Pub Date : 2024-11-20 DOI: 10.1101/gr.279095.124

Anupama Jha, Stephanie C Bohaczuk, Yizi Mao, Jane Ranchalis, Benjamin J Mallory, Alan T Min, Morgan O Hamm, Elliott Swanson, Danilo Dubocanin, Connor Finkbeiner, Tony Li, Dale Whittington, William Stafford Noble, Andrew B Stergachis, Mitchell R Vollger

{"title":"DNA-m6A calling and integrated long-read epigenetic and genetic analysis with fibertools.","authors":"Anupama Jha, Stephanie C Bohaczuk, Yizi Mao, Jane Ranchalis, Benjamin J Mallory, Alan T Min, Morgan O Hamm, Elliott Swanson, Danilo Dubocanin, Connor Finkbeiner, Tony Li, Dale Whittington, William Stafford Noble, Andrew B Stergachis, Mitchell R Vollger","doi":"10.1101/gr.279095.124","DOIUrl":"10.1101/gr.279095.124","url":null,"abstract":"Long-read DNA sequencing has recently emerged as a powerful tool for studying both genetic and epigenetic architectures at single-molecule and single-nucleotide resolution. Long-read epigenetic studies encompass both the direct identification of native cytosine methylation and the identification of exogenously placed DNA N 6 -methyladenine (DNA-m6A). However, detecting DNA-m6A modifications using single-molecule sequencing, as well as coprocessing single-molecule genetic and epigenetic architectures, is limited by computational demands and a lack of supporting tools. Here, we introduce fibertools, a state-of-the-art toolkit that features a semisupervised convolutional neural network for fast and accurate identification of m6A-marked bases using Pacific Biosciences (PacBio) single-molecule long-read sequencing, as well as the coprocessing of long-read genetic and epigenetic data produced using either the PacBio or Oxford Nanopore Technologies (ONT) sequencing platforms. We demonstrate accurate DNA-m6A identification (>90% precision and recall) along >20 kb long DNA molecules with an ∼1000-fold improvement in speed. In addition, we demonstrate that fibertools can readily integrate genetic and epigenetic data at single-molecule resolution, including the seamless conversion between molecular and reference coordinate systems, allowing for accurate genetic and epigenetic analyses of long-read data within structurally and somatically variable genomic regions.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"1976-1986"},"PeriodicalIF":6.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610455/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141288010","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: 0

Visualization and analysis of medically relevant tandem repeats in nanopore sequencing of control cohorts with pathSTR. 纳米孔测序中与医学相关的串联重复序列的可视化和分析，以及病理序列对照组。

IF 6.2 2区生物学

Genome research Pub Date : 2024-11-20 DOI: 10.1101/gr.279265.124

Wouter De Coster, Ida Höijer, Inge Bruggeman, Svenn D'Hert, Malin Melin, Adam Ameur, Rosa Rademakers

{"title":"Visualization and analysis of medically relevant tandem repeats in nanopore sequencing of control cohorts with pathSTR.","authors":"Wouter De Coster, Ida Höijer, Inge Bruggeman, Svenn D'Hert, Malin Melin, Adam Ameur, Rosa Rademakers","doi":"10.1101/gr.279265.124","DOIUrl":"10.1101/gr.279265.124","url":null,"abstract":"The lack of population-scale databases hampers research and diagnostics for medically relevant tandem repeats and repeat expansions. We attempt to fill this gap using our pathSTR web tool, which leverages long-read sequencing of large cohorts to determine repeat length and sequence composition in a healthy population. The current version includes 1040 individuals of The 1000 Genomes Project cohort sequenced on the Oxford Nanopore Technologies PromethION. A comprehensive set of medically relevant tandem repeats has been genotyped using STRdust and LongTR to determine the tandem repeat length and sequence composition. PathSTR provides rich visualizations of this data set and the feature to upload one's data for comparison along the control cohort. We demonstrate the implementation of this application using data from targeted nanopore sequencing of a patient with myotonic dystrophy type 1. This resource will empower the genetics community to get a more complete overview of normal variation in tandem repeat length and sequence composition and, as such, enable a better assessment of rare tandem repeat alleles observed in patients.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"2074-2080"},"PeriodicalIF":6.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610575/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987779","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: 0

Full-resolution HLA and KIR gene annotations for human genome assemblies. 人类基因组组装的全分辨率 HLA 和 KIR 基因注释。

IF 6.2 2区生物学

Genome research Pub Date : 2024-11-20 DOI: 10.1101/gr.278985.124

Ying Zhou, Li Song, Heng Li

{"title":"Full-resolution HLA and KIR gene annotations for human genome assemblies.","authors":"Ying Zhou, Li Song, Heng Li","doi":"10.1101/gr.278985.124","DOIUrl":"10.1101/gr.278985.124","url":null,"abstract":"The human leukocyte antigen (HLA) genes and the killer cell immunoglobulin-like receptor (KIR) genes are critical to immune responses and are associated with many immune-related diseases. Located in highly polymorphic regions, it is difficult to study them with traditional short-read alignment-based methods. Although modern long-read assemblers can often assemble these genes, using existing tools to annotate HLA and KIR genes in these assemblies remains a nontrivial task. Here, we describe Immuannot, a new computation tool to annotate the gene structures of HLA and KIR genes and to type the allele of each gene. Applying Immuannot to 56 regional and 212 whole-genome assemblies from previous studies, we annotate 9931 HLA and KIR genes and found that almost half of these genes, 4068, have novel sequences compared with the current Immuno Polymorphism Database (IPD). These novel gene sequences are represented by 2664 distinct alleles, some of which contained nonsynonymous variations, resulting in 92 novel protein sequences. We demonstrate the complex haplotype structures at the two loci and report the linkage between HLA/KIR haplotypes and gene alleles. We anticipate that Immuannot will speed up the discovery of new HLA/KIR alleles and enable the association of HLA/KIR haplotype structures with clinical outcomes in the future.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"1931-1941"},"PeriodicalIF":6.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141261620","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: 0

Long-read Ribo-STAMP simultaneously measures transcription and translation with isoform resolution. 长读数 Ribo-STAMP 可同时测量转录和翻译，并具有同种异构体分辨率。

IF 6.2 2区生物学

Genome research Pub Date : 2024-11-20 DOI: 10.1101/gr.279176.124

Pratibha Jagannatha, Alexandra T Tankka, Daniel A Lorenz, Tao Yu, Brian A Yee, Kristopher W Brannan, Cathy J Zhou, Jason G Underwood, Gene W Yeo

{"title":"Long-read Ribo-STAMP simultaneously measures transcription and translation with isoform resolution.","authors":"Pratibha Jagannatha, Alexandra T Tankka, Daniel A Lorenz, Tao Yu, Brian A Yee, Kristopher W Brannan, Cathy J Zhou, Jason G Underwood, Gene W Yeo","doi":"10.1101/gr.279176.124","DOIUrl":"10.1101/gr.279176.124","url":null,"abstract":"Transcription and translation are intertwined processes in which mRNA isoforms are crucial intermediaries. However, methodological limitations in analyzing translation at the mRNA isoform level have left gaps in our understanding of critical biological processes. To address these gaps, we developed an integrated computational and experimental framework called long-read Ribo-STAMP (LR-Ribo-STAMP) that capitalizes on advancements in long-read sequencing and RNA-base editing-mediated technologies to simultaneously profile translation and transcription at both the gene and mRNA isoform levels. We also developed the EditsC metric to quantify editing and leverage the single-molecule, full-length transcript information provided by long-read sequencing. Here, we report concordance between gene-level translation profiles obtained with long-read and short-read Ribo-STAMP. We show that LR-Ribo-STAMP successfully profiles translation of mRNA isoforms and links regulatory features, such as upstream open reading frames (uORFs), to translation measurements. We apply LR-Ribo-STAMP to discovering translational differences at both the gene and isoform levels in a triple-negative breast cancer cell line under normoxia and hypoxia and find that LR-Ribo-STAMP effectively delineates orthogonal transcriptional and translation shifts between conditions. We also discover regulatory elements that distinguish translational differences at the isoform level. We highlight GRK6, in which hypoxia is observed to increase expression and translation of a shorter mRNA isoform, giving rise to a truncated protein without the AGC Kinase domain. Overall, LR-Ribo-STAMP is an important advance in our repertoire of methods that measures mRNA translation with isoform sensitivity.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":" ","pages":"2012-2024"},"PeriodicalIF":6.2,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11610582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141436763","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: 0

Modeling gene interactions in polygenic prediction via geometric deep learning 通过几何深度学习为多基因预测中的基因相互作用建模

IF 7 2区生物学

Genome research Pub Date : 2024-11-19 DOI: 10.1101/gr.279694.124

Han Li, Jianyang Zeng, Michael P Snyder, Sai Zhang

{"title":"Modeling gene interactions in polygenic prediction via geometric deep learning","authors":"Han Li, Jianyang Zeng, Michael P Snyder, Sai Zhang","doi":"10.1101/gr.279694.124","DOIUrl":"https://doi.org/10.1101/gr.279694.124","url":null,"abstract":"Polygenic risk score (PRS) is a widely-used approach for predicting individuals' genetic risk of complex diseases, playing a pivotal role in advancing precision medicine. Traditional PRS methods, predominantly following a linear structure, often fall short in capturing the intricate relationships between genotype and phenotype. In this study, we present PRS-Net, an interpretable geometric deep learning-based framework that effectively models the nonlinearity of biological systems for enhanced disease prediction and biological discovery. PRS-Net begins by deconvoluting the genome-wide PRS at the single-gene resolution, and then explicitly encapsulates gene-gene interactions leveraging a graph neural network (GNN) for genetic risk prediction, enabling a systematic characterization of molecular interplay underpinning diseases. An attentive readout module is introduced to facilitate model interpretation. Extensive tests across multiple complex traits and diseases demonstrate the superior prediction performance of PRS-Net compared to conventional PRS methods. The interpretability of PRS-Net further enhances the identification of disease-relevant genes and gene programs. PRS-Net provides a potent tool for concurrent genetic risk prediction and biological discovery for complex diseases.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"99 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142673941","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

ISWI1 complex proteins facilitate developmental genome editing in Paramecium ISWI1复合蛋白促进了鹦鹉螺的发育基因组编辑

IF 7 2区生物学

Genome research Pub Date : 2024-11-14 DOI: 10.1101/gr.278402.123

Aditi Singh, Lilia Häußermann, Christiane Emmerich, Emily Nischwitz, Brandon KB Seah, Falk Butter, Mariusz Nowacki, Estienne C. Swart

{"title":"ISWI1 complex proteins facilitate developmental genome editing in Paramecium","authors":"Aditi Singh, Lilia Häußermann, Christiane Emmerich, Emily Nischwitz, Brandon KB Seah, Falk Butter, Mariusz Nowacki, Estienne C. Swart","doi":"10.1101/gr.278402.123","DOIUrl":"https://doi.org/10.1101/gr.278402.123","url":null,"abstract":"One of the most extensive forms of natural genome editing occurs in ciliates, a group of microbial eukaryotes. Ciliate germline and somatic genomes are contained in distinct nuclei within the same cell. During the massive reorganization process of somatic genome development, ciliates eliminate tens of thousands of DNA sequences from a germline genome copy. Recently, we showed that the chromatin remodeler ISWI1 is required for somatic genome development in the ciliate Paramecium tetraurelia. Here, we describe two high similarity paralogous proteins, ICOPa and ICOPb, essential for their genome editing. ICOPa and ICOPb are highly divergent from known proteins; the only domain detected showed distant homology to the WSD (WHIM2+WHIM3) motif. We show that both ICOPa and ICOPb interact with the chromatin remodeler ISWI1. Upon ICOP knockdown, changes in alternative DNA excision boundaries and nucleosome densities are similar to those observed for ISWI1 knockdown. We thus propose that a complex comprising ISWI1 and either or both ICOPa and ICOPb are needed for Paramecium's precise genome editing.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"9 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610480","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

High-quality sika deer omics data and integrative analysis reveal genic and cellular regulation of antler regeneration 高质量梅花鹿全息数据和综合分析揭示了鹿茸再生的基因和细胞调控机制

IF 7 2区生物学

Genome research Pub Date : 2024-11-14 DOI: 10.1101/gr.279448.124

Zihe Li, Ziyu Xu, Lei Zhu, Tao Qin, Jinrui Ma, Zhanying Feng, Huishan Yue, Qing Guan, Botong Zhou, Ge Han, Guokun Zhang, Chunyi Li, Shuaijun Jia, Qiang Qiu, Dingjun Hao, Yong Wang, Wen Wang

{"title":"High-quality sika deer omics data and integrative analysis reveal genic and cellular regulation of antler regeneration","authors":"Zihe Li, Ziyu Xu, Lei Zhu, Tao Qin, Jinrui Ma, Zhanying Feng, Huishan Yue, Qing Guan, Botong Zhou, Ge Han, Guokun Zhang, Chunyi Li, Shuaijun Jia, Qiang Qiu, Dingjun Hao, Yong Wang, Wen Wang","doi":"10.1101/gr.279448.124","DOIUrl":"https://doi.org/10.1101/gr.279448.124","url":null,"abstract":"Antler is the only organ that can fully regenerate annually in mammals. However, the regulatory pattern and mechanism of gene expression and cell differentiation during this process remain largely unknown. Here, we obtain comprehensive assembly and gene annotation of the sika deer (Cervus nippon) genome. Together with large-scale chromatin accessibility and gene expression data, we construct gene regulatory networks involved in antler regeneration, identifying four transcription factors, MYC, KLF4, NFE2L2, and JDP2 with high regulatory activity across whole regeneration process. Comparative studies and luciferase reporter assay suggest the MYC expression driven by a cervid-specific regulatory element might be important for antler regenerative ability. We further develop a model called cTOP which integrates single-cell data with bulk regulatory networks and find PRDM1, FOSL1, BACH1, and NFATC1 as potential pivotal factors in antler stem cell activation and osteogenic differentiation. Additionally, we uncover interactions within and between cell programs and pathways during the regeneration process. These findings provide insights into the gene and cell regulatory mechanisms of antler regeneration, particularly in stem cell activation and differentiation.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"22 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610479","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

Multiple paralogues and recombination mechanisms contribute to the high incidence of 22q11.2 Deletion Syndrome 多种旁系基因和重组机制导致 22q11.2 缺失综合征的高发病率

IF 7 2区生物学

Genome research Pub Date : 2024-11-13 DOI: 10.1101/gr.279331.124

Lisanne Vervoort, Nicolas Dierckxsens, Marta Sousa Santos, Senne Meynants, Erika Souche, Ruben Cools, Tracy Heung, Koen Devriendt, Hilde Peeters, Donna McDonald-McGinn, Ann Swillen, Jeroen Breckpot, Beverly S. Emanuel, Hilde Van Esch, Anne S. Bassett, Joris R. Vermeesch

{"title":"Multiple paralogues and recombination mechanisms contribute to the high incidence of 22q11.2 Deletion Syndrome","authors":"Lisanne Vervoort, Nicolas Dierckxsens, Marta Sousa Santos, Senne Meynants, Erika Souche, Ruben Cools, Tracy Heung, Koen Devriendt, Hilde Peeters, Donna McDonald-McGinn, Ann Swillen, Jeroen Breckpot, Beverly S. Emanuel, Hilde Van Esch, Anne S. Bassett, Joris R. Vermeesch","doi":"10.1101/gr.279331.124","DOIUrl":"https://doi.org/10.1101/gr.279331.124","url":null,"abstract":"The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion disorder. Why the incidence of 22q11.2DS is much greater than that of other genomic disorders remains unknown. Short read sequencing cannot resolve the complex segmental duplicon structure to provide direct confirmation of the hypothesis that the rearrangements are caused by nonallelic homologous recombination between the low copy repeats on Chromosome 22 (LCR22s). To enable haplotype-specific assembly and rearrangement mapping in LCR22 regions, we combined fiber-FISH optical mapping with whole genome (ultra-)long read sequencing or rearrangement-specific long-range PCR on 24 duos (22q11.2DS patient and parent-of-origin) comprising several different LCR22-mediated rearrangements. Unexpectedly, we demonstrate that not only different paralogous segmental duplicon but also palindromic AT-rich repeats (PATRR) are driving 22q11.2 rearrangements. In addition, we show the existence of two different inversion polymorphisms preceding rearrangement, and somatic mosaicism. The existence of different recombination sites and mechanisms in paralogues and PATRRs which are copy number expanding in the human population are a likely explanation for the high 22q11.2DS incidence.","PeriodicalId":12678,"journal":{"name":"Genome research","volume":"6 1","pages":""},"PeriodicalIF":7.0,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610482","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