Pub Date : 2024-08-14Epub Date: 2024-07-24DOI: 10.1016/j.xgen.2024.100610
Yuki Sugiyama, Satoshi Okada, Yasukazu Daigaku, Emiko Kusumoto, Takashi Ito
Gene/segmental duplications play crucial roles in genome evolution and variation. Here, we introduce paired nicking-induced amplification (PNAmp) for their experimental induction. PNAmp strategically places two Cas9 nickases upstream and downstream of a replication origin on opposite strands. This configuration directs the sister replication forks initiated from the origin to break at the nicks, generating a pair of one-ended double-strand breaks. If homologous sequences flank the two break sites, then end resection converts them to single-stranded DNAs that readily anneal to drive duplication of the region bounded by the homologous sequences. PNAmp induces duplication of segments as large as ∼1 Mb with efficiencies exceeding 10% in the budding yeast Saccharomyces cerevisiae. Furthermore, appropriate splint DNAs allow PNAmp to duplicate/multiplicate even segments not bounded by homologous sequences. We also provide evidence for PNAmp in mammalian cells. Therefore, PNAmp provides a prototype method to induce structural variations by manipulating replication fork progression.
基因/片段重复在基因组进化和变异中起着至关重要的作用。在这里,我们引入了配对缺口诱导扩增(PNAmp)技术,用于实验诱导。PNAmp 策略性地将两个 Cas9 挑刺酶分别置于复制原点的上游和下游的相对链上。这种配置会引导从原点开始的姐妹复制叉在缺口处断裂,产生一对单端双链断裂。如果同源序列位于两个断裂点的两侧,那么末端切除就会将它们转化为单链 DNA,这些单链 DNA 很容易退火,从而驱动同源序列所包围区域的复制。在芽殖酵母(Saccharomyces cerevisiae)中,PNAmp 能诱导大至 1 Mb 的区段复制,效率超过 10%。此外,适当的拼接 DNA 甚至可以让 PNAmp 复制/增殖没有同源序列限制的片段。我们还提供了哺乳动物细胞中存在 PNAmp 的证据。因此,PNAmp 提供了一种通过操纵复制叉进程诱导结构变异的原型方法。
{"title":"Strategic targeting of Cas9 nickase induces large segmental duplications.","authors":"Yuki Sugiyama, Satoshi Okada, Yasukazu Daigaku, Emiko Kusumoto, Takashi Ito","doi":"10.1016/j.xgen.2024.100610","DOIUrl":"10.1016/j.xgen.2024.100610","url":null,"abstract":"<p><p>Gene/segmental duplications play crucial roles in genome evolution and variation. Here, we introduce paired nicking-induced amplification (PNAmp) for their experimental induction. PNAmp strategically places two Cas9 nickases upstream and downstream of a replication origin on opposite strands. This configuration directs the sister replication forks initiated from the origin to break at the nicks, generating a pair of one-ended double-strand breaks. If homologous sequences flank the two break sites, then end resection converts them to single-stranded DNAs that readily anneal to drive duplication of the region bounded by the homologous sequences. PNAmp induces duplication of segments as large as ∼1 Mb with efficiencies exceeding 10% in the budding yeast Saccharomyces cerevisiae. Furthermore, appropriate splint DNAs allow PNAmp to duplicate/multiplicate even segments not bounded by homologous sequences. We also provide evidence for PNAmp in mammalian cells. Therefore, PNAmp provides a prototype method to induce structural variations by manipulating replication fork progression.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100610"},"PeriodicalIF":11.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406185/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141763060","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14Epub Date: 2024-08-02DOI: 10.1016/j.xgen.2024.100627
Jayne A Barbour, Tong Ou, Haocheng Yang, Hu Fang, Noel C Yue, Xiaoqiang Zhu, Michelle W Wong-Brown, Yuen T Wong, Nikola A Bowden, Song Wu, Jason W H Wong
Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.
切除修复交叉互补组 2(ERCC2)编码 DNA 螺旋酶色素沉着病 D 组,它在转录和核苷酸切除修复中发挥作用。ERCC2的点突变是约10%的膀胱癌(BLCA)的潜在诱因,也是顺铂治疗反应的潜在阳性生物标志物。然而,人们对ERCC2突变直接导致的预后意义及其在基因组不稳定性中的致病作用仍然知之甚少。我们首先证明了突变的ERCC2是BLCA预后的独立预测因子。然后,我们利用一组ERCC2野生型(n = 343)和突变型(n = 39)的BLCA全基因组研究了它对体细胞突变景观的影响。在ERCC2突变体中,体细胞突变的全基因组分布发生了显著改变,包括T[C>T]N富集、复制时间相关性改变以及CTCF-粘连素结合位点突变热点。我们利用这些改变开发了一种预测致病性 ERCC2 突变的机器学习模型,这可能有助于为 BLCA 患者的治疗提供信息。
{"title":"ERCC2 mutations alter the genomic distribution pattern of somatic mutations and are independently prognostic in bladder cancer.","authors":"Jayne A Barbour, Tong Ou, Haocheng Yang, Hu Fang, Noel C Yue, Xiaoqiang Zhu, Michelle W Wong-Brown, Yuen T Wong, Nikola A Bowden, Song Wu, Jason W H Wong","doi":"10.1016/j.xgen.2024.100627","DOIUrl":"10.1016/j.xgen.2024.100627","url":null,"abstract":"<p><p>Excision repair cross-complementation group 2 (ERCC2) encodes the DNA helicase xeroderma pigmentosum group D, which functions in transcription and nucleotide excision repair. Point mutations in ERCC2 are putative drivers in around 10% of bladder cancers (BLCAs) and a potential positive biomarker for cisplatin therapy response. Nevertheless, the prognostic significance directly attributed to ERCC2 mutations and its pathogenic role in genome instability remain poorly understood. We first demonstrated that mutant ERCC2 is an independent predictor of prognosis in BLCA. We then examined its impact on the somatic mutational landscape using a cohort of ERCC2 wild-type (n = 343) and mutant (n = 39) BLCA whole genomes. The genome-wide distribution of somatic mutations is significantly altered in ERCC2 mutants, including T[C>T]N enrichment, altered replication time correlations, and CTCF-cohesin binding site mutation hotspots. We leverage these alterations to develop a machine learning model for predicting pathogenic ERCC2 mutations, which may be useful to inform treatment of patients with BLCA.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100627"},"PeriodicalIF":11.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406173/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141891153","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14Epub Date: 2024-07-16DOI: 10.1016/j.xgen.2024.100609
Taehwan Shin, Janet H T Song, Michael Kosicki, Connor Kenny, Samantha G Beck, Lily Kelley, Irene Antony, Xuyu Qian, Julieta Bonacina, Frances Papandile, Dilenny Gonzalez, Julia Scotellaro, Evan M Bushinsky, Rebecca E Andersen, Eduardo Maury, Len A Pennacchio, Ryan N Doan, Christopher A Walsh
Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior.
{"title":"Rare variation in non-coding regions with evolutionary signatures contributes to autism spectrum disorder risk.","authors":"Taehwan Shin, Janet H T Song, Michael Kosicki, Connor Kenny, Samantha G Beck, Lily Kelley, Irene Antony, Xuyu Qian, Julieta Bonacina, Frances Papandile, Dilenny Gonzalez, Julia Scotellaro, Evan M Bushinsky, Rebecca E Andersen, Eduardo Maury, Len A Pennacchio, Ryan N Doan, Christopher A Walsh","doi":"10.1016/j.xgen.2024.100609","DOIUrl":"10.1016/j.xgen.2024.100609","url":null,"abstract":"<p><p>Little is known about the role of non-coding regions in the etiology of autism spectrum disorder (ASD). We examined three classes of non-coding regions: human accelerated regions (HARs), which show signatures of positive selection in humans; experimentally validated neural VISTA enhancers (VEs); and conserved regions predicted to act as neural enhancers (CNEs). Targeted and whole-genome analysis of >16,600 samples and >4,900 ASD probands revealed that likely recessive, rare, inherited variants in HARs, VEs, and CNEs substantially contribute to ASD risk in probands whose parents share ancestry, which enriches for recessive contributions, but modestly contribute, if at all, in simplex family structures. We identified multiple patient variants in HARs near IL1RAPL1 and in VEs near OTX1 and SIM1 and showed that they change enhancer activity. Our results implicate both human-evolved and evolutionarily conserved non-coding regions in ASD risk and suggest potential mechanisms of how regulatory changes can modulate social behavior.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100609"},"PeriodicalIF":11.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141635976","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-14Epub Date: 2024-07-02DOI: 10.1016/j.xgen.2024.100604
Mireia Ramos-Rodríguez, Marc Subirana-Granés, Richard Norris, Valeria Sordi, Ángel Fernández, Georgina Fuentes-Páez, Beatriz Pérez-González, Clara Berenguer Balaguer, Helena Raurell-Vila, Murad Chowdhury, Raquel Corripio, Stefano Partelli, Núria López-Bigas, Silvia Pellegrini, Eduard Montanya, Montserrat Nacher, Massimo Falconi, Ryan Layer, Meritxell Rovira, Abel González-Pérez, Lorenzo Piemonti, Lorenzo Pasquali
Insulinomas are rare neuroendocrine tumors arising from pancreatic β cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in β cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of β cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.
{"title":"Implications of noncoding regulatory functions in the development of insulinomas.","authors":"Mireia Ramos-Rodríguez, Marc Subirana-Granés, Richard Norris, Valeria Sordi, Ángel Fernández, Georgina Fuentes-Páez, Beatriz Pérez-González, Clara Berenguer Balaguer, Helena Raurell-Vila, Murad Chowdhury, Raquel Corripio, Stefano Partelli, Núria López-Bigas, Silvia Pellegrini, Eduard Montanya, Montserrat Nacher, Massimo Falconi, Ryan Layer, Meritxell Rovira, Abel González-Pérez, Lorenzo Piemonti, Lorenzo Pasquali","doi":"10.1016/j.xgen.2024.100604","DOIUrl":"10.1016/j.xgen.2024.100604","url":null,"abstract":"<p><p>Insulinomas are rare neuroendocrine tumors arising from pancreatic β cells, characterized by aberrant proliferation and altered insulin secretion, leading to glucose homeostasis failure. With the aim of uncovering the role of noncoding regulatory regions and their aberrations in the development of these tumors, we coupled epigenetic and transcriptome profiling with whole-genome sequencing. As a result, we unraveled somatic mutations associated with changes in regulatory functions. Critically, these regions impact insulin secretion, tumor development, and epigenetic modifying genes, including polycomb complex components. Chromatin remodeling is apparent in insulinoma-selective domains shared across patients, containing a specific set of regulatory sequences dominated by the SOX17 binding motif. Moreover, many of these regions are H3K27me3 repressed in β cells, suggesting that tumoral transition involves derepression of polycomb-targeted domains. Our work provides a compendium of aberrant cis-regulatory elements affecting the function and fate of β cells in their progression to insulinomas and a framework to identify coding and noncoding driver mutations.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100604"},"PeriodicalIF":11.1,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11406191/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141499822","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10Epub Date: 2024-06-24DOI: 10.1016/j.xgen.2024.100588
Kar-Tong Tan, Michael K Slevin, Mitchell L Leibowitz, Max Garrity-Janger, Jidong Shan, Heng Li, Matthew Meyerson
Alterations in the structure and location of telomeres are pivotal in cancer genome evolution. Here, we applied both long-read and short-read genome sequencing to assess telomere repeat-containing structures in cancers and cancer cell lines. Using long-read genome sequences that span telomeric repeats, we defined four types of telomere repeat variations in cancer cells: neotelomeres where telomere addition heals chromosome breaks, chromosomal arm fusions spanning telomere repeats, fusions of neotelomeres, and peri-centromeric fusions with adjoined telomere and centromere repeats. These results provide a framework for the systematic study of telomeric repeats in cancer genomes, which could serve as a model for understanding the somatic evolution of other repetitive genomic elements.
{"title":"Neotelomeres and telomere-spanning chromosomal arm fusions in cancer genomes revealed by long-read sequencing.","authors":"Kar-Tong Tan, Michael K Slevin, Mitchell L Leibowitz, Max Garrity-Janger, Jidong Shan, Heng Li, Matthew Meyerson","doi":"10.1016/j.xgen.2024.100588","DOIUrl":"10.1016/j.xgen.2024.100588","url":null,"abstract":"<p><p>Alterations in the structure and location of telomeres are pivotal in cancer genome evolution. Here, we applied both long-read and short-read genome sequencing to assess telomere repeat-containing structures in cancers and cancer cell lines. Using long-read genome sequences that span telomeric repeats, we defined four types of telomere repeat variations in cancer cells: neotelomeres where telomere addition heals chromosome breaks, chromosomal arm fusions spanning telomere repeats, fusions of neotelomeres, and peri-centromeric fusions with adjoined telomere and centromere repeats. These results provide a framework for the systematic study of telomeric repeats in cancer genomes, which could serve as a model for understanding the somatic evolution of other repetitive genomic elements.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100588"},"PeriodicalIF":11.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293586/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141452260","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10Epub Date: 2024-06-28DOI: 10.1016/j.xgen.2024.100602
Frederik H Lassen, Samvida S Venkatesh, Nikolas Baya, Barney Hill, Wei Zhou, Alex Bloemendal, Benjamin M Neale, Benedikt M Kessler, Nicola Whiffin, Cecilia M Lindgren, Duncan S Palmer
The phenotypic impact of compound heterozygous (CH) variation has not been investigated at the population scale. We phased rare variants (MAF ∼0.001%) in the UK Biobank (UKBB) exome-sequencing data to characterize recessive effects in 175,587 individuals across 311 common diseases. A total of 6.5% of individuals carry putatively damaging CH variants, 90% of which are only identifiable upon phasing rare variants (MAF < 0.38%). We identify six recessive gene-trait associations (p < 1.68 × 10-7) after accounting for relatedness, polygenicity, nearby common variants, and rare variant burden. Of these, just one is discovered when considering homozygosity alone. Using longitudinal health records, we additionally identify and replicate a novel association between bi-allelic variation in ATP2C2 and an earlier age at onset of chronic obstructive pulmonary disease (COPD) (p < 3.58 × 10-8). Genetic phase contributes to disease risk for gene-trait pairs: ATP2C2-COPD (p = 0.000238), FLG-asthma (p = 0.00205), and USH2A-visual impairment (p = 0.0084). We demonstrate the power of phasing large-scale genetic cohorts to discover phenome-wide consequences of compound heterozygosity.
{"title":"Exome-wide evidence of compound heterozygous effects across common phenotypes in the UK Biobank.","authors":"Frederik H Lassen, Samvida S Venkatesh, Nikolas Baya, Barney Hill, Wei Zhou, Alex Bloemendal, Benjamin M Neale, Benedikt M Kessler, Nicola Whiffin, Cecilia M Lindgren, Duncan S Palmer","doi":"10.1016/j.xgen.2024.100602","DOIUrl":"10.1016/j.xgen.2024.100602","url":null,"abstract":"<p><p>The phenotypic impact of compound heterozygous (CH) variation has not been investigated at the population scale. We phased rare variants (MAF ∼0.001%) in the UK Biobank (UKBB) exome-sequencing data to characterize recessive effects in 175,587 individuals across 311 common diseases. A total of 6.5% of individuals carry putatively damaging CH variants, 90% of which are only identifiable upon phasing rare variants (MAF < 0.38%). We identify six recessive gene-trait associations (p < 1.68 × 10<sup>-7</sup>) after accounting for relatedness, polygenicity, nearby common variants, and rare variant burden. Of these, just one is discovered when considering homozygosity alone. Using longitudinal health records, we additionally identify and replicate a novel association between bi-allelic variation in ATP2C2 and an earlier age at onset of chronic obstructive pulmonary disease (COPD) (p < 3.58 × 10<sup>-8</sup>). Genetic phase contributes to disease risk for gene-trait pairs: ATP2C2-COPD (p = 0.000238), FLG-asthma (p = 0.00205), and USH2A-visual impairment (p = 0.0084). We demonstrate the power of phasing large-scale genetic cohorts to discover phenome-wide consequences of compound heterozygosity.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100602"},"PeriodicalIF":11.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473139","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10Epub Date: 2024-06-27DOI: 10.1016/j.xgen.2024.100585
Leticia Rodríguez-Montes, Henrik Kaessmann
Sexual dimorphism, differences between males and females of the same species, is widespread in mammals. However, good animal models to study human sexually dimorphic phenotypes are currently lacking. In this issue, DeCasien et al.1 explore the potential of rhesus macaque as a model for investigating sexually dimorphic traits in the human brain.
{"title":"Rhesus macaque as a model for sex-biased neurological diseases.","authors":"Leticia Rodríguez-Montes, Henrik Kaessmann","doi":"10.1016/j.xgen.2024.100585","DOIUrl":"10.1016/j.xgen.2024.100585","url":null,"abstract":"<p><p>Sexual dimorphism, differences between males and females of the same species, is widespread in mammals. However, good animal models to study human sexually dimorphic phenotypes are currently lacking. In this issue, DeCasien et al.<sup>1</sup> explore the potential of rhesus macaque as a model for investigating sexually dimorphic traits in the human brain.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100585"},"PeriodicalIF":11.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293562/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141473196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10Epub Date: 2024-06-21DOI: 10.1016/j.xgen.2024.100590
Christopher M Grochowski, Jesse D Bengtsson, Haowei Du, Mira Gandhi, Ming Yin Lun, Michele G Mehaffey, KyungHee Park, Wolfram Höps, Eva Benito, Patrick Hasenfeld, Jan O Korbel, Medhat Mahmoud, Luis F Paulin, Shalini N Jhangiani, James Paul Hwang, Sravya V Bhamidipati, Donna M Muzny, Jawid M Fatih, Richard A Gibbs, Matthew Pendleton, Eoghan Harrington, Sissel Juul, Anna Lindstrand, Fritz J Sedlazeck, Davut Pehlivan, James R Lupski, Claudia M B Carvalho
The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.
{"title":"Inverted triplications formed by iterative template switches generate structural variant diversity at genomic disorder loci.","authors":"Christopher M Grochowski, Jesse D Bengtsson, Haowei Du, Mira Gandhi, Ming Yin Lun, Michele G Mehaffey, KyungHee Park, Wolfram Höps, Eva Benito, Patrick Hasenfeld, Jan O Korbel, Medhat Mahmoud, Luis F Paulin, Shalini N Jhangiani, James Paul Hwang, Sravya V Bhamidipati, Donna M Muzny, Jawid M Fatih, Richard A Gibbs, Matthew Pendleton, Eoghan Harrington, Sissel Juul, Anna Lindstrand, Fritz J Sedlazeck, Davut Pehlivan, James R Lupski, Claudia M B Carvalho","doi":"10.1016/j.xgen.2024.100590","DOIUrl":"10.1016/j.xgen.2024.100590","url":null,"abstract":"<p><p>The duplication-triplication/inverted-duplication (DUP-TRP/INV-DUP) structure is a complex genomic rearrangement (CGR). Although it has been identified as an important pathogenic DNA mutation signature in genomic disorders and cancer genomes, its architecture remains unresolved. Here, we studied the genomic architecture of DUP-TRP/INV-DUP by investigating the DNA of 24 patients identified by array comparative genomic hybridization (aCGH) on whom we found evidence for the existence of 4 out of 4 predicted structural variant (SV) haplotypes. Using a combination of short-read genome sequencing (GS), long-read GS, optical genome mapping, and single-cell DNA template strand sequencing (strand-seq), the haplotype structure was resolved in 18 samples. The point of template switching in 4 samples was shown to be a segment of ∼2.2-5.5 kb of 100% nucleotide similarity within inverted repeat pairs. These data provide experimental evidence that inverted low-copy repeats act as recombinant substrates. This type of CGR can result in multiple conformers generating diverse SV haplotypes in susceptible dosage-sensitive loci.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100590"},"PeriodicalIF":11.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293582/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141441185","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10DOI: 10.1016/j.xgen.2024.100608
Timothy H Ciesielski
Our understanding of sepsis has been hampered by the implicit assumption that sepsis is a homogeneous disease. In this issue of Cell Genomics, Burnham et al.1 have started to characterize the genetic variants and regulatory networks that underlie variations in the individual response to sepsis; this may eventually enable targeted intervention development.
{"title":"Sepsis research: Heterogeneity as a foundation rather than an afterthought.","authors":"Timothy H Ciesielski","doi":"10.1016/j.xgen.2024.100608","DOIUrl":"10.1016/j.xgen.2024.100608","url":null,"abstract":"<p><p>Our understanding of sepsis has been hampered by the implicit assumption that sepsis is a homogeneous disease. In this issue of Cell Genomics, Burnham et al.<sup>1</sup> have started to characterize the genetic variants and regulatory networks that underlie variations in the individual response to sepsis; this may eventually enable targeted intervention development.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":"4 7","pages":"100608"},"PeriodicalIF":11.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11293572/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141592263","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-10Epub Date: 2024-07-01DOI: 10.1016/j.xgen.2024.100603
Hsuanlin Her, Katherine L Rothamel, Grady G Nguyen, Evan A Boyle, Gene W Yeo
The uncovering of protein-RNA interactions enables a deeper understanding of RNA processing. Recent multiplexed crosslinking and immunoprecipitation (CLIP) technologies such as antibody-barcoded eCLIP (ABC) dramatically increase the throughput of mapping RNA binding protein (RBP) binding sites. However, multiplex CLIP datasets are multivariate, and each RBP suffers non-uniform signal-to-noise ratio. To address this, we developed Mudskipper, a versatile computational suite comprising two components: a Dirichlet multinomial mixture model to account for the multivariate nature of ABC datasets and a softmasking approach that identifies and removes non-specific protein-RNA interactions in RBPs with low signal-to-noise ratio. Mudskipper demonstrates superior precision and recall over existing tools on multiplex datasets and supports analysis of repetitive elements and small non-coding RNAs. Our findings unravel splicing outcomes and variant-associated disruptions, enabling higher-throughput investigations into diseases and regulation mediated by RBPs.
{"title":"Mudskipper detects combinatorial RNA binding protein interactions in multiplexed CLIP data.","authors":"Hsuanlin Her, Katherine L Rothamel, Grady G Nguyen, Evan A Boyle, Gene W Yeo","doi":"10.1016/j.xgen.2024.100603","DOIUrl":"10.1016/j.xgen.2024.100603","url":null,"abstract":"<p><p>The uncovering of protein-RNA interactions enables a deeper understanding of RNA processing. Recent multiplexed crosslinking and immunoprecipitation (CLIP) technologies such as antibody-barcoded eCLIP (ABC) dramatically increase the throughput of mapping RNA binding protein (RBP) binding sites. However, multiplex CLIP datasets are multivariate, and each RBP suffers non-uniform signal-to-noise ratio. To address this, we developed Mudskipper, a versatile computational suite comprising two components: a Dirichlet multinomial mixture model to account for the multivariate nature of ABC datasets and a softmasking approach that identifies and removes non-specific protein-RNA interactions in RBPs with low signal-to-noise ratio. Mudskipper demonstrates superior precision and recall over existing tools on multiplex datasets and supports analysis of repetitive elements and small non-coding RNAs. Our findings unravel splicing outcomes and variant-associated disruptions, enabling higher-throughput investigations into diseases and regulation mediated by RBPs.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100603"},"PeriodicalIF":11.1,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494447","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}