Pub Date : 2024-09-15DOI: 10.1101/2024.09.11.612543
ROBERT TASHJIAN, Jared Zitnay, Nikolas Kazmers, Shivakumar Veerabhadraiah, Antonio Zelada, Matthew Honeggar, Matthew Smith, Peter Chalmers, Heath Henninger, Michael Jurynec
The biological factors that affect healing after rotator cuff repair (RCR) are not well understood. Genetic variants in the extracellular matrix protein Tenascin C (TNC) are associated with impaired tendon healing and it is expressed in rotator cuff tendon tissue after injury, suggesting it may have a role in the repair process. The purpose of the current study was to determine the role of TNC on tendon healing after RCR in a murine model. The supraspinatus tendon was transected and repaired on the left shoulder of Wild-Type (WT-RCR), Tenascin C null (Tnc--RCR) and Tnc heterozygous (Tnc+/--RCR) mice. Controls included the unoperated, contralateral shoulder of WT-RCR, Tnc-RCR, Tnc+/--RCR mice and unoperated shoulders from age and genotype matched controls. We performed histologic, activity testing, RNA-seq, and biomechanical analyses. At 8-weeks post-RCR, Tnc- and Tnc+/- mice had severe bone and tendon defects following rotator cuff repair. Tnc--RCR mice had reduced activity after rotator cuff repair including reduced wheel rotations, wheel duration, and wheel episode average velocity compared with WT-RCR. Loss of Tnc following RCR altered gene expression in the shoulder, including upregulation of sex hormone and WNT pathways and a downregulation of inflammation and cell cycle pathways. Tnc- mice had similar biomechanical properties after repair as WT. Further research is required to evaluate tissue specific alterations of Tnc, the interactions of Tnc and sex hormone and inflammation pathways as well as possible adjuvants to improve enthesis healing in the setting of reduced TNC function.
{"title":"Tenascin C Deletion Impairs Tendon Healing and Functional Recovery After Rotator Cuff Repair","authors":"ROBERT TASHJIAN, Jared Zitnay, Nikolas Kazmers, Shivakumar Veerabhadraiah, Antonio Zelada, Matthew Honeggar, Matthew Smith, Peter Chalmers, Heath Henninger, Michael Jurynec","doi":"10.1101/2024.09.11.612543","DOIUrl":"https://doi.org/10.1101/2024.09.11.612543","url":null,"abstract":"The biological factors that affect healing after rotator cuff repair (RCR) are not well understood. Genetic variants in the extracellular matrix protein Tenascin C (TNC) are associated with impaired tendon healing and it is expressed in rotator cuff tendon tissue after injury, suggesting it may have a role in the repair process. The purpose of the current study was to determine the role of TNC on tendon healing after RCR in a murine model. The supraspinatus tendon was transected and repaired on the left shoulder of Wild-Type (WT-RCR), Tenascin C null (Tnc--RCR) and Tnc heterozygous (Tnc+/--RCR) mice. Controls included the unoperated, contralateral shoulder of WT-RCR, Tnc-RCR, Tnc+/--RCR mice and unoperated shoulders from age and genotype matched controls. We performed histologic, activity testing, RNA-seq, and biomechanical analyses. At 8-weeks post-RCR, Tnc- and Tnc+/- mice had severe bone and tendon defects following rotator cuff repair. Tnc--RCR mice had reduced activity after rotator cuff repair including reduced wheel rotations, wheel duration, and wheel episode average velocity compared with WT-RCR. Loss of Tnc following RCR altered gene expression in the shoulder, including upregulation of sex hormone and WNT pathways and a downregulation of inflammation and cell cycle pathways. Tnc- mice had similar biomechanical properties after repair as WT. Further research is required to evaluate tissue specific alterations of Tnc, the interactions of Tnc and sex hormone and inflammation pathways as well as possible adjuvants to improve enthesis healing in the setting of reduced TNC function.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"196 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247597","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}
Pub Date : 2024-09-14DOI: 10.1101/2024.09.10.612244
Matthias Benoit, Katharine M Jenike, James W Satterlee, Srividya Ramakrishnan, Iacopo Gentile, Anat Hendelman, Michael J Passalacqua, Hamsini Suresh, Hagai Shohat, Gina M Robitaille, Blaine Fitzgerald, Michael M Alonge, Xingang Wang, Ryan Santos, Jia He, Shujun Ou, Hezi Golan, Yumi Green, Kerry Swartwood, Gina P Sierra, Andres Orejuela, Federico Fornaguera, Sara Goodwin, William Richard McCombie, Elizabeth Balyejusa Kizito, Edeline Gagnon, Sandra Knapp, Tiina Sarkinen, Amy Frary, Jesse Gillis, Joyce Van Eck, Michael C Schatz, Zachary B Lippman
Pan-genomics and genome editing technologies are revolutionizing the breeding of globally cultivated crops. A transformative opportunity lies in the reciprocal exchange of genotype-to-phenotype knowledge of agricultural traits between these major crops and hundreds of locally cultivated indigenous crops, thereby enhancing the diversity and resilience of our food system. However, species-specific genetic variants and their interactions with desired natural or engineered mutations pose barriers to achieving predictable phenotypic effects, even between closely related crops or genotypes. Here, by establishing a pan-genome of the crop-rich genus Solanum and integrating functional genomics and genetics, we show that gene duplication and subsequent paralog diversification are a major obstacle to genotype-phenotype predictability. Despite broad conservation of gene macrosynteny among chromosome-scale references for 22 species, including 13 indigenous crops, hundreds of global and lineage-specific gene duplications exhibited dynamic evolutionary trajectories in paralog sequence, expression, and function, including among members of key domestication gene families. Extending our pan-genome with 10 cultivars of African eggplant and leveraging quantitative genetics and genome editing, we uncovered an intricate history of paralog emergence and evolution within this indigenous crop. The loss of an ancient redundant paralog of the classical regulator of stem cell proliferation and fruit organ number, CLAVATA3 (CLV3), was compensated by a lineage-specific tandem duplication. Subsequent pseudogenization of the derived copy followed by a cultivar-specific structural variant resulted in a single fused functional copy of CLV3 that modifies locule number alongside a newly identified gene controlling the same trait. Our findings demonstrate that paralog diversifications over short evolutionary periods are critical yet underexplored contingencies in trait evolvability and independent crop domestication histories. Unraveling these contingencies is crucial for translating genotype-to-phenotype relationships across related species.
{"title":"Solanum pan-genomics and pan-genetics reveal paralogs as contingencies in crop engineering","authors":"Matthias Benoit, Katharine M Jenike, James W Satterlee, Srividya Ramakrishnan, Iacopo Gentile, Anat Hendelman, Michael J Passalacqua, Hamsini Suresh, Hagai Shohat, Gina M Robitaille, Blaine Fitzgerald, Michael M Alonge, Xingang Wang, Ryan Santos, Jia He, Shujun Ou, Hezi Golan, Yumi Green, Kerry Swartwood, Gina P Sierra, Andres Orejuela, Federico Fornaguera, Sara Goodwin, William Richard McCombie, Elizabeth Balyejusa Kizito, Edeline Gagnon, Sandra Knapp, Tiina Sarkinen, Amy Frary, Jesse Gillis, Joyce Van Eck, Michael C Schatz, Zachary B Lippman","doi":"10.1101/2024.09.10.612244","DOIUrl":"https://doi.org/10.1101/2024.09.10.612244","url":null,"abstract":"Pan-genomics and genome editing technologies are revolutionizing the breeding of globally cultivated crops. A transformative opportunity lies in the reciprocal exchange of genotype-to-phenotype knowledge of agricultural traits between these major crops and hundreds of locally cultivated indigenous crops, thereby enhancing the diversity and resilience of our food system. However, species-specific genetic variants and their interactions with desired natural or engineered mutations pose barriers to achieving predictable phenotypic effects, even between closely related crops or genotypes. Here, by establishing a pan-genome of the crop-rich genus Solanum and integrating functional genomics and genetics, we show that gene duplication and subsequent paralog diversification are a major obstacle to genotype-phenotype predictability. Despite broad conservation of gene macrosynteny among chromosome-scale references for 22 species, including 13 indigenous crops, hundreds of global and lineage-specific gene duplications exhibited dynamic evolutionary trajectories in paralog sequence, expression, and function, including among members of key domestication gene families. Extending our pan-genome with 10 cultivars of African eggplant and leveraging quantitative genetics and genome editing, we uncovered an intricate history of paralog emergence and evolution within this indigenous crop. The loss of an ancient redundant paralog of the classical regulator of stem cell proliferation and fruit organ number, CLAVATA3 (CLV3), was compensated by a lineage-specific tandem duplication. Subsequent pseudogenization of the derived copy followed by a cultivar-specific structural variant resulted in a single fused functional copy of CLV3 that modifies locule number alongside a newly identified gene controlling the same trait. Our findings demonstrate that paralog diversifications over short evolutionary periods are critical yet underexplored contingencies in trait evolvability and independent crop domestication histories. Unraveling these contingencies is crucial for translating genotype-to-phenotype relationships across related species.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"61 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142247605","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}
Pub Date : 2024-09-14DOI: 10.1101/2024.09.10.612314
Shijia Bian, Andrew J. Bass, Yue Liu, Aliza P. Wingo, Thomas Wingo, David J. Cutler, Michael P. Epstein
Family-based heritability estimates of complex traits are often considerably larger than their single-nucleotide polymorphism (SNP) heritability estimates. This discrepancy may be due to non-additive effects of genetic variation, including variation that interacts with other genes or environmental factors to influence the trait. Variance-based procedures provide a computationally efficient strategy to screen for SNPs with potential interaction effects without requiring the specification of the interacting variable. While valuable, such variance-based tests consider only a single trait and ignore likely pleiotropy among related traits that, if present, could improve power to detect such interaction effects. To fill this gap, we propose SCAMPI (Scalable Cauchy Aggregate test using Multiple Phenotypes to test Interactions), which screens for variants with interaction effects across multiple traits. SCAMPI is motivated by the observation that SNPs with pleiotropic interaction effects induce genotypic differences in the patterns of correlation among traits. By studying such patterns across genotype categories among multiple traits, we show that SCAMPI has improved performance over traditional univariate variance-based methods. Like those traditional variance-based tests, SCAMPI permits the screening of interaction effects without requiring the specification of the interaction variable and is further computationally scalable to biobank data. We employed SCAMPI to screen for interacting SNPs associated with four lipid-related traits in the UK Biobank and identified multiple gene regions missed by existing univariate variance-based tests. SCAMPI is implemented in software for public use.
{"title":"SCAMPI: A scalable statistical framework for genome-wide interaction testing harnessing cross-trait correlations","authors":"Shijia Bian, Andrew J. Bass, Yue Liu, Aliza P. Wingo, Thomas Wingo, David J. Cutler, Michael P. Epstein","doi":"10.1101/2024.09.10.612314","DOIUrl":"https://doi.org/10.1101/2024.09.10.612314","url":null,"abstract":"Family-based heritability estimates of complex traits are often considerably larger than their single-nucleotide polymorphism (SNP) heritability estimates. This discrepancy may be due to non-additive effects of genetic variation, including variation that interacts with other genes or environmental factors to influence the trait. Variance-based procedures provide a computationally efficient strategy to screen for SNPs with potential interaction effects without requiring the specification of the interacting variable. While valuable, such variance-based tests consider only a single trait and ignore likely pleiotropy among related traits that, if present, could improve power to detect such interaction effects. To fill this gap, we propose SCAMPI (Scalable Cauchy Aggregate test using Multiple Phenotypes to test Interactions), which screens for variants with interaction effects across multiple traits. SCAMPI is motivated by the observation that SNPs with pleiotropic interaction effects induce genotypic differences in the patterns of correlation among traits. By studying such patterns across genotype categories among multiple traits, we show that SCAMPI has improved performance over traditional univariate variance-based methods. Like those traditional variance-based tests, SCAMPI permits the screening of interaction effects without requiring the specification of the interaction variable and is further computationally scalable to biobank data. We employed SCAMPI to screen for interacting SNPs associated with four lipid-related traits in the UK Biobank and identified multiple gene regions missed by existing univariate variance-based tests. SCAMPI is implemented in software for public use.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268419","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}
Pub Date : 2024-09-14DOI: 10.1101/2024.09.10.612280
Shiela Pearl Quiobe, Ata Kalirad, Waltraud Roeseler, Hanh Witte, Yinan Wang, Christian Roedelsperger, Ralf J. Sommer
Environmental influences on traits and associated transgenerational epigenetic inheritance have widespread implications, but remain controversial and underlying mechanisms poorly understood. We introduce long-term environmental induction experiments on alternative diets in Pristionchus pacificus, a nematode exhibiting mouth-form plasticity including predation, by propagating 110 isogenic lines for 101 generations with associated food-reversal experiments. We found dietary induction and subsequent transgenerational memory of the predatory morph and identified a role of ubiquitin ligase EBAX-1/ZSWIM8 in this process. Ppa-ebax-1 mutants have no memory and Ppa-EBAX-1 destabilizes the clustered microRNA family miR-2235a/miR-35. Deletions of a cluster of 44 identical miR-2235a copies resulted in precocious and extended transgenerational inheritance of the predatory morph. These findings indicate that EBAX-1/ZSWIM8 destabilizes miRNAs resulting in transgenerational memory, suggesting a role for target-directed miRNA degradation.
{"title":"EBAX-1/ZSWIM8 destabilizes miRNAs resulting in transgenerational memory of a predatory trait","authors":"Shiela Pearl Quiobe, Ata Kalirad, Waltraud Roeseler, Hanh Witte, Yinan Wang, Christian Roedelsperger, Ralf J. Sommer","doi":"10.1101/2024.09.10.612280","DOIUrl":"https://doi.org/10.1101/2024.09.10.612280","url":null,"abstract":"Environmental influences on traits and associated transgenerational epigenetic inheritance have widespread implications, but remain controversial and underlying mechanisms poorly understood. We introduce long-term environmental induction experiments on alternative diets in <em>Pristionchus pacificus</em>, a nematode exhibiting mouth-form plasticity including predation, by propagating 110 isogenic lines for 101 generations with associated food-reversal experiments. We found dietary induction and subsequent transgenerational memory of the predatory morph and identified a role of ubiquitin ligase EBAX-1/ZSWIM8 in this process. <em>Ppa-ebax-1</em> mutants have no memory and <em>Ppa</em>-EBAX-1 destabilizes the clustered microRNA family <em>miR-2235a/miR-35</em>. Deletions of a cluster of 44 identical <em>miR-2235a</em> copies resulted in precocious and extended transgenerational inheritance of the predatory morph. These findings indicate that EBAX-1/ZSWIM8 destabilizes miRNAs resulting in transgenerational memory, suggesting a role for target-directed miRNA degradation.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"21 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268414","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}
Pub Date : 2024-09-14DOI: 10.1101/2024.09.10.612265
Merel Stemerdink, Tabea Riepe, Nick Zomer, Renee Salz, Michael Kwint, Raoul Timmermans, Barbara Ferrari, Stefano Ferrari, Alfredo Duenas Rey, Emma Delanote, Suzanne E de Bruijn, Hannie Kremer, Susanne Roosing, Frauke Coppieters, Alexander Hoischen, Frans P.M. Cremers, Peter A.C. 't Hoen, Erwin van Wijk, Erik de Vrieze
Sequencing technologies have long limited the comprehensive investigation of large transcripts associated with inherited retinal diseases (IRDs) like Usher syndrome, which involves 11 associated genes with transcripts up to 19.6 kb. To address this, we used PacBio long-read mRNA isoform sequencing (Iso-Seq) following standard library preparation and an optimized workflow to enrich for long transcripts in the human neural retina. While our workflow achieved sequencing of transcripts up to 15 kb, this was insufficient for Usher syndrome-associated genes USH2A and ADGRV1, with transcripts of 18.9 kb and 19.6 kb, respectively. To overcome this, we employed the Samplix Xdrop System for indirect target enrichment of cDNA, a technique typically used for genomic DNA capture. This method facilitated the successful capture and sequencing of ADGRV1 transcripts as well as the full-length 18.9 kb USH2A transcripts. By combining algorithmic analysis with detailed manual curation of sequenced reads, we identified novel isoforms and alternative splicing events across the 11 Usher syndrome-associated genes, with implications for diagnostics and therapy development. Our findings demonstrate the Xdrop systems adaptability for cDNA capture and the advantages of integrating computational and manual transcript analyses. The full neural retina sequencing dataset is available via EGA under identifier EGAD50000000720.
{"title":"Pushing the limits of single molecule transcript sequencing to uncover the largest disease-associated transcript isoforms in the human neural retina","authors":"Merel Stemerdink, Tabea Riepe, Nick Zomer, Renee Salz, Michael Kwint, Raoul Timmermans, Barbara Ferrari, Stefano Ferrari, Alfredo Duenas Rey, Emma Delanote, Suzanne E de Bruijn, Hannie Kremer, Susanne Roosing, Frauke Coppieters, Alexander Hoischen, Frans P.M. Cremers, Peter A.C. 't Hoen, Erwin van Wijk, Erik de Vrieze","doi":"10.1101/2024.09.10.612265","DOIUrl":"https://doi.org/10.1101/2024.09.10.612265","url":null,"abstract":"Sequencing technologies have long limited the comprehensive investigation of large transcripts associated with inherited retinal diseases (IRDs) like Usher syndrome, which involves 11 associated genes with transcripts up to 19.6 kb. To address this, we used PacBio long-read mRNA isoform sequencing (Iso-Seq) following standard library preparation and an optimized workflow to enrich for long transcripts in the human neural retina. While our workflow achieved sequencing of transcripts up to 15 kb, this was insufficient for Usher syndrome-associated genes USH2A and ADGRV1, with transcripts of 18.9 kb and 19.6 kb, respectively. To overcome this, we employed the Samplix Xdrop System for indirect target enrichment of cDNA, a technique typically used for genomic DNA capture. This method facilitated the successful capture and sequencing of ADGRV1 transcripts as well as the full-length 18.9 kb USH2A transcripts. By combining algorithmic analysis with detailed manual curation of sequenced reads, we identified novel isoforms and alternative splicing events across the 11 Usher syndrome-associated genes, with implications for diagnostics and therapy development. Our findings demonstrate the Xdrop systems adaptability for cDNA capture and the advantages of integrating computational and manual transcript analyses. The full neural retina sequencing dataset is available via EGA under identifier EGAD50000000720.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268420","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}
We have recently established the Zucker fatty diabetes mellitus (ZFDM) rat as a novel model of obese type 2 diabetes (T2D), originating from the obese Zucker fatty (ZF) rat harboring a missense mutation in the leptin receptor gene. Pathogenesis of dysfunction of the pancreatic islets and genetic factors of T2D in ZFDM rats remain unknown. Here, we perform comparative transcriptome and variant analyses of the pancreatic islets between the two strains. Among differentially expressed genes irrespective of obesity and glucose intolerance states, we identify a nonsense mutation, c.409C>T (p.Gln137X), in the lipocalin 2 (Lcn2) gene which encodes a secreted protein called neutrophil gelatinase-associated lipocalin, a well-known biomarker for inflammation. Interestingly, we find that the Lcn2 mutation is distributed widely in rat species, such as commonly used DA and F344 strains. We examine the Lcn2 mutation as a strong candidate gene for T2D in ZFDM rats by using genome editing of ZFDM rats in which the nonsense mutation is replaced with a wild-type nucleotide. We find that the genome editing well works but also observe that there is no significant difference in the development of T2D between genome-edited and original ZFDM rats. Finally, we perform a genetic linkage analysis by using backcross progeny between ZF and ZFDM rats and confirm that the Lcn2 mutation exhibits no significant association with the onset of T2D. Our data indicate that several rat strains would serve as Lcn2 deficient models, contributing to elucidate pathophysiological roles of Lcn2 in a wide variety of phenotypes.
{"title":"Comparative transcriptome and variant analyses of the pancreatic islets of a rat model of obese type 2 diabetes identifies a frequently distributed nonsense mutation in the lipocalin 2 gene","authors":"Norihide Yokoi, Naoki Adachi, Tomoki Hirokoji, Kenta Nakano, Minako Yoshihara, Saki Shigenaka, Ryuya Urakawa, Yukio Taniguchi, Yusaku Yoshida, Shigeo Yokose, Mikita Suyama, Tadashi Okamura","doi":"10.1101/2024.09.13.609843","DOIUrl":"https://doi.org/10.1101/2024.09.13.609843","url":null,"abstract":"We have recently established the Zucker fatty diabetes mellitus (ZFDM) rat as a novel model of obese type 2 diabetes (T2D), originating from the obese Zucker fatty (ZF) rat harboring a missense mutation in the leptin receptor gene. Pathogenesis of dysfunction of the pancreatic islets and genetic factors of T2D in ZFDM rats remain unknown. Here, we perform comparative transcriptome and variant analyses of the pancreatic islets between the two strains. Among differentially expressed genes irrespective of obesity and glucose intolerance states, we identify a nonsense mutation, c.409C>T (p.Gln137X), in the lipocalin 2 (Lcn2) gene which encodes a secreted protein called neutrophil gelatinase-associated lipocalin, a well-known biomarker for inflammation. Interestingly, we find that the Lcn2 mutation is distributed widely in rat species, such as commonly used DA and F344 strains. We examine the Lcn2 mutation as a strong candidate gene for T2D in ZFDM rats by using genome editing of ZFDM rats in which the nonsense mutation is replaced with a wild-type nucleotide. We find that the genome editing well works but also observe that there is no significant difference in the development of T2D between genome-edited and original ZFDM rats. Finally, we perform a genetic linkage analysis by using backcross progeny between ZF and ZFDM rats and confirm that the Lcn2 mutation exhibits no significant association with the onset of T2D. Our data indicate that several rat strains would serve as Lcn2 deficient models, contributing to elucidate pathophysiological roles of Lcn2 in a wide variety of phenotypes.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"46 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268196","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}
Pub Date : 2024-09-13DOI: 10.1101/2024.09.11.612525
Antonio Marco, Amarachi C Akachukwu, Jasmine Samantha Ratcliff
Genes on sex chromosomes have higher evolutionary rates than those on autosomes. However, this does not necessarily apply to somatic evolution in cancer. Many dominant mutations have been described in the so-called proto-oncogenes (OGs), while recessive mutations are typically described in tumor-suppressor genes (TSGs). Evidence indicates that mutations in X-chromosome TSGs are more likely to contribute to cancer than those in autosomal TSGs. Here, we formalize this in several dynamic models and predict, as expected, that mutations spread faster in TSGs located on the X chromosome than on autosomes (faster-X effect). Conversely, mutations in OGs spread faster on autosomes than on the X chromosome, but under high selective pressure, this difference is negligible. Published genomic screenings of cancer samples show evidence of the faster-X effect in TSGs. This pattern is observed in both sexes, suggesting that the maintenance of X-chromosome inactivation during cancer progression plays an important role in the evolution of TSGs. Strikingly, the relative mutation incidence in X-linked TSGs among females across individual studies is bimodal, with one group of studies showing a faster-X effect and another group showing similar incidences for X-linked and autosomal TSGs. This differentiation between cancer samples is not associated with the specific type of cancer or the tissue of origin. This may indicate that X-chromosome inactivation plays a differential role in the involvement of X-linked TSGs across individual cancers.
性染色体上的基因比常染色体上的基因有更高的进化率。然而，这并不一定适用于癌症的体细胞进化。在所谓的原癌基因（OGs）中出现了许多显性突变，而隐性突变通常出现在抑癌基因（TSGs）中。有证据表明，X 染色体 TSG 基因突变比常染色体 TSG 基因突变更有可能导致癌症。在这里，我们用几个动态模型正式说明了这一点，并预测，与常染色体相比，位于 X 染色体上的 TSG 中的突变传播速度更快（更快-X 效应）。相反，OGs 中的突变在常染色体上比在 X 染色体上传播得更快，但在高选择压力下，这种差异可以忽略不计。已发表的癌症样本基因组筛查结果显示，TSGs 中存在较快的 X 效应。这种模式在男女两性中均可观察到，这表明在癌症进展过程中维持 X 染色体失活在 TSG 的进化过程中起着重要作用。令人震惊的是，在各项研究中，女性 X 连锁 TSG 的相对突变发生率呈双峰分布，一组研究显示了较快的 X 效应，另一组研究显示 X 连锁 TSG 和常染色体 TSG 的发生率相似。癌症样本之间的这种差异与癌症的具体类型或原发组织无关。这可能表明，X 染色体失活在不同癌症的 X 连锁 TSG 参与中起着不同的作用。
{"title":"Somatic evolution of cancer genes in sex chromosomes","authors":"Antonio Marco, Amarachi C Akachukwu, Jasmine Samantha Ratcliff","doi":"10.1101/2024.09.11.612525","DOIUrl":"https://doi.org/10.1101/2024.09.11.612525","url":null,"abstract":"Genes on sex chromosomes have higher evolutionary rates than those on autosomes. However, this does not necessarily apply to somatic evolution in cancer. Many dominant mutations have been described in the so-called proto-oncogenes (OGs), while recessive mutations are typically described in tumor-suppressor genes (TSGs). Evidence indicates that mutations in X-chromosome TSGs are more likely to contribute to cancer than those in autosomal TSGs. Here, we formalize this in several dynamic models and predict, as expected, that mutations spread faster in TSGs located on the X chromosome than on autosomes (faster-X effect). Conversely, mutations in OGs spread faster on autosomes than on the X chromosome, but under high selective pressure, this difference is negligible. Published genomic screenings of cancer samples show evidence of the faster-X effect in TSGs. This pattern is observed in both sexes, suggesting that the maintenance of X-chromosome inactivation during cancer progression plays an important role in the evolution of TSGs. Strikingly, the relative mutation incidence in X-linked TSGs among females across individual studies is bimodal, with one group of studies showing a faster-X effect and another group showing similar incidences for X-linked and autosomal TSGs. This differentiation between cancer samples is not associated with the specific type of cancer or the tissue of origin. This may indicate that X-chromosome inactivation plays a differential role in the involvement of X-linked TSGs across individual cancers.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142268291","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}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.12.612687
Anil PS Ori, Carla Giner-Delgado, Clive Julian Hoggart, Paul F O'Reilly
Establishing the relative contribution of common and rare variants to complex trait heritability is a key goal of biomedical research. Recent statistical genetics inference suggests that common variants explain most complex trait heritability, but little is known about how genetic architecture varies across the trait continuum. If rare variants make a small contribution to heritability but have their effects concentrated in the tails of complex traits, where disease typically manifests, then they may have a greater clinical impact than previously inferred. Here, we perform simulations using the forward-in-time simulator SLiM to generate realistic population genetic and complex trait data, in which traits evolve under neutrality or stabilising selection. Recent studies suggest that stabilising selection is the dominant force shaping the genetic architecture of complex traits, consistent with our simulations in that data simulated under stabilising selection here more closely resembles real data. Moreover, we observe a shift of rare, large-effect alleles towards the tails of the complex trait distribution under stabilising selection. In our simulations, individuals in the tails of complex traits are, depending on the strength of selection, 10-20x more likely to harbour singleton or extremely rare alleles of large effect under stabilising selection than neutrality. Such an enrichment of rare, large-effect alleles in the tails of real complex traits subject to stabilising selection could have important implications for the design of studies to detect rare variants, as well as for the prediction and prevention of complex disease.
{"title":"Stabilising selection enriches the tails of complex traits with rare alleles of large effect","authors":"Anil PS Ori, Carla Giner-Delgado, Clive Julian Hoggart, Paul F O'Reilly","doi":"10.1101/2024.09.12.612687","DOIUrl":"https://doi.org/10.1101/2024.09.12.612687","url":null,"abstract":"Establishing the relative contribution of common and rare variants to complex trait heritability is a key goal of biomedical research. Recent statistical genetics inference suggests that common variants explain most complex trait heritability, but little is known about how genetic architecture varies across the trait continuum. If rare variants make a small contribution to heritability but have their effects concentrated in the tails of complex traits, where disease typically manifests, then they may have a greater clinical impact than previously inferred. Here, we perform simulations using the forward-in-time simulator SLiM to generate realistic population genetic and complex trait data, in which traits evolve under neutrality or stabilising selection. Recent studies suggest that stabilising selection is the dominant force shaping the genetic architecture of complex traits, consistent with our simulations in that data simulated under stabilising selection here more closely resembles real data. Moreover, we observe a shift of rare, large-effect alleles towards the tails of the complex trait distribution under stabilising selection. In our simulations, individuals in the tails of complex traits are, depending on the strength of selection, 10-20x more likely to harbour singleton or extremely rare alleles of large effect under stabilising selection than neutrality. Such an enrichment of rare, large-effect alleles in the tails of real complex traits subject to stabilising selection could have important implications for the design of studies to detect rare variants, as well as for the prediction and prevention of complex disease.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"109 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179732","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}
Pub Date : 2024-09-12DOI: 10.1101/2024.08.28.610086
Claire Paltenghi, Jolanda van Leeuwen
Genetic suppression occurs when the phenotypic defects caused by a deleterious mutation are rescued by another mutation. Suppression interactions are of particular interest for genetic diseases, as they identify ways to reduce disease severity, thereby potentially highlighting avenues for therapeutic intervention. To what extent suppression interactions are influenced by the genetic background in which they operate remains largely unknown. However, a high degree of suppression conservation would be crucial for developing therapeutic strategies that target suppressors. To gain an understanding of the effect of the genetic context on suppression, we isolated spontaneous suppressor mutations of temperature sensitive alleles of SEC17, TAO3, and GLN1 in three genetically diverse natural isolates of the budding yeast Saccharomyces cerevisiae. After identifying and validating the genomic variants responsible for suppression, we introduced the suppressors in all three genetic backgrounds, as well as in a laboratory strain, to assess their specificity. Ten out of eleven tested suppression interactions were conserved in the four yeast strains, although the extent to which a suppressor could rescue the temperature sensitive mutant varied across genetic backgrounds. These results suggest that suppression mechanisms are highly conserved across genetic contexts, a finding that is potentially reassuring for the development of therapeutics that mimic genetic suppressors.
{"title":"Genetic suppression interactions are highly conserved across genetic backgrounds","authors":"Claire Paltenghi, Jolanda van Leeuwen","doi":"10.1101/2024.08.28.610086","DOIUrl":"https://doi.org/10.1101/2024.08.28.610086","url":null,"abstract":"Genetic suppression occurs when the phenotypic defects caused by a deleterious mutation are rescued by another mutation. Suppression interactions are of particular interest for genetic diseases, as they identify ways to reduce disease severity, thereby potentially highlighting avenues for therapeutic intervention. To what extent suppression interactions are influenced by the genetic background in which they operate remains largely unknown. However, a high degree of suppression conservation would be crucial for developing therapeutic strategies that target suppressors. To gain an understanding of the effect of the genetic context on suppression, we isolated spontaneous suppressor mutations of temperature sensitive alleles of SEC17, TAO3, and GLN1 in three genetically diverse natural isolates of the budding yeast Saccharomyces cerevisiae. After identifying and validating the genomic variants responsible for suppression, we introduced the suppressors in all three genetic backgrounds, as well as in a laboratory strain, to assess their specificity. Ten out of eleven tested suppression interactions were conserved in the four yeast strains, although the extent to which a suppressor could rescue the temperature sensitive mutant varied across genetic backgrounds. These results suggest that suppression mechanisms are highly conserved across genetic contexts, a finding that is potentially reassuring for the development of therapeutics that mimic genetic suppressors.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"2 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142223723","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}
Pub Date : 2024-09-12DOI: 10.1101/2024.09.10.610174
Selina M Vattathil, Ekaterina S Gerasimov, Se Min Canon, Adriana Lori, Sarah Sze Min Tan, Paul J Kim, Yue Liu, Eric C Lai, David A C. Bennett, Thomas S Wingo, Aliza P Wingo
MicroRNAs are essential post-transcriptional regulators of gene expression and involved in many biological processes; however, our understanding of their genetic regulation and role in brain illnesses is limited. Here, we mapped brain microRNA expression quantitative trait loci (miR-QTLs) using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex (dlPFC) samples of 604 older adult donors of European ancestry. miR-QTLs were identified for 224 miRNAs (48% of 470 tested miRNAs) at false discovery rate < 1%. We found that miR-QTLs were enriched in brain promoters and enhancers, and that intragenic miRNAs often did not share QTLs with their host gene. Additionally, we integrated the brain miR-QTLs with results from 16 GWAS of psychiatric and neurodegenerative diseases using multiple independent integration approaches and identified four miRNAs that contribute to the pathogenesis of bipolar disorder, major depression, post-traumatic stress disorder, schizophrenia, and Parkinson's disease. This study provides novel insights into the contribution of miRNAs to the complex biological networks that link genetic variation to disease.
{"title":"Genetic regulation of microRNAs in the older adult brain and their contribution to neuropsychiatric conditions","authors":"Selina M Vattathil, Ekaterina S Gerasimov, Se Min Canon, Adriana Lori, Sarah Sze Min Tan, Paul J Kim, Yue Liu, Eric C Lai, David A C. Bennett, Thomas S Wingo, Aliza P Wingo","doi":"10.1101/2024.09.10.610174","DOIUrl":"https://doi.org/10.1101/2024.09.10.610174","url":null,"abstract":"MicroRNAs are essential post-transcriptional regulators of gene expression and involved in many biological processes; however, our understanding of their genetic regulation and role in brain illnesses is limited. Here, we mapped brain microRNA expression quantitative trait loci (miR-QTLs) using genome-wide small RNA sequencing profiles from dorsolateral prefrontal cortex (dlPFC) samples of 604 older adult donors of European ancestry. miR-QTLs were identified for 224 miRNAs (48% of 470 tested miRNAs) at false discovery rate < 1%. We found that miR-QTLs were enriched in brain promoters and enhancers, and that intragenic miRNAs often did not share QTLs with their host gene. Additionally, we integrated the brain miR-QTLs with results from 16 GWAS of psychiatric and neurodegenerative diseases using multiple independent integration approaches and identified four miRNAs that contribute to the pathogenesis of bipolar disorder, major depression, post-traumatic stress disorder, schizophrenia, and Parkinson's disease. This study provides novel insights into the contribution of miRNAs to the complex biological networks that link genetic variation to disease.","PeriodicalId":501246,"journal":{"name":"bioRxiv - Genetics","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142179720","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}
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