Marian F. Laughery, Hannah E. Wilson, Allysa Sewell, Scott Stevison, John J. Wyrick
Ultraviolet (UV) light is the most pervasive environmental mutagen and the primary cause of skin cancer. Genome sequencing of melanomas and other skin cancers has revealed that the vast majority of somatic mutations in these tumors are cytosine-to-thymine (C>T) substitutions in dipyrimidine sequences, which, together with tandem CC>TT substitutions, comprise the canonical UV mutation “signature”. These mutation classes are caused by DNA damage directly induced by UV absorption, namely cyclobutane pyrimidine dimers (CPDs) or 6-4 pyrimidine-pyrimidone photoproducts (6-4PP), which form between neighboring pyrimidine bases. However, many of the key driver mutations in melanoma do not fit this mutation signature, but instead are caused by T>A, T>C, C>A, or AC>TT substitutions, frequently occurring in non-dipyrimidine sequence contexts. This article describes recent studies indicating that UV light causes a more diverse spectrum of mutations than previously appreciated, including many of the mutation classes observed in melanoma driver mutations. Potential mechanisms for these diverse mutation signatures are discussed, including UV-induced pyrimidine-purine photoproducts and indirect DNA damage induced by UVA light. Finally, the article reviews recent findings indicating that human DNA polymerase eta normally suppresses these non-canonical UV mutation classes, which can potentially explain why canonical C>T substitutions predominate in human skin cancers.
紫外线(UV)是最普遍的环境诱变剂,也是导致皮肤癌的主要原因。黑色素瘤和其他皮肤癌的基因组测序显示,这些肿瘤中的绝大多数体细胞突变都是二嘧啶序列中胞嘧啶-胸腺嘧啶(C>T)的置换,它们与串联的 CC>TT 置换一起构成了典型的紫外线突变 "特征"。这些突变类别是由紫外线吸收直接诱导的 DNA 损伤引起的,即在相邻嘧啶碱基之间形成的环丁烷嘧啶二聚体(CPD)或 6-4 嘧啶-嘧啶酮光致产物(6-4PP)。然而,黑色素瘤中的许多关键驱动突变并不符合这种突变特征,而是由T>A、T>C、C>A或AC>TT置换引起的,而且经常发生在非二嘧啶序列上下文中。本文介绍了最近的一些研究,这些研究表明,紫外线导致的突变比以前认识到的更为多样,其中包括在黑色素瘤驱动突变中观察到的许多突变类别。文章讨论了这些不同突变特征的潜在机制,包括紫外线诱导的嘧啶-嘌呤光产物和紫外线诱导的间接 DNA 损伤。最后,文章回顾了最近的研究结果,这些结果表明人类DNA聚合酶eta通常会抑制这些非典型紫外线突变类别,这有可能解释了为什么典型的C>T置换在人类皮肤癌中占主导地位。
{"title":"The Surprising Diversity of UV-Induced Mutations","authors":"Marian F. Laughery, Hannah E. Wilson, Allysa Sewell, Scott Stevison, John J. Wyrick","doi":"10.1002/ggn2.202300205","DOIUrl":"https://doi.org/10.1002/ggn2.202300205","url":null,"abstract":"<p>Ultraviolet (UV) light is the most pervasive environmental mutagen and the primary cause of skin cancer. Genome sequencing of melanomas and other skin cancers has revealed that the vast majority of somatic mutations in these tumors are cytosine-to-thymine (C>T) substitutions in dipyrimidine sequences, which, together with tandem CC>TT substitutions, comprise the canonical UV mutation “signature”. These mutation classes are caused by DNA damage directly induced by UV absorption, namely cyclobutane pyrimidine dimers (CPDs) or 6-4 pyrimidine-pyrimidone photoproducts (6-4PP), which form between neighboring pyrimidine bases. However, many of the key driver mutations in melanoma do not fit this mutation signature, but instead are caused by T>A, T>C, C>A, or AC>TT substitutions, frequently occurring in non-dipyrimidine sequence contexts. This article describes recent studies indicating that UV light causes a more diverse spectrum of mutations than previously appreciated, including many of the mutation classes observed in melanoma driver mutations. Potential mechanisms for these diverse mutation signatures are discussed, including UV-induced pyrimidine-purine photoproducts and indirect DNA damage induced by UVA light. Finally, the article reviews recent findings indicating that human DNA polymerase eta normally suppresses these non-canonical UV mutation classes, which can potentially explain why canonical C>T substitutions predominate in human skin cancers.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"5 2","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202300205","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141315358","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}
Jack Gemayel, Alain Chebly, Hampig Kourie, Colette Hanna, Kayane Mheidly, Melissa Mhanna, Farah Karam, Daniel Ghoussaini, Paula El Najjar, Charbel Khalil
Cancer is one of the foremost causes of mortality. The human genome remains stable over time. However, human activities and environmental factors have the power to influence the prevalence of certain types of mutations. This goes to the excessive progress of xenobiotics and industrial development that is expanding the territory for cancers to develop. The mechanisms involved in immune responses against cancer are widely studied. Genome editing has changed the genome-based immunotherapy process in the human body and has opened a new era for cancer treatment. In this review, recent cancer immunotherapies and the use of genome engineering technology are largely focused on.
{"title":"Genome Engineering as a Therapeutic Approach in Cancer Therapy: A Comprehensive Review","authors":"Jack Gemayel, Alain Chebly, Hampig Kourie, Colette Hanna, Kayane Mheidly, Melissa Mhanna, Farah Karam, Daniel Ghoussaini, Paula El Najjar, Charbel Khalil","doi":"10.1002/ggn2.202300201","DOIUrl":"10.1002/ggn2.202300201","url":null,"abstract":"<p>Cancer is one of the foremost causes of mortality. The human genome remains stable over time. However, human activities and environmental factors have the power to influence the prevalence of certain types of mutations. This goes to the excessive progress of xenobiotics and industrial development that is expanding the territory for cancers to develop. The mechanisms involved in immune responses against cancer are widely studied. Genome editing has changed the genome-based immunotherapy process in the human body and has opened a new era for cancer treatment. In this review, recent cancer immunotherapies and the use of genome engineering technology are largely focused on.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202300201","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139864999","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}
Plant biology studies in the post-genome era have been focused on annotating genome sequences’ functions. The established plant mutant collections have greatly accelerated functional genomics research in the past few decades. However, most plant genome sequences' roles and the underlying regulatory networks remain substantially unknown. Clustered, regularly interspaced short palindromic repeat (CRISPR)-associated systems are robust, versatile tools for manipulating plant genomes with various targeted DNA perturbations, providing an excellent opportunity for high-throughput interrogation of DNA elements’ roles. This study compares methods frequently used for plant functional genomics and then discusses different DNA multi-targeted strategies to overcome gene redundancy using the CRISPR-Cas9 system. Next, this work summarizes recent reports using CRISPR libraries for high-throughput gene knockout and function discoveries in plants. Finally, this work envisions the future perspective of optimizing and leveraging CRISPR library screening in plant genomes' other uncharacterized DNA sequences.
后基因组时代的植物生物学研究主要集中在注释基因组序列的功能上。已经建立的植物突变体库在过去几十年中大大加速了功能基因组学的研究。然而,大多数植物基因组序列的作用及其背后的调控网络仍然鲜为人知。与聚类、规则间隔短回文重复(CRISPR)相关的系统是一种强大的多功能工具,可通过各种有针对性的 DNA 干扰来操纵植物基因组,为高通量检测 DNA 元素的作用提供了绝佳机会。本研究比较了植物功能基因组学常用的方法,然后讨论了利用 CRISPR-Cas9 系统克服基因冗余的不同 DNA 多靶点策略。接下来,本研究总结了最近利用 CRISPR 文库在植物中进行高通量基因敲除和功能发现的报道。最后,本文展望了在植物基因组其他未表征 DNA 序列中优化和利用 CRISPR 文库筛选的未来前景。
{"title":"Plant Functional Genomics Based on High-Throughput CRISPR Library Knockout Screening: A Perspective","authors":"Jianjie He, Can Zeng, Maoteng Li","doi":"10.1002/ggn2.202300203","DOIUrl":"https://doi.org/10.1002/ggn2.202300203","url":null,"abstract":"<p>Plant biology studies in the post-genome era have been focused on annotating genome sequences’ functions. The established plant mutant collections have greatly accelerated functional genomics research in the past few decades. However, most plant genome sequences' roles and the underlying regulatory networks remain substantially unknown. Clustered, regularly interspaced short palindromic repeat (CRISPR)-associated systems are robust, versatile tools for manipulating plant genomes with various targeted DNA perturbations, providing an excellent opportunity for high-throughput interrogation of DNA elements’ roles. This study compares methods frequently used for plant functional genomics and then discusses different DNA multi-targeted strategies to overcome gene redundancy using the CRISPR-Cas9 system. Next, this work summarizes recent reports using CRISPR libraries for high-throughput gene knockout and function discoveries in plants. Finally, this work envisions the future perspective of optimizing and leveraging CRISPR library screening in plant genomes' other uncharacterized DNA sequences.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"5 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202300203","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140063864","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}
Deep learning (DL) approaches have the ability to accurately recognize promoter regions and predict their strength. Here, the potential for controllably designing active Escherichia coli promoter is explored by combining multiple deep learning models. First, “DRSAdesign,” which relies on a diffusion model to generate different types of novel promoters is created, followed by predicting whether they are real or fake and strength. Experimental validation showed that 45 out of 50 generated promoters are active with high diversity, but most promoters have relatively low activity. Next, “Ndesign,” which relies on generating random sequences carrying functional −35 and −10 motifs of the sigma70 promoter is introduced, and their strength is predicted using the designed DL model. The DL model is trained and validated using 200 and 50 generated promoters, and displays Pearson correlation coefficients of 0.49 and 0.43, respectively. Taking advantage of the DL models developed in this work, possible 6-mers are predicted as key functional motifs of the sigma70 promoter, suggesting that promoter recognition and strength prediction mainly rely on the accommodation of functional motifs. This work provides DL tools to design promoters and assess their functions, paving the way for DL-assisted metabolic engineering.
{"title":"Deep Learning-Assisted Design of Novel Promoters in Escherichia coli","authors":"Xinglong Wang, Kangjie Xu, Yameng Tan, Shangyang Yu, Xinyi Zhao, Jingwen Zhou","doi":"10.1002/ggn2.202300184","DOIUrl":"https://doi.org/10.1002/ggn2.202300184","url":null,"abstract":"<p>Deep learning (DL) approaches have the ability to accurately recognize promoter regions and predict their strength. Here, the potential for controllably designing active <i>Escherichia coli</i> promoter is explored by combining multiple deep learning models. First, “DRSAdesign,” which relies on a diffusion model to generate different types of novel promoters is created, followed by predicting whether they are real or fake and strength. Experimental validation showed that 45 out of 50 generated promoters are active with high diversity, but most promoters have relatively low activity. Next, “Ndesign,” which relies on generating random sequences carrying functional −35 and −10 motifs of the sigma70 promoter is introduced, and their strength is predicted using the designed DL model. The DL model is trained and validated using 200 and 50 generated promoters, and displays Pearson correlation coefficients of 0.49 and 0.43, respectively. Taking advantage of the DL models developed in this work, possible 6-mers are predicted as key functional motifs of the sigma70 promoter, suggesting that promoter recognition and strength prediction mainly rely on the accommodation of functional motifs. This work provides DL tools to design promoters and assess their functions, paving the way for DL-assisted metabolic engineering.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202300184","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138578122","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}
Observational studies have shown that alterations in gut microbiota composition are associated with low back pain. However, it remains unclear whether the association is causal. To reveal the causal association between gut microbiota and low back pain, a two-sample bidirectional Mendelian randomization (MR) analysis is performed. The inverse variance weighted regression (IVW) is performed as the principal MR analysis. MR-Egger and Weighted Median is further conducted as complementary analysis to validate the robustness of the results. Finally, a reverse MR analysis is performed to evaluate the possibility of reverse causation. The inverse variance weighted (IVW) method suggests that Peptostreptococcaceae (odds ratio [OR] 1.056, 95% confidence interval [CI] [1.015–1.098], PIVW = 0.010), and Lactobacillaceae (OR 1.070, 95% CI [1.026–1.115], PIVW = 0.003) are positively associated with back pain. The Ruminococcaceae (OR 0.923, 95% CI [0.849–0.997], PIVW = 0.033), Butyricicoccus (OR 0.920, 95% CI [0.868 - 0.972], PIVW = 0.002), and Lachnospiraceae (OR 0.948, 95% CI [0.903–0.994], PIVW = 0.022) are negatively associated with back pain. In this study, underlying causal relationships are identified among gut microbiota and low back pain. Notably, further research is needed on the biological mechanisms by which gut microbiota influences low back pain.
观察性研究表明,肠道微生物群组成的改变与腰背痛有关。然而,这种关联是否是因果关系仍不清楚。为了揭示肠道微生物群与腰背痛之间的因果关系,我们进行了双样本双向孟德尔随机(MR)分析。反方差加权回归(IVW)作为主要的 MR 分析。作为补充分析,还进一步进行了 MR-Egger 和加权中位数分析,以验证结果的稳健性。最后,还进行了反向 MR 分析,以评估反向因果关系的可能性。反向方差加权(IVW)法表明,胨链球菌科(几率比[OR]1.056,95% 置信区间[CI][1.015-1.098],PIVW = 0.010)和乳酸菌科(OR 1.070,95% 置信区间[CI][1.026-1.115],PIVW = 0.003)与背痛呈正相关。反刍球菌科(OR 0.923,95% CI [0.849-0.997],PIVW = 0.033)、丁酸球菌科(OR 0.920,95% CI [0.868-0.972],PIVW = 0.002)和漆树科(OR 0.948,95% CI [0.903-0.994],PIVW = 0.022)与背痛呈负相关。本研究确定了肠道微生物群与腰背痛之间的潜在因果关系。值得注意的是,还需要进一步研究肠道微生物群影响腰背痛的生物学机制。
{"title":"Insight into the Causal Relationship between Gut Microbiota and Back Pain: A Two Sample Bidirectional Mendelian Randomization Study","authors":"Jingni Hui, Yujing Chen, Chun'e Li, Yifan Gou, Ye Liu, Ruixue Zhou, Meijuan Kang, Chen Liu, Bingyi Wang, Panxing Shi, Shiqiang Cheng, Xuena Yang, Chuyu Pan, Yumeng Jia, Bolun Cheng, Huan Liu, Yan Wen, Feng Zhang","doi":"10.1002/ggn2.202300192","DOIUrl":"10.1002/ggn2.202300192","url":null,"abstract":"<p>Observational studies have shown that alterations in gut microbiota composition are associated with low back pain. However, it remains unclear whether the association is causal. To reveal the causal association between gut microbiota and low back pain, a two-sample bidirectional Mendelian randomization (MR) analysis is performed. The inverse variance weighted regression (IVW) is performed as the principal MR analysis. MR-Egger and Weighted Median is further conducted as complementary analysis to validate the robustness of the results. Finally, a reverse MR analysis is performed to evaluate the possibility of reverse causation. The inverse variance weighted (IVW) method suggests that <i>Peptostreptococcaceae</i> (odds ratio [OR] 1.056, 95% confidence interval [CI] [1.015–1.098], <i>P</i><sub>IVW</sub> = 0.010), and <i>Lactobacillaceae</i> (OR 1.070, 95% CI [1.026–1.115], <i>P</i><sub>IVW</sub> = 0.003) are positively associated with back pain. The <i>Ruminococcaceae</i> (OR 0.923, 95% CI [0.849–0.997], <i>P</i><sub>IVW</sub> = 0.033), <i>Butyricicoccus</i> (OR 0.920, 95% CI [0.868 - 0.972], <i>P</i><sub>IVW</sub> = 0.002), and <i>Lachnospiraceae</i> (OR 0.948, 95% CI [0.903–0.994], <i>P</i><sub>IVW</sub> = 0.022) are negatively associated with back pain. In this study, underlying causal relationships are identified among gut microbiota and low back pain. Notably, further research is needed on the biological mechanisms by which gut microbiota influences low back pain.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202300192","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135391598","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}
Infectious diseases such as malaria, tuberculosis (TB), human immunodeficiency virus (HIV), and the coronavirus disease of 2019 (COVID-19) are problematic globally, with high prevalence particularly in Africa, attributing to most of the death rates. There have been immense efforts toward developing effective preventative and therapeutic strategies for these pathogens globally, however, some remain uncured. Disease susceptibility and progression for malaria, TB, HIV, and COVID-19 vary among individuals and are attributed to precautionary measures, environment, host, and pathogen genetics. While studying individuals with similar attributes, it is suggested that host genetics contributes to most of an individual's susceptibility to disease. Several host genes are identified to associate with these pathogens. Interestingly, many of these genes and polymorphisms are common across diseases. This paper analyzes genes and genetic variations within host genes associated with HIV, TB, malaria, and COVID-19 among different ethnic groups. The differences in host–pathogen interaction among these groups, particularly of Caucasian and African descent, and which gene polymorphisms are prevalent in an African population that possesses protection or risk to disease are reviewed. The information in this review could potentially help develop personalized treatment that could effectively combat the high disease burden in Africa.
{"title":"Host Genetic Impact on Infectious Diseases among Different Ethnic Groups","authors":"Lisa Naidoo, Thilona Arumugam, Veron Ramsuran","doi":"10.1002/ggn2.202300181","DOIUrl":"10.1002/ggn2.202300181","url":null,"abstract":"<p>Infectious diseases such as malaria, tuberculosis (TB), human immunodeficiency virus (HIV), and the coronavirus disease of 2019 (COVID-19) are problematic globally, with high prevalence particularly in Africa, attributing to most of the death rates. There have been immense efforts toward developing effective preventative and therapeutic strategies for these pathogens globally, however, some remain uncured. Disease susceptibility and progression for malaria, TB, HIV, and COVID-19 vary among individuals and are attributed to precautionary measures, environment, host, and pathogen genetics. While studying individuals with similar attributes, it is suggested that host genetics contributes to most of an individual's susceptibility to disease. Several host genes are identified to associate with these pathogens. Interestingly, many of these genes and polymorphisms are common across diseases. This paper analyzes genes and genetic variations within host genes associated with HIV, TB, malaria, and COVID-19 among different ethnic groups. The differences in host–pathogen interaction among these groups, particularly of Caucasian and African descent, and which gene polymorphisms are prevalent in an African population that possesses protection or risk to disease are reviewed. The information in this review could potentially help develop personalized treatment that could effectively combat the high disease burden in Africa.</p>","PeriodicalId":72071,"journal":{"name":"Advanced genetics (Hoboken, N.J.)","volume":"4 4","pages":""},"PeriodicalIF":0.0,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ggn2.202300181","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135725050","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}