{"title":"Toward Realizing the Promise of AI in Precision Health Across the Spectrum of Care.","authors":"Jenna Wiens, Kayte Spector-Bagdady, Bhramar Mukherjee","doi":"10.1146/annurev-genom-010323-010230","DOIUrl":"10.1146/annurev-genom-010323-010230","url":null,"abstract":"<p><p>Significant progress has been made in augmenting clinical decision-making using artificial intelligence (AI) in the context of secondary and tertiary care at large academic medical centers. For such innovations to have an impact across the spectrum of care, additional challenges must be addressed, including inconsistent use of preventative care and gaps in chronic care management. The integration of additional data, including genomics and data from wearables, could prove critical in addressing these gaps, but technical, legal, and ethical challenges arise. On the technical side, approaches for integrating complex and messy data are needed. Data and design imperfections like selection bias, missing data, and confounding must be addressed. In terms of legal and ethical challenges, while AI has the potential to aid in leveraging patient data to make clinical care decisions, we also risk exacerbating existing disparities. Organizations implementing AI solutions must carefully consider how they can improve care for all and reduce inequities.</p>","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":" ","pages":"141-159"},"PeriodicalIF":7.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140896966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ana Luiza Arruda, Georgia Katsoula, Shibo Chen, Ene Reimann, Peter Kreitmaier, Eleftheria Zeggini
{"title":"The Genetics and Functional Genomics of Osteoarthritis.","authors":"Ana Luiza Arruda, Georgia Katsoula, Shibo Chen, Ene Reimann, Peter Kreitmaier, Eleftheria Zeggini","doi":"10.1146/annurev-genom-010423-095636","DOIUrl":"https://doi.org/10.1146/annurev-genom-010423-095636","url":null,"abstract":"<p><p>Osteoarthritis is the most prevalent whole-joint degenerative disorder, and is characterized by the degradation of articular cartilage and the underlying bone structures. Almost 600 million people are affected by osteoarthritis worldwide. No curative treatments are available, and management strategies focus mostly on pain relief. Here, we provide a comprehensive overview of the available human genetic and functional genomics studies for osteoarthritis to date and delineate how these studies have helped shed light on disease etiopathology. We highlight genetic discoveries from genome-wide association studies and provide a detailed overview of molecular-level investigations in osteoarthritis tissues, including methylation-, transcriptomics-, and proteomics-level analyses. We review how functional genomics data from different molecular levels have helped to prioritize effector genes that can be used as drug targets or drug-repurposing opportunities. Finally, we discuss future directions with the potential to drive a step change in osteoarthritis research.</p>","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":"25 1","pages":"239-257"},"PeriodicalIF":7.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142078933","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Gabriel M Morin, Lola Zerbib, Sophie Kaltenbach, Antoine Fraissenon, Estelle Balducci, Vahid Asnafi, Guillaume Canaud
{"title":"<i>PIK3CA</i>-Related Disorders: From Disease Mechanism to Evidence-Based Treatments.","authors":"Gabriel M Morin, Lola Zerbib, Sophie Kaltenbach, Antoine Fraissenon, Estelle Balducci, Vahid Asnafi, Guillaume Canaud","doi":"10.1146/annurev-genom-121222-114518","DOIUrl":"10.1146/annurev-genom-121222-114518","url":null,"abstract":"<p><p>Recent advances in genetic sequencing are transforming our approach to rare-disease care. Initially identified in cancer, gain-of-function mutations of the <i>PIK3CA</i> gene are also detected in malformation mosaic diseases categorized as <i>PIK3CA</i>-related disorders (PRDs). Over the past decade, new approaches have enabled researchers to elucidate the pathophysiology of PRDs and uncover novel therapeutic options. In just a few years, owing to vigorous global research efforts, PRDs have been transformed from incurable diseases to chronic disorders accessible to targeted therapy. However, new challenges for both medical practitioners and researchers have emerged. Areas of uncertainty remain in our comprehension of PRDs, especially regarding the relationship between genotype and phenotype, the mechanisms underlying mosaicism, and the processes involved in intercellular communication. As the clinical and biological landscape of PRDs is constantly evolving, this review aims to summarize current knowledge regarding <i>PIK3CA</i> and its role in nonmalignant human disease, from molecular mechanisms to evidence-based treatments.</p>","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":" ","pages":"211-237"},"PeriodicalIF":7.7,"publicationDate":"2024-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691072","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Yuki Noguchi, Risa Matsui, Jaeyeon Suh, Yu Dou, Jun Suzuki
{"title":"Genome-Wide Screening Approaches for Biochemical Reactions Independent of Cell Growth","authors":"Yuki Noguchi, Risa Matsui, Jaeyeon Suh, Yu Dou, Jun Suzuki","doi":"10.1146/annurev-genom-121222-115958","DOIUrl":"https://doi.org/10.1146/annurev-genom-121222-115958","url":null,"abstract":"Genome-wide screening is a potent approach for comprehensively understanding the molecular mechanisms of biological phenomena. However, despite its widespread use in the past decades across various biological targets, its application to biochemical reactions with temporal and reversible biological outputs remains a formidable challenge. To uncover the molecular machinery underlying various biochemical reactions, we have recently developed the revival screening method, which combines flow cytometry–based cell sorting with library reconstruction from collected cells. Our refinements to the traditional genome-wide screening technique have proven successful in revealing the molecular machinery of biochemical reactions of interest. In this article, we elucidate the technical basis of revival screening, focusing on its application to CRISPR-Cas9 single guide RNA (sgRNA) library and complementary DNA (cDNA) library screening. Finally, we also discuss the future of genome-wide screening while describing recent achievements from in vitro and in vivo screening.","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":"31 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-05-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140831318","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"The Genetics of Human Sleep and Sleep Disorders","authors":"Xianlin Zou, Louis J. Ptáček, Ying-Hui Fu","doi":"10.1146/annurev-genom-121222-120306","DOIUrl":"https://doi.org/10.1146/annurev-genom-121222-120306","url":null,"abstract":"Healthy sleep is vital for humans to achieve optimal health and longevity. Poor sleep and sleep disorders are strongly associated with increased morbidity and mortality. However, the importance of good sleep continues to be underrecognized. Mechanisms regulating sleep and its functions in humans remain mostly unclear even after decades of dedicated research. Advancements in gene sequencing techniques and computational methodologies have paved the way for various genetic analysis approaches, which have provided some insights into human sleep genetics. This review summarizes our current knowledge of the genetic basis underlying human sleep traits and sleep disorders. We also highlight the use of animal models to validate genetic findings from human sleep studies and discuss potential molecular mechanisms and signaling pathways involved in the regulation of human sleep.","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":"20 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140800036","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Genomic Interactions Between Mycobacterium tuberculosis and Humans","authors":"Prasit Palittapongarnpim, Pornpen Tantivitayakul, Pakorn Aiewsakun, Surakameth Mahasirimongkol, Bharkbhoom Jaemsai","doi":"10.1146/annurev-genom-021623-101844","DOIUrl":"https://doi.org/10.1146/annurev-genom-021623-101844","url":null,"abstract":"<jats:italic>Mycobacterium tuberculosis</jats:italic> is considered by many to be the deadliest microbe, with the estimated annual cases numbering more than 10 million. The bacteria, including <jats:italic>Mycobacterium africanum</jats:italic>, are classified into nine major lineages and hundreds of sublineages, each with different geographical distributions and levels of virulence. The phylogeographic patterns can be a result of recent and early human migrations as well as coevolution between the bacteria and various human populations, which may explain why many studies on human genetic factors contributing to tuberculosis have not been replicable in different areas. Moreover, several studies have revealed the significance of interactions between human genetic variations and bacterial genotypes in determining the development of tuberculosis, suggesting coadaptation. The increased availability of whole-genome sequence data from both humans and bacteria has enabled a better understanding of these interactions, which can inform the development of vaccines and other control measures.","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":"122 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140623985","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Miguel Correa Marrero, Jürgen Jänes, Delora Baptista, Pedro Beltrao
{"title":"Integrating Large-Scale Protein Structure Prediction into Human Genetics Research","authors":"Miguel Correa Marrero, Jürgen Jänes, Delora Baptista, Pedro Beltrao","doi":"10.1146/annurev-genom-120622-020615","DOIUrl":"https://doi.org/10.1146/annurev-genom-120622-020615","url":null,"abstract":"The last five years have seen impressive progress in deep learning models applied to protein research. Most notably, sequence-based structure predictions have seen transformative gains in the form of AlphaFold2 and related approaches. Millions of missense protein variants in the human population lack annotations, and these computational methods are a valuable means to prioritize variants for further analysis. Here, we review the recent progress in deep learning models applied to the prediction of protein structure and protein variants, with particular emphasis on their implications for human genetics and health. Improved prediction of protein structures facilitates annotations of the impact of variants on protein stability, protein–protein interaction interfaces, and small-molecule binding pockets. Moreover, it contributes to the study of host–pathogen interactions and the characterization of protein function. As genome sequencing in large cohorts becomes increasingly prevalent, we believe that better integration of state-of-the-art protein informatics technologies into human genetics research is of paramount importance.","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":"31 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579683","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ann M. Mc Cartney, Amber Hartman Scholz, Mathieu Groussin, Ciara Staunton
{"title":"Benefit-Sharing by Design: A Call to Action for Human Genomics Research","authors":"Ann M. Mc Cartney, Amber Hartman Scholz, Mathieu Groussin, Ciara Staunton","doi":"10.1146/annurev-genom-021623-104241","DOIUrl":"https://doi.org/10.1146/annurev-genom-021623-104241","url":null,"abstract":"The ethical standards for the responsible conduct of human research have come a long way; however, concerns surrounding equity remain in human genetics and genomics research. Addressing these concerns will help society realize the full potential of human genomics research. One outstanding concern is the fair and equitable sharing of benefits from research on human participants. Several international bodies have recognized that benefit-sharing can be an effective tool for ethical research conduct, but international laws, including the Convention on Biological Diversity and its Nagoya Protocol on Access and Benefit-Sharing, explicitly exclude human genetic and genomic resources. These agreements face significant challenges that must be considered and anticipated if similar principles are applied in human genomics research. We propose that benefit-sharing from human genomics research can be a bottom-up effort and embedded into the existing research process. We propose the development of a “benefit-sharing by design” framework to address concerns of fairness and equity in the use of human genomic resources and samples and to learn from the aspirations and decade of implementation of the Nagoya Protocol.","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":"88 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579547","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Andrea J. Betancourt, Kevin H.-C. Wei, Yuheng Huang, Yuh Chwen G. Lee
{"title":"Causes and Consequences of Varying Transposable Element Activity: An Evolutionary Perspective","authors":"Andrea J. Betancourt, Kevin H.-C. Wei, Yuheng Huang, Yuh Chwen G. Lee","doi":"10.1146/annurev-genom-120822-105708","DOIUrl":"https://doi.org/10.1146/annurev-genom-120822-105708","url":null,"abstract":"Transposable elements (TEs) are genomic parasites found in nearly all eukaryotes, including humans. This evolutionary success of TEs is due to their replicative activity, involving insertion into new genomic locations. TE activity varies at multiple levels, from between taxa to within individuals. The rapidly accumulating evidence of the influence of TE activity on human health, as well as the rapid growth of new tools to study it, motivated an evaluation of what we know about TE activity thus far. Here, we discuss why TE activity varies, and the consequences of this variation, from an evolutionary perspective. By studying TE activity in nonhuman organisms in the context of evolutionary theories, we can shed light on the factors that affect TE activity. While the consequences of TE activity are usually deleterious, some have lasting evolutionary impacts by conferring benefits on the host or affecting other evolutionary processes.","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":"94 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579428","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ksenia Sokolova, Kathleen M. Chen, Yun Hao, Jian Zhou, Olga G. Troyanskaya
{"title":"Deep Learning Sequence Models for Transcriptional Regulation","authors":"Ksenia Sokolova, Kathleen M. Chen, Yun Hao, Jian Zhou, Olga G. Troyanskaya","doi":"10.1146/annurev-genom-021623-024727","DOIUrl":"https://doi.org/10.1146/annurev-genom-021623-024727","url":null,"abstract":"Deciphering the regulatory code of gene expression and interpreting the transcriptional effects of genome variation are critical challenges in human genetics. Modern experimental technologies have resulted in an abundance of data, enabling the development of sequence-based deep learning models that link patterns embedded in DNA to the biochemical and regulatory properties contributing to transcriptional regulation, including modeling epigenetic marks, 3D genome organization, and gene expression, with tissue and cell-type specificity. Such methods can predict the functional consequences of any noncoding variant in the human genome, even rare or never-before-observed variants, and systematically characterize their consequences beyond what is tractable from experiments or quantitative genetics studies alone. Recently, the development and application of interpretability approaches have led to the identification of key sequence patterns contributing to the predicted tasks, providing insights into the underlying biological mechanisms learned and revealing opportunities for improvement in future models.","PeriodicalId":8231,"journal":{"name":"Annual review of genomics and human genetics","volume":"98 1","pages":""},"PeriodicalIF":8.7,"publicationDate":"2024-04-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140579567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}