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Genome-Wide Screening Approaches for Biochemical Reactions Independent of Cell Growth Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-05-02 Yuki Noguchi, Risa Matsui, Jaeyeon Suh, Yu Dou, Jun Suzuki
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
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The Genetics of Human Sleep and Sleep Disorders Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-26 Xianlin Zou, Louis J. Ptáček, Ying-Hui Fu
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
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Beyond the Human Genome Project: The Age of Complete Human Genome Sequences and Pangenome References Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-25 Dylan J. Taylor, Jordan M. Eizenga, Qiuhui Li, Arun Das, Katharine M. Jenike, Eimear E. Kenny, Karen H. Miga, Jean Monlong, Rajiv C. McCoy, Benedict Paten, Michael C. Schatz
The Human Genome Project was an enormous accomplishment, providing a foundation for countless explorations into the genetics and genomics of the human species. Yet for many years, the human genome reference sequence remained incomplete and lacked representation of human genetic diversity. Recently, two major advances have emerged to address these shortcomings: complete gap-free human genome sequences
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Genomic Interactions Between Mycobacterium tuberculosis and Humans Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-19 Prasit Palittapongarnpim, Pornpen Tantivitayakul, Pakorn Aiewsakun, Surakameth Mahasirimongkol, Bharkbhoom Jaemsai
Mycobacterium tuberculosis is considered by many to be the deadliest microbe, with the estimated annual cases numbering more than 10 million. The bacteria, including Mycobacterium africanum, 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
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Integrating Large-Scale Protein Structure Prediction into Human Genetics Research Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-15 Miguel Correa Marrero, Jürgen Jänes, Delora Baptista, Pedro Beltrao
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
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Benefit-Sharing by Design: A Call to Action for Human Genomics Research Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-12 Ann M. Mc Cartney, Amber Hartman Scholz, Mathieu Groussin, Ciara Staunton
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
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Causes and Consequences of Varying Transposable Element Activity: An Evolutionary Perspective Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-11 Andrea J. Betancourt, Kevin H.-C. Wei, Yuheng Huang, Yuh Chwen G. Lee
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
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Deep Learning Sequence Models for Transcriptional Regulation Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-10 Ksenia Sokolova, Kathleen M. Chen, Yun Hao, Jian Zhou, Olga G. Troyanskaya
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
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Polygenic Risk Scores Driving Clinical Change in Glaucoma Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-10 Antonia Kolovos, Mark M. Hassall, Owen M. Siggs, Emmanuelle Souzeau, Jamie E. Craig
Glaucoma is a clinically heterogeneous disease and the world's leading cause of irreversible blindness. Therapeutic intervention can prevent blindness but relies on early diagnosis, and current clinical risk factors are limited in their ability to predict who will develop sight-threatening glaucoma. The high heritability of glaucoma makes it an ideal substrate for genetic risk prediction, with the
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Mapping Human Immunity and the Education of Waldeyer's Ring Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-04-10 Benjamin J. Talks, Michael W. Mather, Manisha Chahal, Matthew Coates, Menna R. Clatworthy, Muzlifah Haniffa
The development and deployment of single-cell genomic technologies have driven a resolution revolution in our understanding of the immune system, providing unprecedented insight into the diversity of immune cells present throughout the body and their function in health and disease. Waldeyer's ring is the collective name for the lymphoid tissue aggregations of the upper aerodigestive tract, comprising
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The Myriad Decision at 10 Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-03-01 Jacob S. Sherkow, Robert Cook-Deegan, Henry T. Greely
A decade ago, the US Supreme Court decided Association for Molecular Pathology v. Myriad Genetics, Inc., concluding that isolated genes were not patentable subject matter. Beyond being a mere patent dispute, the case was a political and cultural phenomenon, viewed as a harbinger for the health of the biotechnology industry. With a decade of perspective, though, Myriad’s impact seems much narrower.
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Population Diversity at the Single-Cell Level Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-02-21 M. Grace Gordon, Pooja Kathail, Bryson Choy, Min Cheol Kim, Thomas Mazumder, Melissa Gearing, Chun Jimmie Ye
Population-scale single-cell genomics is a transformative approach for unraveling the intricate links between genetic and cellular variation. This approach is facilitated by cutting-edge experimental methodologies, including the development of high-throughput single-cell multiomics and advances in multiplexed environmental and genetic perturbations. Examining the effects of natural or synthetic genetic
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RNA Sequencing in Disease Diagnosis Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-02-16 Craig Smail, Stephen B. Montgomery
RNA sequencing (RNA-seq) enables the accurate measurement of multiple transcriptomic phenotypes for modeling the impacts of disease variants. Advances in technologies, experimental protocols, and analysis strategies are rapidly expanding the application of RNA-seq to identify disease biomarkers, tissue- and cell-type-specific impacts, and the spatial localization of disease-associated mechanisms. Ongoing
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PIK3CA-Related Disorders: From Disease Mechanism to Evidence-Based Treatments Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2024-02-06 Gabriel M. Morin, Lola Zerbib, Sophie Kaltenbach, Antoine Fraissenon, Estelle Balducci, Vahid Asnafi, Guillaume Canaud
Recent advances in genetic sequencing are transforming our approach to rare-disease care. Initially identified in cancer, gain-of-function mutations of the PIK3CA gene are also detected in malformation mosaic diseases categorized as PIK3CA-related disorders (PRDs). Over the past decade, new approaches have enabled researchers to elucidate the pathophysiology of PRDs and uncover novel therapeutic options
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The Genetic Determinants of Axial Length: From Microphthalmia to High Myopia in Childhood Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-08-25 Daniel Jackson, Mariya Moosajee
The axial length of the eye is critical for normal visual function by enabling light to precisely focus on the retina. The mean axial length of the adult human eye is 23.5 mm, but the molecular mechanisms regulating ocular axial length remain poorly understood. Underdevelopment can lead to microphthalmia (defined as a small eye with an axial length of less than 19 mm at 1 year of age or less than 21
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TGF-β and BMP Signaling Pathways in Skeletal Dysplasia with Short and Tall Stature Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-08-25 Alice Costantini, Alessandra Guasto, Valérie Cormier-Daire
The transforming growth factor β (TGF-β) and bone morphogenetic protein (BMP) signaling pathways play a pivotal role in bone development and skeletal health. More than 30 different types of skeletal dysplasia are now known to be caused by pathogenic variants in genes that belong to the TGF-β superfamily and/or regulate TGF-β/BMP bioavailability. This review describes the latest advances in skeletal
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The SWI/SNF Complex in Neural Crest Cell Development and Disease Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-08-25 Daniel M. Fountain, Tatjana Sauka-Spengler
While the neural crest cell population gives rise to an extraordinary array of derivatives, including elements of the craniofacial skeleton, skin pigmentation, and peripheral nervous system, it is today increasingly recognized that Schwann cell precursors are also multipotent. Two mammalian paralogs of the SWI/SNF (switch/sucrose nonfermentable) chromatin-remodeling complexes, BAF (Brg1-associated
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Sickle Cell Disease: From Genetics to Curative Approaches Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-08-25 Giulia Hardouin, Elisa Magrin, Alice Corsia, Marina Cavazzana, Annarita Miccio, Michaela Semeraro
Sickle cell disease (SCD) is a monogenic blood disease caused by a point mutation in the gene coding for β-globin. The abnormal hemoglobin [sickle hemoglobin (HbS)] polymerizes under low-oxygen conditions and causes red blood cells to sickle. The clinical presentation varies from very severe (with acute pain, chronic pain, and early mortality) to normal (few complications and a normal life span). The
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DECIPHER: Improving Genetic Diagnosis Through Dynamic Integration of Genomic and Clinical Data Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-06-07 Julia Foreman, Daniel Perrett, Erica Mazaika, Sarah E. Hunt, James S. Ware, Helen V. Firth
DECIPHER (Database of Genomic Variation and Phenotype in Humans Using Ensembl Resources) shares candidate diagnostic variants and phenotypic data from patients with genetic disorders to facilitate research and improve the diagnosis, management, and therapy of rare diseases. The platform sits at the boundary between genomic research and the clinical community. DECIPHER aims to ensure that the most up-to-date
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Federated Analysis for Privacy-Preserving Data Sharing: A Technical and Legal Primer Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-05-31 James Casaletto, Alexander Bernier, Robyn McDougall, Melissa S. Cline
Continued advances in precision medicine rely on the widespread sharing of data that relate human genetic variation to disease. However, data sharing is severely limited by legal, regulatory, and ethical restrictions that safeguard patient privacy. Federated analysis addresses this problem by transferring the code to the data—providing the technical and legal capability to analyze the data within their
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Methods for Assessing Population Relationships and History Using Genomic Data Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-05-23 Priya Moorjani, Garrett Hellenthal
Genetic data contain a record of our evolutionary history. The availability of large-scale datasets of human populations from various geographic areas and timescales, coupled with advances in the computational methods to analyze these data, has transformed our ability to use genetic data to learn about our evolutionary past. Here, we review some of the widely used statistical methods to explore and
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A Journey from Blood Cells to Genes and Back Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-05-23 Lucio Luzzatto
I was attracted to hematology because by combining clinical findings with the use of a microscope and simple laboratory tests, one could often make a diagnosis. I was attracted to genetics when I learned about inherited blood disorders, at a time when we had only hints that somatic mutations were also important. It seemed clear that if we understood not only what genetic changes caused what diseases
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Methods and Insights from Single-Cell Expression Quantitative Trait Loci Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-05-17 Joyce B. Kang, Alessandro Raveane, Aparna Nathan, Nicole Soranzo, Soumya Raychaudhuri
Recent advancements in single-cell technologies have enabled expression quantitative trait locus (eQTL) analysis across many individuals at single-cell resolution. Compared with bulk RNA sequencing, which averages gene expression across cell types and cell states, single-cell assays capture the transcriptional states of individual cells, including fine-grained, transient, and difficult-to-isolate populations
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Meiotic Chromosome Structure, the Synaptonemal Complex, and Infertility Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-05-09 Ian R. Adams, Owen R. Davies
In meiosis, homologous chromosome synapsis is mediated by a supramolecular protein structure, the synaptonemal complex (SC), that assembles between homologous chromosome axes. The mammalian SC comprises at least eight largely coiled-coil proteins that interact and self-assemble to generate a long, zipper-like structure that holds homologous chromosomes in close proximity and promotes the formation
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Long-Read DNA Sequencing: Recent Advances and Remaining Challenges Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-04-19 Peter E. Warburton, Robert P. Sebra
DNA sequencing has revolutionized medicine over recent decades. However, analysis of large structural variation and repetitive DNA, a hallmark of human genomes, has been limited by short-read technology, with read lengths of 100–300 bp. Long-read sequencing (LRS) permits routine sequencing of human DNA fragments tens to hundreds of kilobase pairs in size, using both real-time sequencing by synthesis
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RNA Crossing Membranes: Systems and Mechanisms Contextualizing Extracellular RNA and Cell Surface GlycoRNAs Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-04-17 Peiyuan Chai, Charlotta G. Lebedenko, Ryan A. Flynn
The subcellular localization of a biopolymer often informs its function. RNA is traditionally confined to the cytosolic and nuclear spaces, where it plays critical and conserved roles across nearly all biochemical processes. Our recent observation of cell surface glycoRNAs may further explain the extracellular role of RNA. While cellular membranes are efficient gatekeepers of charged polymers such
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Padlock Probe–Based Targeted In Situ Sequencing: Overview of Methods and Applications Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-04-05 Anastasia Magoulopoulou, Sergio Marco Salas, Katarína Tiklová, Erik Reinhold Samuelsson, Markus M. Hilscher, Mats Nilsson
Elucidating spatiotemporal changes in gene expression has been an essential goal in studies of health, development, and disease. In the emerging field of spatially resolved transcriptomics, gene expression profiles are acquired with the tissue architecture maintained, sometimes at cellular resolution. This has allowed for the development of spatial cell atlases, studies of cell–cell interactions, and
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Return of Results in Genomic Research Using Large-Scale or Whole Genome Sequencing: Toward a New Normal Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-03-13 Susan M. Wolf, Robert C. Green
Genome sequencing is increasingly used in research and integrated into clinical care. In the research domain, large-scale analyses, including whole genome sequencing with variant interpretation and curation, virtually guarantee identification of variants that are pathogenic or likely pathogenic and actionable. Multiple guidelines recommend that findings associated with actionable conditions be offered
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The p-Arms of Human Acrocentric Chromosomes Play by a Different Set of Rules Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-02-28 Brian McStay
The p-arms of the five human acrocentric chromosomes bear nucleolar organizer regions (NORs) comprising ribosomal gene (rDNA) repeats that are organized in a homogeneous tandem array and transcribed in a telomere-to-centromere direction. Precursor ribosomal RNA transcripts are processed and assembled into ribosomal subunits, the nucleolus being the physical manifestation of this process. I review current
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Open Data in the Era of the GDPR: Lessons from the Human Cell Atlas Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-02-15 Bartha Maria Knoppers, Alexander Bernier, Sarion Bowers, Emily Kirby
The Human Cell Atlas (HCA) is striving to build an open community that is inclusive of all researchers adhering to its principles and as open as possible with respect to data access and use. However, open data sharing can pose certain challenges. For instance, being a global initiative, the HCA must contend with a patchwork of local and regional privacy rules. A notable example is the implementation
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Avoiding Liability and Other Legal Land Mines in the Evolving Genomics Landscape Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2023-01-11 Ellen Wright Clayton, Alex M. Tritell, Adrian M. Thorogood
This article reviews evolving legal implications for clinicians and researchers as genomics is used more widely in both the clinic and in translational research, reflecting rapid changes in scientific knowledge as well as the surrounding cultural and political environment. Professionals will face new and changing duties to make or act upon a genetic diagnosis, address direct-to-consumer genetic testing
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The Genetics and Typical Traits of Thoracic Aortic Aneurysm and Dissection Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-08-31 Jotte Rodrigues Bento, Josephina Meester, Ilse Luyckx, Silke Peeters, Aline Verstraeten, Bart Loeys
Genetic predisposition and risk factors such as hypertension and smoking can instigate the development of thoracic aortic aneurysm (TAA), which can lead to highly lethal aortic wall dissection and/or rupture. Monogenic defects in multiple genes involved in the elastin-contractile unit and the TGFβ signaling pathway have been associated with TAA in recent years, along with several genetic modifiers
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Mosaicism in Tumor Suppressor Gene Syndromes: Prevalence, Diagnostic Strategies, and Transmission Risk Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-08-31 Jillian L. Chen, David T. Miller, Laura S. Schmidt, David Malkin, Bruce R. Korf, Charis Eng, David J. Kwiatkowski, Krinio Giannikou
A mosaic state arises when pathogenic variants are acquired in certain cell lineages during postzygotic development, and mosaic individuals may present with a generalized or localized phenotype. Here, we review the current state of knowledge regarding mosaicism for eight common tumor suppressor genes— NF1, NF2, TSC1, TSC2, PTEN, VHL, RB1, and TP53—and their related genetic syndromes/entities. We compare
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Regulation of Molecular Diagnostics Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-08-31 Gail H. Javitt, Erik R. Vollebregt
Molecular diagnostic tests enable rapid analysis of genomic and proteomic markers. These tests are subject to diverging premarket access and postmarket surveillance requirements and mechanisms in the United States and the European Union. Each of these jurisdictions has its own challenges in keeping the regulations up to date with technological developments. A specific area of attention is that of
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The Role of Genome Sequencing in Neonatal Intensive Care Units Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-06-09 Stephen F. Kingsmore, F. Sessions Cole
Genetic diseases disrupt the functionality of an infant's genome during fetal–neonatal adaptation and represent a leading cause of neonatal and infant mortality in the United States. Due to disease acuity, gene locus and allelic heterogeneity, and overlapping and diverse clinical phenotypes, diagnostic genome sequencing in neonatal intensive care units has required the development of methods to shorten
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The Genomics of Auditory Function and Disease Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-06-06 Shahar Taiber, Kathleen Gwilliam, Ronna Hertzano, Karen B. Avraham
Current estimates suggest that nearly half a billion people worldwide are affected by hearing loss. Because of the major psychological, social, economic, and health ramifications, considerable efforts have been invested in identifying the genes and molecular pathways involved in hearing loss, whether genetic or environmental, to promote prevention, improve rehabilitation, and develop therapeutics.
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The Joubert–Meckel–Nephronophthisis Spectrum of Ciliopathies Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-06-03 Julie C. Van De Weghe, Arianna Gomez, Dan Doherty
The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century. Progress in understanding these conditions illustrates many core concepts of human genetics. The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the
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Structural Variation in Cancer: Role, Prevalence, and Mechanisms Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-06-03 Marco Raffaele Cosenza, Bernardo Rodriguez-Martin, Jan O. Korbel
Somatic rearrangements resulting in genomic structural variation drive malignant phenotypes by altering the expression or function of cancer genes. Pan-cancer studies have revealed that structural variants (SVs) are the predominant class of driver mutation in most cancer types, but because they are difficult to discover, they remain understudied when compared with point mutations. This review provides
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Extrachromosomal DNA in Cancer Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-25 Vineet Bafna, Paul S. Mischel
In cancer, complex genome rearrangements and other structural alterations, including the amplification of oncogenes on circular extrachromosomal DNA (ecDNA) elements, drive the formation and progression of tumors. ecDNA is a particularly challenging structural alteration. By untethering oncogenes from chromosomal constraints, it elevates oncogene copy number, drives intratumoral genetic heterogeneity
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The Role of Telomeres in Human Disease Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-25 Mary Armanios
Telomere biology was first studied in maize, ciliates, yeast, and mice, and in recent decades, it has informed understanding of common disease mechanisms with broad implications for patient care. Short telomere syndromes are the most prevalent premature aging disorders, with prominent phenotypes affecting the lung and hematopoietic system. Less understood are a newly recognized group of cancer-prone
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Five Priorities of African Genomics Research: The Next Frontier Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-16 Ambroise Wonkam, Nchangwi S. Munung, Collet Dandara, Kevin K. Esoh, Neil A. Hanchard, Guida Landoure
To embrace the prospects of accurately diagnosing thousands of monogenic conditions, predicting disease risks for complex traits or diseases, tailoring treatment to individuals’ pharmacogenetic profiles, and potentially curing some diseases, research into African genomic variation is a scientific imperative. African genomes harbor millions of uncaptured variants accumulated over 300,000 years of modern
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The Genetics of Brugada Syndrome Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-14 Marina Cerrone, Sarah Costa, Mario Delmar
Brugada syndrome is a heritable channelopathy characterized by a peculiar electrocardiogram (ECG) pattern and increased risk of cardiac arrhythmias and sudden death. The arrhythmias originate because of an imbalance between the repolarizing and depolarizing currents that modulate the cardiac action potential. Even if an overt structural cardiomyopathy is not typical of Brugada syndrome, fibrosis and
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Mapping Human Reproduction with Single-Cell Genomics Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-14 Magda Marečková, Hassan Massalha, Valentina Lorenzi, Roser Vento-Tormo
The trillions of cells in the human body develop as a result of the fusion of two extremely specialized cells: an oocyte and a sperm. This process is essential for the continuation of our species, as it ensures that parental genetic information is mixed and passed on from generation to generation. In addition to producing oocytes, the female reproductive system must provide the environment for the
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A Journey Through Genetics to Biology Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-14 Veronica van Heyningen
Although my engagement with human genetics emerged gradually, and sometimes serendipitously, it has held me spellbound for decades. Without my teachers, students, postdocs, colleagues, and collaborators, I would not be writing this review of my scientific adventures. Early gene and disease mapping was a satisfying puzzle-solving exercise, but building biological insight was my main goal. The project
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Ethical Guidance in Human Paleogenomics: New and Ongoing Perspectives Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-10 Raquel E. Fleskes, Alyssa C. Bader, Krystal S. Tsosie, Jennifer K. Wagner, Katrina G. Claw, Nanibaa’ A. Garrison
Over the past two decades, the study of ancient genomes from Ancestral humans, or human paleogenomic research, has expanded rapidly in both scale and scope. Ethical discourse has subsequently emerged to address issues of social responsibility and scientific robusticity in conducting research. Here, we highlight and contextualize the primary sources of professional ethical guidance aimed at paleogenomic
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Advancing Pharmacogenomics from Single-Gene to Preemptive Testing Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-10 Cyrine E. Haidar, Kristine R. Crews, James M. Hoffman, Mary V. Relling, Kelly E. Caudle
Pharmacogenomic testing can be an effective tool to enhance medication safety and efficacy. Pharmacogenomically actionable medications are widely used, and approximately 90–95% of individuals have an actionable genotype for at least one pharmacogene. For pharmacogenomic testing to have the greatest impact on medication safety and clinical care, genetic information should be made available at the time
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Genetic Disorders of the Extracellular Matrix: From Cell and Gene Therapy to Future Applications in Regenerative Medicine Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-10 Shukti Chakravarti, Elena Enzo, Maithê Rocha Monteiro de Barros, Maria Benedetta Rizzarda Maffezzoni, Graziella Pellegrini
Metazoans have evolved to produce various types of extracellular matrix (ECM) that provide structural support, cell adhesion, cell–cell communication, and regulated exposure to external cues. Epithelial cells produce and adhere to a specialized sheet-like ECM, the basement membrane, that is critical for cellular homeostasis and tissue integrity. Mesenchymal cells, such as chondrocytes in cartilaginous
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The UK Biobank: A Shining Example of Genome-Wide Association Study Science with the Power to Detect the Murky Complications of Real-World Epidemiology Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-05-04 Vanessa Y. Tan, Nicholas J. Timpson
Genome-wide association studies (GWASs) have successfully identified thousands of genetic variants that are reliably associated with human traits. Although GWASs are restricted to certain variant frequencies, they have improved our understanding of the genetic architecture of complex traits and diseases. The UK Biobank (UKBB) has brought substantial analytical opportunity and performance to association
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Decoding the Human Face: Progress and Challenges in Understanding the Genetics of Craniofacial Morphology Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-28 Sahin Naqvi, Hanne Hoskens, Franziska Wilke, Seth M. Weinberg, John R. Shaffer, Susan Walsh, Mark D. Shriver, Joanna Wysocka, Peter Claes
Variations in the form of the human face, which plays a role in our individual identities and societal interactions, have fascinated scientists and artists alike. Here, we review our current understanding of the genetics underlying variation in craniofacial morphology and disease-associated dysmorphology, synthesizing decades of progress on Mendelian syndromes in addition to more recent results from
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Natural and Experimental Rewiring of Gene Regulatory Regions Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-26 Damien J. Downes, Jim R. Hughes
The successful development and ongoing functioning of complex organisms depend on the faithful execution of the genetic code. A critical step in this process is the correct spatial and temporal expression of genes. The highly orchestrated transcription of genes is controlled primarily by cis-regulatory elements: promoters, enhancers, and insulators. The medical importance of this key biological process
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Obtaining Complete Human Proteomes Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-20 Ana Martinez-Val, Ulises H. Guzmán, Jesper V. Olsen
Proteins are the molecular effectors of the information encoded in the genome. Proteomics aims at understanding the molecular functions of proteins in their biological context. In contrast to transcriptomics and genomics, the study of proteomes provides deeper insight into the dynamic regulatory layers encoded at the protein level, such as posttranslational modifications, subcellular localization,
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Maintaining Transcriptional Specificity Through Mitosis Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-20 Kenji Ito, Kenneth S. Zaret
Virtually all cell types have the same DNA, yet each type exhibits its own cell-specific pattern of gene expression. During the brief period of mitosis, the chromosomes exhibit changes in protein composition and modifications, a marked condensation, and a consequent reduction in transcription. Yet as cells exit mitosis, they reactivate their cell-specific programs with high fidelity. Initially, the
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Predicting Archaic Hominin Phenotypes from Genomic Data Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-20 Colin M. Brand, Laura L. Colbran, John A. Capra
Ancient DNA provides a powerful window into the biology of extant and extinct species, including humans’ closest relatives: Denisovans and Neanderthals. Here, we review what is known about archaic hominin phenotypes from genomic data and how those inferences have been made. We contend that understanding the influence of variants on lower-level molecular phenotypes—such as gene expression and protein
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Diverse Molecular Mechanisms Underlying Pathogenic Protein Mutations: Beyond the Loss-of-Function Paradigm Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-08 Lisa Backwell, Joseph A. Marsh
Most known disease-causing mutations occur in protein-coding regions of DNA. While some of these involve a loss of protein function (e.g., through premature stop codons or missense changes that destabilize protein folding), many act via alternative molecular mechanisms and have dominant-negative or gain-of-function effects. In nearly all cases, these non-loss-of-function mutations can be understood
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Genome-Wide Analysis of Human Long Noncoding RNAs: A Provocative Review Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-08 Chris P. Ponting, Wilfried Haerty
Do long noncoding RNAs (lncRNAs) contribute little or substantively to human biology? To address how lncRNA loci and their transcripts, structures, interactions, and functions contribute to human traits and disease, we adopt a genome-wide perspective. We intend to provoke alternative interpretation of questionable evidence and thorough inquiry into unsubstantiated claims. We discuss pitfalls of lncRNA
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Equity in Genomic Medicine Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-01 Chanita Hughes Halbert
Since the completion of the Human Genome Project, considerable progress has been made in translating knowledge about the genetic basis of disease risk and treatment response into clinical services and public health interventions that have greater precision. It is anticipated that more precision approaches to early detection, prevention, and treatment will be developed and will enhance equity in healthcare
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Establishing the Medical Actionability of Genomic Variants Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-04-01 Katrina A.B. Goddard, Kristy Lee, Adam H. Buchanan, Bradford C. Powell, Jessica Ezzell Hunter
Actionability is an important concept in medicine that does not have a well-accepted standard definition, nor is there a general consensus on how to establish it. Medical actionability is often conflated with clinical utility, a related but distinct concept. This lack of clarity contributes to practice variation and inconsistent coverage decisions in genomic medicine, leading to the potential for systematic
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The Next Frontier in Noninvasive Prenatal Diagnostics: Cell-Free Fetal DNA Analysis for Monogenic Disease Assessment Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-03-22 Lilian Pok Wa Zhong, Rossa W.K. Chiu
With the widespread clinical adoption of noninvasive screening for fetal chromosomal aneuploidies based on cell-free DNA analysis from maternal plasma, more researchers are turning their attention to noninvasive prenatal assessment for single-gene disorders. The development of a spectrum of approaches to analyze cell-free DNA in maternal circulation, including relative mutation dosage, relative haplotype
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Population Screening in Health Systems Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2022-02-17 Marc S. Williams
Applications of genomics to population screening are expanding in the United States and internationally. Many of these programs are being implemented in the context of healthcare systems, mostly in a clinical research setting, but there are some emerging examples of clinical models. This review examines these genomic population screening programs to identify common features and differences in screened
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Global Governance of Human Genome Editing: What Are the Rules? Annu. Rev. Genomics Hum. Genet. (IF 8.7) Pub Date : 2021-08-31 Gary E. Marchant
Human gene editing, particularly using the new CRISPR/Cas9 technology, will greatly increase the capability to make precise changes to human genomes. Human gene editing can be broken into four major categories: somatic therapy, heritable gene editing, genetic enhancement, and basic and applied research. Somatic therapy is generally well governed by national regulatory systems, so the need for global