The roadmap for the development of the Human Variome - Development of functional multi-omics analyses for the understanding of human biology

The human variome encompasses the full spectrum of genetic variation underlying human biology, health, and disease. Recent advances in next-generation sequencing and multi-omics, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics, have enabled unprecedented insights into the functional elements of the genome and their clinical relevance. Collaborative efforts, such as ClinVar and the Rare Diseases Models and Mechanisms initiatives, have accelerated the integration of clinical and research data; however, the interpretation of variants of uncertain significance (VUS) remains a significant challenge in genomic analysis. High-throughput functional assays, including CRISPR-based perturbations, single-cell multi-omics, and multiplexed variant effect mapping, now allow systematic dissection of variant function at both molecular and cellular levels, directly linking genotype to phenotype. The emergence of comprehensive resources, such as the human pangenome and improved population databases, is enhancing variant interpretation. This interplay of omics disciplines, computational tools, and model organisms provides powerful insights into the intricate network of the human variome, helping to shorten the diagnostic odyssey to targeted therapies for rare diseases, and paving the way for precision medicine. As collaborative efforts among researchers and clinicians intensify, the pathway toward improved diagnostic accuracy and personalized treatment strategies becomes clearer, ultimately fostering enhanced patient outcomes and advancing our overall understanding of human health.

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Publication Details

Journal
Zenodo (CERN European Organization for Nuclear Research)
Published
2026-08-17
DOI
https://doi.org/10.5281/zenodo.21980385
Primary Topic
Genomics and Rare Diseases
Type
preprint

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preprint

The roadmap for the development of the Human Variome - Development of functional multi-omics analyses for the understanding of human biology

Gaurav K. Varshney, Saumya Shekhar Jamuar, Tudor Groza, David R. Adams et al.
Zenodo (CERN European Organization for Nuclear Research)
Genomics and Rare Diseases
preprint

The roadmap for the development of the Human Variome - Development of functional multi-omics analyses for the understanding of human biology

Gaurav K. Varshney, Saumya Shekhar Jamuar, Tudor Groza, David R. Adams, Ratna Dua Puri, Biruté Tumiene, Robert J. Allaway, Ruty Mehrian‐Shai, Claudia Fuchs, Francois H. van der Westhuizen, Juergen K. V. Reichardt, María J. Barrero, Vanessa S. Fear, Richa Madan Lomash, Shinya Yamamoto, Elisa J. F. Houwink, Víctor Faúndes, Gareth S Baynam, Mary Catherine V. Letinturier, Chun‐Hung Chan, Polina Glezer, Elena-Alexandra Tataru
preprint en

Abstract

The human variome encompasses the full spectrum of genetic variation underlying human biology, health, and disease. Recent advances in next-generation sequencing and multi-omics, including genomics, epigenomics, transcriptomics, proteomics, and metabolomics, have enabled unprecedented insights into the functional elements of the genome and their clinical relevance. Collaborative efforts, such as ClinVar and the Rare Diseases Models and Mechanisms initiatives, have accelerated the integration of clinical and research data; however, the interpretation of variants of uncertain significance (VUS) remains a significant challenge in genomic analysis. High-throughput functional assays, including CRISPR-based perturbations, single-cell multi-omics, and multiplexed variant effect mapping, now allow systematic dissection of variant function at both molecular and cellular levels, directly linking genotype to phenotype. The emergence of comprehensive resources, such as the human pangenome and improved population databases, is enhancing variant interpretation. This interplay of omics disciplines, computational tools, and model organisms provides powerful insights into the intricate network of the human variome, helping to shorten the diagnostic odyssey to targeted therapies for rare diseases, and paving the way for precision medicine. As collaborative efforts among researchers and clinicians intensify, the pathway toward improved diagnostic accuracy and personalized treatment strategies becomes clearer, ultimately fostering enhanced patient outcomes and advancing our overall understanding of human health.

Zenodo (CERN European Organization for Nuclear Research)
European Organisation for Rare Diseases (FR), Sage Bionetworks (US), Inserm (FR), SingHealth (SG), Vilnius University (LT), Baylor College of Medicine (US), North-West University (ZA), Sheba Medical Center (IL), Princess Margaret Hospital for Children (AU), Australian Institute of Tropical Health and Medicine (AU), King Edward Memorial Hospital (AU), Instituto de Salud Carlos III (ES), WinnMed (US), Oklahoma Medical Research Foundation (US), National Human Genome Research Institute (US), Sanford Research (US), KK Women's and Children's Hospital (SG), Chan Zuckerberg Initiative (United States) (US), Duke-NUS Medical School (SG), National Center for Advancing Translational Sciences (US), Instituto de Investigación de Enfermedades Raras (ES), Vilnius University Hospital Santariskiu Klinikos (LT), Perth Children's Hospital, University of Chile (CL), James Cook University (AU)
European Commission, National Medical Research Council
Partnerships for the goals
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
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