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  • Perspective
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MorPhiC Consortium: towards functional characterization of all human genes

Nature volume 638, pages 351–359 (2025) Cite this article

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Abstract

Recent advances in functional genomics and human cellular models have substantially enhanced our understanding of the structure and regulation of the human genome. However, our grasp of the molecular functions of human genes remains incomplete and biased towards specific gene classes. The Molecular Phenotypes of Null Alleles in Cells (MorPhiC) Consortium aims to address this gap by creating a comprehensive catalogue of the molecular and cellular phenotypes associated with null alleles of all human genes using in vitro multicellular systems. In this Perspective, we present the strategic vision of the MorPhiC Consortium and discuss various strategies for generating null alleles, as well as the challenges involved. We describe the cellular models and scalable phenotypic readouts that will be used in the consortium’s initial phase, focusing on 1,000 protein-coding genes. The resulting molecular and cellular data will be compiled into a catalogue of null-allele phenotypes. The methodologies developed in this phase will establish best practices for extending these approaches to all human protein-coding genes. The resources generated—including engineered cell lines, plasmids, phenotypic data, genomic information and computational tools—will be made available to the broader research community to facilitate deeper insights into human gene functions.

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Fig. 1: Publications that mention human genes.
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Fig. 2: Experimental strategies and assays.
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Fig. 3: Comparison of experimental strategies for null-allele generation.
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Acknowledgements

The MorPhiC Consortium is funded by the NHGRI MorPhiC Initiative (UM1HG012649, UM1HG012654, UM1HG012651, UM1 HG012660, U24HG012674, U01HG013176, U01HG013177 and U01HG013175).

Author information

Author notes

  1. These authors contributed equally: Mazhar Adli, Laralynne Przybyla

Authors and Affiliations

  1. Robert H. Lurie Comprehensive Cancer Center, Department of Obstetrics and Gynecology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    Mazhar Adli, Neda Abbaszadeh, Tao Bai, Alexandra M. Griffiths, Ozlem Neyisci, Fidan Seker & De Xing

  2. Department of Biochemistry and Biophysics, University of California, San Francisco, CA, USA

    Laralynne Przybyla

  3. Omics Section, European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, UK

    Tony Burdett, Dipayan Gupta, Orges A. Koci, Enrique Sapena Ventura, Anu Shivalikanjli & Galabina N. Yordanova

  4. Department of Pharmacology, Center for Pharmacogenomics, Northwestern University, Feinberg School of Medicine, Evanston, IL, USA

    Paul W. Burridge

  5. William Harvey Research Institute, Clinical Pharmacology and Precision Medicine, Queen Mary University of London, London, UK

    Pilar Cacheiro, Damian Smedley & Gabriel Marengo

  6. Department of Dermatology, Stanford University, Stanford, CA, USA

    Howard Y. Chang, Yung-Hsin Huang & Katerina Kraft

  7. Department of Genetics, Stanford University, Stanford, CA, USA

    Jesse M. Engreitz, William J. Greenleaf, Sijie Chen, Basak Eraslan, Revant Gupta, Nianping Liu, Eyal Metzl-Raz, Wenzhuo Tang, Tony Zeng & Stephen Zhang

  8. Basic Science and Engineering (BASE) Initiative, Stanford University, Stanford, CA, USA

    Jesse M. Engreitz, Xiaojie Qiu, Revant Gupta, Yuzhen Mao & Tony Zeng

  9. Department of Urology, University of California, San Francisco, CA, USA

    Luke A. Gilbert, Anthony Doty, Juhee Goyal & Aaron J. Huebner

  10. Department of Biostatistics, Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA

    Li Hsu, Wei Sun, Si Liu & Bo Yu

  11. Developmental Biology Program, Sloan Kettering Institute, New York, NY, USA

    Danwei Huangfu, Lorenz Studer, Thomas Vierbuchen, Ting Zhou, Chia Chan, Hyein S. Cho, Rachel A. Glenn, Tingfeng Guo, Nan Hu, Dingyu Liu, Renhe Luo, Arushi Rana, Denis Torre, Xianming Wang, Dapeng Yang, Nan Zhang & Aaron Zhong

  12. School of Engineering and Technology, University of Washington Tacoma, Tacoma, WA, USA

    Ling-Hong Hung, Ka Yee Yeung, Rohan N. V. S. R. K. Avireddy, Thomas J. Dahlstrom, Jesse Flores, Bryce Nobutoshi Fukuda, Varun Mittal & Niharika Nasam

  13. Departments of Genetics and Computer Science, Stanford University, Stanford, CA, USA

    Anshul Kundaje, Xiaojie Qiu & Yuzhen Mao

  14. The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

    Sheng Li, Paul Robson, William C. Skarnes, Brian S. White, Juliana Alcoforado Diniz, Anahita Amiri, Dylan S. Baker, Anshul Choudhary, Patrick J. Fleming, Jessica L. Garofalo, Shuzhao Li, Zukai Liu, Adrian Melo-Carrillo, Joshua M. Mitchell, Olivier B. Poirion, Kaustav Sengupta & Shujian Zheng

  15. Knowledge Management Section, European Bioinformatics Institute (EMBL-EBI), European Molecular Biology Laboratory, Hinxton, UK

    Helen Parkinson

  16. Molecular and Cellular Pharmacology; Sylvester Comprehensive Cancer Center, University of Miami, Coral Gables, FL, USA

    Stephan C. Schürer, Dušica Vidović, Marcin Pilarczyk & Nicolette C. Ross

  17. Department of Biostatistics, University of Washington, Seattle, WA, USA

    Ali Shojaie, Zhaoheng Li & Justina Žurauskienė

  18. Department of Biochemistry and Molecular Genetics, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    Feng Yue, Xintong Chen, Yihao Fu, Ping Wang & Hengqiang Zhao

  19. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA

    Jacob J. Baroch, Adam L. Felsenfeld, Colin F. Fletcher, Carolyn Hutter & Ajay Pillai

  20. Frost Institute for Data Science and Computing, University of Miami, Coral Gables, FL, USA

    Caty E. Chung

  21. Scientific Services, Single Cell Biology Laboratory, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

    William F. Flynn

  22. Cellular Engineering, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

    Angelina Kendra, Chen Meng, Gang Ning, Devon Parker & Jamilex Rivera-Diaz

  23. Robert Lurie Comprehensive Cancer Center, Department of Medicine, Division of Hematology and Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    Gina Kirsammer

  24. Robert Lurie Comprehensive Cancer Center, Department of Pharmacology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    Davi Lyra Leite & Praeploy Pongpamorn

  25. Scientific Services, Cellular Engineering, The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA

    Justin A. McDonough & Zhehao Zhang

Authors
  1. Mazhar Adli
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  2. Laralynne Przybyla
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  3. Tony Burdett
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  4. Paul W. Burridge
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  5. Pilar Cacheiro
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  6. Howard Y. Chang
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  7. Jesse M. Engreitz
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  8. Luke A. Gilbert
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  10. Li Hsu
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  11. Danwei Huangfu
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  13. Anshul Kundaje
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  14. Sheng Li
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  15. Helen Parkinson
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  17. Paul Robson
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  18. Stephan C. Schürer
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  19. Ali Shojaie
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Consortia

The MorPhiC Consortium

  • Neda Abbaszadeh
  • , Juliana Alcoforado Diniz
  • , Anahita Amiri
  • , Rohan N. V. S. R. K. Avireddy
  • , Tao Bai
  • , Dylan S. Baker
  • , Jacob J. Baroch
  • , Chia Chan
  • , Sijie Chen
  • , Xintong Chen
  • , Hyein S. Cho
  • , Anshul Choudhary
  • , Caty E. Chung
  • , Thomas J. Dahlstrom
  • , Anthony Doty
  • , Basak Eraslan
  • , Adam L. Felsenfeld
  • , Patrick J. Fleming
  • , Colin F. Fletcher
  • , Jesse Flores
  • , William F. Flynn
  • , Yihao Fu
  • , Bryce Nobutoshi Fukuda
  • , Jessica L. Garofalo
  • , Rachel A. Glenn
  • , Juhee Goyal
  • , Alexandra M. Griffiths
  • , Tingfeng Guo
  • , Revant Gupta
  • , Dipayan Gupta
  • , Nan Hu
  • , Yung-Hsin Huang
  • , Aaron J. Huebner
  • , Carolyn Hutter
  • , Angelina Kendra
  • , Gina Kirsammer
  • , Orges A. Koci
  • , Katerina Kraft
  • , Zhaoheng Li
  • , Shuzhao Li
  • , Si Liu
  • , Zukai Liu
  • , Dingyu Liu
  • , Nianping Liu
  • , Renhe Luo
  • , Davi Lyra Leite
  • , Yuzhen Mao
  • , Gabriel Marengo
  • , Justin A. McDonough
  • , Adrian Melo-Carrillo
  • , Chen Meng
  • , Eyal Metzl-Raz
  • , Joshua M. Mitchell
  • , Varun Mittal
  • , Niharika Nasam
  • , Ozlem Neyisci
  • , Gang Ning
  • , Devon Parker
  • , Marcin Pilarczyk
  • , Ajay Pillai
  • , Olivier B. Poirion
  • , Praeploy Pongpamorn
  • , Arushi Rana
  • , Jamilex Rivera-Diaz
  • , Nicolette C. Ross
  • , Enrique Sapena Ventura
  • , Fidan Seker
  • , Kaustav Sengupta
  • , Anu Shivalikanjli
  • , Wenzhuo Tang
  • , Denis Torre
  • , Ping Wang
  • , Xianming Wang
  • , De Xing
  • , Dapeng Yang
  • , Galabina N. Yordanova
  • , Bo Yu
  • , Tony Zeng
  • , Stephen Zhang
  • , Zhehao Zhang
  • , Nan Zhang
  • , Hengqiang Zhao
  • , Shujian Zheng
  • , Aaron Zhong
  •  & Justina Žurauskienė

Contributions

M.A. and L.P. wrote the manuscript. All listed authors contributed to the editing, revision and discussion of the main ideas in this article. The MorPhiC Consortium participated in the development, execution and integration of the scientific and analytical strategies described.

Corresponding author

Correspondence to Mazhar Adli.

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Nature thanks Kristen Brennand and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Adli, M., Przybyla, L., Burdett, T. et al. MorPhiC Consortium: towards functional characterization of all human genes. Nature 638, 351–359 (2025). https://doi.org/10.1038/s41586-024-08243-w

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