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Peer-reviewedCC BYNature

Transcriptomic convergence and the female protective effect in autism

  • Rebecca Andersen1,2,3,4,5,6
  • Maya Talukdar7,8,9,10,11,12,13
  • Tyler Sakamoto8,9,14,11,6
  • David Exposito-Alonso15,8,9,11,6
  • Janet H. T. Song15,16,8,9,11,6
  • Xuyu Qian15,17,8,9,11,6
  • Seungil Lee8,9,14,11,13
  • Nila Murugan8,9,11,18,6
  • Ryan Nicholas Delgado19,20
  • Sijing Zhao8,9,21,11,22
  • Gwenyth C. Eichfeld23,8,9,11,6
  • Julia Harms8,9,11,24
2 more authors
  • David C. Page25,26,12
  • Christopher A. Walsh27,28,29,30,31
31 affiliations
  1. 1Allen Discovery Center for Human Brain Evolution, Boston, MA, USA. [email protected]
  2. 2Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  3. 3Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. [email protected]
  4. 4Division of Genetics and Genomics and Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA. [email protected]
  5. 5Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. [email protected]
  6. 6Boston Children's Hospital
  7. 7Broad Institute of MIT and Harvard, Cambridge, MA, USA
  8. 8Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA
  9. 9Division of Genetics and Genomics and Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA
  10. 10Harvard-MIT MD/PhD Program and Harvard PhD Program in Biomedical Informatics, Harvard Medical School, Boston, MA, USA
  11. 11Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA
  12. 12Whitehead Institute, Cambridge, MA, USA
  13. 13Harvard Medical School
  14. 14Harvard College, Cambridge, MA, USA
  15. 15Allen Discovery Center for Human Brain Evolution, Boston, MA, USA
  16. 16Department of Human Evolutionary Biology, Harvard University, Cambridge, MA, USA
  17. 17Department of Pediatrics, Division of Neurology, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
  18. 18University of Massachusetts Boston, Boston, MA, USA
  19. 19Department of Genetics, Blavatnik Institute and Howard Hughes Medical Institute, Harvard Medical School, Boston, MA, USA
  20. 20Colgate University
  21. 21Harvard BBS PhD Program, Harvard Medical School, Boston, MA, USA
  22. 22University of California, Berkeley
  23. 23Colgate University, Hamilton, NY, USA
  24. 24University of California Berkeley, Berkeley, CA, USA
  25. 25Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA
  26. 26Howard Hughes Medical Institute, Whitehead Institute, Cambridge, MA, USA
  27. 27Allen Discovery Center for Human Brain Evolution, Boston, MA, USA. [email protected]
  28. 28Broad Institute of MIT and Harvard, Cambridge, MA, USA. [email protected]
  29. 29Departments of Pediatrics and Neurology, Harvard Medical School, Boston, MA, USA. [email protected]
  30. 30Division of Genetics and Genomics and Manton Center for Orphan Diseases, Boston Children's Hospital, Boston, MA, USA. [email protected]
  31. 31Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA, USA. [email protected]
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Abstract

Autism spectrum disorder (ASD) is highly heritable, and mutations in hundreds of genes have been implicated as individually rare causes of ASD 1–3 . Understanding how disruptions to these functionally diverse genes lead to the core features of ASD remains a major challenge 4 . Moreover, ASD is three- to four-fold more common in males than females 5 , and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males 6,7 , but the biological basis of this “female protective effect” (FPE) is unknown 8,9 . Here we show that individual perturbations of 18 ASD genes in human neural progenitor cells converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network (GRN) enabled the identification of central transcriptional regulators, including the prominent ASD gene CHD8 as well as novel candidates such as REST , that drive this transcriptomic convergence. Furthermore, the X-linked transcription factor ZFX , which is expressed from both the active and the inactive X chromosomes in females 10 , emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in female brain can buffer damaging mutations in diverse ASD genes, contributing to the FPE. Together, these results reveal how key GRNs can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.

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Cite

BibTeXRIS
BibTeX
@article{andersen2026transcriptomic,
  title = {{Transcriptomic convergence and the female protective effect in autism}},
  author = {Rebecca Andersen and Maya Talukdar and Tyler Sakamoto and David Exposito-Alonso and Janet H. T. Song and Xuyu Qian and Seungil Lee and Nila Murugan and Ryan Nicholas Delgado and Sijing Zhao and Gwenyth C. Eichfeld and Julia Harms and David C. Page and Christopher A. Walsh},
  journal = {Nature},
  year = {2026},
  month = nov,
  doi = {10.1038/s41586-026-11236-6},
  url = {https://doi.org/10.1038/s41586-026-11236-6},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Transcriptomic convergence and the female protective effect in autism
AU  - Rebecca Andersen
AU  - Maya Talukdar
AU  - Tyler Sakamoto
AU  - David Exposito-Alonso
AU  - Janet H. T. Song
AU  - Xuyu Qian
AU  - Seungil Lee
AU  - Nila Murugan
AU  - Ryan Nicholas Delgado
AU  - Sijing Zhao
AU  - Gwenyth C. Eichfeld
AU  - Julia Harms
AU  - David C. Page
AU  - Christopher A. Walsh
PY  - 2026
DA  - 2026/11/04
JO  - Nature
DO  - 10.1038/s41586-026-11236-6
UR  - https://doi.org/10.1038/s41586-026-11236-6
AB  - Autism spectrum disorder (ASD) is highly heritable, and mutations in hundreds of genes have been implicated as individually rare causes of ASD 1–3 . Understanding how disruptions to these functionally diverse genes lead to the core features of ASD remains a major challenge 4 . Moreover, ASD is three- to four-fold more common in males than females 5 , and autistic females tend to carry more autosomal risk alleles for ASD compared to autistic males 6,7 , but the biological basis of this “female protective effect” (FPE) is unknown 8,9 . Here we show that individual perturbations of 18 ASD genes in human neural progenitor cells converge on shared effects on gene expression, including widespread downregulation of other ASD genes. De novo reconstruction of a gene regulatory network (GRN) enabled the identification of central transcriptional regulators, including the prominent ASD gene CHD8 as well as novel candidates such as REST , that drive this transcriptomic convergence. Furthermore, the X-linked transcription factor ZFX , which is expressed from both the active and the inactive X chromosomes in females 10 , emerged as a key activator of many ASD genes: we propose that the higher ZFX expression level observed in female brain can buffer damaging mutations in diverse ASD genes, contributing to the FPE. Together, these results reveal how key GRNs can become broadly and similarly dysregulated upon disruption of individual ASD genes and provide molecular insight into the female protective effect in ASD.
SN  - 0028-0836
SN  - 1476-4687
ER  -