Phenotypic heterogeneity in human genetic diseases: ultrasensitivity-mediated threshold effects as a unifying molecular mechanism

Y. Henry Sun, Yueh Lin Wu, Ben Yang Liao

Research output: Contribution to journalReview articlepeer-review

8 Citations (Scopus)

Abstract

Phenotypic heterogeneity is very common in genetic systems and in human diseases and has important consequences for disease diagnosis and treatment. In addition to the many genetic and non-genetic (e.g., epigenetic, environmental) factors reported to account for part of the heterogeneity, we stress the importance of stochastic fluctuation and regulatory network topology in contributing to phenotypic heterogeneity. We argue that a threshold effect is a unifying principle to explain the phenomenon; that ultrasensitivity is the molecular mechanism for this threshold effect; and discuss the three conditions for phenotypic heterogeneity to occur. We suggest that threshold effects occur not only at the cellular level, but also at the organ level. We stress the importance of context-dependence and its relationship to pleiotropy and edgetic mutations. Based on this model, we provide practical strategies to study human genetic diseases. By understanding the network mechanism for ultrasensitivity and identifying the critical factor, we may manipulate the weak spot to gently nudge the system from an ultrasensitive state to a stable non-disease state. Our analysis provides a new insight into the prevention and treatment of genetic diseases.

Original languageEnglish
Article number58
JournalJournal of Biomedical Science
Volume30
Issue number1
DOIs
Publication statusPublished - Dec 2023

Keywords

  • Edgetic mutation
  • Expressivity
  • Network
  • Penetrance
  • Phenotypic heterogeneity
  • Pleiotropy
  • Stochasticity
  • Threshold
  • Ultrasensitive response motif (URM)
  • Ultrasensitivity

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology
  • Biochemistry, medical
  • Pharmacology (medical)

Fingerprint

Dive into the research topics of 'Phenotypic heterogeneity in human genetic diseases: ultrasensitivity-mediated threshold effects as a unifying molecular mechanism'. Together they form a unique fingerprint.

Cite this