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Why do humans need thrombospondin-1?

Sukhbir Kaur1, David D Roberts2

  • 1Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Building 10 Room 2S235, 10 Center Dr, Bethesda, MD, 20892-1500, USA.

Journal of Cell Communication and Signaling
|January 23, 2023
PubMed
Summary
This summary is machine-generated.

Thrombospondin-1 (THBS1) is essential for human survival, unlike in mice, due to its critical roles in cardiovascular and immune responses to environmental stresses. This explains why THBS1 mutations are rare in humans.

Keywords:
Essential genesHuman genetic variationLoss of function variantsMatricellular proteinsThrombospondin-1

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Area of Science:

  • Biochemistry
  • Genetics
  • Developmental Biology

Background:

  • Matricellular proteins, including thrombospondins (THBS), are crucial for cell-extracellular matrix interactions.
  • While some matricellular proteins are essential for embryonic development in mice, THBS family members do not cause lethality.
  • Human genetic data suggests THBS1 is essential, indicating a potential discrepancy in function or evolutionary pressure.

Purpose of the Study:

  • To investigate the reasons behind the high loss-intolerance of THBS1 in humans.
  • To explore the functions of thrombospondin-1 (THBS1) that may be critical for human survival in the face of environmental challenges.
  • To understand why THBS1 loss-of-function mutations are rare in human populations.

Main Methods:

  • Analysis of human deep exome sequencing data to identify loss-of-function mutants.
  • Generation and study of Thbs1 knockout (Thbs1-/-) mice.
  • Subjecting Thbs1-/- mice to defined environmental stresses to model human exposures.
  • Investigating the protective roles of THBS1 in cardiovascular and immune systems.

Main Results:

  • Human exome data revealed a deficit in THBS1 loss-of-function mutants, suggesting high loss-intolerance.
  • Thbs1-/- mice, while viable and fertile, exhibited impaired responses to stress.
  • Stress response models identified critical protective functions of thrombospondin-1 in the cardiovascular system and immune defenses.
  • These functions are likely essential for human survival against pathogens and injury.

Conclusions:

  • THBS1 is an essential gene in humans, crucial for surviving environmental stresses.
  • The loss-intolerance of THBS1 in humans is attributed to its vital roles in cardiovascular health and immune defense.
  • Understanding THBS1's stress-protective functions provides insight into human evolutionary pressures and disease susceptibility.