Disentangling cell-intrinsic and cell-extrinsic factors underlying evolution.

Area of Science:

• Evolutionary biology
• Cell biology
• Genomics

Background:

• Understanding cellular function requires distinguishing cell-intrinsic autonomy from cell-extrinsic interactions.
• Evolutionary divergence of cellular traits is complex, involving both internal cellular mechanisms and external environmental influences.

Purpose of the Study:

• To develop a novel framework using interspecies chimeras to dissect cellular trait evolution into cell-intrinsic and cell-extrinsic components.
• To investigate the relative contributions of intrinsic and extrinsic factors to gene expression divergence.

Main Methods:

• Development of a conceptual framework for analyzing interspecies chimeras.
• Application of the framework to analyze thousands of gene expression levels in reciprocal rat-mouse chimeras.
• Analysis of imprinted gene expression in chimeric models.

Main Results:

• The majority of evolutionary divergence in gene expression is cell-intrinsic.
• Cell-extrinsic factors significantly influence gene regulation, impacting transcription factors and their downstream targets at both mRNA and protein levels.
• Imprinted genes exhibit substantial misexpression in chimeras, indicating a conflict between evolving intrinsic and extrinsic imprinting mechanisms.

Conclusions:

• The developed chimera-based framework effectively decomposes cellular trait evolution into intrinsic and extrinsic components.
• Cell-intrinsic factors are the primary drivers of evolutionary divergence, but cell-extrinsic factors are integral to gene regulation.
• Rapid evolution of imprinting mechanisms may lead to incompatibilities in interspecies chimeras, offering insights into developmental regulation.