PHYFUM: Phylogenetic Reconstruction of Normal and Pre-malignant Tissue Evolution Using Fluctuating Methylation

Area of Science:

• Genomics
• Evolutionary Biology
• Computational Biology

Background:

• Understanding the evolutionary history of normal tissues is crucial for deciphering disease development.
• Epigenetic modifications, such as DNA methylation, provide valuable markers for tracing cellular lineages.
• Existing phylogenetic methods may not be optimally suited for analyzing complex methylation data in tissue evolution.

Purpose of the Study:

• To introduce PHYFUM, a novel Bayesian phylogenetic method designed for methylation data.
• To reconstruct the evolutionary history of stem cells and associated glandular structures in normal tissues.
• To investigate the divergence patterns of glandular structures in the human gut and endometrium.

Main Methods:

• Development and validation of PHYFUM, a Bayesian phylogenetic approach.
• Utilizing DNA methylation data to infer evolutionary relationships.
• Application of the method to analyze tissue samples from 22 patients.

Main Results:

• PHYFUM was validated using simulations, confirming its accuracy in phylogenetic reconstruction.
• Analysis revealed early divergence of glandular structures in the human gut.
• A significantly later common ancestor for endometrial glands was identified, contrasting with gut findings.
• Evidence suggests gland division is not driven by the segregation of individual stem cells.

Conclusions:

• PHYFUM is a validated and accurate tool for phylogenetic analysis of methylation data.
• Glandular evolution in the human gut and endometrium follows distinct temporal patterns.
• The findings challenge the hypothesis that stem cell segregation alone drives gland division, suggesting alternative mechanisms at play.