Divergence of Noncoding Regulatory Elements Explains Gene-Phenotype Differences between Human and Mouse Orthologous...

Area of Science:

• Genomics
• Comparative Biology
• Bioinformatics

Background:

• Mice are common model organisms for studying human gene-phenotype links.
• Orthologous genes in humans and mice often exhibit different phenotypes.
• Existing methods lack quantitative comparison of mouse and human phenotype annotations.

Purpose of the Study:

• To develop a quantitative method for comparing mouse and human phenotype annotations.
• To identify orthologous genes with divergent phenotypic associations.
• To understand the molecular basis of gene-phenotype discrepancies between species.

Main Methods:

• Devised a quantitative method for comparing phenotype annotations.
• Utilized semantic similarity comparisons to assess gene-phenotype relationships.
• Analyzed sequence evolution and transcriptomic data for orthologous genes.

Main Results:

• Identified orthologous genes with significantly different phenotype annotations.
• Found that phenotypic divergence correlates with changes in noncoding regulatory elements.
• Observed that tissue-specific expression profiles also contribute to phenotypic differences.
• Protein-coding sequence changes were less correlated with observed phenotypic differences.

Conclusions:

• Orthologous genes can have dissimilar phenotypes between humans and mice.
• Evolutionary divergence in noncoding regulatory elements and transcriptomic profiles drives these differences.
• Accurate gene-phenotype mapping requires considering these evolutionary changes in model organisms.