Human disease locus discovery and mapping to molecular pathways through phylogenetic profiling

Area of Science:

• Genomics
• Evolutionary Biology
• Systems Biology

Background:

• Genes with conserved presence/absence patterns across genomes frequently participate in the same biological pathways.
• Understanding gene conservation aids in deciphering functional relationships and disease etiologies.

Purpose of the Study:

• To map human genes into phylogenetic clusters to reveal evolutionary connections between molecular pathways and human diseases.
• To identify candidate genes for specific disorders by analyzing gene clusters enriched for known disease genes or pathways.

Main Methods:

• Clustering of all human genes based on patterns of presence and absence across eukaryotic phylogeny.
• Analysis of overlaps between phylogenetic gene clusters and gene sets defined by coexpression or pathway annotation.
• Investigation of proteins coevolved with the microphthalmia-associated transcription factor (MITF).

Main Results:

• Genes with similar phylogenetic profiles were found to function within the same pathways.
• Sets of genes associated with specific diseases exhibited similar phylogenetic profiles.
• The study identified the Notch pathway suppressor of hairless (RBP-Jk/SuH) transcription factor as coevolved with MITF.
• RBP-Jk was demonstrated to function as an MITF cofactor.

Conclusions:

• Phylogenetic gene clustering provides an evolutionary map connecting molecular pathways and human diseases.
• This approach can identify novel candidate genes involved in disease pathogenesis.
• The discovery of RBP-Jk as an MITF cofactor highlights conserved regulatory mechanisms in development and disease.