Question

When annotating variants, which specific evolutionary metric is used to classify a non-synonymous mutation as likely deleterious based on its conservation across multiple species?

Accepted Answer

The specific evolutionary metric used to classify non-synonymous mutations as likely deleterious based on cross-species conservation is PhyloP, which stands for Phylogenetic P-values. A non-synonymous mutation changes the amino acid sequence of a protein, which can potentially disrupt its biological function. PhyloP measures conservation by comparing the rate of substitution at a specific nucleotide site across multiple species against the neutral substitution rate expected if there were no evolutionary pressure. The evolutionary model calculates a score for each site, where a positive PhyloP score indicates that the site is evolving more slowly than expected under neutrality, meaning it is evolutionarily conserved and likely subject to purifying selection. Purifying selection is the process where natural selection removes harmful mutations to maintain the function of essential genetic regions. Because these sites are conserved over millions of years of evolution, changing the amino acid at such a position is predicted to be deleterious, or harmful, to the organism. While other metrics like GERP, which stands for Genomic Evolutionary Rate Profiling, also measure conservation by counting the number of substitutions that did not occur compared to neutral expectation, PhyloP is the formal statistical metric used to derive conservation significance across an alignment of species.

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When annotating variants, which specific evolutionary metric is used to classify a non-synonymous mutation as likely deleterious based on its conservation across multiple species?