Conservation Scores

Why Conservation Matters

Genomic positions that remain unchanged across millions of years of evolution are under evolutionary constraint -- meaning changes at those positions are more likely to be functionally important. If a specific nucleotide is the same in humans, mice, chickens, and fish, it suggests that changes at that position are harmful enough to be removed by natural selection. Conservation scores quantify this constraint.

Two conservation metrics are displayed in Helix Insight: PhyloP (measuring conservation) and GERP (measuring constraint). They use different statistical approaches but address the same question: is this genomic position under evolutionary pressure to remain unchanged?

PhyloP (100-Way Vertebrate)

PhyloP measures evolutionary conservation across 100 vertebrate species using phylogenetic models. It compares the observed substitution rate at each position against the neutral expectation derived from the phylogenetic tree.

GERP++ (Genomic Evolutionary Rate Profiling)

GERP++ measures evolutionary constraint by comparing observed substitutions against the expected number at each position across a multi-species alignment. The difference between expected and observed substitutions is the "rejected substitution" score -- higher values indicate that more mutations have been eliminated by natural selection.

Why Conservation Scores Are Context, Not Evidence

Conservation tells you that a position is important, but it does not tell you whether a specific change at that position is damaging. A highly conserved position could tolerate certain amino acid substitutions (for example, leucine to isoleucine at a hydrophobic core position) while being completely intolerant of others (for example, leucine to proline, which would break the helix). This is why conservation scores are displayed as additional context rather than used as direct ACMG evidence.