Neutral Theory, Disease Mutations, and Personal Exomes.

Area of Science:

• Molecular evolution
• Population genetics
• Bioinformatics

Background:

• The neutral theory of molecular evolution posits that most evolutionary substitutions are nearly neutral.
• Evolutionarily permissible (ePerm) variation can be inferred from multispecies sequence alignments and evolutionary trees.

Purpose of the Study:

• To investigate the evolutionary permissibility of amino acid variants linked to genetic diseases and found in personal exomes.
• To assess the consistency of observed variation patterns with neutral theory predictions.

Main Methods:

• Analysis of multispecies sequence alignments.
• Application of statistical methods to evolutionary trees.
• Comparison of disease-associated variants with variants in personal exomes.

Main Results:

• Disease-associated amino acid variants are rarely ePerm, biochemically radical, and located at conserved positions.
• Only 10% of mutations are ePerm, yet they constitute two-thirds of human lineage substitutions.
• Personal exomes contain a minority of ePerm variants, with evolutionarily forbidden variants potentially offering protection.

Conclusions:

• Observed patterns of genetic variation in disease and personal exomes align with the neutral theory of molecular evolution.
• Evolutionarily forbidden variants may play a significant, underappreciated role in disease protection.
• Long-term evolutionary history provides insights into the functional biomedical properties of personal exomic variation.