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Human Molecular Genetics Advance Access published online on July 13, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi243
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 30, 2005
Revised July 1, 2005
Accepted July 1, 2005

Article

Prediction of pathogenic mutations in mitochondrially encoded human tRNAs

Fyodor A. Kondrashov 1*

1 Section on Ecology, Behavior and Evolution, Division of Biological Sciences, University of California at San Diego, 2218 Muir Biology Building, La Jolla, CA 92093, USA; Engelhardt Institute of Molecular Biology, Vavilova 32, 119991 Moscow, Russian Federation

* To whom correspondence should be addressed.
Fyodor A. Kondrashov, E-mail: mailto:kondrashov{at}ucdavis.edu


  Abstract

Some mutations in human mitochondrial tRNAs are severely pathogenic. The available computational methods have a poor record of predicting the impact of a tRNA mutation on the phenotype and fitness. I compare patterns of evolution at tRNA sites that harbor pathogenic mutations and at sites that harbor phenotypically cryptic polymorphisms. Mutations that are pathogenic to humans occupy more conservative sites, are only rarely fixed in closely related species, and, when located in stem structures, often disrupt Watson-Crick pairing and display signs of compensatory evolution. These observations make it possible to classify ~90% of all known pathogenic mutations as deleterious, together with only ~30% of polymorphisms. These polymorphisms segregate at frequencies that are more than two times lower than frequencies of polymorphisms classified as benign, indicating that at least ~30% of known polymorphisms in mitochondrial tRNAs affect fitness negatively.


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