PHYLOGENETIC ANALYSIS OF THE MITOCHONDRIAL GENOMES FROM LEBER HEREDITARY OPTIC NEUROPATHY PEDIGREES

The nucleotide sequences of the mitochondrial genomes from patients wi th Leber hereditary optic neuropathy (LHON) were used for phylogenetic analysis to study the origin and population history of pathogenic mit ochondrial mutations. Sequences of both the coding region (8300 bp) an d the more rapidly evolving noncoding control region (1300 bp) were an alyzed. Patients with the primary LHON mutations at nucleotides 3460, 11,778, and 14,484 were included in this study, as were LHON patients and non-LHON controls that lacked these primary mutations; some of the subjects also carried secondary LHON mutations. The phylogenetic anal yses demonstrate that primary LHON mutations arose and were fixed mult iple times within the population, even for the small set of LHON patie nts that was analyzed in these initial studies. In contrast, the secon dary LHON mutations at nucleotides 4216, 4917, and 13,708 arose once: the mitochondrial genomes that carried these secondary mutations forme d a well-supported phylogenetic cluster that apparently arose 60,000 t o 100,000 years ago. Previous studies found secondary LHON mutations a t a higher frequency among LHON patients than among control subjects. However, this finding does not prove a pathogenetic role of these muta tions in LHON. Instead, the increased frequency is more likely to refl ect the population genetic history of secondary mutations relative to that of primary LHON mutations.