MITOCHONDRIAL-DNA POLYMORPHISM IN DISEASE - A POSSIBLE CONTRIBUTOR TORESPIRATORY DYSFUNCTION

Intergenomic variation in the human mitochondrial genome was examined in 27 mtDNA sequences using a pairwise analysis technique. Analysis of 16 of these mtDNA sequences from patients with mitochondrial cytopath ies indicated a wide range between different mitochondrial genes in th e degree of nucleotide variation from the standard Cambridge sequence. Mean complex I polymorphic frequencies in cytopathic (CPEO, MERRF, ME LAS and LHON collectively) patients and in LHON patients differed sign ificantly from controls (P less than or equal to 0.05, t). Total mean sequence divergence (mean number of diverging nucleotides between two sequences per 100 bp) over the entire mtDNA coding region was 0.21% fo r cytopathies (n = 16) as opposed to 0.18% for a control group (n = 4) . Within the cytopathy group, the greatest pairwise divergence was obs erved in ND3 and ND6 subunits of complex I (0.46 and 0.70% respectivel y) and the magnitude of specific gene divergences differed considerabl y from those observed for the corresponding genes in the control popul ation. The extent to which the increased variation in ND3 and ND6 is a general phenomenon applicable to all subjects rather than a finding s pecific to cytopathies cannot be stated with certainty given the small control group. Regardless as to which of these suggestions is correct , the possibility exists that increased nucleotide variation in certai n mitochondrial ND subunits may contribute to respiratory inefficiency through a cumulative effect of a series of polymorphisms of minor ind ividual mutagenic potential.