MULTIPLE ORIGINS OF A MITOCHONDRIAL MUTATION CONFERRING DEAFNESS

A point mutation (1555G) in the smaller ribosomal subunit of the mitoc hondrial DNA (mtDNA) has been associated with maternally inherited tra its of hypersensitivity to streptomycin and sensorineural deafness in a number of families from China, Japan, Israel, and Africa. To determi ne whether this distribution was the result of a single or multiple mu tational events, we carried out genetic distance analysis and phylogen etic analysis of 16 independent mtDNA D-loop sequences from Africa and Asia. The mtDNA sequence diversity was high (2.21%). Phylogenetic ana lysis assigned 1555G-bearing haplotypes at very divergent points in th e human mtDNA evolutionary tree, and the 1555G mutations occur in many cases on race-specific mtDNA haplotypes, both facts are inconsistent with a recent introgression of the mutation into these races. The simp lest interpretation of the available data is that there have been mult iple origins of the 1555G mutation. The genetic distance among mtDNAs bearing the pathogenic 1555G mutation is much larger than among mtDNAs bearing either evolutionarily neutral or weakly deleterious nucleotid e substitutions (such as the 4336G mutation). These results are consis tent with the view that pathogenic mtDNA haplotypes such as 1555G aris e on disparate mtDNA lineages which because of negative natural select ion leave relatively few related descendants. The co-existence of the same mutation with deafness in individuals with very different nuclear and mitochondrial genetic backgrounds confirms the pathogenicity of t he 1555G mutation.