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Multiple origins of a mitochondrial mutation conferring deafness
1University of California, Davis 95616, USA.
Abstract:
A point mutation (1555G) in the smaller ribosomal subunit of the mitochondrial DNA (mtDNA) has been associated with maternally inherited traits of hypersensitivity to streptomycin and sensorineural deafness in a number of families from China, Japan, Israel, and Africa. To determine whether this distribution was the result of a single or multiple mutational events, we carried out genetic distance analysis and phylogenetic analysis of 10 independent mtDNA D-loop sequences from Africa and Asia. The mtDNA sequence diversity was high (2.21%). Phylogenetic analysis assigned 1555G-bearing haplotypes at very divergent points in the 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 simplest interpretation of the available data is that there have been multiple 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 nucleotide substitutions (such as the 4336G mutation). These results are consistent with the view that pathogenic mtDNA haplotypes such as 1555G arise on disparate mtDNA lineages which because of negative natural selection 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 the 1555G mutation.
Insights
The 1555G mitochondrial DNA mutation, linked to deafness, likely arose multiple times independently across diverse populations. This suggests independent origins rather than a single recent event, confirmed by genetic and phylogenetic analyses.
Area of Science:
- Genetics
- Mitochondrial DNA Research
- Human Evolution
Background:
- A specific mitochondrial DNA (mtDNA) point mutation (1555G) is linked to maternally inherited streptomycin hypersensitivity and sensorineural deafness.
- This mutation has been observed in diverse populations across China, Japan, Israel, and Africa.
Purpose of the Study:
- To investigate whether the widespread distribution of the 1555G mutation resulted from a single or multiple independent mutational events.
- To analyze the evolutionary origins and phylogenetic relationships of the 1555G mutation in different human populations.
Main Methods:
- Genetic distance analysis of 10 independent mtDNA D-loop sequences from Africa and Asia.
- Phylogenetic analysis to determine the evolutionary placement of 1555G-bearing haplotypes.
- Comparison of genetic distances between mtDNAs with the 1555G mutation and those with neutral or weakly deleterious mutations.
Main Results:
- High mtDNA sequence diversity (2.21%) was observed.
- Phylogenetic analysis placed 1555G-bearing haplotypes at divergent points in the human mtDNA evolutionary tree.
- The 1555G mutation frequently occurred on race-specific mtDNA haplotypes, inconsistent with recent introgression.
Conclusions:
- The simplest interpretation is that the 1555G mutation has multiple independent origins.
- The large genetic distance among mtDNAs bearing the 1555G mutation supports its origin on disparate mtDNA lineages subject to negative selection.
- The consistent association of the 1555G mutation with deafness across diverse genetic backgrounds confirms its pathogenicity.