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Strong purifying selection in transmission of mammalian mitochondrial DNA.

Stewart JB, Freyer C, Elson JL, Wredenberg A, Cansu Z, Trifunovic A, Larsson NG - PLoS Biol. (2008)

Bottom Line: Purifying selection is thought to be important in shaping mtDNA sequence evolution, but the strength of this selection has been debated, mainly due to the threshold effect of pathogenic mtDNA mutations and an observed excess of new mtDNA mutations in human population data.These data show strong purifying selection against mutations within mtDNA protein-coding genes.To our knowledge, our study presents the first direct experimental observations of the fate of random mtDNA mutations in the mammalian germ line and demonstrates the importance of purifying selection in shaping mitochondrial sequence diversity.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. Jim.Stewart@ki.se

ABSTRACT
There is an intense debate concerning whether selection or demographics has been most important in shaping the sequence variation observed in modern human mitochondrial DNA (mtDNA). Purifying selection is thought to be important in shaping mtDNA sequence evolution, but the strength of this selection has been debated, mainly due to the threshold effect of pathogenic mtDNA mutations and an observed excess of new mtDNA mutations in human population data. We experimentally addressed this issue by studying the maternal transmission of random mtDNA mutations in mtDNA mutator mice expressing a proofreading-deficient mitochondrial DNA polymerase. We report a rapid and strong elimination of nonsynonymous changes in protein-coding genes; the hallmark of purifying selection. There are striking similarities between the mutational patterns in our experimental mouse system and human mtDNA polymorphisms. These data show strong purifying selection against mutations within mtDNA protein-coding genes. To our knowledge, our study presents the first direct experimental observations of the fate of random mtDNA mutations in the mammalian germ line and demonstrates the importance of purifying selection in shaping mitochondrial sequence diversity.

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Relaxed Selection on rRNA and tRNA Genes in mtDNA Mutator LinesPlot of observed mtDNA mutations grouped by positional category.(A) Observed mutations in tRNA, rRNA, and control region sequences compared with (B) mouse strain sequences and (C) human mtDNA sequences. Due to the larger number of human sequences available, the y-axis is larger for the human dataset.
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pbio-0060010-g004: Relaxed Selection on rRNA and tRNA Genes in mtDNA Mutator LinesPlot of observed mtDNA mutations grouped by positional category.(A) Observed mutations in tRNA, rRNA, and control region sequences compared with (B) mouse strain sequences and (C) human mtDNA sequences. Due to the larger number of human sequences available, the y-axis is larger for the human dataset.

Mentions: In contrast to the patterns found in the protein-coding genes, we found higher levels of mutations in tRNA and rRNA genes in the mtDNA mutator lines (Figure 4A) in comparison to the levels in mouse strains and humans (Figure 4B and 4C). There are several observations from human mtDNA disease that imply that tRNA genes may be subject to a less rapid form of purifying selection than that observed for the protein-coding genes of our mtDNA mutator mouse lines: (1) Population-level sampling has revealed an increase in recent mtDNA sequence variation within tRNA and rRNA genes in humans [30,41]; (2) 58.2% of the known pathogenic human mtDNA mutations are located in the tRNA genes, although these genes only occupy 9.1% of the genome [42], implying that these changes are, at low levels of heteroplasmy, more compatible with life than some protein-coding mutations; and (3) disease-causing tRNA gene mutations reach high heteroplasmic levels, or sometimes must be homoplasmic, before the onset of disease [43,44]. A less acute, but equally important, mechanism of purifying selection appears to be acting on tRNA genes. This may explain why the corresponding mutations are not removed as rapidly from the mtDNA mutator mouse lines.


Strong purifying selection in transmission of mammalian mitochondrial DNA.

Stewart JB, Freyer C, Elson JL, Wredenberg A, Cansu Z, Trifunovic A, Larsson NG - PLoS Biol. (2008)

Relaxed Selection on rRNA and tRNA Genes in mtDNA Mutator LinesPlot of observed mtDNA mutations grouped by positional category.(A) Observed mutations in tRNA, rRNA, and control region sequences compared with (B) mouse strain sequences and (C) human mtDNA sequences. Due to the larger number of human sequences available, the y-axis is larger for the human dataset.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2214808&req=5

pbio-0060010-g004: Relaxed Selection on rRNA and tRNA Genes in mtDNA Mutator LinesPlot of observed mtDNA mutations grouped by positional category.(A) Observed mutations in tRNA, rRNA, and control region sequences compared with (B) mouse strain sequences and (C) human mtDNA sequences. Due to the larger number of human sequences available, the y-axis is larger for the human dataset.
Mentions: In contrast to the patterns found in the protein-coding genes, we found higher levels of mutations in tRNA and rRNA genes in the mtDNA mutator lines (Figure 4A) in comparison to the levels in mouse strains and humans (Figure 4B and 4C). There are several observations from human mtDNA disease that imply that tRNA genes may be subject to a less rapid form of purifying selection than that observed for the protein-coding genes of our mtDNA mutator mouse lines: (1) Population-level sampling has revealed an increase in recent mtDNA sequence variation within tRNA and rRNA genes in humans [30,41]; (2) 58.2% of the known pathogenic human mtDNA mutations are located in the tRNA genes, although these genes only occupy 9.1% of the genome [42], implying that these changes are, at low levels of heteroplasmy, more compatible with life than some protein-coding mutations; and (3) disease-causing tRNA gene mutations reach high heteroplasmic levels, or sometimes must be homoplasmic, before the onset of disease [43,44]. A less acute, but equally important, mechanism of purifying selection appears to be acting on tRNA genes. This may explain why the corresponding mutations are not removed as rapidly from the mtDNA mutator mouse lines.

Bottom Line: Purifying selection is thought to be important in shaping mtDNA sequence evolution, but the strength of this selection has been debated, mainly due to the threshold effect of pathogenic mtDNA mutations and an observed excess of new mtDNA mutations in human population data.These data show strong purifying selection against mutations within mtDNA protein-coding genes.To our knowledge, our study presents the first direct experimental observations of the fate of random mtDNA mutations in the mammalian germ line and demonstrates the importance of purifying selection in shaping mitochondrial sequence diversity.

View Article: PubMed Central - PubMed

Affiliation: Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. Jim.Stewart@ki.se

ABSTRACT
There is an intense debate concerning whether selection or demographics has been most important in shaping the sequence variation observed in modern human mitochondrial DNA (mtDNA). Purifying selection is thought to be important in shaping mtDNA sequence evolution, but the strength of this selection has been debated, mainly due to the threshold effect of pathogenic mtDNA mutations and an observed excess of new mtDNA mutations in human population data. We experimentally addressed this issue by studying the maternal transmission of random mtDNA mutations in mtDNA mutator mice expressing a proofreading-deficient mitochondrial DNA polymerase. We report a rapid and strong elimination of nonsynonymous changes in protein-coding genes; the hallmark of purifying selection. There are striking similarities between the mutational patterns in our experimental mouse system and human mtDNA polymorphisms. These data show strong purifying selection against mutations within mtDNA protein-coding genes. To our knowledge, our study presents the first direct experimental observations of the fate of random mtDNA mutations in the mammalian germ line and demonstrates the importance of purifying selection in shaping mitochondrial sequence diversity.

Show MeSH
Related in: MedlinePlus