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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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Mutation Distribution by Codon Position Reveals Purifying Selection on Protein-Coding Genes in mtDNA Mutator LinesPlot of observed mtDNA mutations grouped by positional category.(A) Observed mutations per base pair for each codon position from mtDNA mutator lines compared to (B), mtDNA sequences of 21 mouse strains obtained from GenBank, and (C), human mtDNA sequences obtained from the mtDB database. The reduction in observed first and second codon position mutations signifies selection against amino acid–changing mutations. Due to the larger number of human sequences available, the y-axis is larger for the human dataset.
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pbio-0060010-g002: Mutation Distribution by Codon Position Reveals Purifying Selection on Protein-Coding Genes in mtDNA Mutator LinesPlot of observed mtDNA mutations grouped by positional category.(A) Observed mutations per base pair for each codon position from mtDNA mutator lines compared to (B), mtDNA sequences of 21 mouse strains obtained from GenBank, and (C), human mtDNA sequences obtained from the mtDB database. The reduction in observed first and second codon position mutations signifies selection against amino acid–changing mutations. Due to the larger number of human sequences available, the y-axis is larger for the human dataset.

Mentions: We found a strong decrease in the number of mutations at the first and second codon positions of the protein-coding genes when compared to the third codon positions (Figure 2A and Table S2A). This distribution of mutations is a hallmark of purifying selection, because changes in the first and second codon position usually result in an amino acid substitution, whereas many third codon position changes do not. This purifying selection is strong and rapid as the same codon distribution bias is evident in the N2 generation (Figure S1). The observed nucleotide mutational bias in protein-coding genes varied significantly from those observed for the other sites in the mtDNA molecule (chi-square contingency table, p = 0.0023) thus showing differential selection pressures on the protein-coding genes versus other sites (Table 1).


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)

Mutation Distribution by Codon Position Reveals Purifying Selection on Protein-Coding Genes in mtDNA Mutator LinesPlot of observed mtDNA mutations grouped by positional category.(A) Observed mutations per base pair for each codon position from mtDNA mutator lines compared to (B), mtDNA sequences of 21 mouse strains obtained from GenBank, and (C), human mtDNA sequences obtained from the mtDB database. The reduction in observed first and second codon position mutations signifies selection against amino acid–changing mutations. 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-g002: Mutation Distribution by Codon Position Reveals Purifying Selection on Protein-Coding Genes in mtDNA Mutator LinesPlot of observed mtDNA mutations grouped by positional category.(A) Observed mutations per base pair for each codon position from mtDNA mutator lines compared to (B), mtDNA sequences of 21 mouse strains obtained from GenBank, and (C), human mtDNA sequences obtained from the mtDB database. The reduction in observed first and second codon position mutations signifies selection against amino acid–changing mutations. Due to the larger number of human sequences available, the y-axis is larger for the human dataset.
Mentions: We found a strong decrease in the number of mutations at the first and second codon positions of the protein-coding genes when compared to the third codon positions (Figure 2A and Table S2A). This distribution of mutations is a hallmark of purifying selection, because changes in the first and second codon position usually result in an amino acid substitution, whereas many third codon position changes do not. This purifying selection is strong and rapid as the same codon distribution bias is evident in the N2 generation (Figure S1). The observed nucleotide mutational bias in protein-coding genes varied significantly from those observed for the other sites in the mtDNA molecule (chi-square contingency table, p = 0.0023) thus showing differential selection pressures on the protein-coding genes versus other sites (Table 1).

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