Mutation patterns of mtDNA: Empirical inferences for the coding region

Center for Research in Natural Resources (CIRN), University of the Azores, 9500 Ponta Delgada, S, Miguel, Azores, Portugal.
BMC Evolutionary Biology (Impact Factor: 3.37). 06/2008; 8(1):167. DOI: 10.1186/1471-2148-8-167
Source: PubMed

ABSTRACT Human mitochondrial DNA (mtDNA) has been extensively used in population and evolutionary genetics studies. Thus, a valid estimate of human mtDNA evolutionary rate is important in many research fields. The small number of estimations performed for the coding region of the molecule, showed important differences between phylogenetic and empirical approaches. We analyzed a portion of the coding region of mtDNA (tRNALeu, ND1 and tRNAIle genes), using individuals belonging to extended families from the Azores Islands (Portugal) with the main aim of providing empirical estimations of the mutation rate of the coding region of mtDNA under different assumptions, and hence to better understand the mtDNA evolutionary process.
Heteroplasmy was detected in 6.5% (3/46) of the families analyzed. In all of the families the presence of mtDNA heteroplasmy resulted from three new point mutations, and no cases of insertions or deletions were identified. Major differences were found in the proportion and type of heteroplasmy found in the genes studied when compared to those obtained in a previous report for the D-loop. Our empirical estimation of mtDNA coding region mutation rate, calculated taking into account the sex of individuals carrying new mutations, the probability of intra-individual fixation of mutations present in heteroplasmy and, to the possible extent, the effect of selection, is similar to that obtained using phylogenetic approaches.
Based on our results, the discrepancy previously reported between the human mtDNA coding region mutation rates observed along evolutionary timescales and estimations obtained using family pedigrees can be resolved when correcting for the previously cited factors.

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Available from: Rafael Montiel, Sep 28, 2015
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    • "Our pedigree mutation rate (0.034/site/My) turns out twice as high as the phylogenetic rate (0.017/site/My) [23]. Encountered on different evolutionary time scales, this discrepancy may be resolved by taking into account the probability of intra-individual fixation of mutations present in heteroplasmy, and the sex of individuals carrying a new mutation, since males will not transmit them [29,30]. We had to consider the heteroplasmic mutations as somatic because they were not found at detectable levels in other family members. "
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    ABSTRACT: Background Complete mitochondrial DNA (mtDNA) genome analyses have greatly improved the phylogeny and phylogeography of human mtDNA. Human mitochondrial DNA haplogroup U6 has been considered as a molecular signal of a Paleolithic return to North Africa of modern humans from southwestern Asia. Results Using 230 complete sequences we have refined the U6 phylogeny, and improved the phylogeographic information by the analysis of 761 partial sequences. This approach provides chronological limits for its arrival to Africa, followed by its spreads there according to climatic fluctuations, and its secondary prehistoric and historic migrations out of Africa colonizing Europe, the Canary Islands and the American Continent. Conclusions The U6 expansions and contractions inside Africa faithfully reflect the climatic fluctuations that occurred in this Continent affecting also the Canary Islands. Mediterranean contacts drove these lineages to Europe, at least since the Neolithic. In turn, the European colonization brought different U6 lineages throughout the American Continent leaving the specific sign of the colonizers origin.
    BMC Evolutionary Biology 05/2014; DOI:10.1186/1471-2148-14-109 · 3.37 Impact Factor
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    • "In a metanalysis of studies of human mtDNA, Howell et al. (2003) documented a total per-transmission (i.e., mother to daughter) mutation rate of 0.011 across 1,122 bp of the control region. Santos et al. (2008) measured a mutation rate of 0.006 across 1,102 bp of coding mtDNA. The pertransmission mutation rate across the whole mtDNA genome (roughly 17,000 bp) would be much larger (e.g., extrapolating from the above, roughly 0.1). "
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    ABSTRACT: Coalescent theory has provided a basis for evolutionary biologists to build sophisticated methods for inferring population history from variation in genetic markers, but these methods leave out a major conceptual cornerstone of modern evolutionary theory: natural selection. I provide the first quantitative analysis of the effects of selection on genealogical patterns in a continuously distributed population in which the selective optimum for a trait linked to the marker varies gradually and continuously across the landscape. Simulations show that relatively weak selection for local adaptation can lead to strong phylogeographic structure, in which highly divergent genealogical groups (i.e., clades) are geographically localized and differentially adapted, and dramatically increased standing variation (e.g., coalescence time) compared to neutral expectations. This pattern becomes more likely with increasing population size and with decreasing dispersal distances, mutation rates, and mutation sizes. Under some conditions, the system alternates between a nearly neutral behavior and a behavior in which highly divergent clades are locally adapted. Natural selection on markers commonly used in phylogeographic studies (such as mitochondrial DNA) presents a major challenge to the inference of biogeographic history but also provides exciting opportunities to study how selection affects both between- and within-species biodiversity.
    The American Naturalist 07/2012; 180(1):35-49. DOI:10.1086/666002 · 3.83 Impact Factor
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    • "To evaluate whether the heteroplasmic mtDNA somatic mutations detected in the normal tissues of cancer patients is a normal phenomenon, we investigated the frequency of heteroplasmic mtDNA somatic mutations in the general human populations (embracing a total of 4738 mtDNA genome sequences retrieved from the literature). Our result revealed that the frequency of individuals harboring heteroplasmic somatic mtDNA mutation(s) is less than 4%, suggesting that heteroplasmy in mtDNA from the general population is a rare phenomenon, at least when detected by direct DNA sequencing method [34], [35], [36]. Then we thoroughly reviewed the previous studies on mtDNA mutation in different tumor types and found that heteroplasmic somatic mtDNA mutations were also observed in the normal tissues of cancer patients [9], [22], [27], [33], [37], with a significant higher frequency (38.6%) than in the general population (3.2%; p<0.001) but still lower than that in the cancerous tissue (52.9%; p<0.05) (Table S2). "
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    ABSTRACT: In the past decade, a high incidence of somatic mitochondrial DNA (mtDNA) mutations has been observed, mostly based on a fraction of the molecule, in various cancerous tissues; nevertheless, some of them were queried due to problems in data quality. Obviously, without a comprehensive understanding of mtDNA mutational profile in the cancerous tissue of a specific patient, it is unlikely to disclose the genuine relationship between somatic mtDNA mutations and tumorigenesis. To achieve this objective, the most straightforward way is to directly compare the whole mtDNA genome variation among three tissues (namely, cancerous tissue, para-cancerous tissue, and distant normal tissue) from the same patient. Considering the fact that most of the previous studies on the role of mtDNA in colorectal tumor focused merely on the D-loop or partial segment of the molecule, in the current study we have collected three tissues (cancerous, para-cancerous and normal tissues) respectively recruited from 20 patients with colorectal tumor and completely sequenced the mitochondrial genome of each tissue. Our results reveal a relatively lower incidence of somatic mutations in these patients; intriguingly, all somatic mutations are in heteroplasmic status. Surprisingly, the observed somatic mutations are not restricted to cancer tissues, for the para-cancer tissues and distant normal tissues also harbor somatic mtDNA mutations with a lower frequency than cancerous tissues but higher than that observed in the general population. Our results suggest that somatic mtDNA mutations in cancerous tissues could not be simply explained as a consequence of tumorigenesis; meanwhile, the somatic mtDNA mutations in normal tissues might reflect an altered physiological environment in cancer patients.
    PLoS ONE 06/2011; 6(6):e21613. DOI:10.1371/journal.pone.0021613 · 3.23 Impact Factor
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