Article

R EPORTS Effects of Purifying and Adaptive Selection on Regional Variation

Center for Molecular and Mitochondrial Medicine and Genetics, University of California, Irvine, CA 92697-3940, USA.
Science (Impact Factor: 31.48). 02/2004; 303(5655):223-6. DOI: 10.1126/science.1088434
Source: PubMed

ABSTRACT A phylogenetic analysis of 1125 global human mitochondrial DNA (mtDNA) sequences permitted positioning of all nucleotide substitutions according to their order of occurrence. The relative frequency and amino acid conservation of internal branch replacement mutations was found to increase from tropical Africa to temperate Europe and arctic northeastern Siberia. Particularly highly conserved amino acid substitutions were found at the roots of multiple mtDNA lineages from higher latitudes. These same lineages correlate with increased propensity for energy deficiency diseases as well as longevity. Thus, specific mtDNA replacement mutations permitted our ancestors to adapt to more northern climates, and these same variants are influencing our health today.

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    • "ROS have been implicated in inflammatory cytokine production, suggesting a connection between oxidative stress and inflammatory processes [23]. MtDNA haplogroups may also affect the coupling of the respiratory chain [24], which can result in increased endogenous ROS in mitochondria [25]. Recent work has demonstrated that mtDNA haplogroups modify the relationship of traffic-related air pollution exposures with systemic biomarkers of inflammation [26], suggesting a role of mitochondrial haplogroups on systemic inflammation. "
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    ABSTRACT: Background Traffic-related air pollution has been linked with impaired cognition in older adults, possibly due to effects of oxidative stress on the brain. Mitochondria are the main source of cellular oxidation. Haplogroups in mitochondrial DNA (mtDNA) mark individual differences in oxidative potential and are possible determinants of neurodegeneration. The aim of this study was to investigate whether mtDNA haplogroups determined differential susceptibility to cognitive effects of long-term exposure to black carbon (BC), a marker of traffic-related air pollution. Methods We investigated 582 older men (72 ± 7 years) in the VA Normative Aging Study cohort with ≤4 visits per participant (1.8 in average) between 1995–2007. Low (≤25) Mini Mental State Examination (MMSE) was used to assess impaired cognition in multiple domains. We fitted repeated-measure logistic regression using validated-LUR BC estimated in the year before their first visit at the participant’s address. Results Mitochondrial haplotyping identified nine haplogroups phylogenetically categorized in four clusters. BC showed larger effect on MMSE in Cluster 4 carriers, including I, W and X haplogroups, [OR = 2.7; 95% CI (1.3-5.6)], moderate effect in Cluster 1, including J and T haplogroups [OR = 1.6; 95% CI: (0.9-2.9)], and no effect in Cluster 2 (H and V haplogroups) [OR = 1.1; 95% CI: (0.8-1.5)] or Cluster 3 (K and U haplogroups) [OR = 1.0; 95% CI: (0.6-1.6)]. BC effect varied only moderately across the I, X, and W haplogroups or across the J and T haplogroups. Conclusions The association of BC with impaired cognition was worsened in carriers of phylogenetically-related mtDNA haplogroups in Cluster 4. No BC effects were detected in Cluster 2 and 3 carriers. MtDNA haplotypes may modify individual susceptibility to the particle cognitive effects.
    Environmental Health 05/2014; 13(1):42. DOI:10.1186/1476-069X-13-42 · 2.71 Impact Factor
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    • "The selective neutrality assumption of mtDNA has been empirically tested and refuted across a broad range of organisms [12]. Recent studies have found evidence for molecular adaptations in the 13 protein-coding genes in the mtGenome [13], [14]. Some mutations have been associated with pathogenic disorders in humans and mice including exercise intolerance, neurological diseases and myopathy [15], [16], while others have been shown to have positive outcomes including greater aerobic energy metabolism [17]. "
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    ABSTRACT: As species evolve, they become adapted to their local environments. Detecting the genetic signature of selection and connecting that to the phenotype of the organism, however, is challenging. Here we report using an integrative approach that combines DNA sequencing with structural biology analyses to assess the effect of selection on residues in the mitochondrial DNA of the two species of African elephants. We detected evidence of positive selection acting on residues in complexes I and V, and we used homology protein structure modeling to assess the effect of the biochemical properties of the selected residues on the enzyme structure. Given the role these enzymes play in oxidative phosphorylation, we propose that the selected residues may contribute to the metabolic adaptation of forest and savanna elephants to their unique habitats.
    PLoS ONE 04/2014; 9(4):e92587. DOI:10.1371/journal.pone.0092587 · 3.23 Impact Factor
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    • "A mitochondrial haplogroup is defined as a collection of groups characterized by specific Single Nucleotide Polymorphisms [7]. Several studies have shown mitochondrial haplogroups to be associated with differences in the amount of superoxide and other ROS produced by the electron transport chain [27] [28] [29]. For example, haplogroup F mtDNAs are associated with low complex I activity [30] and predilection to diabetes [31] and individuals with haplogroup J present lower oxygen consumption than other haplogroup variants [32]. "
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    ABSTRACT: Mitochondrial disorders cannot be ignored anymore in most medical disciplines; indeed their minimum estimated prevalence is superior to 1 in 5000 births. Despite the progress made in the last 25 years on the identification of gene mutations causing mitochondrial pathologies, only slow progress was made towards their effective treatments. Ocular involvement is a frequent feature in mitochondrial diseases and corresponds to severe and irreversible visual handicap due to retinal neuron loss and optic atrophy. Interestingly, three clinical trials for Leber Congenital Amaurosis due to RPE65 mutations are ongoing since 2007. Overall, the feasibility and safety of ocular Adeno-Associated Virus delivery in adult and younger patients and consistent visual function improvements have been demonstrated. The success of gene-replacement therapy for RPE65 opens the way for the development of similar approaches for a broad range of eye disorders, including those with mitochondrial etiology such as Leber Hereditary Optic Neuropathy (LHON).
    Comptes rendus biologies 03/2014; 337(3):193-206. DOI:10.1016/j.crvi.2013.11.011 · 1.68 Impact Factor
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