Comparing Phylogeny and the Predicted Pathogenicity of Protein Variations Reveals Equal Purifying Selection across the Global Human mtDNA Diversity (original) (raw)
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20 years of human mtDNA pathologic point mutations: Carefully reading the pathogenicity criteria
Biochimica et Biophysica Acta (BBA) - Bioenergetics, 2009
Despite the strong purifying selection that occurs during embryonic development, the particular location and features of mitochondrial DNA make it especially susceptible to accumulating point mutations, giving rise to a large number of mitochondrial DNA variants. Many of these will have moderate or no phenotypic effects but others will be the cause of very dramatic diseases, usually known as mitochondriopathies. Because of the abundance of different mitochondrial DNA variants, it is not easy to determine whether a new mutation is pathogenic. To facilitate this task, different criteria have been proposed, but they are often either too severely or too loosely applied. Citing examples from the literature, in this paper we discuss some critical aspects of these criteria.
Human Molecular Genetics, 2006
Knowledge about the world phylogeny of human mitochondrial DNA (mtDNA) is essential not only for evaluating the pathogenic role of specific mtDNA mutations but also for performing reliable association studies between mtDNA haplogroups and complex disorders. In the past few years, the main features of the East Asian portion of the mtDNA phylogeny have been determined on the basis of complete sequencing efforts, but representatives of several basal lineages were still lacking. Moreover, some recently published complete mtDNA sequences did apparently not fit into the known phylogenetic tree and conflicted with the established nomenclature. To refine the East Asian mtDNA tree and resolve data conflicts, we first completely sequenced 20 carefully selected mtDNAs-likely representatives of novel sub-haplogroups-and then, in order to distinguish diagnostic mutations of novel haplogroups from private variants, we applied a 'motifsearch' procedure to a large sample collection. The novel information was incorporated into an updated East Asian mtDNA tree encompassing more than 1000 (near-) complete mtDNA sequences. A reassessment of the mtDNA data from a series of disease studies testified to the usefulness of such a refined mtDNA tree in evaluating the pathogenicity of mtDNA mutations. In particular, the claimed pathogenic role of mutations G3316A, T3394C, A4833G and G15497A appears to be most questionable as those initial claims were derived from anecdotal findings rather than e.g. appropriate association studies. Following a guideline based on the phylogenetic knowledge as proposed here could help avoiding similar problems in the future.
A collection of 33 novel human mtDNA homoplasmic variants
Human Mutation, 2002
Mitochondria are involved in cellular energy production via oxidative phosphorylation and this function may be damaged by any mutation in mitochondrial DNA (mtDNA). To identify novel mtDNA mutations, we have developed a program to systematically screen the entire mitochondrial genome in a large number of individuals with clinical and/or morphological features of mitochondrial dysfunction, but still no genetic diagnosis. The sequence-data were obtained with an automated rapid system, which gave us a series of information: in the eleven mitochondrial genomes analyzed we observed the presence of 33 differences from the revised Cambridge Reference Sequence , but they were all homoplasmic in the patients' tissues analyzed (skeletal muscle and blood), suggesting that they are unlikely to be primarily pathogenic though they may be co-responsible in the determination of the disease. This work can therefore help complete the already ample mtDNA polymorphism existent database.
What is a ‘novel’ mtDNA mutation – and does ‘novelty’ really matter?
Journal of Human Genetics, 2006
The hunt for pathogenic mitochondrial DNA (mtDNA) mutations is often fueled by the seeming novelty of mutations that are either nonsynonymous or affect the protein synthesis machinery in patients. In order to determine the novelty of a detected mutation, the working geneticist nearly always consults MITOMAP – often exclusively. By reanalyzing some case studies of refractory anemia with ring sideroblasts, prostate cancer, and hearing impairment, we demonstrate that the practice of solely relying on MITOMAP can be most misleading. A notorious example is the T1243C mutation, which was assessed to be novel and deemed to be associated with some (rare) disease simply because researchers did not realize that T1243C defines a deep branch in the Eurasian mtDNA phylogeny. The majority of ‘novel’ mutations suspected of being pathogenic are in actual fact known (and presumably neutral) polymorphisms (although unknown to MITOMAP), and this becomes glaringly evident when proper database searches and straightforward Internet queries are carried out.
An enhanced MITOMAP with a global mtDNA mutational phylogeny
Nucleic acids …, 2007
The MITOMAP (http://www.mitomap.org) data system for the human mitochondrial genome has been greatly enhanced by the addition of a navigable mutational mitochondrial DNA (mtDNA) phylogenetic tree of ~3000 mtDNA coding region sequences plus expanded pathogenic mutation tables and a nuclear-mtDNA pseudogene (NUMT) data base. The phylogeny reconstructs the entire mutational history of the human mtDNA, thus defining the mtDNA haplogroups and differentiating ancient from recent mtDNA mutations. Pathogenic mutations are classified by both genotype and phenotype, and the NUMT sequences permits detection of spurious inclusion of pseudogene variants during mutation analysis. These additions position MITOMAP for the implementation of our automated mtDNA sequence analysis system, Mitomaster.
The American Journal of Human Genetics, 2004
This article provides evidence that selection has been a significant force during the evolution of the human mitochondrial genome. Both gene-by-gene and whole-genome approaches were used here to assess selection in the 560 mitochondrial DNA (mtDNA) coding-region sequences that were used previously for reduced-median-network analysis. The results of the present analyses were complex, in that the action of selection was not indicated by all tests, but this is not surprising, in view of the characteristics and limitations of the different analytical methods. Despite these limitations, there is evidence for both gene-specific and lineage-specific variation in selection. Whole-genome sliding-window approaches indicated a lack of selection in large-scale segments of the coding region. In other tests, we analyzed the ratio of nonsynonymous-to-synonymous substitutions in the 13 protein-encoding mtDNA genes. The most straightforward interpretation of those results is that negative selection has acted on the mtDNA during evolution. Single-gene analyses indicated significant departures from neutrality in the CO1, ND4, and ND6 genes, although the data also suggested the possible operation of positive selection on the AT6 gene. Finally, our results and those of other investigators do not support a simple model in which climatic adaptation has been a major force during human mtDNA evolution.
Prevalence of rare mitochondrial DNA mutations in mitochondrial disorders
Journal of Medical Genetics, 2013
Background Mitochondrial DNA (mtDNA) diseases are rare disorders whose prevalence is estimated around 1 in 5000. Patients are usually tested only for deletions and for common mutations of mtDNA which account for 5-40% of cases, depending on the study. However, the prevalence of rare mtDNA mutations is not known. Methods We analysed the whole mtDNA in a cohort of 743 patients suspected of manifesting a mitochondrial disease, after excluding deletions and common mutations. Both heteroplasmic and homoplasmic variants were identified using two complementary strategies (Surveyor and MitoChip). Multiple correspondence analyses followed by hierarchical ascendant cluster process were used to explore relationships between clinical spectrum, age at onset and localisation of mutations. Results 7.4% of deleterious mutations and 22.4% of novel putative mutations were identified. Pathogenic heteroplasmic mutations were more frequent than homoplasmic mutations (4.6% vs 2.8%). Patients carrying deleterious mutations showed symptoms before 16 years of age in 67% of cases. Early onset disease (<1 year) was significantly associated with mutations in protein coding genes (mainly in complex I) while late onset disorders (>16 years) were associated with mutations in tRNA genes. MTND5 and MTND6 genes were identified as 'hotspots' of mutations, with Leigh syndrome accounting for the large majority of associated phenotypes. Conclusions Rare mitochondrial DNA mutations probably account for more than 7.4% of patients with respiratory chain deficiency. This study shows that a comprehensive analysis of mtDNA is essential, and should include young children, for an accurate diagnosis that is now accessible with the development of next generation sequencing technology.
mtDNA mutation pattern in tumors and human evolution are shaped by similar selective constraints
Genome Research, 2009
Multiple human mutational landscapes of normal and cancer conditions are currently available. However, while the unique mutational patterns of tumors have been extensively studied, little attention has been paid to similarities between malignant and normal conditions. Here we compared the pattern of mutations in the mitochondrial genomes (mtDNAs) of cancer (98 sequences) and natural populations (2400 sequences). De novo mtDNA mutations in cancer preferentially colocalized with ancient variants in human phylogeny. A significant portion of the cancer mutations was organized in recurrent combinations (COMs), reaching a length of seven mutations, which also colocalized with ancient variants. Thus, by analyzing similarities rather than differences in patterns of mtDNA mutations in tumor and human evolution, we discovered evidence for similar selective constraints, suggesting a functional potential for these mutations.