Low “penetrance” of phylogenetic knowledge in mitochondrial disease studies (original) (raw)
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Ancient mitochondrial DNA pathogenic variants putatively associated with mitochondrial disease
2020
Mitochondrial DNA variants associated with diseases are widely studied in contemporary populations, but their prevalence has not yet been investigated in ancient populations. The publicly available AmtDB database contains 1443 ancient mtDNA Eurasian genomes from different periods. The objective of this study was to use this data to establish the presence of pathogenic mtDNA variants putatively associated with mitochondrial diseases in ancient populations. The clinical significance, pathogenicity prediction and contemporary frequency of mtDNA variants were determined using online platforms. The analyzed ancient mtDNAs contain six variants designated as being “confirmed pathogenic” in modern patients. The oldest of these, m.7510T>C in the MT-TS1 gene, was found in a sample from the Neolithic period dated 5800-5400 BCE. All six have well established clinical association, and their pathogenic effect is corroborated by very low population frequencies in contemporary populations. In ad...
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.
Biochemical and Biophysical Research Communications, 2005
Several suggestions have been made for avoiding errors in mitochondrial DNA (mtDNA) sequencing and documentation. Unfortunately, the current clinical, forensic, and population genetic literature on mtDNA still delivers a large number of studies with flawed sequence data, which, in extreme cases, damage the whole message of a study. The phylogenetic approach has been shown to be useful for pinpointing most of the errors. However, many geneticists, especially in the forensic and medical fields, are not familiar with either effective search strategies or the evolutionary terminology. We here provide a manual that should help prevent errors at any stage by reexamining data fresh from the sequencer in the light of previously published data. A fictitious case study of a European mtDNA data set (albeit composed from the literature) then demonstrates the steps one has to go through in order to assess the quality of sequencing and documentation.
ZARAMIT: A System for the Evolutionary Study of Human Mitochondrial DNA
Lecture Notes in Computer Science, 2009
ZARAMIT is an information system capable of fully automated phylogeny reconstruction. Methods have been tailored to mitochondrial DNA sequences, with focus on subproblem partitioning. We have built exhaustive human mitochondrial phylogenies (approximately 5500 sequences) and detected problems in existing haplogroup hierarchies through data-driven classification. Information on the project can be found on zaramit.org. 1 The case for mitochondrial DNA Mitochondria, organelles present in most eukaryotic cells, are responsible for the generation of most of the cell's chemical energy. They are also remarkable for possessing their own, separate genome, which coexists with nuclear DNA and is inherited independently. Further, mitochondrial DNA (mtDNA) has several features which make it an ideal candidate for conducting evolutionary studies. Firstly, it is small in mammals (15000 to 17000 base pairs) and encodes a homogeneous set of genes with little variation between species. Secondly, it exists within a very reactive environment where ROS are common: this provokes high mutation rates, approximately an order of magnitude above those of nuclear DNA. Thirdly, it displays matrilineal inheritance, which coupled with the virtual absence of recombination results in a pure evolutionary marker. These properties make mtDNA suitable for studying evolutionary relations between closely related organisms due to its comparatively high resolution. Despite the high proportion of changes between individuals, their absolute number is small, owing to the short length of these sequences. This, in turn, permits a compact expression of mtDNA sequences as differences from a canonical reference sequence [1]. We are especially interested in the reconstruction of exhaustive human mitochondrial phylogenies which may let us spot potentially deleterious mutations. These are among the most common causes of rare genetic diseases, such as LHON This research was supported in part by Projects PM063/2007 of the Government of Aragon and TIN2008-06582-C03-02 of the Spanish Government's MICINN View publication stats View publication stats
Updated comprehensive phylogenetic tree of global human mitochondrial DNA variation
Human Mutation, 2009
Human mitochondrial DNA is widely used as tool in many fields including evolutionary anthropology and population history, medical genetics, genetic genealogy, and forensic science. Many applications require detailed knowledge about the phylogenetic relationship of mtDNA variants. Although the phylogenetic resolution of global human mtDNA diversity has greatly improved as a result of increasing sequencing efforts of complete mtDNA genomes, an updated overall mtDNA tree is currently not available. In order to facilitate a better use of known mtDNA variation, we have constructed an updated comprehensive phylogeny of global human mtDNA variation, based on both coding-and control region mutations. This complete mtDNA tree includes previously published as well as newly identified haplogroups, is easily navigable, will be continuously and regularly updated in the future, and is online available at http://www.phylotree.org.
2017
Mitochondrial DNA (mtDNA) mutations are well recognized as an important cause of inherited disease. Diseases caused by mtDNA mutations exhibit a high degree of clinical heterogeneity with a complex genotype-phenotype relationship, with many such mutations exhibiting incomplete penetrance. There is evidence that the spectrum of mutations causing mitochondrial disease might differ between different mitochondrial lineages (haplogroups) seen in different global populations. This would point to the importance of sequence context in the expression of mutations. To explore this possibility, we looked for mutations which are known to cause disease in humans, in animals of other species unaffected by mtDNA disease. The mt-tRNA genes are the location of many pathogenic mutations, with the m.3243A>G mutation on the mt-tRNA-Leu(UUR) being the most frequently seen mutation in humans. This study looked for the presence of m.3243A>G in 2784 sequences from 33 species, as well as any of the ot...
We report the results of the Spanish and Portuguese working group (GEP) of the International Society for Forensic Genetics (ISFG) Collaborative Exercise 2002-2003 on mitochondrial DNA (mtDNA) analysis. Six different samples were submitted to the participating laboratories: four blood stains (M1-M2-M3-M4), one mixture blood sample (M5), and two hair shaft fragments (M6). Most of the labs reported consensus results for the blood stains, slightly improving the results of previous collaborative exercises. Although hair shaft analysis is still carried out by a small number of laboratories, this analysis yielded a high rate of success. On the contrary, the analysis of the mixture blood stain (M5) yielded a lower rate of success; in spite of this, the whole results on M5 typing demonstrated the suitability of mtDNA analysis in mixture samples. We have found that edition errors are among the most common mistakes reported by the different labs. In addition, we have detected contamination events as well as other minor problems, i.e. lack of standarization in nomenclature for punctual and length heteroplasmies, and indels. In the present edition of the GEP-ISFG exercise we have paid special attention to the visual phylogenetic inspection for detecting common sequencing errors.
Journal of Human Genetics, 2009
Sequence analysis of the mitochondrial genome has become a routine method in the study of mitochondrial diseases. Quite often, the sequencing efforts in the search of pathogenic or disease-associated mutations are affected by technical and interpretive problems, caused by sample mix-up, contamination, biochemical problems, incomplete sequencing, misdocumentation and insufficient reference to previously published data. To assess data quality in case studies of mitochondrial diseases, it is recommended to compare any mtDNA sequence under consideration to their phylogenetically closest lineages available in the Web. The median network method has proven useful visualizing potential problems with the data. We contrast some early reports of complete mtDNA sequences to more recent total mtDNA sequencing efforts in studies of various mitochondrial diseases. We conclude that the quality of complete mtDNA sequences generated in the medical field in the past few years is somewhat unsatisfactory and may even fall behind that of pioneer manual sequencing in the early nineties. Our study provides a paradigm for an a posteriori evaluation of sequence quality and for detection of potential problems with inferring a pathogenic status of a particular mutation.
Frontiers in Genetics, 2018
Bris et al. Bioinformatics and mtDNA Variant Interpretation KEY POINTS FOR IN SILICO PRIORITIZATION AND INTERPRETATION OF mtDNA VARIANTS • Query dedicated mtDNA databases which are regularly updated (e.g., Mitomap, HmtDB). • Consider the variant's frequency both within the general population and specific haplogroup. • Detection and interpretation of low heteroplasmy levels should be carefully evaluated. • Integrate additional information that might modulate the clinical penetrance (e.g., mitochondrial haplogroup, synergistic or helper mtDNA variants, nuclear variants). • Evaluate inter-species and primates amino-acid or nucleotide conservation. • Favor in silico prediction tools dedicated to mtDNA (e.g., APOGEE, Mitotip, Mtool Box).