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      Evidence for Sub-Haplogroup H5 of Mitochondrial DNA as a Risk Factor for Late Onset Alzheimer's Disease

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          Abstract

          Background

          Alzheimer's Disease (AD) is the most common neurodegenerative disease and the leading cause of dementia among senile subjects. It has been proposed that AD can be caused by defects in mitochondrial oxidative phosphorylation. Given the fundamental contribution of the mitochondrial genome (mtDNA) for the respiratory chain, there have been a number of studies investigating the association between mtDNA inherited variants and multifactorial diseases, however no general consensus has been reached yet on the correlation between mtDNA haplogroups and AD.

          Methodology/Principal Findings

          We applied for the first time a high resolution analysis (sequencing of displacement loop and restriction analysis of specific markers in the coding region of mtDNA) to investigate the possible association between mtDNA-inherited sequence variation and AD in 936 AD patients and 776 cognitively assessed normal controls from central and northern Italy. Among over 40 mtDNA sub-haplogroups analysed, we found that sub-haplogroup H5 is a risk factor for AD (OR = 1.85, 95% CI:1.04–3.23) in particular for females (OR = 2.19, 95% CI:1.06–4.51) and independently from the APOE genotype. Multivariate logistic regression revealed an interaction between H5 and age. When the whole sample is considered, the H5a subgroup of molecules, harboring the 4336 transition in the tRNA Gln gene, already associated to AD in early studies, was about threefold more represented in AD patients than in controls (2.0% vs 0.8%; p = 0.031), and it might account for the increased frequency of H5 in AD patients (4.2% vs 2.3%). The complete re-sequencing of the 56 mtDNAs belonging to H5 revealed that AD patients showed a trend towards a higher number (p = 0.052) of sporadic mutations in tRNA and rRNA genes when compared with controls.

          Conclusions

          Our results indicate that high resolution analysis of inherited mtDNA sequence variation can help in identifying both ancient polymorphisms defining sub-haplogroups and the accumulation of sporadic mutations associated with complex traits such as AD.

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          Most cited references41

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          Restriction isotyping of human apolipoprotein E by gene amplification and cleavage with HhaI.

          We have used restriction isotyping (restriction enzyme isoform genotyping) for rapid typing of common apolipoprotein E isoforms (E2, E3, E4). ApoE restriction isotyping used oligonucleotides to amplify apolipoprotein E gene sequences containing amino acid positions 112 and 158. The amplification products were digested with HhaI and subjected to electrophoresis on polyacrylamide gels. Each of the isoforms was distinguished by a unique combination of HhaI fragment sizes that enabled unambiguous typing of all homozygotic and heterozygotic combinations. HhaI cleaves at GCGC encoding 112arg (E4) and 158arg (E3, E4), but does not cut at GTGC encoding 112cys (E2, E3) and 158cys (E2).
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            Effects of purifying and adaptive selection on regional variation in human mtDNA.

            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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              Mitochondrial portraits of human populations using median networks.

              Analysis of variation in the hypervariable region of mitochondrial DNA (mtDNA) has emerged as an important tool for studying human evolution and migration. However, attempts to reconstruct optimal intraspecific mtDNA phylogenies frequently fail because parallel mutation events partly obscure the true evolutionary pathways. This makes it inadvisable to present a single phylogenetic tree at the expense of neglecting equally acceptable ones. As an alternative, we propose a novel network approach for portraying mtDNA relationships. For small sample sizes (< approximately 50), an unmodified median network contains all most parsimonious trees, displays graphically the full information content of the sequence data, and can easily be generated by hand. For larger sample sizes, we reduce the complexity of the network by identifying parallelisms. This reduction procedure is guided by a compatibility argument and an additional source of phylogenetic information: the frequencies of the mitochondrial haplotypes. As a spin-off, our approach can also assist in identifying sequencing errors, which manifest themselves in implausible network substructures. We illustrate the advantages of our approach with several examples from existing data sets.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2010
                6 August 2010
                : 5
                : 8
                : e12037
                Affiliations
                [1 ]Department of Experimental Pathology, University of Bologna, Bologna, Italy
                [2 ]CIG-Interdepartmental Center for Biophysics and Biocomplexity Studies, University of Bologna, Bologna, Italy
                [3 ]Department of Genetics and Microbiology, University of Pavia, Pavia, Italy
                [4 ]Department of Cell and Environmental Biology, University of Perugia, Perugia, Italy
                [5 ]National Council Research, Institute of Neuroscience, Padova, Italy
                [6 ]Institute of Biochemistry, Medical Faculty Charité, Berlin, Germany
                [7 ]Italian National Research Center for Aging (I.N.R.C.A.), Ancona, Italy
                [8 ]Department of Molecular Pathology and Innovative Therapies, Polytechnic University of Marche, Ancona, Italy
                [9 ]Department of Neurological and Psychiatric Sciences, University of Florence, Florence, Italy
                [10 ]Regional Center for Cerebral Aging, Valdagno, Vicenza, Italy
                [11 ]NeuroBioGen Lab-Memory Clinic, “Centro S.Giovanni di Dio-Fatebenefratelli”, Brescia, Italy
                [12 ]Proteomics Unit, “Centro S.Giovanni di Dio-Fatebenefratelli”, Brescia, Italy
                [13 ]Department of Cell Biology, University of Calabria, Rende, Cosenza, Italy
                Mental Health Research Institute of Victoria, Australia
                Author notes

                Conceived and designed the experiments: AS AT CF. Performed the experiments: AS EB CP FR FT. Analyzed the data: AS VB EB PS NM GR GP. Contributed reagents/materials/analysis tools: AS AA EB MM SS FM MC FO BN AMC LB RG CG GB SS GC. Wrote the paper: AS VB GR AT CF.

                Article
                10-PONE-RA-15464R2
                10.1371/journal.pone.0012037
                2917370
                20700462
                d8af4aa3-3d6b-40be-8dc8-e440f56720d9
                Santoro et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
                History
                : 12 January 2010
                : 26 May 2010
                Page count
                Pages: 11
                Categories
                Research Article
                Genetics and Genomics/Complex Traits
                Neurological Disorders/Alzheimer Disease
                Public Health and Epidemiology/Epidemiology
                Evolutionary Biology/Human Evolution

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