The link between mitochondrial DNA hypervariable segment I heteroplasmy and ageing among genetically unrelated Latvians

Abstract

To cite this version:This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT A C C E P T E D M A N U S C R I P T ACCEPTED MANUSCRIPT AbstractVarious studies have demonstrated that mitochondrial DNA (mtDNA) heteroplasmy tends to increase with age and that the observed frequency of heteroplasmy among populations mostly depends on the way it is measured. Therefore, we investigated age-related association on the presence of mtDNA heteroplasmy within the hypervariable segment 1 (HVS-I) in a selected study group. The study group consisted of 300 maternally unrelated Latvians ranging in age from 18 to over 90 years. To determine the optimal method for mtDNA heteroplasmy detection, three The results indicate that heteroplasmy in HVS-I is relatively common and occurs in a broad spectrum of sites. The above is supported by evidence to eventual increase of the probability of heteroplasmy with age due to specific mitochondrial haplogroup background. Research HighlightsThe results indicate that heteroplasmy in HVS-I is relatively common and occurs in a broad spectrum of sites. Consequently, a strong association is found to exist between the mtDNA heteroplasmy and ageing in the studied population.We found that the Denaturing Gradient Gel Electrophoresis (DGGE) and the SURVEYOR TM Mutation Detection Kit assay exhibited a lower limit of detection (LOD) of mtDNA heteroplasmy and revealed the presence of heteroplasmy at the already existing 1% and 5% occurrence in the sample.

Mitophagy plays a central role in mitochondrial ageing

“…An array-generated single-nucleotide polymorphism study has shown that even if overall the heteroplasmy increases with age, some sites lose variation while some increase it (Sondheimer et al 2011 ). In the hypervariable segment 1, especially at nucleotides 16189, 16304, and 16311, heteroplasmy seems to increase with age (Pliss et al 2011 ). This may well reflect any effect that these polymorphisms have on mitochondrial function: investigation of mtDNA heteroplasmy in platelets from 137 people revealed an association between increasing low level heteroplasmy with age for known pathogenic mutations and ageing phenotypes (Tranah et al 2015 ).…”

Length heteroplasmy in the predominate mitochondrial DNA haplogroups in the Croatian population

“…37 This locus is among the top 50 fastest evolving sites. 27 Length heteroplasmy associated with the T to C substitution at np 16189 was predominantly found in two mitochondrial lineages, haplogroups H and U 17,19 which encompass more than 60% of all mitochondrial genomes in the Croatian population. 38 In the present study, of all individuals with observed HVSI length heteroplasmy, more than 70% belong to haplogroup U.…”

“…14,16,[27][28][29] The T16189C mutation was suggested to interfere with the replication process of mtDNA generating instable C-stretch, which in turn decreases mtDNA copy number and causes mitochondrial disfunction. 30 This substitution is described as a strong mutational hotspot and has been associated with aging, 18,19 coronary artery disease, 20 metabolic syndrome, 31 type 2 diabetes, 32 obesity 33 and a variety of tumors. 13,[34][35][36] In the context of phylogeny, the position 16189 is often observed in different mtDNA lineages.…”

“…17 The biological relevance of length heteroplasmy is not yet fully understood. According to previous reports, heteroplasmy accumulates during aging 18,19 and has been associated with several multifactorial disorders. [20][21][22] The main goals of this study were to determine the frequency of length heteroplasmy in two major mtDNA haplogroups in the Croatian population sample and to investigate the association between certain polymorphisms in HVSI and the occurrence of length heteroplasmy.…”

Association of genetic variations in the mitochondrial DNA control region with presbycusis

“… 10 , 28 , 29 Investigation of the mtDNA control region also indicated a relationship between 16,311 T>C and both prostate cancer and acute myeloid leukemia. 30 – 32 Pliss et al 33 identified 16,311 T>C as the most frequent variant in HRV-I among genetically unrelated Latvians during the aging process. Manwaring et al 34 reported an association between haplogroup K and presbycusis.…”