The co‐occurrence of mtDNA mutations on different oxidative phosphorylation subunits, not detected by haplogroup analysis, affects human longevity and is population specific

Abstract

To re-examine the correlation between mtDNA variability and longevity, we examined mtDNAs from samples obtained from over 2200 ultranonagenarians (and an equal number of controls) collected within the framework of the GEHA EU project. The samples were categorized by high-resolution classification, while about 1300 mtDNA molecules (650 ultranonagenarians and an equal number of controls) were completely sequenced. Sequences, unlike standard haplogroup analysis, made possible to evaluate for the first time the cumulative effects of specific, concomitant mtDNA mutations, including those that per se have a low, or very low, impact. In particular, the analysis of the mutations occurring in different OXPHOS complex showed a complex scenario with a different mutation burden in 90+ subjects with respect to controls. These findings suggested that mutations in subunits of the OXPHOS complex I had a beneficial effect on longevity, while the simultaneous presence of mutations in complex I and III (which also occurs in J subhaplogroups involved in LHON) and in complex I and V seemed to be detrimental, likely explaining previous contradictory results. On the whole, our study, which goes beyond haplogroup analysis, suggests that mitochondrial DNA variation does affect human longevity, but its effect is heavily influenced by the interaction between mutations concomitantly occurring on different mtDNA genes.

A Mitochondrial Haplogroup Is Associated with Decreased Longevity in a Historic New World Population

“…The fact that we found an association between decreased longevity and haplogroup C, which has not been reported before, might be explained by Raule et al's assertion that the effect of mitochondrial DNA variation on human longevity is influenced by the interaction between mutations in the mtDNA genome concomitantly inherited (Raule et al, 2014). Such inheritance may be at the root of the question why there are so many different longevity-mtDNA associations reported in the literature.…”

“…Some researchers have chosen to focus on specific longevity-associated polymorphisms (LAPS) or have sequenced entire chromosomal regions (Castri et al, 2009;Lv et al, 2010;Nijiati et al, 2013;Raule et al, 2014;von Wurmb-Schwark et al, 2010;Yang et al, 2012), finding associations between markers and extended longevity. Others have chosen to focus on haplogroups, reporting that some haplogroups extend longevity (Cai et al, 2009;Courtenay et al, 2012;Dominguez-Garrido et al, 2009;Feng et al, 2011;Guney, Ak, Atay, Ozkaya, & Aydin, 2014;Nishigaki, Fuku, & Tanaka, 2010).…”

“…A few papers report no association between mtDNA haplogroups and longevity (Costa et al, 2009;Pinos et al, 2012), and no paper reports a negative effect of mtDNA haplogroups on longevity. A review of these papers indicates that the association between markers such as the C150T SNP and extended longevity is well established [see (Castri et al, 2009) and references therein], while the association between haplogroups and longevity is population-specific (Raule et al, 2014;Zapico & Ubelaker, 2013). Unfortunately, haplogroup and longevity studies have been limited to a small number of populations, predominantly Chinese (Cai et al, 2009;Feng et al, 2011;Lv et al, 2010;Yang et al, 2012), Japanese (Nishigaki et al, 2010), and European (Courtenay et al, 2012;Dominguez-Garrido et al, 2009;Guney et al, 2014;Pinos et al, 2012) [see (Castri et al, 2009) for older citations] and have only worked with living subjects.…”

Novel Complex Interactions between Mitochondrial and Nuclear DNA in Schizophrenia and Bipolar Disorder

“…Deep sequencing of the genome can provide rare mutations at the gene level to unravel the complex relationship among multiple rare mtDNA variants that might not be found with traditional haplogroup analysis [71]. Applying SKAT [72] to a sample of Swedes ( n = 10, 771) and analyzing a set of rare SNPs with minor allele frequency (MAF) < 0.01, a nominal rare variant association with SZ ( p = 0.007) was reported [3].…”

Mitochondrial haplogroup influences motor function in long-term HIV-1 infected individuals

“…Haplogroups were assigned using FASTA files uploaded to the Haplofind.unibo.it website, Haplogroup assignments for each patient are listed in S3 Table. R-Studio (v0.98.1091) and SPSS (v22) were used for statistical analysis and further data manipulation. Specific R packages used include SNPRelate for PCA analysis of genomic data [23][24][25].…”