Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: Implications for population susceptibility to diseases

Kenney, M. Cristina; Chwa, Marilyn; Atilano, Shari R.; Falatoonzadeh, Payam; Ramírez, Claudio; Malik, Deepika; Mohamed, Tarek; Carpio, Javier Caceres del; Nesburn, Anthony B.; Boyer, David S.; Kuppermann, Baruch D.; Vawter, Marquis P.; Jazwinski, S. Michal; Miceli, Michael V.; Wallace, Douglas C.; Udar, Nitin

doi:10.1016/j.bbadis.2013.10.016

Cited by 138 publications

(127 citation statements)

References 75 publications

(79 reference statements)

Supporting

Mentioning

118

Contrasting

Unclassified

Order By: Relevance

“…In one instance we found a disease-associated mutation present at high allele frequencies in child tissues. Genetic background (both mtDNA and nuclear), known to significantly modulate mtDNA disease manifestation (56), may be preventing symptoms in this individual.…”

Section: Estimating the Size Of The Germ-line Mtdna Bottleneck And Mumentioning

confidence: 99%

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

Rebolledo‐Jaramillo¹,

Su²,

Stoler³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

211

307

View full text Add to dashboard Cite

The manifestation of mitochondrial DNA (mtDNA) diseases depends on the frequency of heteroplasmy (the presence of several alleles in an individual), yet its transmission across generations cannot be readily predicted owing to a lack of data on the size of the mtDNA bottleneck during oogenesis. For deleterious heteroplasmies, a severe bottleneck may abruptly transform a benign (low) frequency in a mother into a disease-causing (high) frequency in her child. Here we present a high-resolution study of heteroplasmy transmission conducted on blood and buccal mtDNA of 39 healthy mother-child pairs of European ancestry (a total of 156 samples, each sequenced at ∼20,000× per site). On average, each individual carried one heteroplasmy, and one in eight individuals carried a disease-associated heteroplasmy, with minor allele frequency ≥1%. We observed frequent drastic heteroplasmy frequency shifts between generations and estimated the effective size of the germline mtDNA bottleneck at only ∼30-35 (interquartile range from 9 to 141). Accounting for heteroplasmies, we estimated the mtDNA germ-line mutation rate at 1.3 × 10 −8 (interquartile range from 4.2 × 10 −9 to 4.1 × 10) mutations per site per year, an order of magnitude higher than for nuclear DNA. Notably, we found a positive association between the number of heteroplasmies in a child and maternal age at fertilization, likely attributable to oocyte aging. This study also took advantage of droplet digital PCR (ddPCR) to validate heteroplasmies and confirm a de novo mutation. Our results can be used to predict the transmission of disease-causing mtDNA variants and illuminate evolutionary dynamics of the mitochondrial genome. mitochondria | heteroplasmy

show abstract

Section: Estimating the Size Of The Germ-line Mtdna Bottleneck And Mumentioning

confidence: 99%

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

Rebolledo‐Jaramillo¹,

Su²,

Stoler³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

211

307

View full text Add to dashboard Cite

show abstract

“…The concept that mtDNA can direct the mode of energy production of the cell was supported by recent cybrid studies conducted by Dr. C. Kenney’s group [75, 76]. Cybrids are created by removing mitochondria from a cell line by passaging in presence of ethidium bromide.…”

Section: Interaction Analysis Of Mitochondrial and Nuclear-encoded Genesmentioning

confidence: 99%

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

et al. 2019

View full text Add to dashboard Cite

Mitochondrial dysfunction has been associated with schizophrenia (SZ) and bipolar disorder (BD). This review examines recent publications and novel associations between mitochondrial genes and SZ and BD. Associations of nuclear-encoded mitochondrial variants with SZ were found using gene- and pathway-based approaches. Two control region mitochondrial DNA (mtDNA) SNPs, T16519C and T195C, both showed an association with SZ and BD. A review of 4 studies of A15218G located in the cytochrome B oxidase gene (CYTB, SZ = 11,311, control = 35,735) shows a moderate association with SZ (p = 2.15E-03). Another mtDNA allele A12308G was nominally associated with psychosis in BD type I subjects and SZ. The first published study testing the epistatic interaction between nuclear-encoded and mitochondria-encoded genes demonstrated evidence for potential interactions between mtDNA and the nuclear genome for BD. A similar analysis for the risk of SZ revealed significant joint effects (34 nuclear-mitochondria SNP pairs with joint effect p ≤ 5E-07) and significant enrichment of projection neurons. The mitochondria-encoded gene CYTB was found in both the epistatic interactions for SZ and BD and the single SNP association of SZ. Future efforts considering population stratification and polygenic risk scores will test the role of mitochondrial variants in psychiatric disorders.

show abstract

“…12, 2017; epidemiological characteristics of SZ obviously increase the risk of spurious associations caused by subtle admixture and 2GLD. However, it does not per se refute the mitochondrial pathogenic paradigm 34 where variation in mitochondrial function, believed to interfere with ATP production 35,36 , inflammation and signaling 37,38 as well as Ca 2+ -homeostasis 39 , and apoptosis 38 , is considered to be of paramount importance for development of disease. Several neuroanatomical postmortem findings in SZ brains indicate perturbed mitochondrial function 40 , but such findings are difficult to distinguish from changes caused by drug treatment.…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

Hagen

Gonçalves

Hedley

et al. 2017

Preprint

View full text Add to dashboard Cite

Mitochondria play a significant role in human diseases. However, disease associations with mitochondrial DNA (mtDNA) SNPs have proven difficult to replicate. A reanalysis of eight schizophrenia-associated mtDNA SNPs, in 23,743 normal Danes and 2,538 schizophrenia patients, revealed marked inter-allelic differences in haplogroup affiliation and nuclear ancestry, genogeophraphic affinity (GGA). This bi-genomic linkage disequilibrium (2GLD) could entail population stratification. Only two mitochondrial SNPs, m.15043A and m.15218G, were significantly associated with schizophrenia. However, these associations disappeared when corrected for haplogroup affiliation. The extensive 2GLD documented is a major concern when interpreting historic as well as designing future mtDNA association studies.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The copyright holder for this preprint (which was . http://dx.doi.org/10.1101/149070 doi: bioRxiv preprint first posted online 3 Genetic variants in mitochondrial DNA (mtDNA) -and in nuclear genes coding for mitochondrial function -have been associated with disease 1-3 . More than 300 variants 4,5 in mtDNA and genes involved in mitochondrial function 6 have been reported to cause mitochondrial disease which is clinically characterised by complex metabolic, neurological, muscular and psychiatric symptoms 7,8 .SNPs in mtDNA and mitochondrial haplogroups (mtDNA hgs), which are evolutionarily fixed SNP sets with a characteristic geographical distribution, have been proposed as potential disease modifiers 8 . This has been reported in neurological degenerative diseases such as Alzheimer's disease 9-12 and Parkinson's disease 12-14 , metabolic diseases and cancers 15 , as well as psychiatric diseases, notably schizophrenia (SZ) and bipolar disease [16][17][18] .Association studies of mtDNA variants and disease have been difficult to replicate 8 . However, the definition of a methodological paradigm for association studies with mtDNA variants 19 implicitly assumes that mtDNA variants are independent of the nuclear genome. In a recent Danish study on mtDNA haplogroups and their nuclear ancestry or nuclear genogeographical affinity (GGA), we demonstrated a marked difference in nuclear ancestry between individual haplogroups 20 . This means that mtDNA hgs entail population stratification also at the level of gDNA. The effect of such a stratification on disease association, will depend on the admixture structure of the particular population, the population history, epidemiology and genetic epidemiology of the disease, as well as the number of persons included in the study. The extensive fine-scale heterogeneity of gDNA and significant admixture documented in the UK 21 and Europe 22 further increase the risk of spurious false positive associations, if the mtDNA/gDNA interaction is not corrected phenomenon for in association studies.not peer-reviewed) is the author/funder. All rights reserved. No reuse allowed without permission.The co...

show abstract

Molecular and bioenergetic differences between cells with African versus European inherited mitochondrial DNA haplogroups: Implications for population susceptibility to diseases

Cited by 138 publications

References 75 publications

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

Maternal age effect and severe germ-line bottleneck in the inheritance of human mitochondrial DNA

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

Mitochondrial DNA SNPs associated with Schizophrenia exhibit Highly Variable Inter-allelic Haplogroup Affiliation and Nuclear Genogeographic Affinity: Bi-Genomic Linkage Disequilibrium raises Major Concerns for Link to Disease

Contact Info

Product

Resources

About