Evolution and disease converge in the mitochondrion

Mo, Dan; Zhidkov, Ilia

doi:10.1016/j.bbabio.2010.04.315

Cited by 3 publications

(3 citation statements)

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“…In the last decade, the controversy surrounding the rate of mtDNA evolutionary change has increased to include discussions of the rate of change in coding regions (Elson et al, 2004; Kivisild et al, 2006), the role of purifying selection (Soares et al, 2009), the relation between mtDNA phylogeny and pathogenicity of mitochondrial variants (Elson et al, 2004; Mishmar and Zhidkov, 2010), the possible role of climate as a selective force on mtDNA diversity and the relation between time scale and molecular rate estimates (Emerson, 2007; Endicott et al, 2009; Ho et al, 2007; Macaulay et al, 1997). Bandelt (2008) stressed that every individual is likely heteroplasmic, i.e., harbors several related variants; this within-individual variation creates uncertainty about the estimates obtained comparing mother and child As a matter of fact, the process through which a mutation initially occurring in a single mtDNA molecule reaches fixation in an individual’s cells is far from being understood.…”

Section: Discussionmentioning

confidence: 99%

High mitochondrial mutation rates estimated from deep‐rooting costa rican pedigrees

Madrigal

Posthumously

Melendez-Obando³

et al. 2012

American J Phys Anthropol

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Estimates of mutation rates for the noncoding hypervariable Region I (HVR-I) of mitochondrial DNA (mtDNA) vary widely, depending on whether they are inferred from phylogenies (assuming that molecular evolution is clock-like) or directly from pedigrees. All pedigree-based studies so far were conducted on populations of European origin. In this paper we analyzed 19 deep-rooting pedigrees in a population of mixed origin in Costa Rica. We calculated two estimates of the HVR-I mutation rate, one considering all apparent mutations, and one disregarding changes at sites known to be mutational hot spots and eliminating genealogy branches which might be suspected to include errors, or unrecognized adoptions along the female lines. At the end of this procedure, we still observed a mutation rate equal to 1.24 × 10−6, per site per year, i.e., at least three-fold as high as estimates derived from phylogenies. Our results confirm that mutation rates observed in pedigrees are much higher than estimated assuming a neutral model of long-term HVRI evolution. We argue that, until the cause of these discrepancies will be fully understood, both lower estimates (i.e., those derived from phylogenetic comparisons) and higher, direct estimates such as those obtained in this study, should be considered when modeling evolutionary and demographic processes.

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Section: Discussionmentioning

confidence: 99%

High mitochondrial mutation rates estimated from deep‐rooting costa rican pedigrees

Madrigal

Posthumously

Melendez-Obando³

et al. 2012

American J Phys Anthropol

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“…Accordingly, a number of research groups, including our own, have demonstrated the association of ancient common mitochondrial DNA (mtDNA) genetic backgrounds with altered susceptibility to diabetes and its complications 10–12. Other complex and age-related disorders were also identified as being associated with mtDNA variation (recently reviewed) 13. Not only correlative evidence supports this line of thinking but also experimental findings establishing the functionality of certain human mitochondrial genetic variants, thus revealing them to serve as the “radar” of natural selection 14,15.…”

Section: Ancient Genetic Variants and Genetic Backgrounds Play A Rolementioning

confidence: 99%

The Impact of Darwinian Evolution on Medicine: The Maternal Side of the Story

Mo¹

2010

RMMJ

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Complex disorders are common in the human population and are caused by interplay between genetic and environmental factors. Therefore the quest for the genetic basis of such disorders has much similarity to deciphering the genetic basis of macro-evolutionary processes, such as speciation. Here I discuss conceptual connections between the principles underlying and processes occurring in disease and evolution. Special focus is given to the tremendous mitochondrial genetic variability in the population and within individuals and the impact of both types of variability on evolutionary processes and diseases.

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“…They are the only organelles that contain their own genome. The mitochondrial genome is a double stranded 16.5 kb long molecule which resembles that of prokaryotes [1]. The two strands differ in nucleotide (G +T) composition - the one which contains more guanines is named heavy (H) strand; the other, which is cystosine-rich is called L-strand (light strand).…”

Section: Introductionmentioning

confidence: 99%

Title: “Mitochondrial GWAS and Association of Nuclear - Mitochondrial Epistasis with BMI in T1DM Patients”

Ludwig-Słomczyńska

Seweryn

Kapusta

et al. 2018

Preprint

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UM, KC, PG and ŁD gathered study cohort and phenotypic data; EWO and MTM supervised 22 cohort construction; AHLS and EP performed genotyping; AHLS, MTS and PK analyzed and 23 interpreted data; AHLS, MTS, PK and PPW wrote the paper; AHLS and PPW and guarantors 24 of this work. All authors contributed to critical revision of the manuscript and approved its 25 publication. Abstract 27Mitochondria are organelles whose main role is energy production and might influence obesity. 28They are the only organelles with their own genome. Here we have genotyped 435 patients with 29 type 1 diabetes using Illumina Infinium Omni Express Exome-8 v1.4 arrays and performed 30 mitoGWAS on BMI. We have analyzed additive interactions between mitochondrial and 31 nuclear variants in genes known to be associated with mitochondrial functioning 32 (MitoCarta2.0) and confirmed and refined the results on external cohorts -Framingham Heart 33 Study (FHS) and GTEx data. The linear mixed model analysis was performed using the 34 GENESIS package in R/Bioconductor We have found a nominal association between 35 rs28357980 localized to MT-ND2 and BMI (β=-0.69, p=0.056). This was confirmed on 1889 36 patients from FHS cohort (β =-0.312, p=0.047). Next, we have searched for additive 37interactions between mitochondrial and nuclear variants. MT-ND2 variants interacted with 38 variants in SIRT3, ATP5B, CYCS, TFB2M and POLRMT genes. TFB2M is a mitochondrial 39 transcription factor and together with TFAM creates transcription promoter complex for 40 mitochondrial polymerase POLRMT. We have found that the interaction between rs3021088 41 of MT-ND2 gene and rs6701836 in TFB2M has led to BMI decrease (inter_pval=0.0241), while 42 interaction of rs3021088in MT-ND2 and rs41542013 in POLRMT gene led to BMI increase 43 (inter_pval=0.0004). The influence of these interactions on BMI was confirmed on external 44 cohorts. Here, we have shown that variants in mitochondrial genome as well as additive 45 interactions between mitochondrial and nuclear SNPs influence BMI in T1DM and general 46 cohorts. 48Author summary: 49 Obesity is an epidemic of our times. It is known that it results from an imbalance between 50 energy intake and its expenditure, while mitochondria are organelles whose main role is energy 3 51 production. They are the only organelles that contain their own genome. Thus, we have 52 genotyped 435 patients with type 1 diabetes and looked on single mitochondrial variant 53 influence as well as on additive interactions between mitochondrial and nuclear variants which 54 might affect BMI. Our analysis has shown, that rs28357980 localized to MT-ND2 is associated 55 with BMI. Next, we looked whether variants in this gene, which builds complex I of the electron 56 transport chain, might interact with nuclear variants and together they modify obesity risk. We 57 focused mainly on mitochondrial biogenesis and found that interactions between variants in 58 TFB2M (rs6701836) or POLRMT (rs41542013) and MT-ND2 (rs3021088) affect patients 59 BMI. TFB2M is a mit...

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Evolution and disease converge in the mitochondrion

Cited by 3 publications

References 0 publications

High mitochondrial mutation rates estimated from deep‐rooting costa rican pedigrees

High mitochondrial mutation rates estimated from deep‐rooting costa rican pedigrees

The Impact of Darwinian Evolution on Medicine: The Maternal Side of the Story

Title: “Mitochondrial GWAS and Association of Nuclear - Mitochondrial Epistasis with BMI in T1DM Patients”

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