Epistatic interactions modulate the evolution of mammalian mitochondrial respiratory complex components

Azevedo, Luı́sa; Carneiro, João; Asch, Bárbara van; Moleirinho, Ana; Pereira, Filipe; Amorim, António

doi:10.1186/1471-2164-10-266

Cited by 35 publications

(32 citation statements)

References 60 publications

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“…In invertebrate PNCs, most interactions are maintained while additional hydrogen bonds and hydrophobic contacts were found. These new interactions might derive from complementary amino acid changes as a result of epistatic interactions between residues [21], [45], which is consistent with a structural conservation of PNCs.…”

Section: Discussionsupporting

confidence: 75%

The Evolutionary Portrait of Metazoan NAD Salvage

et al. 2013

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Nicotinamide Adenine Dinucleotide (NAD) levels are essential for cellular homeostasis and survival. Main sources of intracellular NAD are the salvage pathways from nicotinamide, where Nicotinamide phosphoribosyltransferases (NAMPTs) and Nicotinamidases (PNCs) have a key role. NAMPTs and PNCs are important in aging, infection and disease conditions such as diabetes and cancer. These enzymes have been considered redundant since either one or the other exists in each individual genome. The co-occurrence of NAMPT and PNC was only recently detected in invertebrates though no structural or functional characterization exists for them. Here, using expression and evolutionary analysis combined with homology modeling and protein-ligand docking, we show that both genes are expressed simultaneously in key species of major invertebrate branches and emphasize sequence and structural conservation patterns in metazoan NAMPT and PNC homologues. The results anticipate that NAMPTs and PNCs are simultaneously active, raising the possibility that NAD salvage pathways are not redundant as both are maintained to fulfill the requirement for NAD production in some species.

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Section: Discussionsupporting

confidence: 75%

The Evolutionary Portrait of Metazoan NAD Salvage

et al. 2013

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“…The software incorporates updated homology modelling methodology [47] for building the human structural models for COI, COII, COIII and CYB. The accuracy of the predicted 3D human models was evaluated in Verify 3D, SOLVX and ANOLEA [48]–[50].…”

Section: Methodsmentioning

confidence: 99%

Frequency and Pattern of Heteroplasmy in the Complete Human Mitochondrial Genome

et al. 2013

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Determining the levels of human mitochondrial heteroplasmy is of utmost importance in several fields. In spite of this, there are currently few published works that have focused on this issue. In order to increase the knowledge of mitochondrial DNA (mtDNA) heteroplasmy, the main goal of this work is to investigate the frequency and the mutational spectrum of heteroplasmy in the human mtDNA genome. To address this, a set of nine primer pairs designed to avoid co-amplification of nuclear DNA (nDNA) sequences of mitochondrial origin (NUMTs) was used to amplify the mitochondrial genome in 101 individuals. The analysed individuals represent a collection with a balanced representation of genders and mtDNA haplogroup distribution, similar to that of a Western European population. The results show that the frequency of heteroplasmic individuals exceeds 61%. The frequency of point heteroplasmy is 28.7%, with a widespread distribution across the entire mtDNA. In addition, an excess of transitions in heteroplasmy were detected, suggesting that genetic drift and/or selection may be acting to reduce its frequency at population level. In fact, heteroplasmy at highly stable positions might have a greater impact on the viability of mitochondria, suggesting that purifying selection must be operating to prevent their fixation within individuals. This study analyses the frequency of heteroplasmy in a healthy population, carrying out an evolutionary analysis of the detected changes and providing a new perspective with important consequences in medical, evolutionary and forensic fields.

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“…However, this expectation has been challenged by the realization that there are numerous examples where human mutant alleles correspond to the wild-type alleles in other mammalian species. [1][2][3][4][5][6][7] Such variants have become known as compensated pathogenic deviations (CPDs) following their original designation 5 because it is assumed that the apparently benign nature of these missense variants in non-human species is due to the coexistence of other amino-acid substitutions (AASs) that compensate for their otherwise dysfunctional consequences. Among those human mutant residues corresponding to the wild-type residue in mouse 5 are an p.(Ala53Thr) (NM_000345.3:c.157G4A) substitution at the α-synuclein (SNCA) locus reported to be associated with familial Parkinson disease; 8 the ADA-p.(Arg142Gln) (NM_000022.2: c.425G4A) causing severe combined immunodeficiency; 9 and the CFTR-p.(Phe87Leu) (NM_000492.3:c.259T4C) in the cystic fibrosis transmembrane conductance regulator gene underlying cystic fibrosis.…”

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confidence: 99%

“…Intriguingly, a different OTC variant p.(Thr125Met) associated with fatal hyperammonemia 14 was found to correspond to the wild-type allele in chimpanzees. 1,15,16 Among the CPDs identified through a comparison with the recently reported mountain gorilla genome 6 was the NPC1-p.(Asn961Ser) (NM_000271.4:c.2882A4G) that leads to Niemann-Pick disease C. 17 Finally, variants associated with ciliopathies at the BBS4 and RPGRIP1L genes associated with Bardet-Biedl and Meckel-Gruber syndromes, respectively, constitute the wild-type alleles in the genomes of several vertebrates. 7 The same study reported a de novo variant at the BTG2 locus in which the disease-associated allele corresponded to the wild-type allele in more than 50 vertebrate species.…”

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confidence: 99%

Improving the in silico assessment of pathogenicity for compensated variants

et al. 2016

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Understanding the functional sequelae of amino-acid replacements is of fundamental importance in medical genetics. Perhaps, the most intuitive way to assess the potential pathogenicity of a given human missense variant is by measuring the degree of evolutionary conservation of the substituted amino-acid residue, a feature that generally serves as a good proxy metric for the functional/ structural importance of that residue. However, the presence of putatively compensated variants as the wild-type alleles in orthologous proteins of other mammalian species not only challenges this classical view of amino-acid essentiality but also precludes the accurate evaluation of the functional impact of this type of missense variant using currently available bioinformatic prediction tools. Compensated variants constitute at least 4% of all known missense variants causing human-inherited disease and hence represent an important potential source of error in that they are likely to be disproportionately misclassified as benign variants. The consequent under-reporting of compensated variants is exacerbated in the context of next-generation sequencing where their inappropriate exclusion constitutes an unfortunate natural consequence of the filtering and prioritization of the very large number of variants generated. Here we demonstrate the reduced performance of currently available pathogenicity prediction tools when applied to compensated variants and propose an alternative machine-learning approach to assess likely pathogenicity for this particular type of variant.

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Epistatic interactions modulate the evolution of mammalian mitochondrial respiratory complex components

Cited by 35 publications

References 60 publications

The Evolutionary Portrait of Metazoan NAD Salvage

The Evolutionary Portrait of Metazoan NAD Salvage

Frequency and Pattern of Heteroplasmy in the Complete Human Mitochondrial Genome

Improving the in silico assessment of pathogenicity for compensated variants

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