scholarly journals Mitochondrial mutational spectrum is associated with mammalian longevity: a novel signature of oxidative damage.

2021 ◽  
Author(s):  
Alina G. Mikhailova ◽  
Alina A. Mikhailova ◽  
Kristina Ushakova ◽  
Evgenii Tretiakov ◽  
Viktor A Shamanskiy ◽  
...  
Keyword(s):  
Oxidative Damage ◽  
Heavy Chain ◽  
Mammalian Species ◽  
Experimental Studies ◽  
Nuclear Genome ◽  
Life History Trait ◽  
Mutational Bias ◽  
Mutational Spectra ◽  
Mutational Signature ◽  
Mutational Spectrum

The mutational spectrum of the mitochondrial DNA (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different tissues and organisms is still incomprehensible. Since mitochondria is tightly involved in aerobic energy production, it is expected that mtDNA mutational spectra may be affected by the oxidative damage which is increasing with organismal aging. However, the well-documented mutational signature of the oxidative damage, G>T substitutions, is typical only for the nuclear genome while it is extremely rare in mtDNA. Thus it is still unclear if there is a mitochondria-specific mutational signature of the oxidative damage. Here, reconstructing mtDNA mutational spectra for 424 mammalian species with variable generation length which is a proxy for oocyte age, we observed that the frequency of AH>GH substitutions (H - heavy chain notation) is positively correlated with organismal longevity. This mutational bias from AH to GH significantly affected the nucleotide content of analyzed 650 complete mammalian mitochondrial genomes, where fourfold degenerative synonymous positions of long-lived species become more AH poor and GH rich. Because (i) A>G is a substitution, typical for mtDNA; (ii) it is characterized by very strong asymmetry: A>G is several-fold more frequent on a heavy chain as compared to the light one; (iii) it is sensitive to the time being single-stranded during mtDNA asynchronous replication; (iv) it is associated with oxidative damage of single-stranded DNA in recent experimental studies we propose that A>G is a novel mutational signature of age-associated oxidative damage of single-stranded mtDNA. The described association of the mtDNA mutational spectra with a species-specific life-history trait can significantly affect general patterns of molecular evolution of mtDNA.

scholarly journals Mitochondrial mutational spectrum in mammals is sensitive to cellular and organismal longevity by means of A>G transitions

2019 ◽  
Author(s):  
A. G. Mikhaylova ◽  
A. A. Mikhailova ◽  
K. Ushakova ◽  
E.O. Tretiakov ◽  
A. Yurchenko ◽  
...  
Keyword(s):  
Energy Production ◽  
De Novo ◽  
Mammalian Species ◽  
Nuclear Genome ◽  
Mutational Signatures ◽  
Mutational Spectra ◽  
Mtdna Mutations ◽  
Mutational Spectrum ◽  
Heavy Strand ◽  
Different Tissues

AbstractMutational spectrum of the mitochondrial genome (mtDNA) does not resemble any of the known mutational signatures of the nuclear genome and variation in mtDNA mutational spectra between different tissues and organisms is still incomprehensible. Since mitochondria is tightly involved in energy production, we expect that mtDNA mutational spectra can reflect the level of cellular aerobic metabolism, which varies in different tissues. Analyzing a collection of somatic mtDNA mutations from human cancers, de novo mtDNA germline mutations from the human mother-offspring pairs, as well as mtDNA substitutions in hundreds of mammalian species, we observed that the frequency of AH>GH (heavy strand notation) substitutions is positively correlated with cellular and organismal longevity. For example, epithelium, oocytes of young mothers and mice have decreased AH>GH frequencies. We propose that AH>GH is a marker of cellular and organismal age, which is driven by oxidative damage of the single-stranded mtDNA during replication.Graphical abstractwhy melanoma is similar to a mouse and glioblastome resembles an elephant?

scholarly journals A mitochondrial mutational signature of temperature and longevity in ectothermic and endothermic vertebrates

2020 ◽  
Author(s):  
Alina G. Mikhailova ◽  
Victor Shamansky ◽  
Alina A. Mikhailova ◽  
Kristina Ushakova ◽  
Evgenii Tretyakov ◽  
...  
Keyword(s):  
Special Focus ◽  
Species Variation ◽  
Metabolic Rates ◽  
Mutational Spectra ◽  
Mutational Signature ◽  
Mutational Spectrum ◽  
Mole Rat ◽  
Naked Mole Rat ◽  
Main Factors ◽  
Species Specific

ABSTRACTMitochondrial mutational signature is very conserved and low deviations between species have been associated with longevity. By reconstructing species-specific mtDNA mutational spectrum for ray-finned fishes (Actinopterygii), we observed that temperature is a strong additional factor shaping the mtDNA mutational spectrum in ectotherms. The analysis of mammalian endotherms, with a special focus on species with temporarily or permanently low metabolic rates (hibernators, daily torpors, naked mole rat, etc.), confirmed the temperature effect, suggesting that two main factors shape between-species variation in mitochondrial mutational spectra: longevity and temperature.

scholarly journals Centromere Protein B Null Mice are Mitotically and Meiotically Normal but Have Lower Body and Testis Weights

1998 ◽  
Vol 141 (2) ◽  
pp. 309-319 ◽  
Author(s):  
Damien F. Hudson ◽  
Kerry J. Fowler ◽  
Elizabeth Earle ◽  
Richard Saffery ◽  
Paul Kalitsis ◽  
...  
Keyword(s):  
Cell Cycle Progression ◽  
Mammalian Species ◽  
Experimental Studies ◽  
Conflicting Evidence ◽  
Body Weights ◽  
Reduced Rate ◽  
And Function ◽  
Centromere Assembly ◽  
Mitosis And Meiosis

CENP-B is a constitutive centromere DNA-binding protein that is conserved in a number of mammalian species and in yeast. Despite this conservation, earlier cytological and indirect experimental studies have provided conflicting evidence concerning the role of this protein in mitosis. The requirement of this protein in meiosis has also not previously been described. To resolve these uncertainties, we used targeted disruption of the Cenpb gene in mouse to study the functional significance of this protein in mitosis and meiosis. Male and female Cenpb null mice have normal body weights at birth and at weaning, but these subsequently lag behind those of the heterozygous and wild-type animals. The weight and sperm content of the testes of Cenpb null mice are also significantly decreased. Otherwise, the animals appear developmentally and reproductively normal. Cytogenetic fluorescence-activated cell sorting and histological analyses of somatic and germline tissues revealed no abnormality. These results indicate that Cenpb is not essential for mitosis or meiosis, although the observed weight reduction raises the possibility that Cenpb deficiency may subtly affect some aspects of centromere assembly and function, and result in reduced rate of cell cycle progression, efficiency of microtubule capture, and/or chromosome movement. A model for a functional redundancy of this protein is presented.

scholarly journals Does testosterone affect lateralization of brain and behaviour? A meta-analysis in humans and other animal species

2008 ◽  
Vol 364 (1519) ◽  
pp. 929-942 ◽  
Author(s):  
Kristina A Pfannkuche ◽  
Anke Bouma ◽  
Ton G.G Groothuis
Keyword(s):  
Sex Differences ◽  
Animal Species ◽  
Meta Analysis ◽  
Mammalian Species ◽  
Experimental Studies ◽  
Fundamental Principle ◽  
Sufficient Information ◽  
Visuospatial Cognition ◽  
Organizational Effects ◽  
Meta Analyses

Lateralization of brain and behaviour has been the topic of research for many years in neuropsychology, but the factors guiding its development remain elusive. Based on sex differences in human lateralization, four hypotheses have been postulated that suggest a role for androgens, specifically testosterone. With the discovery that lateralization is a fundamental principle in the organization of brain and behaviour among vertebrates, it has now become possible to experimentally test such hypotheses in animal models. The use of different taxa, humans, other mammalian species and birds (with oestradiol and not testosterone involved in sexual differentiation in birds) facilitates to differentiate between the hypotheses. We used meta-analyses for analysing papers that provided sufficient information, and a semi-quantitative approach based on all relevant studies that we extracted from the literature. We tested the predictions of these hypotheses regarding strength and direction of lateralization for motor output, language and visuospatial cognition in these three taxa. We tested for sex differences and early organizational effects of testosterone (both correlative and experimental studies). We found sex differences in the direction of lateralization for non-human mammals (motor biases similar to humans) and in direction and strength in birds (visual cognitive tasks). However, the prediction that prenatal testosterone exposure affects the direction of lateralization was not supported for humans. In birds and non-human mammals, opposite trends were found, with the effect in non-human mammals being opposite to the expectation based on sex differences. None of the four hypotheses was sufficiently supported and more studies, testing a wider array of functions in different taxa while reporting the data more completely are needed.

scholarly journals sigfit: flexible Bayesian inference of mutational signatures

2018 ◽  
Author(s):  
Kevin Gori ◽  
Adrian Baez-Ortega
Keyword(s):  
Bayesian Inference ◽  
Probabilistic Models ◽  
R Package ◽  
Signature Analysis ◽  
Mutational Signatures ◽  
Mutational Spectra ◽  
Mutational Signature ◽  
Linear Optimisation ◽  
Biological Patterns ◽  
User Friendly

Mutational signature analysis aims to infer the mutational spectra and relative exposures of processes that contribute mutations to genomes. Different models for signature analysis have been developed, mostly based on non-negative matrix factorisation or non-linear optimisation. Here we present sigfit, an R package for mutational signature analysis that applies Bayesian inference to perform fitting and extraction of signatures from mutation data. We compare the performance of sigfit to prominent existing software, and find that it compares favourably. Moreover, sigfit introduces novel probabilistic models that enable more robust, powerful and versatile fitting and extraction of mutational signatures and broader biological patterns. The package also provides user-friendly visualisation routines and is easily integrable with other bioinformatic packages.

scholarly journals Electrophoretic separation and quantitation of cardiac myosin heavy chain isoforms in eight mammalian species

1998 ◽  
Vol 274 (3) ◽  
pp. H1048-H1053 ◽  
Author(s):  
Peter J. Reiser ◽  
William O. Kline
Keyword(s):  
Skeletal Muscle ◽  
Sample Preparation ◽  
Myosin Heavy Chain ◽  
Heavy Chain ◽  
Mammalian Species ◽  
Myosin Heavy Chain Isoforms ◽  
Glycerol Concentration ◽  
Cardiac Myosin ◽  
Homogenization Step

A protocol for sample preparation and gel electrophoresis is described that reliably results in the separation of the α- and β-isoforms of cardiac myosin heavy chain (MHC-α and MHC-β) in eight mammalian species. The protocol is based on a simple, nongradient denaturing gel. The magnitude of separation of MHC-α and MHC-β achieved with this protocol is sufficient for quantitative determination of the relative amounts of these two isoforms in mouse, rat, guinea pig, rabbit, canine, pig, baboon, and human myocardial samples. The sensitivity of the protocol is sufficient for the detection of MHC isoforms in samples at least as small as 1 μg. The glycerol concentration in the separating gel is an important factor for successfully separating MHC-α and MHC-β in myocardial samples from different species. The effect of sample load on MHC-α and MHC-β band resolution is illustrated. The results also indicate that inclusion of a homogenization step during sample preparation increases the amount of MHC detected on the gel for cardiac samples to a much greater extent than for skeletal muscle samples. Although the protocol described in this study is excellent for analyzing cardiac samples, it should be noted that the same protocol is not optimal for separating MHC isoforms expressed in skeletal muscle, as is illustrated.

scholarly journals Postreproductive killer whale grandmothers improve the survival of their grandoffspring

2019 ◽  
Vol 116 (52) ◽  
pp. 26669-26673 ◽  
Author(s):  
Stuart Nattrass ◽  
Darren P. Croft ◽  
Samuel Ellis ◽  
Michael A. Cant ◽  
Michael N. Weiss ◽  
...  
Keyword(s):  
Life History ◽  
Inclusive Fitness ◽  
Killer Whale ◽  
Mammalian Species ◽  
Life History Trait ◽  
Killer Whales ◽  
Reproductive Conflict ◽  
Significant Survival ◽  
Fitness Benefits ◽  
Difficult Times

Understanding why females of some mammalian species cease ovulation prior to the end of life is a long-standing interdisciplinary and evolutionary challenge. In humans and some species of toothed whales, females can live for decades after stopping reproduction. This unusual life history trait is thought to have evolved, in part, due to the inclusive fitness benefits that postreproductive females gain by helping kin. In humans, grandmothers gain inclusive fitness benefits by increasing their number of surviving grandoffspring, referred to as the grandmother effect. Among toothed whales, the grandmother effect has not been rigorously tested. Here, we test for the grandmother effect in killer whales, by quantifying grandoffspring survival with living or recently deceased reproductive and postreproductive grandmothers, and show that postreproductive grandmothers provide significant survival benefits to their grandoffspring above that provided by reproductive grandmothers. This provides evidence of the grandmother effect in a nonhuman menopausal species. By stopping reproduction, grandmothers avoid reproductive conflict with their daughters, and offer increased benefits to their grandoffspring. The benefits postreproductive grandmothers provide to their grandoffspring are shown to be most important in difficult times where the salmon abundance is low to moderate. The postreproductive grandmother effect we report, together with the known costs of late-life reproduction in killer whales, can help explain the long postreproductive life spans of resident killer whales.

scholarly journals Mammalian membrane block to polyspermy: new insights into how mammalian eggs prevent fertilisation by multiple sperm

2006 ◽  
Vol 18 (2) ◽  
pp. 53 ◽  
Author(s):  
Allison J. Gardner ◽  
Janice P. Evans
Keyword(s):  
Plasma Membrane ◽  
Zona Pellucida ◽  
Animal Species ◽  
Mammalian Species ◽  
Experimental Studies ◽  
Present Review ◽  
Cellular Signalling ◽  
Classical Studies ◽  
Vitelline Envelope ◽  
Mammalian Eggs

To inhibit fertilisation by more than one sperm (a condition known as polyspermy), eggs have developed preventative mechanisms known as blocks to polyspermy. The block at the level of the egg extracellular coat (the zona pellucida in mammals, the vitelline envelope in non-mammals) has been well characterised in many different animal species and the block at the level of the egg plasma membrane is understood in some non-mammalian species. However, virtually nothing is known about the membrane block to polyspermy in mammalian eggs, despite data dating back 50–90 years that provide evidence for its existence. In the present review, we will discuss the background on blocks to polyspermy used by animal eggs and then focus on the membrane block to polyspermy in mammalian eggs. This will include a summary of classical studies that provide evidence for this block in mammalian eggs, assays used to study the mammalian membrane block and what has been elucidated from recent experimental studies about the cellular signalling events that lead to membrane block establishment and the mechanism of how the membrane block may prevent additional fertilisation.

scholarly journals 215.Analysis of DNA damage induced by pro-oxidant treatment of mammalian spermatozoa in vitro

2004 ◽  
Vol 16 (9) ◽  
pp. 215
Author(s):  
L. E. Bennetts ◽  
R. J. Aitken
Keyword(s):  
Dna Damage ◽  
Oxidative Damage ◽  
Dna Sequences ◽  
Nuclear Dna ◽  
Quantitative Polymerase Chain Reaction ◽  
Mammalian Species ◽  
Dose Range ◽  
Tammar Wallaby ◽  
Sperm Chromatin ◽  
Sperm Dna

Defects in the male genome produced as a consequence of oxidative insult have been associated with decreased fertility levels, an elevated incidence of childhood cancer and dominant genetic disease in the offspring (1). The objective of this study was to determine the relative susceptibility of sperm DNA of different mammalian species to oxidative injury. We applied a highly sensitive quantitative PCR assay (QPCR) to measure gene-specific DNA damage in nuclear and mitochondrial compartments of spermatozoa treated with H2O2. Human, murine and tammar wallaby (Macropus eugenii) spermatozoa were treated with H2O2 (0–5�mM) over a 1�h period. After DNA purification, DNA damage was assessed in a nuclear and a mitochondrial fragment of DNA by quantitative polymerase chain reaction assay (QPCR). DNA damage was detected as a decrease amplification of the target sequences. In murine and human spermatozoa, mitochondrial DNA exhibited greater sensitivity to oxidative damage than nuclear DNA. Doses ranging from 0.25–5�mM H2O2 induced DNA damage of up to 0.65 lesions/10�kb in the mouse, and 1.42 lesions /10�kb in the human. No significant effect on DNA damage was observed over this dose range in the nuclear DNA fragments investigated in these species. In contrast, tammar wallaby spermatozoa were susceptible to DNA damage at the 5�mM H2O2 dose in both nuclear (0.51 lesions/10�kb) and mitochondrial (0.55 lesions/10�kb) genomes. This study is the first to compare DNA damage in specific DNA sequences in spermatozoa of different mammalian species. Nuclear DNA of the metatherian species, the tammar wallaby, was more susceptible to oxidative damage than that of the eutherian species. A major difference between metatherian and eutherian spermatozoa is that, in general, the former possess protamines that are not stabilised by disulfide cross-linkage. These findings therefore suggest that sperm chromatin packaging affects the susceptibility of sperm DNA to oxidative damage. (1) Sawyer and Aitken (2000) Reprod. Med. Rev. 8, 107–126.

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