Relationship between mtdna and nuclear dna

relationship between mtdna and nuclear dna

To sum it up, the basic difference between them are: 1. Nuclear DNA is found inside the nucleus of the cell while mitochondrial DNA is found only in the. The three-way interaction between human genetics, and pattern of relationship inferred from the analysis of the similar to that inferred from host mitochondrial DNA. Mitochondrion. Sep; doi: / Epub Aug 5. Interactions between mitochondrial and nuclear DNA in mammalian.

They included in their analysis families with at least two long-living siblings and they evaluated standardised mortality ratios, finding a survival benefit for all siblings of the long-living participants, for their parents, and for their offspring but not for their spouses. This result allowed authors to sustain that the families considered are genetically enriched for extreme survival and that it is unlikely that environmental factors play a major causative role in familial longevity. The environment effect on longevity was studied also by Montesanto et al.

Authors compared the survival functions of nonagenarians' siblings to those of their spouses to estimate the genetic component of longevity, minimizing the effects of environmental factors. Authors confirmed that both parents and siblings of the nonagenarians had a significant survival benefit. They also reported for the first time a gender-effect restricted to males.

Indeed, only male siblings showed a substantial survival advantage and the presence of a male nonagenarian in a family significantly decreased the mortality rate throughout lifetime for all the siblings, suggesting that genetic factors in males strongly affect the possibility of becoming long-lived.

relationship between mtdna and nuclear dna

Family studies of exceptional longevity were performed also to identify rare genetic variants that cannot be discovered with population-based studies. One of the largest European projects aimed at identifying genes involved in healthy ageing, the Genetics of Healthy Ageing GEHA project, was focused on a sophisticated familial model of longevity, that is, nonagenarian sib pairs, that is, two or more siblings aged 90 years or older [ 4950 ].

During GEHA project, families comprising nonagenarian siblings were recruited from 15 regions in 11 European countries. In addition, younger persons aged 50—75 years were included as unrelated controls but coming from the same geographical area as the sib pairs. The comprehensive phenotype description and an estimation of the survival rate of a subset of GEHA subjects were performed on this exceptional cohort to identify survival predictors [ 51 ].

A genome-wide linkage analysis on European nonagenarian full sibships of the GEHA project was performed to identify chromosomal regions involved in longevity [ 52 ].

relationship between mtdna and nuclear dna

The Mitochondrial Genome Several theories on ageing process and longevity posed mitochondria in a central position. Mitochondria produce the cellular energy through oxidative phosphorylation OXPHOS and many metabolic pathways are located in these organelles as well as the pathway controlling apoptosis.

The relative contribution of these two mechanisms and their interplay in the ageing process are still matter of debate, but a detailed analysis of the history of these theories is out of the scope of this review and it is well described elsewhere [ 53 ].

relationship between mtdna and nuclear dna

However, the more recent hypothesis states that ROS generation is not per se a cause of ageing, but rather a consequence of the age-dependent accumulation of mtDNA damage. Indeed, it is well known that mtDNA mutations increase with age, and recent findings show that this increment is likely due to errors in replication machinery or to unrepaired damage, placing ROS mutagenic effect in the background.

Two studies support this hypothesis: In humans, the processes influenced by mitochondrial activity and their effects on degenerative diseases and ageing appear to be modulated by mtDNA common variants as addressed by many studies [ 6063 — 73 ].

relationship between mtdna and nuclear dna

Recently, the association between recurrent or sporadic mtDNA mutations and longevity has been highlighted by the results of the GEHA project. A haplogroup classification and a specific analysis for evaluating the burden of nonsynonymous mutations in different mtDNA regions were performed [ 75 ].

In particular, the presence of mutations on complex I may be beneficial for longevity, while the cooccurrence of mutations on both complexes I and III or on both I and V might be detrimental to attain longevity.

As haplogroup J is characterized by mutations in complex I genes, this result might explain previous contrasting findings emerging from association studies on J haplogroup and longevity [ 65677076 — 78 ].

This result points out the need of complete sequencing of mtDNA in this type of genetic studies and the inadequacy of studies based on haplogroup classification. In conclusion, a major result of the GEHA study is that the interaction between mutations concomitantly occurring on different mtDNA genes can affect human longevity [ 74 ].

Moreover, such an effect of mtDNA variability on longevity seems to be mainly due to the cooccurrence of rare, private mutations, which are not detected by haplogroup analysis. The complex relationship between mitochondrial genetics and longevity has been further puzzled when somatic mtDNA variability is considered.

Indeed in one cell many mitochondrial genomes exist and the cooccurrence of mutated and wild type copies of mtDNAs is named heteroplasmy.

Many studies [ 81 — 83 ] showed an accumulation of heteroplasmy during ageing in different tissues such as muscle, brain, etc.

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Recent findings demonstrated that even low-frequency heteroplasmic mutations can be inherited from the mother [ 84 ] suggesting a potential role of these variants as primer to potentiate the effect of somatic mutations that accumulate during ageing [ 85 ].

This component of mtDNA variability is difficult to study, as heteroplasmy pattern observed in adulthood is a mixture of both inherited and somatic acquired mtDNA mutations. Moreover, the proportion of mutated mtDNA can vary according to the tissues and cells considered.

Only few studies were able to establish a link between heteroplasmy and healthy ageing and longevity [ 8687 ] and even less studies addressed the role that these accumulations may have in promoting longevity. A high incidence of the CT transition in centenarians' leukocytes was observed and a remodeling event of mtDNA replication origin associated with this mutation was hypothesized.

These studies also indicate that the level of heteroplasmy at position is similar between relatives and correlates in parent-offspring pairs, thus suggesting a genetic influence. However previous technologies such as DHPLC, pyrosequencing have not allowed a high-resolution analysis of mtDNA variants occurring at a very low frequency.

Nuclear DNA - Wikipedia

The advent of NGS technologies, with their capability for very high coverage, allows the analysis of mtDNA mutations at very low frequency with high accuracy [ 88 ].

This new technology applied to powerful models of longevity, such as centenarians and their offsprings, is expected to answer some of the open questions in this hot topic. Gut Microbiome In humans most of the microorganisms reside in the intestinal tract and their role is so central that all these microbes are considered as an additional organ, characterized by its own genome [ 89 ].

The relationship between human GM and the host is highly plastic, with the potential to readily adapt to changes in diet, life style, and geography, as well as to the different host ages, defining a process which is fundamental to maintain host health and homeostasis [ 91 ]. This plasticity has been recently highlighted by David and colleagues [ 92 ] that reported the effects on GM composition of different diets, that is, one based on animal products and another one based on plant products.

Authors observed that the short-term consumption of these two kinds of diet alters microbial community structure and bypasses the interindividual differences in the microbial gene expression.

The composition of the microbiota strongly impacts on the host health. Indeed, several studies report that the dysbiosis of the microbiome occurs in different chronic conditions, including obesity, inflammatory bowel diseases, and diabetes [ 93 — 96 ]. Regardless of whether it is a cause or a consequence of diseases, the GM can actively contribute to diseases consolidation. Indeed, several studies on disorders show that a pathologic phenotype can be transmitted from a diseased animal to a healthy recipient through the graft of the microbiota and this also applies to complex diseases where host genetics and environmental factors play a role [ 9798 ].

The first study that linked microbiota to human ageing dates back to when Metchnikoff postulated that ageing can be caused by gut microbiota dysbiosis [ 99 ]. The age-related changes in gut microbiota are very controversial and results from recent studies are not always concordant. In fact the study by Biagi et al.

This observation is obviously complicated by a high level of interindividual variability in the composition of gut microbiota. Interestingly, in centenarians this GM profile has been associated with inflammaging, a condition that is characterized by a high level of blood inflammatory markers. A shift in microbial composition towards an age-related pattern was observed in inflammatory disorders [ ], supporting the proinflammatory nature of an aged-type microbiota. However, the causes and the effects of a direct association between microbiota modifications and immunosenescence and inflammaging are still unclear [ ].

Recently, an alteration of GM functional profile was also observed in extreme ageing. The age-related trajectory of the human gut microbiome was shown to be characterized by loss of genes for short chain fatty acid production—well-known anti-inflammatory GM metabolites [ ]—and an overall decrease in the saccharolytic potential, while proteolytic functions were more abundant in centenarians'GM than in the intestinal metagenome of younger adults.

The Remodeling Theory of Ageing Human physiology undergoes profound changes from birth to old age. In the elderly, these changes are mainly the result of adaptive strategies at the molecular and cellular levels to compensate the damage accumulation that occurs over time. A major contribution to these changes is played by the cell microenvironment. A growing body of evidence supports the idea that the systemic environment is the repository of danger signal products and of the whole garbage that the senescent cells and the impaired tissues produce.

In yeast, inheritance of mitochondria is biparental. The mtDNA consists of a maternal lineage of inheritance in humans. Little or no cytoplasm is contributed to the zygote by the sperm in mammals.

Nuclear DNA

Therefore, in the embryoalmost all the mitochondria are derived from the ovum. In plants, the inheritance of mtDNA is the same as in mammals. Hence, diseases associated with mtDNA is gained by maternal inheritance. Large deletions in mtDNA cause Kearns-Sayre syndrome and chronic progressive external ophthalmoplegia. Circular mtDNA is shown in figure 2. The nDNA is located in the nucleus of a eukaryotic cell.

It is composed of The nDNA or the genome of a eukaryotic cell is organized into several linear chromosomes, which are found tightly packed inside the nucleus. Human bodies consist of 46 individual chromosomes. Sometimes, nDNA exists in several copies.

The number of copies of nDNA in the genome is described by the term ploidy. Human somatic cells are diploidcontaining two copies of nDNA, which are called homologous chromosomes.

relationship between mtdna and nuclear dna

Gametes are found haploid in humans. The size of the human genome is 3. These genes are encoded for almost all the characters exhibited by the organism.

They carry information for the growth, development, and reproduction. Genes are expressed into proteins according to the universal genetic code through transcription and translation. The nDNA is only replicated during the S phase of the cell cycle. Organization of nDNA is shown in figure 3.

Each of the two copies of the human genome is inherited from one parent, either from mother or father. The nDNA contains huge variations of the traits they exhibit due to the presence of various alleles per a particular gene.

Therefore, nDNA is used in paternity testing in order to find out which daughter organism belongs to which parent in humans. On the other hand, inheritance of diseases is also characteristic to the parents.

The nDNA is less prone to mutations. For example, human nDNA is arranged into 46 chromosomes. The size of the mtDNA is 16, base pairs. The size of the nDNA is 3.