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PubMed1993

Pedigree models for complex human traits involving the mitochondrial genome.

Recent biochemical and molecular-genetic discoveries concerning variations in human mtDNA have suggested a role for mtDNA mutations in a number of human traits and disorders. Although the importance of these discoveries cannot be emphasized enough, the complex natures of mitochondrial biogenesis, mutant mtDNA phenotype expression, and the maternal inheritance pattern exhibited by mtDNA transmission make it difficult to develop models that can be used routinely in pedigree analyses to quantify and test hypotheses about the role of mtDNA in the expression of a trait. In the present paper, we describe complexities inherent in mitochondrial biogenesis and genetic transmission and show how these complexities can be incorporated into appropriate mathematical models. We offer a variety of likelihood-based models which account for the complexities discussed. The derivation of our models is meant to stimulate the construction of statistical tests for putative mtDNA contribution to a trait. Results of simulation studies which make use of the proposed models are described. The results of the simulation studies suggest that, although pedigree models of mtDNA effects can be reliable, success in mapping chromosomal determinants of a trait does not preclude the possibility that mtDNA determinants exists for the trait as well. Shortcomings inherent in the proposed models are described in an effort to expose areas in need of additional research.

Computer Simulation↗

PubMed2004

The evolution of non-reciprocal nuclear exchange in mushrooms as a consequence of genomic conflict.

Heterothallic mushrooms accomplish sex by exchanging nuclei without cytoplasm. Hyphal fusions occur between haploid mycelia resulting from germinated spores and subsequent reciprocal nuclear exchange without cytoplasmic mixing. The resulting dikaryon is therefore a cytoplasmic mosaic with uniformly distributed nuclei (two in each cell). Cytoplasmic inheritance is doubly uniparental: both mated monokaryons can potentially transmit their cytoplasm to the sexual spores, but normally only a single type per spore is found. Intracellular competition between mitochondria is thus limited, but at the dikaryon level, the two types of mitochondria compete over transmission. This creates the conditions for genomic conflict: within the dikaryon, a selfish mitochondrial mutant with increased relative transmission can be favoured, but selection between dikaryons will act against such a mitochondrial mutant. Moreover, because nuclear fitness is directly dependent on dikaryon fitness, a reduction in dikaryon fitness directly conflicts with nuclear interests. We propose that genomic conflict explains the frequent occurrence of non-reciprocal nuclear exchange in mushrooms. With non-reciprocal exchange, one monokaryon donates a nucleus and the other accepts it, but not vice versa as in the typical life cycle. We propose a model where non-reciprocal nuclear exchange is primarily driven by mitochondria inducing male sterility and the evolution of nuclear suppressors.

Agaricales↗

PubMed1999

Mitochondrial DNA mutation at np 3243 in a family with maternally inherited diabetes mellitus.

Mitochondrial DNA (mtDNA) gene defects may play a role in the development of maternally inherited diabetes mellitus and deafness (MIDD). A family from Southern Italy who showed maternal transmission of type 2 diabetes mellitus with three individuals affected is described. A 10.4 kb deletion and mutations at nucleotide positions (np) 3243, 7445 and 11778 in the mtDNA of six relatives were sought. The mitochondrial np 3243 mutation of the tRNA Leu (UUR) gene was identified in a boy affected by optic atrophy and mental retardation, as well as in his diabetic mother. No other mutations or deletions were found. Our study points out the variable phenotypic expression of the np 3243 mtDNA mutation. This may suggest the presence of other mitochondrial or nuclear mutations required to modulate the phenotype. A clinical and metabolic follow-up of all family members was necessary to understand the role of the np 3243 mutation, especially in one child affected by optic atrophy and mental retardation. Further studies will be aimed at investigating the prevalence of mutations and deletions of mtDNA in type 2 diabetes mellitus.

Blood Glucose↗

PubMed2002

Tissue-specific expression of male-transmitted mitochondrial DNA and its implications for rates of molecular evolution in Mytilus mussels (Bivalvia: Mytilidae).

Mytilus and other bivalves exhibit an unusual system of mitochondrial DNA (mtDNA) transmission termed doubly uniparental inheritance (DUI). Specifically, males transmit the mtDNA they have received from their fathers to their sons. Females transmit their mother's mtDNA to both sons and daughters. Males are normally heteroplasmic and females are normally homoplasmic, but not exclusively. This system is associated with an unusual pattern of molecular evolution. Male-transmitted mtDNA (M type) evolves faster than female-transmitted (F type) mtDNA. Relatively relaxed selection on the M type has been proposed as an explanation for this phenomenon. To further evaluate the selective forces acting upon the M-type genome, we used RT-PCR to determine where it is expressed. M-type mtDNA expression was detected in all gonad samples and in 50% of somatic tissues of males, and in a single female tissue. F-type mtDNA expression was detected in all female tissues, all male somatic tissues, and all but one male gonad sample. We argue that the expression of M-type mtDNA in male somatic and male gonad tissues has implications for the strength of selection acting upon it.

Animals↗

PubMedDate not supplied

Maternal inheritance of mitochondrial cytochrome c oxidase activity in mice.

The RR mouse strain has unique restriction fragment patterns of mitochondrial DNA and shows lower activity of cytochrome c oxidase in fresh liver mitochondria than do C57BL/6 and BALB/c mice after nine weeks of age. In reciprocal F1 crosses between RR and the other two strains, the activity of crosses from RR mothers was lower than that in reciprocal crosses, although both F1 crosses had values intermediate between those of the parental strains. Cross-nursing tests demonstrated that strain differences probably are determined before or immediately after birth. Successive backcrossing was performed in order to transfer mitochondrial DNA from one strain to the nuclear background of another strain, and after eight and 10 generations, the cytochrome c oxidase activities of the backcross lines were compared with those of the maternal and paternal strains. The activity of the backcross line that started with C57BL/6 or BALB/c females and was successively backcrossed to RR males was still higher than that of RR. Similarly, the line that started with RR females and was backcrossed to C57BL/6 or BALB/c males showed lower activity than that of the paternal strain. These observations suggest that part of the strain difference of cytochrome c oxidase activity is transmitted by mitochondrial DNA, although our evidence does not exclude the possible involvement of other maternally transmitted components.

Aging↗

PubMed2000

Fertilization and elimination of the paternal mitochondrial genome.

With rare exceptions, mammalian mitochondria are inherited through the female. This probably serves to minimize lethal cytoplasmic gene competition and to prevent the inheritance of sperm mitochondrial DNA that has been subject to degradation by free radicals. In general, organisms are intolerant of mitochondrial heteroplasmy and, when this occurs in humans, it frequently presents as progressive and lethal bioenergetic or neurological disease. The mitochondria of spermatozoa are specifically destroyed by proteolysis in early embryonic development, in mice at the 4- to 8-cell transition. While there are concerns in human assisted reproduction that microinjection of abnormal or immature sperm cells could lead to lasting harm in the offspring through transmission of abnormal mitochondria, there is no clinical evidence to support this. There is more potential for harm through attempts to 'rescue' poor quality oocytes by cytoplasmic or nuclear transfer, as it is not currently possible to control the final fate of the donated mitochondria in relation to nuclear-mitochondrial interactions or the embryonic axes. Moreover, the balance between nuclear and mitochondrial genes and the role of cytoplasmic factors in epigenesis are still poorly understood. The future challenge for biologists is to comprehend the nature of the selective destruction of paternal mitochondria, as it appears to be a species-specific recognition phenomenon.

Animals↗

PubMed2005

Maternal inheritance in cyclic vomiting syndrome.

Cyclic vomiting syndrome (CVS), characterized by severe discrete episodes of nausea, vomiting, and lethargy, is a fairly common, disabling, predominately-childhood condition most often associated with migraine and dysautonomic features. Our group recently reported that children with CVS and additional neuromuscular disease manifestations demonstrate strong maternal inheritance of multiple disease manifestations and abnormal urine organic acids, suggesting the presence of predisposing mitochondrial DNA (mtDNA) sequence variants. In order to determine if maternal inheritance is present in CVS in general, a clinical interview was administered regarding 80 unrelated individuals with CVS ascertained randomly from the database of the Cyclic Vomiting Syndrome Association (CVSA). Disease manifestations consistent with potential mitochondrial dysfunction were far more common in matrilineal (sharing the same mtDNA sequence) versus in non-matrilineal relatives, including mothers versus fathers (P = 3 x 10(-9)) and maternal versus paternal grandmothers (P = 2 x 10(-6)). Maternal inheritance is suggested in 52% of the 23 subjects with two or more neuromuscular abnormalities ("CVS+") and in 54% of the 44 subjects without any neuromuscular abnormalities ("CVS-"). In both the CVS+ and CVS- sub-groups, subjects, and affected matrilineal relatives of all ages suffer at a far higher incidence from several dysautonomic-related conditions, including migraine and irritable bowel, as well as depression and hypothyroidism, while neuromuscular and cognitive disorders such as hypotonia and ADHD are common only in affected children. We conclude that mtDNA sequences predispose towards the development of protean disease manifestations in CVS patients ascertained through a disease-specific association, as well as among their matrilineal relatives, whether or not neuromuscular disease is present in the proband. Since CVS was absent in all but one matrilineal relative of our probands, CVS is apparently a rare clinical presentation in individuals carrying the predisposing mtDNA sequences. The four conditions reported most frequently among the matrilineal relatives of our cases, migraine, depression, irritable bowel, and hypothyroidism, are known to segregate together in families, and our findings suggest that a common predisposing genetic factor is likely present on the mtDNA.

DNA, Mitochondrial↗

PubMed1986

A further look at evidence for cytoplasmic inheritance of production traits in dairy cattle.

A recent study interpreted significant effects of source of cytoplasm as evidence for cytoplasmic inheritance. An alternative interpretation that observed results reflected residual additive genetic effects unaccounted for by statistical models used was tested by computer simulation of records over 60 yr for milk yield (h2 = .30) and fat percentage (h2 = .60) under an additive genetic model with no cytoplasmic effects. First lactation records for the last 30 yr were analyzed by least squares according to models that included effects of cytoplasmic source, generations to cytoplasmic source, herd, and year as well as effects of sire (model 1), sire and record of dam (model 2), Predicted Difference of sire (model 3), or Predicted Difference of sire and 1/2 Predicted Difference of maternal grandsire (model 4). Ten replicates were performed. Significant cytoplasmic effects were observed for all models in at least 8 of 10 replicates for milk yield and in all replicates for fat percentage. Average F ratios for cytoplasmic effects were 1.43, 1.25, 1.46, and 1.43 for milk yield and 2.00, 1.29, 2.04, and 1.96 for fat percentage for models 1, 2, 3, and 4. Cytoplasmic variances were 1.4 and 3.2% of residual variances for milk yield and fat percentage for model 1. Unaccounted for additive genetic effects can produce spurious cytoplasmic effects.

Animals↗

PubMed2007

Quantitation of the male and female types of mitochondrial DNA in a blue mussel, Mytilus galloprovincialis, using real-time polymerase chain reaction assay.

The system termed doubly uniparental inheritance (DUI) of mitochondrial transmission to progeny has been reported in Mytilus. Under DUI, it has been thought that males have both paternally (M type) and maternally (F type) transmitted mitochondrial DNA (mtDNA), and females have only F type. However, the presence of M type in females has been reported. To clarify the ratio of M type to F type mtDNA in female and male tissues to further our understanding of mitochondrial transmission, we developed a procedure to measure the copy numbers of the two types of mtDNA in Mytilus galloprovincialis using a real-time polymerase chain reaction assay. The following results were obtained by this method. In females, the copy numbers of M type mtDNA detected in adductor muscle, gonad and eggs were approximately 10 000-fold lower than those of F type. In males, F type dominated in adductor muscle, as in the female tissue. However, copy numbers of M type mtDNA were approximately 1000-fold higher than those of F type in gonad and 100 000-fold higher than those of F type in sperm. We examined the quantity relationship between the two types of mtDNA and the transmission mechanism of mtDNA in M. galloprovincialis.

Animals↗

PubMed2000

Mitochondrial DNA segregation in the developing embryo.

Mitochondrial (mt)DNA is strictly maternally inherited in mammals; new mutations thus segregate along maternal lineages without the benefit of homologous recombination with mtDNA of paternal origin. Despite the high mtDNA copy number (approximately 100000 or more) in mature oocytes, and despite the relatively small number of cell divisions during oogenesis, mtDNA sequence variants segregate rapidly between generations. This paradoxical behaviour has been ascribed to the presence of a mtDNA 'bottleneck' in oogenesis or early embryogenesis. The nature and size of this bottleneck have been the subject of much controversy. This review argues that segregation of mtDNA sequence variants in the female germline occurs primarily during mitosis in the oocyte precursor population. Segregation is rapid because the precursor cells (primordial germ cells and oogonia) contain a relatively small number of mtDNA templates (the bottleneck) and because the replication of mtDNA is under relaxed control. For the most part, the process appears similar in mice segregating polymorphic sequence variants and in human pedigrees segregating pathogenic point mutations. In particular, there is no evidence for selection against high levels of pathogenic mtDNA point mutations in oogenesis, in early embryonic development, or in fetal development, thus suggesting that efficient respiratory chain function is not critical until post-natal life. These results have important practical implications for clinical genetics.

Chromosome Segregation↗

PubMed2006

Competition affects gene flow from oilseed rape (female symbol) to Brassica rapa (male symbol).

Unlike most studies on hybridisation between oilseed rape and Brassica rapa, this study focused on hybridisation with oilseed rape as the maternal parent. This is a key cross because, assuming that plastids are inherited maternally, F(1)-hybrid production with maternal oilseed rape (B. napus) is the only transgene escape route from transplastomic oilseed rape. We investigated such F(1)-hybrid production in winter oilseed rape co-cultivated with weedy B. rapa at three plant densities each with two proportions of the different species. The paternity of the progeny produced on oilseed rape was assessed, and several fitness parameters were determined in oilseed rape mother plants in order to correlate hybridisation and plant competition. At higher density, the vegetative fitness per mother plant decreased significantly, but the density only affected the frequency of F(1)-hybrids significantly (a decrease) in the treatment with equal proportions of each species. As to the proportions, at higher B. napus frequencies, there were fewer F(1)-hybrids per mother plant and a significant increase in most biomass components. Thus, B. rapa was the stronger competitor in its effect on both the vegetative and reproductive fitness in B. napus, and the hybridisation frequency. In conclusion, the relative frequency of the two species was a more influential parameter than the density. Hybridisation with B. napus as the female will be most likely at current field densities of B. napus and when B. rapa is an abundant weed.

Biomass↗

PubMed1994

Rickettsial relative associated with male killing in the ladybird beetle (Adalia bipunctata).

A cytoplasmically inherited microorganism associated with male killing in the two-spot ladybird beetle, Adalia bipunctata, is shown to be closely related to bacteria in the genus Rickettsia. Sequencing of a PCR-amplified product of the 16S genes coding for rRNA (16S rDNA) shows the organism associated with male killing in ladybirds to share a common ancestry with the Rickettsias relative to other genera (e.g., Anaplasma, Ehrlichia, and Cowdria). The rickettsial 16S rDNA product is found in four strains of ladybird beetle showing male embryo lethality and is absent from two uninfected strains and an antibiotic-cured strain. In addition, a revertant strain that had naturally lost the male-killing trait failed to amplify the rickettsial 16S rDNA product. Use of PCR primers for a 17-kDa protein antigen which is found only in rickettsias also resulted in an amplified product from infected strains. Uninfected, cured, and revertant strains and insect species infected with related bacteria (cytoplasmic-incompatibility bacteria from Nasonia wasps) failed to amplify the product. Discovery of a close relative of rickettsias associated with sex ratio distortion in insects has implications for the evolution and population dynamics of this bacterial genus.

Animals↗

PubMed1991

Fertilization of cultured Xenopus oocytes and use in studies of maternally inherited molecules.

The methods described here of fertilizing stage VI oocytes are lengthy and quite difficult techniques. They would become more attractive if the success rate (i.e., the number of fertilizations compared to the numbers of matured oocytes) could be improved. An important step toward this for the host transfer technique would be to monitor carefully the status of mature Xenopus females ovaries in relation to cyclical HCG stimulation, so that we could predict more accurately whether stage VI oocytes are fertilizable. The in vitro technique would obviously be improved if oocytes could be fertilized without removing their membranes, perhaps by using oviduct extracts. So far, this approach has had only limited success. It seems that the rewards of using these techniques could be great, in terms of understanding the maternal contribution to development. Although our experiments have not yet shown that oocyte injection of DNA has any advantage over egg injection, it is clear that it is possible to make "mRNA-minus mutants" by this approach. In the message depletion experiments mentioned here, we targeted the cleavage of an mRNA which is of low abundance in the full grown oocyte, but preliminary experiments have shown that we can deplete more abundant messages and produce specific phenotypes. Of course such experiments need to be controlled to show that the effect is specific, and the best proof that this is the case is to rescue the effect with injection of the appropriate mRNA. Finally, it seems likely that the method can be used to study the function of both localized molecules, such as the putative primordial germ cell (PGC) or dorsal determinants, and more ubiquitous molecules such as cytoskeletal elements.

Animals↗

PubMed1999

Retinitis pigmentosa and progressive sensorineural hearing loss caused by a C12258A mutation in the mitochondrial MTTS2 gene.

Family ZMK is a large Irish kindred that segregates progressive sensorineural hearing loss and retinitis pigmentosa. The symptoms in the family are almost identical to those observed in Usher syndrome type III. Unlike that in Usher syndrome type III, the inheritance pattern in this family is compatible with dominant, X-linked dominant, or maternal inheritance. Prior linkage studies had resulted in exclusion of most candidate loci and >90% of the genome. A tentative location for a causative nuclear gene had been established on 9q; however, it is notable that no markers were found at zero recombination with respect to the disease gene. The marked variability in symptoms, together with the observation of subclinical muscle abnormalities in a single muscle biopsy, stimulated sequencing of the entire mtDNA in affected and unaffected individuals. This revealed a number of previously reported polymorphisms and/or silent substitutions. However, a C-->A transversion at position 12258 in the gene encoding the second mitochondrial serine tRNA, MTTS2, was heteroplasmic and was found in family members only. This sequence change was not present in 270 normal individuals from the same ethnic background. The consensus C at this position is highly conserved and is present in species as divergent from Homo sapiens as vulture and platypus. The mutation probably disrupts the amino acid-acceptor stem of the tRNA molecule, affecting aminoacylation of the tRNA and thereby reducing the efficiency and accuracy of mitochondrial translation. In summary, the data presented provide substantial evidence that the C12258A mtDNA mutation is causative of the disease phenotype in family ZMK.

Animals↗

PubMed2006

Fitness effects of Wolbachia and Spiroplasma in Drosophila melanogaster.

Maternally inherited endosymbionts that manipulate the reproduction of their insect host are very common. Aside from the reproductive manipulation they produce, the fitness of these symbionts depends in part on the direct impact they have on the female host. Although this parameter has commonly been investigated for single infections, it has much more rarely been established in dual infections. We here establish the direct effect of infection with two different symbionts exhibiting different reproductive manipulation phenotypes, both alone and in combination, in the fruit fly Drosophila melanogaster. This species carries a cytoplasmic incompatibility inducing Wolbachia and a male-killing Spiroplasma, occurring as single or double (co-) infections in natural populations. We assessed direct fitness effects of these bacteria on their host, by comparing larval competitiveness and adult fecundity of uninfected, Wolbachia, Spiroplasma and Wolbachia-Spiroplasma co-infected females. We found no effect of infection status on the fitness of females for both estimates, that is, no evidence of any benefits or costs to either single or co-infection. This leads to the conclusion that both bacteria probably have other sources of benefits to persist in D. melanogaster populations, either by means of their reproductive manipulations (fitness compensation from male death in Spiroplasma infection and cytoplasmic incompatibility in Wolbachia infection) or by positive fitness interactions on other fitness components.

Animals↗

PubMed2002

Novel non-Mendelian determinant involved in the control of translation accuracy in Saccharomyces cerevisiae.

Two cytoplasmically inherited determinants related by their manifestation to the control of translation accuracy were previously described in yeast. Cells carrying one of them, [PSI(+)], display a nonsense suppressor phenotype and contain a prion form of the Sup35 protein. Another element, [PIN(+)], determines the probability of de novo generation of [PSI(+)] and results from a prion form of several proteins, which can be functionally unrelated to Sup35p. Here we describe a novel nonchromosomal determinant related to the SUP35 gene. This determinant, designated [ISP(+)], was identified as an antisuppressor of certain sup35 mutations. We observed its loss upon growth on guanidine hydrochloride and subsequent spontaneous reappearance with high frequency. The reversible curability of [ISP(+)] resembles the behavior of yeast prions. However, in contrast to known prions, [ISP(+)] does not depend on the chaperone protein Hsp104. Though manifestation of both [ISP(+)] and [PSI(+)] is related to the SUP35 gene, the maintenance of [ISP(+)] does not depend on the prionogenic N-terminal domain of Sup35p and Sup35p is not aggregated in [ISP(+)] cells, thus ruling out the possibility that [ISP(+)] is a specific form of [PSI(+)]. We hypothesize that [ISP(+)] is a novel prion involved in the control of translation accuracy in yeast.

Alleles↗

PubMed1984

The persistence of maternal inheritance in Chlamydomonas despite hypomethylation of chloroplast DNA induced by inhibitors.

We have used inhibitors of methylation to evaluate the proposal that the extent of methylation of chloroplast DNA ( cpDNA ) of the mating type-plus (mt+) parent occurring during gametogenesis in wild-type Chlamydomonas renhardtii is directly correlated with the uniparental transmission of chloroplast genes by this parent [ Sager , R., Grabowy , C. & Sano , H. (1981) Cell 24, 41-47]. As detected by high-pressure liquid chromatography, the methylation of cpDNA was at its lowest level in the vegetative stage; the mt+ cells had a deoxycytidine methylation index (the percentage of deoxycytidine methylated) of 0.5, while the mating type-minus (mt-) index was lower by at least a factor of 3. This basal level of cpDNA methylation increased more than 20-fold after gametogenesis to give a methylation index of 12.1 and 4.3 for mt+ and mt- gametes, respectively. Another striking increase was detected at the 7-hr-zygote stage, resulting in the methylation of nearly half of the total deoxycytidine residues. The extent of zygotic cpDNA methylation was shown to be dependent on the preexisting methylation level of both parental gametic cpDNAs . L-Ethionine and 5-azacytidine effectively inhibited cpDNA methylation during gametogenesis and ensuing zygotic development as shown by both Hpa II/Msp I digestion patterns and HPLC. The transmission of chloroplast genes was analyzed concomitantly with the inhibitor studies. The two inhibitors produced different patterns of inhibition of methylation in mt- and mt+ cells at a given developmental stage. Our overall results demonstrate that the extent of mating type-specific and gamete-specific methylation during gametogenesis is not correlated with the frequency of maternal transmission of chloroplast genes.

Azacitidine↗

PubMed2006

DNA recombination-initiation plays a role in the extremely biased inheritance of yeast [rho-] mitochondrial DNA that contains the replication origin ori5.

Hypersuppressiveness, as observed in Saccharomyces cerevisiae, is an extremely biased inheritance of a small mitochondrial DNA (mtDNA) fragment that contains a replication origin (HS [rho(-)] mtDNA). Our previous studies showed that concatemers (linear head-to-tail multimers) are obligatory intermediates for mtDNA partitioning and are primarily formed by rolling-circle replication mediated by Mhr1, a protein required for homologous mtDNA recombination. In this study, we found that Mhr1 is required for the hypersuppressiveness of HS [ori5] [rho(-)] mtDNA harboring ori5, one of the replication origins of normal ([rho(+)]) mtDNA. In addition, we detected an Ntg1-stimulated double-strand break at the ori5 locus. Purified Ntg1, a base excision repair enzyme, introduced a double-stranded break by itself into HS [ori5] [rho(-)] mtDNA at ori5 isolated from yeast cells. Both hypersuppressiveness and concatemer formation of HS [ori5] [rho(-)] mtDNA are simultaneously suppressed by the ntg1 null mutation. These results support a model in which, like homologous recombination, rolling-circle HS [ori5] [rho(-)] mtDNA replication is initiated by double-stranded breakage in ori5, followed by Mhr1-mediated homologous pairing of the processed nascent DNA ends with circular mtDNA. The hypersuppressiveness of HS [ori5] [rho(-)] mtDNA depends on a replication advantage furnished by the higher density of ori5 sequences and on a segregation advantage furnished by the higher genome copy number on transmitted concatemers.

Alloxan↗