Patel et al. The glycine variant at position is conserved across eukaryotes. The serine variant conferred a reduction in male, but not female fertility, with the magnitude of the reduced fertility in males increasing with advancing age and also greatly exacerbated at higher temperatures.
While the former examples involve genetic polymorphisms that evolve and segregate naturally in wild or laboratory populations, further evidence for male infertility-impairing mtDNA mutations in D. Xu and coworkers Xu et al. Using this approach, they identified three sequence variants, one of which possessed a normal phenotype mt:CoI AT , normal for fertility, cytochrome c oxidase activity and ATP production , while the other two conferred male sterility.
More specifically, males carrying mt:CoI RQ were sterile, producing low numbers of motile sperm, but were otherwise healthy, exhibiting normal cytochrome c oxidase activity and ATP levels. A fertility effect on females was not reported, but presumed absent. In sum, in D. Evidence therefore exists in D. Studies of mice have also provided evidence that mtDNA mutations exist that confer negative effects on male, but not female, fertility.
Nakada et al. The authors reported various pathologies, the expression of which depended on the proportion of the mutant mtDNA molecules level of heteroplasmy per individual mouse. These males with the highest mutant loads also exhibited widespread respiratory deficiencies, and other pathologies associated with mitochondrial disease myopathy, lactic acidosis, renal failure, deafness. The approach of Nakada and colleagues is complemented by two other studies in mice. Firstly, Trifunovic and colleagues Trifunovic et al.
While mtDNA-mutator mice of both sexes exhibited fertility reductions relative to wild-type mice, the magnitude of reduction was again male biased. Almost all mtDNA-mutator females produced one or two litters of normal size up until the age of 20 weeks, at which point they were no longer reproductive. Mutator males, however, were mostly infertile, with only one of eight males tested producing a litter; and mtDNA-mutator males possessed testes of much smaller size relative to wild-type males, even early in adult life at 12 weeks.
Secondly, Ma et al. Male offspring carrying PWD mtDNA in a B6 nuclear autosomal background exhibited reduced fertility, as gauged by number of litters produced, but females were unaffected. This male infertility effect is likely attributable to mutations in the mtDNA sequence of the PWD mice, which are normally rescued by modifier mutations that lie within the PWD nuclear background, but which were not present in the experimental mice carrying the B6 background Ma et al.
In sum, there have been three studies in mice that have examined effects of mtDNA variation on reproductive outcomes of both sexes Inoue et al. Each of these studies has documented male biases in fertility reductions that map to mutations in the mitochondrial genome. Again, consistent with the Drosophila case studies reviewed above, the studies on mice provide empirical support for the tenet that mtDNA sequences are enriched for mutations that specifically depress male components of reproduction.
Unlike the Drosophila and mouse studies, which are able to leverage experimental approaches to partition mitochondrial genetic, from nuclear genetic and environmental effects on fertility outcomes, human studies must rely principally on inferences drawn from correlations between mtDNA variants and fertility outcomes.
Various associations have been reported between naturally occurring mtDNA haplogroups and incidences of male infertility. Ruiz-Pesini et al. Montiel-Sosa et al. Yet, some caution must be applied to interpreting correlations of the type presented in these studies, since the patterns could be mediated by other confounding factors, such as differences in nuclear genetic structure between groups of individuals possessing the different mtDNA haplotypes.
Furthermore, it remains unknown whether similar correlations exist between these human haplotypes and candidate mutations to patterns of female fertility. However, in a recent development, Martikainen and colleagues Martikainen et al.
The magnitude of the effect on reproductive success increased with the severity of the mitochondrial disease symptoms in these males. The effects on fertility were equally evident among the cohort of males whose disease symptoms were caused by pathogenic mutations in the mtDNA or mutations in nuclear genes that encode mitochondrial function. Many of the patients suffering from mtDNA-mediated mitochondrial disease in this study carried the m. Remarkably, these patterns linking mtDNA mutations to reduced reproductive success were not found in female patients of the same database carrying pathogenic mtDNA mutations Gorman et al.
Generally, little is known about putative reproductive effects in females carrying the m. In sum, the recent evidence in humans is consistent with the evolutionary hypothesis prediction that mitochondrial genomes will harbour mutations that confer male biases in reproductive outcomes and aligns with the experimental evidence acquired from the study of Drosophila and mice.
Future association studies in humans should, however, focus on the possible effects of the mutations under study on components of female reproductive success, to redress what appears to be a sex bias in the study of human mtDNA variation and its effects on fertility.
Our literature search revealed a striking technical sex bias in research examining effects of mtDNA mutations on reproductive outcomes.
We have focused our discussion on robust case studies from Drosophila , mice and humans, because these encompass the vast majority of studies conducted to date and are underscored by reproductive data collected from both sexes. We note, however, that these case studies are supported in several cases by intriguing patterns of male bias in mitochondrial effects on fertility in non-model species Smith et al.
Taken together, these findings suggest that mitochondrial genomes might be enriched for male fertility-impairing mutations across metazoans. Yet, challenges lie ahead before such a suggestion can be confirmed, and the most obvious is the need to redress the large technical sex bias in research linking the mtDNA to fertility outcomes.
For example, almost all of the association studies conducted in humans, which have studied the effects of particular mtDNA haplotypes or mutations on reproductive performance, focused exclusively on males. As such, while several cases of male-specific mtDNA-mediated infertility have now been confirmed across model species, it remains unclear whether these cases represent anomalies specific to a few mtDNA mutations appearing in one or a few animal species or whether they represent a small fraction of the total male-biased mtDNA variants that might be segregating in animal mitochondrial genomes.
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of this review. PNAS 93 — Annual Review of Ecology and Systematics 18 — Molecular Reproduction and Development 80 — Molecular Biology Reports 40 — Trends in Ecology and Evolution 10 — Functional Ecology 28 — Annual Review of Ecology, Evolution, and Systematics 36 — Molecular Ecology 13 — Philosophical Transactions of the Royal Society B Trends in Genetics 17 — Trends in Ecology and Evolution 24 — Evolutionary Biology 43 37 — Trends in Ecology and Evolution 18 2 — 4.
Journal of Bioenergetics and Biomembranes 26 — Current Biology 22 — Current Biology 25 — International Journal of Fertility and Sterility 8 BMC Medical Genetics 12 8. Annals of Neurology 48 — Clancy DJ Variation in mitochondrial genotype has substantial lifespan effects which may be modulated by nuclear background. Aging Cell 7 — Heredity Iranian Red Crescent Medical Journal 15 Journal of Evolutionary Biology 27 — Ecology and Evolution 4 — Dowling DK Evolutionary perspectives on the links between mitochondrial genotype and disease phenotype.
Trends in Ecology and Evolution 23 — Journal of Evolutionary Biology 22 — Evolutionary Applications 8 — American Journal of Human Genetics 83 — Comparative Biochemistry and Physiology 17 — Neurology 49 — Human Reproduction 8 — Sperm-derived paternal mitochondria and their mtDNA enter the oocyte cytoplasm upon fertilization and then normally disappear during early embryogenesis. However, the mechanism underlying this clearance of paternal mitochondria has remained largely unknown.
Recently, we showed that autophagy is required for the elimination of paternal mitochondria in Caenorhabditis elegans embryos. This suggests that in heteroplasmic females the frequency of the rare haplotype was above the detection limit of the method, whereas in the females that we identified as homoplasmic it was below the detection limit of the method.
Both, the heteroplasmic mothers and mothers that were scored as homoplasmic transmitted the rare haplotype to a similar number of offspring but in case of homoplasmic mothers there was a higher shift in heteroplasmy levels between mothers and offspring 12 , If drift alone was responsible for the transmission of heteroplasmy, we would expect that mothers with higher levels of heteroplasmy those that identified as heteroplasmic would have transmitted their heteroplasmy in higher number of progeny.
However, we have not observed such a pattern. There were two more rather interesting results from this study. First, there were significantly higher number of families and individuals in F2 with paternal leakage originated from mothers that were scored as homoplasmic. If we accept that PCR is at least semi-quantitative method 40 this result suggests that the observed 5. It also suggests that the levels of heteroplasmy increased significantly in the progeny of mothers which themselves had lower levels of heteroplasmy.
Second, there is a potential connection between the paternal leakage and the maternal transmission of heteroplasmy, because an individual with paternal leakage is more prone to have inherited heteroplasmy from its mother. Their connection makes sense if we assume that selection operates on the levels of heteroplasmy itself, without distinction for its origin.
The results from hybrids should be cautiously extrapolated to the pure species because some of the observations are expected to occur because of the mixing up of the pure-species genomes such as the increased number of individuals with paternal mtDNA 24 , 25 , 26 , 27 , Other observations however, might reveal characteristics of the heteroplasmy mechanisms themselves.
Obviously, a detailed investigation is needed to clarify the mechanistic basis of the processes and to provide experimental evidence for the potential advantage of heteroplasmy. In the parental generation P generation we performed four different types of crosses: two D. Therefore, in P generation we had four types of crosses Table 2. For each type of cross, we set up 10 replicates and in each replicate we crossed 1 virgin female D.
Some of the replicates did not produce hybrids and we ended up with different number of successful replicates per cross type. The individuals in the P generation were left to mate and were transferred to a new vial after the first pupae appeared.
The interspecific cross simulans x mauritiana produces fertile females and sterile males We preserved all F1 male hybrids in absolute ethanol. We crossed one-by-one all F1 female hybrids to a D.
That way, we could distinguish between the transmission of heteroplasmy from the mother in this example, mother would have haplotypes siI and maI in heteroplasmic state and the leakage of paternal mtDNA in F2 generation, because F1 hybrids had the maternal mtDNA in this case siI , which was distinct from the paternal mtDNA siII.
Each F1 female hybrid was crossed with three male D. Given that we did not know whether the mother was homoplasmic or heteroplasmic beforehand, and that the percentage of heteroplasmy in female hybrids is low 24 we performed crosses with all F1 females.
In total, we performed crosses with F1 female hybrids. After collecting the F2 generation the F1 parents were stored in ethanol as well as the individuals of F2 generation.
DNA was extracted from single flies, using a protocol previously described Heteroplasmy was detected with PCR, using specific primers for each mitotype. We also used the same primers when siI and siII were present together in F2 generation. The detection limit was the last dilution that we observed PCR product. In every PCR reaction positive and negative controls were used. In all samples we amplified the maternal, common mtDNA type.
We discarded from further analysis samples that the maternal mtDNA was not successfully amplified. In F2 hybrids, apart from the presence of paternal mtDNA, we also checked for the presence of the second maternal mitotype. For all cases in which heteroplasmy was detected, we could distinguish between the heteroplasmy generated from paternal leakage and the heteroplasmy inherited from the mother in F2 generation.
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