Human diseases with impaired mitochondrial protein synthesis

Mitochondrial respiratory chain deficiencies represent one of the major causes of metabolic disorders that are related to genetic defects in mitochondrial or nuclear DNA. The mitochondrial protein synthesis allows the synthesis of the 13 respiratory chain subunits encoded by mtDNA. Altogether, about 100 different proteins are involved in the translation of the 13 proteins encoded by the mitochondrial genome emphasizing the considerable investment required to maintain mitochondrial genetic system. Mitochondrial protein synthesis deficiency can be caused by mutations in any component of the translation apparatus including tRNA, rRNA and proteins. Mutations in mitochondrial rRNA and tRNAs have been first identified in various forms of mitochondrial disorders. Moreover abnormal translation due to mutation in nuclear genes encoding tRNA-modifying enzymes, ribosomal proteins, aminoacyl-tRNA synthetases, elongation and termination factors and translational activators have been successively described. These deficiencies are characterized by a huge clinical and genetic heterogeneity hampering to establish genotype-phenotype correlations and an easy diagnosis. One can hypothesize that a new technique for gene identification, such as exome sequencing will rapidly allow to expand the list of genes involved in abnormal mitochondrial protein synthesis.     

Genetic introgression, incomplete lineage sorting and faulty taxonomy create multiple cases of polyphyly in a montane clade of tyrant-flycatchers (Elaenia, Tyrannidae)

Species-level paraphyly and polyphyly are pervasive phenomena in modern phylogenetic research and can be due to a number of factors. We explore a complicated pattern of nuclear and mitochondrial polyphyly in montane Neotropical Elaenia flycatchers. Using a combination of phylogenetic and population genetic methods, we demonstrate that no single factor is sufficient to account for this pattern of polyphyly, and that it is likely based on an interplay of three different factors: (i) faulty taxonomy which has led to the recognition of two polyphyletic species that are better classified as four biological species; (ii) a late Pleistocene hybridization event that resulted in two morphologically and ecologically distinct species sharing extremely similar mitochondrial DNA but distinct nuclear DNA profiles; and (iii) incomplete lineage sorting in a nuclear marker that results in a polyphyletic placement of species that are otherwise well-differentiated in mitochondrial DNA, morphology and ecology. Additionally, we demonstrate that the two clades of montane Elaenia exhibit a reverse pattern of mitochondrial and nuclear diversity, with high mitochondrial and low nuclear genetic diversity in one clade and vice versa in the other clade. A possible cause for this pattern is differences in population histories, with large panmictic population structures being conducive to the retention of ancient nuclear polymorphisms in Elaenia albiceps chilensis .     

Population genetics of bisexual and unisexual populations of the scaly-winged bark louse Echmepteryx hageni (Insecta: Psocoptera)

The scaly-winged bark louse, Echmepteryx hageni, exhibits a unique pattern of co-existence of apparently differnt reproductive modes. Unisexuality is widespread in eastern North America, while sexual populations are restricted to isolated rock out-croppings in southern Illinois and eastern Kentucky. Three of the four nuclear loci examined show greater genetic diversity in the unisexual form compared to the sexual form of E. hageni, in accordance with the pattern previously shown in mitochondrial genetic data. Neutrality tests of the nuclear loci indicate a consistent signal of demographic expansion in asexual populations, but not in sexual populations. There was evidence of inbreeding in the isolated sexual populations at three of the nuclear loci, and one locus had signs of gene specific balancing selection. However, there is no significant genetic differentiation between bisexual and unisexual populations, possibly due to the greater effective population size of nuclear loci relative to mitochondrial loci. The mitochondrial differentiation of E. hageni populations in the northwestern part of their range (Minnesota and Wisconsin) was also not reflected in the nuclear data. We present three hypotheses that may explain the disparity in observed nuclear and mitochondrial genetic diversity between the reproductive forms of E. hageni.     

Aberrant heteroplasmic transmission of mtDNA in cloned pigs arising from double nuclear transfer

Double nuclear transfer begins with the transfer of nuclear DNA from a donor cell into an enucleated recipient oocyte. This reconstructed oocyte is allowed to develop to the pronuclear stage, where the pronuclei are transferred into an enucleated zygote. This reconstructed zygote is then transferred to a surrogate sow. The genetic integrity of cloned offspring can be compromised by the transmission of mitochondrial DNA from the donor cell, the recipient oocyte and the recipient zygote. We have verified through the use of sequence analysis, restriction fragment length polymorphism analysis, allele specific PCR and primer extension polymorphism analysis that following double nuclear transfer the donor cell mtDNA is eliminated. However, it is likely that the recipient oocyte and zygote mitochondrial DNA are transmitted to the offspring, indicating bimaternal mitochondrial DNA transmission. This pattern of mtDNA inheritance is similar to that observed following cytoplasmic transfer and violates the strict unimaternal inheritance of mitochondrial DNA to offspring. This form of transmission raises concerns regarding the genetic integrity of cloned offspring and their uses in studies that require metabolic analysis or a stable genetic environment where only one variable is under analysis, such as in knockout technology.     

Widespread mito‐nuclear discordance with evidence for introgressive hybridization and selective sweeps in Lycaeides

We investigated the extent and potential cause(s) of mitochondrial introgression within the polytypic North American Lycaeides species complex (Lepidoptera). By comparing population genetic structure based on mitochondrial DNA (COI and COII) and nuclear DNA (251 polymorphic amplified fragment length polymorphism markers), we detected substantial mito‐nuclear discordance, primarily involving a single mitochondrial haplotype (h01), which is likely due to mitochondrial introgression between differentiated Lycaeides populations and/or species. We detected reduced mitochondrial genetic diversity relative to nuclear genetic diversity in populations where mitochondrial haplotype h01 occurs, suggesting that the spread of this haplotype was facilitated by selection. We found no evidence that haplotype h01 is associated with increased fitness (in terms of survival to eclosion, fresh adult weight, and adult longevity) in a polymorphic Lycaeides melissa population. However, we did find a positive association between mitochondrial haplotype h01 and infection by the endoparasitic bacterium Wolbachia in one out of three lineages tested. Linkage disequilibrium between mitochondrial haplotype h01 and Wolbachia infection status may have resulted in indirect selection favouring the spread of haplotype h01 in at least one lineage of North American Lycaeides. These results illustrate the potential for introgressive hybridization to produce substantial mito‐nuclear discordance and demonstrate that an individual's mitochondrial and nuclear genome may have strikingly different evolutionary histories resulting from non‐neutral processes and intrinsic differences in the inheritance and biology of these genomes.     

Some highlights of mitochondrial research based on analyses of Neurospora crassa mitochondrial DNA

Research on mitochondrial nucleic acids has produced major surprises. These include: (1) a novel mechanism for reading the genetic code, (2) the first examples of deviations from the ‘universal’ genetic code, and (3) the finding that protein genes can be located totally within introns of other genes. The first indication that sequences within introns are important in RNA splicing came from analyses of mitochondrial introns and recent studies have revealed a close relationship between the majority of mitochondrial introns on the one hand and one class of nuclear introns, the ‘self-splicing’ rRNA introns, on the other.     

Energy biogenesis: one key for coordinating two genomes

In metazoan organisms, energy production is the only example of a process that is under dual genetic control: nuclear and mitochondrial. We used a genomic approach to examine how energy genes of both the nuclear and mitochondrial genomes are coordinated, and discovered a novel genetic regulatory circuit in Drosophila melanogaster that is surprisingly simple and parsimonious. This circuit is based on a single DNA regulatory element and can explain both intra- and inter-genomic coordinated expression of genes involved in energy production, including the full complement of mitochondrial and nuclear oxidative phosphorylation genes, and the genes involved in the Krebs cycle.     

Phylogeography of the pine processionary moth Thaumetopoea wilkinsoni in the Near East

Phylogeographic structure of the eastern pine processionary moth Thaumetopoea wilkinsoni was explored in this study by means of nested clade phylogeographic analyses of COI and COII sequences of mitochondrial DNA and Bayesian estimates of divergence times. Intraspecific relationships were inferred and hypotheses tested to understand historical spread patterns and spatial distribution of genetic variation. Analyses revealed that all T. wilkinsoni sequences were structured in three clades, which were associated with two major biogeographic events, the colonization of the island of Cyprus and the separation of southwestern and southeastern Anatolia during the Pleistocene. Genetic variation in populations of T. wilkinsoni was also investigated using amplified fragment length polymorphisms and four microsatellite loci. Contrasting nuclear with mitochondrial data revealed recurrent gene flow between Cyprus and the mainland, related to the long-distance male dispersal. In addition, a reduction in genetic variability was observed at both mitochondrial and nuclear markers at the expanding boundary of the range, consistent with a recent origin of these populations, founded by few individuals expanding from nearby localities. In contrast, several populations fixed for one single mitochondrial haplotype showed no reduction in nuclear variability, a pattern that can be explained by recurrent male gene flow or selective sweeps at the mitochondrial level. The use of both mitochondrial and nuclear markers was essential in understanding the spread patterns and the population genetic structure of T. wilkinsoni, and is recommended to study colonizing species characterized by sex-biased dispersal.     

Biased introgression of mitochondrial and nuclear genes: a comparison of diploid and haplodiploid systems

Hybridization between recently diverged species, even if infrequent, can lead to the introgression of genes from one species into another. The rates of mitochondrial and nuclear introgression often differ, with some taxa showing biases for mitochondrial introgression and others for nuclear introgression. Several hypotheses exist to explain such biases, including adaptive introgression, sex differences in dispersal rates, sex‐specific prezygotic isolation and sex‐specific fitness of hybrids (e.g. Haldane's rule). We derive a simple population genetic model that permits an analysis of sex‐specific demographic and fitness parameters and measures the relative rates of mitochondrial and nuclear introgression between hybridizing pairs. We do this separately for diploid and haplodiploid species. For diploid taxa, we recover results consistent with previous hypotheses: an excess of one sex among the hybridizing migrants or sex‐specific prezygotic isolation causes a bias for one type of marker or the other; when Haldane's rule is obeyed, we find a mitochondrial bias in XY systems and a nuclear bias in ZW systems. For haplodiploid taxa, the model reveals that owing to their unique transmission genetics, they are seemingly assured of strong mitochondrial biases in introgression rates, unlike diploid taxa, where the relative fitness of male and female hybrids can tip the bias in either direction. This heretofore overlooked aspect of hybridization in haplodiploids provides what is perhaps the most likely explanation for differential introgression of mitochondrial and nuclear markers and raises concerns about the use of mitochondrial DNA barcodes for species delimitation in these taxa.     

The mitochondrial and nuclear genetic structure of Myotis capaccinii (Chiroptera: Vespertilionidae) in the Eurasian transition, and its taxonomic implications

Allopatric isolation in glacial refugia has caused differentiation and speciation in many taxa globally. In this study, we investigated the nuclear and mitochondrial genetic differentiation of the long fingered bat, Myotis capaccinii during the ice ages in south-eastern Europe and Anatolia. The mitochondrial DNA (mtDNA) analyses indicated a suture zone similar to those recorded in other animal species, including bats, suggesting the association of more than one refugium with the region. Contrary to most of the other species where a suture zone was seen in Anatolia, for M. capaccinii the geographical location of the genetic break was in south-eastern Europe. This mitochondrial differentiation was not reflected in the nuclear microsatellites, however, suggesting that the lack of contact during the ice ages did not result in reproductive isolation. Hence taxonomically, the two mitochondrial clades cannot be treated as separate species.     

Population Structure of the Giant Garter Snake, Thamnophis gigas

The giant garter snake, Thamnophis gigas, is a threatened species endemic to California’s Central Valley. We tested the hypothesis that current watershed boundaries have caused genetic differentiation among populations of T. gigas. We sampled 14 populations throughout the current geographic range of T. gigas and amplified 859 bp from the mitochondrial gene ND4 and one nuclear microsatellite locus. DNA sequence variation from the mitochondrial gene indicates there is some genetic structuring of the populations, with high F_ST values and unique haplotypes occurring at high frequency in several populations. We found that clustering populations by watershed boundary results in significant between-region genetic variance for mtDNA. However, analysis of allele frequencies at the microsatellite locus NSU3 reveals very low F_ST values and little between-region variation in allele frequencies. The discordance found between mitochondrial and microsatellite data may be explained by aspects of molecular evolution and/or T. gigas life history characteristics. Differences in effective population size between mitochondrial and nuclear DNA, or male-biased gene flow, result in a lower migration rate of mitochondrial haplotypes relative to nuclear alleles. However, we cannot exclude homoplasy as one explanation for homogeneity found for the single microsatellite locus. The mitochondrial nucleotide sequence data supports conservation practices that identify separate management units for T. gigas.     

Nuclear locus divergence at the early stages of speciation in the Orchard Oriole complex

As two lineages diverge from one another, mitochondrial DNA should evolve fixed differences more rapidly than nuclear DNA due to its smaller effective population size and faster mutation rate. As a consequence, molecular systematists have focused on the criteria of reciprocal monophyly in mitochondrial DNA for delimiting species boundaries. However, mitochondrial gene trees do not necessarily reflect the evolutionary history of the taxa in question, and even mitochondrial loci are not expected to be reciprocally monophyletic when the speciation event happened very recently. The goal of this study was to examine mitochondrial paraphyly within the Orchard Oriole complex, which is composed of Icterus spurius (Orchard Oriole) and Icterus fuertesi (Fuertes' Oriole). We increased the geographic sampling, added four nuclear loci, and used a range of population genetic and coalescent methods to examine the divergence between the taxa. With increased taxon sampling, we found evidence of clear structure between the taxa for mitochondrial DNA. However, nuclear loci showed little evidence of population structure, indicating a very recent divergence between I. spurius and I. fuertesi. Another goal was to examine the genetic variation within each taxon to look for evidence of a past founder event within the I. fuertesi lineage. Based on the high amounts of genetic variation for all nuclear loci, we found no evidence of such an event – thus, we found no support for the possible founding of I. fuertesi through a change in migratory behavior, followed by peripheral isolates speciation. Our results demonstrate that these two taxa are in the earliest stages of speciation, at a point when they have fixed differences in plumage color that are not reflected in monophyly of the mitochondrial or nuclear DNA markers in this study. This very recent divergence makes them ideal for continued studies of species boundaries and the earliest stages of speciation.     

A Clinical,Neuropathological and Genetic Study of Homozygous A467T POLG-Related Mitochondrial Disease

Mutations in the nuclear gene POLG (encoding the catalytic subunit of DNA polymerase gamma) are an important cause of mitochondrial disease. The most common POLG mutation, A467T, appears to exhibit considerable phenotypic heterogeneity. The mechanism by which this single genetic defect results in such clinical diversity remains unclear. In this study we evaluate the clinical, neuropathological and mitochondrial genetic features of four unrelated patients with homozygous A467T mutations. One patient presented with the severe and lethal Alpers-Huttenlocher syndrome, which was confirmed on neuropathology, and was found to have a depletion of mitochondrial DNA (mtDNA). Of the remaining three patients, one presented with mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS), one with a phenotype in the Myoclonic Epilepsy, Myopathy and Sensory Ataxia (MEMSA) spectrum and one with Sensory Ataxic Neuropathy, Dysarthria and Ophthalmoplegia (SANDO). All three had secondary accumulation of multiple mtDNA deletions. Complete sequence analysis of muscle mtDNA using the MitoChip resequencing chip in all four cases demonstrated significant variation in mtDNA, including a pathogenic MT-ND5 mutation in one patient. These data highlight the variable and overlapping clinical and neuropathological phenotypes and downstream molecular defects caused by the A467T mutation, which may result from factors such as the mtDNA genetic background, nuclear genetic modifiers and environmental stressors.     

The role of western Mediterranean islands in the evolutionary diversification of the spotted flycatcher Muscicapa striata,a long‐distance migratory passerine species

We investigated the evolutionary history of the spotted flycatcher Muscicapa striata, a long distance migratory passerine having a widespread range, using mitochondrial markers and nuclear introns. Our mitochondrial results reveal the existence of one insular lineage restricted to the western Mediterranean islands (Balearics, Corsica, Sardinia) and possibly to the Tyrrhenian coast of Italy that diverged from the mainland lineages around 1 Mya. Mitochondrial genetic distance between insular and mainland lineages is around 3.5%. Limited levels of shared nuclear alleles among insular and mainland populations further support the genetic distinctiveness of insular spotted flycatchers with respect to their mainland counterparts. Moreover, lack of mitochondrial haplotypes sharing between Balearic birds (M. s. balearica) and Corso‐Sardinian birds (M. s. tyrrhenica) suggest the absence of recent matrilineal gene flow between these two insular subspecies. Accordingly, we suggest that insular spotted flycatchers could be treated as one polytypic species (Muscicapa tyrrhenica) that differs from M. striata in morphology, migration, mitochondrial and nuclear DNA and comprises two subspecies (the nominate and M. t. balearica) that diverged recently phenotypically and in mitochondrial DNA and but still share the same nuclear alleles. This study provides an interesting case‐study illustrating the crucial role of western Mediterranean islands in the evolution of a passerine showing high dispersal capabilities. Our genetic results highlight the role of glacial refugia of these islands that allowed initial allopatric divergence of insular populations. We hypothesize that differences in migratory and breeding phenology may prevent any current gene flow between insular and mainland populations of the spotted flycatcher that temporarily share the same insular habitats during the spring migration.     

Unique and isolated: population structure has implications for management of the endangered New Zealand sea lion

Female otariids (eared seals) frequently display strong levels of philopatry, a behaviour that has the potential to influence population structure, particularly at the mitochondrial level. Conversely, male otariids often move between breeding colonies, likely facilitating nuclear gene flow between colonies. Such gender-specific movements have the potential to influence species population structure. Here we investigate the genetic population structure of the endangered New Zealand (NZ) sea lion, using nuclear (microsatellite) and mitochondrial molecular markers, with the intention to better inform conservation through identification of management units for the species. The strong levels of female philopatry in this species have potential to lead to population structure at the mitochondrial loci. In contrast, weak or no population structure is expected across nuclear loci. NZ sea lions were sampled from the main breeding areas across the species’ current distribution (three Auckland Islands sites, two Campbell Island sites, one Stewart Island site and one Otago Peninsula site). Individuals were screened for microsatellite (n?=?271; 16 loci) and mitochondrial (n?=?56; 1027 bp D-loop and 1189 bp cytb). Despite a small (c. 9880 individuals) population size, moderate levels of microsatellite variation are observed in the NZ sea lions, in contrast to low levels of mitochondrial genetic variation. Results from mitochondrial DNA analyses revealed no population structure, suggesting that the strong level of female philopatry in NZ sea lions alone is not sufficient to maintain genetic population structure. Due to the frequent male movements between breeding colonies, no population structure was detected across the nuclear loci either. The absence of genetic structure suggests that, from a genetic perspective, NZ sea lions can be considered to be a single population. Despite this, the differing impacts of threats (e.g. fisheries by-catch) to each individual breeding colony must also be taken into consideration when defining management units for this endangered species.     

A reassessment of explanations for discordant introgressions of mitochondrial and nuclear genomes

Hybridization is increasingly recognized as a significant evolutionary process, in particular because it can lead to introgression of genes from one species to another. A striking pattern of discordance in the amount of introgression between mitochondrial and nuclear markers exists such that substantial mitochondrial introgression is often found in combination with no or little nuclear introgression. Multiple mechanisms have been proposed to explain this discordance, including positive selection for introgressing mitochondrial variants, several types of sex‐biases, drift, negative selection against introgression in the nuclear genome, and spatial expansion. Most of these hypotheses are verbal, and have not been quantitatively evaluated so far. We use individual‐based, multilocus, computer simulations of secondary contact under a wide range of demographic and genetic scenarios to evaluate the ability of the different mechanisms to produce discordant introgression. Sex‐biases and spatial expansions fail to produce substantial mito‐nuclear discordance. Drift and nuclear selection can produce strong discordance, but only under a limited range of conditions. In contrast, selection on the mitochondrial genome produces strong discordance, particularly when dispersal rates are low. However, commonly used statistical tests have little power to detect this selection. Altogether, these results dismiss several popular hypotheses, and provide support for adaptive mitochondrial introgression.     

Highly conserved nuclear copies of the mitochondrial control region in the desert locust Schistocerca gregaria: some implications for population studies

Animal mitochondrial DNA has proved a valuable marker in intraspecific systematic studies. However, if nucleotide sequence heterogeneity exists at the individual level, its usefulness will be much reduced. This study demonstrates that the presence of highly conserved non-coding mitochondrial sequences in the nuclear genome of Schistocerca gregaria greatly impairs the use of mtDNA in population genetic studies. Caution is called for in other organisms; and it seems necessary to check for conserved nuclear copies of mitochondrial sequences before launching into a large scale analysis of populations using mtDNA as a genetic marker. Experimental procedures are suggested for this purpose.     

Parental genetic effects in a cavefish adaptive behavior explain disparity between nuclear and mitochondrial DNA

Epigenetic parental genetic effects are important in many biological processes but their roles in the evolution of adaptive traits and their consequences in naturally evolving populations remain to be addressed. By comparing two divergent blind cave-dwelling cavefish populations with a sighted surface-dwelling population (surface fish) of the teleost Astyanax mexicanus, we report here that convergences in vibration attraction behavior (VAB), the lateral line sensory receptors underlying this behavior, and the feeding benefits of this behavior are controlled by parental genetic effects, either maternal or paternal inheritance. From behavioral studies and mathematical evolutionary simulations, we further demonstrate that disparity in nuclear and mitochondrial DNA in one of these cavefish populations that has hybridized with surface fish can be explained by paternal inheritance of VAB. The results suggest that parental genetic effects in adaptive behaviors may be important factors in biasing mitochondrial DNA inheritance in natural populations that are subject to introgression.     

Sky island diversification meets the multispecies coalescent – divergence in the spruce‐fir moss spider (Microhexura montivaga,Araneae, Mygalomorphae) on the highest peaks of southern Appalachia

Microhexura montivaga is a miniature tarantula‐like spider endemic to the highest peaks of the southern Appalachian mountains and is known only from six allopatric, highly disjunct montane populations. Because of severe declines in spruce‐fir forest in the late 20th century, M. montivaga was formally listed as a US federally endangered species in 1995. Using DNA sequence data from one mitochondrial and seven nuclear genes, patterns of multigenic genetic divergence were assessed for six montane populations. Independent mitochondrial and nuclear discovery analyses reveal obvious genetic fragmentation both within and among montane populations, with five to seven primary genetic lineages recovered. Multispecies coalescent validation analyses [guide tree and unguided Bayesian Phylogenetics and Phylogeography (BPP), Bayes factor delimitation (BFD)] using nuclear‐only data congruently recover six or seven distinct lineages; BFD analyses using combined nuclear plus mitochondrial data favour seven or eight lineages. In stark contrast to this clear genetic fragmentation, a survey of secondary sexual features for available males indicates morphological conservatism across montane populations. While it is certainly possible that morphologically cryptic speciation has occurred in this taxon, this system may alternatively represent a case where extreme population genetic structuring (but not speciation) leads to an oversplitting of lineage diversity by multispecies coalescent methods. Our results have clear conservation implications for this federally endangered taxon and illustrate a methodological issue expected to become more common as genomic‐scale data sets are gathered for taxa found in naturally fragmented habitats.