Mitochondrial Genome Variation Research Articles

Rapid evolutionary divergence of diploid and allotetraploid Gossypium mitochondrial genomes

BackgroundCotton (Gossypium spp.) is commonly grouped into eight diploid genomic groups and an allotetraploid genomic group, AD. The mitochondrial genomes supply new information to understand both the evolution process and the mechanism of cytoplasmic male sterility. Based on previously released mitochondrial genomes of G. hirsutum (AD1), G. barbadense (AD2), G. raimondii (D5) and G. arboreum (A2), together with data of six other mitochondrial genomes, to elucidate the evolution and diversity of mitochondrial genomes within Gossypium.ResultsSix Gossypium mitochondrial genomes, including three diploid species from D and three allotetraploid species from AD genome groups (G. thurberi D1, G. davidsonii D3-d and G. trilobum D8; G. tomentosum AD3, G. mustelinum AD4 and G. darwinii AD5), were assembled as the single circular molecules of lengths about 644 kb in diploid species and 677 kb in allotetraploid species, respectively. The genomic structures of mitochondrial in D group species were identical but differed from the mitogenome of G. arboreum (A2), as well as from the mitogenomes of five species of the AD group. There mainly existed four or six large repeats in the mitogenomes of the A + AD or D group species, respectively. These variations in repeat sequences caused the major inversions and translocations within the mitochondrial genome. The mitochondrial genome complexity in Gossypium presented eight unique segments in D group species, three specific fragments in A + AD group species and a large segment (more than 11 kb) in diploid species. These insertions or deletions were most probably generated from crossovers between repetitive or homologous regions. Unlike the highly variable genome structure, evolutionary distance of mitochondrial genes was 1/6th the frequency of that in chloroplast genes of Gossypium. RNA editing events were conserved in cotton mitochondrial genes. We confirmed two near full length of the integration of the mitochondrial genome into chromosome 1 of G. raimondii and chromosome A03 of G. hirsutum, respectively, with insertion time less than 1.03 MYA.ConclusionTen Gossypium mitochondrial sequences highlight the insights to the evolution of cotton mitogenomes.

Association of mitochondrial copy number variation and T16189C polymorphism with colorectal cancer in North Indian population.

Globally, colorectal cancer is the third most common type of cancer. Genetic instability leading to cancer development is one of the major causes for development of cancer. Alterations in mitochondrial genome, that is, mutations, single-nucleotide polymorphisms, and copy number variations are known to contribute in cancer development. The aim of our study was to investigate association of mitochondrial T16189C polymorphism and copy number variation with colorectal cancer in North Indian population. DNA isolated from peripheral blood of 126 colorectal cancer patients and 114 healthy North Indian subjects was analyzed for T16189C polymorphism and half of them for mitochondrial copy number variation. Genotyping was done using polymerase chain reaction-restriction fragment length polymorphism, and copy number variation was estimated using real-time polymerase chain reaction, numbers of mitochondrial copies and found to be significantly higher in colorectal cancer patients than healthy controls (88 (58-154), p = 0.001). In the regression analysis, increased mitochondrial copy number variation was associated with risk of colorectal cancer (odds ratio = 2.885, 95% confidence interval = 1.3-6.358). However, T16189C polymorphism was found to be significantly associated with the risk of rectal cancer (odds ratio = 5.213, p = 0.001) and non-significantly with colon cancer (odds ratio = 0.867, p = 0.791). Also, false-positive report probability analysis was done to validate the significant findings. Our results here indicate that mitochondrial copy number variation may be playing an important role in the development of colorectal cancer, and detection of mitochondrial copy number variation can be used as a biomarker for predicting the risk of colorectal cancer in North Indian subjects.

Widespread co-occurrence of two distantly related mitochondrial genomes in individuals of the leaf beetle Gonioctena intermedia.

Mitochondrial genome heteroplasmy-the presence of more than one genomic variant in individuals-is considered only occasional in animals, and most often involves molecules differing only by a few recent mutations. Thanks to new sequencing technologies, a large number of DNA fragments from a single individual can now be sequenced and visualized separately, allowing new insights into intra-individual mitochondrial genome variation. Here, we report evidence from both (i) massive parallel sequencing (MPS) of genomic extracts and (ii) Sanger sequencing of PCR products, for the widespread co-occurrence of two distantly related (greater than 1% nucleotide divergence, excluding the control region) mitochondrial genomes in individuals of a natural population of the leaf beetle Gonioctena intermedia Sanger sequencing of PCR products using universal primers previously failed to identify heteroplasmy in this population. Its occurrence was detected with MPS data and may have important implications for evolutionary studies. It suggests the need to re-evaluate, using MPS techniques, the proportion of animal species displaying heteroplasmy.

Clinical utility of the low-density Infinium QC genotyping Array in a genomics-based diagnostics laboratory

BackgroundWith 15,949 markers, the low-density Infinium QC Array-24 BeadChip enables linkage analysis, HLA haplotyping, fingerprinting, ethnicity determination, mitochondrial genome variations, blood groups and pharmacogenomics. It represents an attractive independent QC option for NGS-based diagnostic laboratories, and provides cost-efficient means for determining gender, ethnic ancestry, and sample kinships, that are important for data interpretation of NGS-based genetic tests.MethodsWe evaluated accuracy and reproducibility of Infinium QC genotyping calls by comparing them with genotyping data of the same samples from other genotyping platforms, whole genome/exome sequencing. Accuracy and robustness of determining gender, provenance, and kinships were assessed.ResultsConcordance of genotype calls between Infinium QC and other platforms was above 99%. Here we show that the chip’s ancestry informative markers are sufficient for ethnicity determination at continental and sometimes subcontinental levels, with assignment accuracy varying with the coverage for a particular region and ethnic groups. Mean accuracies of provenance prediction at a regional level were varied from 81% for Asia, to 89% for Americas, 86% for Africa, 97% for Oceania, 98% for Europe, and 100% for India. Mean accuracy of ethnicity assignment predictions was 63%. Pairwise concordances of AFR samples with the samples from any other super populations were the lowest (0.39–0.43), while the concordances within the same population were relatively high (0.55–0.61). For all populations except African, cross-population comparisons were similar in their concordance ranges to the range of within-population concordances (0.54–0.57). Gender determination was correct in all tested cases.ConclusionsOur results indicate that the Infinium QC Array-24 chip is suitable for cost-efficient, independent QC assaying in the settings of an NGS-based molecular diagnostic laboratory; hence, we recommend its integration into the standard laboratory workflow. Low-density chips can provide sample-specific measures for variant call accuracy, prevent sample mix-ups, validate self-reported ethnicities, and detect consanguineous cases. Integration of low-density chips into QC procedures aids proper interpretation of candidate sequence variants. To enhance utility of this low-density chip, we recommend expansion of ADME and mitochondrial markers. Inexpensive Infinium-like low-density human chips have a potential to become a “Swiss army knife” among genotyping assays suitable for many applications requiring high-throughput assays.

Genetic Discontinuity between the Maritime Archaic and Beothuk Populations in Newfoundland, Canada

Situated at the furthest northeastern edge of Canada,the island of Newfoundland (approximately 110,000km2) and Labrador (approximately 295,000km2) today constitute a province characterized by abundant natural resources but low population density. Both landmasses were covered by the Laurentide ice sheet during the Last Glacial Maximum (18,000 years before present [YBP]); after the glacier retreated, ice patches remained on the island until ca. 9,000 calibrated (cal) YBP [1]. Nevertheless, indigenous peoples, whose ancestors had trekked some 5,000km from the west coast, arrived approximately 10,000 cal YBP in Labrador and ca. 6,000 cal YBP in Newfoundland [2, 3]. Differential features in material culture indicate at least three settlement episodes by distinct cultural groups, including the Maritime Archaic, Palaeoeskimo, and Beothuk. Newfoundland has remained home to indigenous peoples until present day with only one apparent hiatus (3,400-2,800 YBP). This record suggests abandonment, severe constriction, or local extinction followed by subsequent immigrations from single or multiple source populations, but the specific dynamics and the cultural and biological relationships, if any, among these successive peoples remain enigmatic [4]. By examining the mitochondrial genome diversity and isotopic ratios of 74 ancient remains in conjunction with the archaeological record, we have provided definitive evidence for the genetic discontinuity between the maternal lineages of these populations. This northeastern margin of North America appears to have been populated multiple times by distinct groups that did not share a recent common ancestry, but rather one much deeper in time at the entry point into the continent.

Mitochondrial genome variation and prostate cancer: a review of the mutational landscape and application to clinical management.

Prostate cancer is a genetic disease. While next generation sequencing has allowed for the emergence of molecular taxonomy, classification is restricted to the nuclear genome. Mutations within the maternally inherited mitochondrial genome are known to impact cancer pathogenesis, as a result of disturbances in energy metabolism and apoptosis. With a higher mutation rate, limited repair and increased copy number compared to the nuclear genome, the clinical relevance of mitochondrial DNA (mtDNA) variation requires deeper exploration. Here we provide a systematic review of the landscape of prostate cancer associated mtDNA variation. While the jury is still out on the association between inherited mtDNA variation and prostate cancer risk, we collate a total of 749 uniquely reported prostate cancer associated somatic mutations. Support exists for number of somatic events, extent of heteroplasmy, and rate of recurrence of mtDNA mutations, increasing with disease aggression. While, the predicted pathogenic impact for recurrent prostate cancer associated mutations appears negligible, evidence exists for carcinogenic mutations impacting the cytochrome c oxidase complex and regulating metastasis through elevated reactive oxygen species production. Due to a lack of lethal cohort analyses, we provide additional unpublished data for metastatic disease. Discussing the advantages of mtDNA as a prostate cancer biomarker, we provide a review of current progress of including elevated mtDNA levels, of a large somatic deletion, acquired tRNAs mutations, heteroplasmy and total number of somatic events (mutational load). We confirm via meta-analysis a significant association between mtDNA mutational load and pathological staging at diagnosis or surgery (p < 0.0001).

High-confidence assessment of functional impact of human mitochondrial non-synonymous genome variations by APOGEE.

24,189 are all the possible non-synonymous amino acid changes potentially affecting the human mitochondrial DNA. Only a tiny subset was functionally evaluated with certainty so far, while the pathogenicity of the vast majority was only assessed in-silico by software predictors. Since these tools proved to be rather incongruent, we have designed and implemented APOGEE, a machine-learning algorithm that outperforms all existing prediction methods in estimating the harmfulness of mitochondrial non-synonymous genome variations. We provide a detailed description of the underlying algorithm, of the selected and manually curated training and test sets of variants, as well as of its classification ability.

Elevated mitochondrial genome variation after 50 generations of radiation exposure in a wild rodent.

Currently, the effects of chronic, continuous low dose environmental irradiation on the mitochondrial genome of resident small mammals are unknown. Using the bank vole (Myodes glareolus) as a model system, we tested the hypothesis that approximately 50 generations of exposure to the Chernobyl environment has significantly altered genetic diversity of the mitochondrial genome. Using deep sequencing, we compared mitochondrial genomes from 131 individuals from reference sites with radioactive contamination comparable to that present in northern Ukraine before the 26 April 1986 meltdown, to populations where substantial fallout was deposited following the nuclear accident. Population genetic variables revealed significant differences among populations from contaminated and uncontaminated localities. Therefore, we rejected the null hypothesis of no significant genetic effect from 50 generations of exposure to the environment created by the Chernobyl meltdown. Samples from contaminated localities exhibited significantly higher numbers of haplotypes and polymorphic loci, elevated genetic diversity, and a significantly higher average number of substitutions per site across mitochondrial gene regions. Observed genetic variation was dominated by synonymous mutations, which may indicate a history of purify selection against nonsynonymous or insertion/deletion mutations. These significant differences were not attributable to sample size artifacts. The observed increase in mitochondrial genomic diversity in voles from radioactive sites is consistent with the possibility that chronic, continuous irradiation resulting from the Chernobyl disaster has produced an accelerated mutation rate in this species over the last 25 years. Our results, being the first to demonstrate this phenomenon in a wild mammalian species, are important for understanding genetic consequences of exposure to low‐dose radiation sources.

Contrasting Patterns of Nucleotide Substitution Rates Provide Insight into Dynamic Evolution of Plastid and Mitochondrial Genomes of Geranium.

Geraniaceae have emerged as a model system for investigating the causes and consequences of variation in plastid and mitochondrial genomes. Incredible structural variation in plastid genomes (plastomes) and highly accelerated evolutionary rates have been reported in selected lineages and functional groups of genes in both plastomes and mitochondrial genomes (mitogenomes), and these phenomena have been implicated in cytonuclear incompatibility. Previous organelle genome studies have included limited sampling of Geranium, the largest genus in the family with over 400 species. This study reports on rates and patterns of nucleotide substitutions in plastomes and mitogenomes of 17 species of Geranium and representatives of other Geraniaceae. As detected across other angiosperms, substitution rates in the plastome are 3.5 times higher than the mitogenome in most Geranium. However, in the branch leading to Geranium brycei/Geranium incanum mitochondrial genes experienced significantly higher dN and dS than plastid genes, a pattern that has only been detected in one other angiosperm. Furthermore, rate accelerations differ in the two organelle genomes with plastomes having increased dN and mitogenomes with increased dS. In the Geranium phaeum/Geranium reflexum clade, duplicate copies of clpP and rpoA genes that experienced asymmetric rate divergence were detected in the single copy region of the plastome. In the case of rpoA, the branch leading to G. phaeum/G. reflexum experienced positive selection or relaxation of purifying selection. Finally, the evolution of acetyl-CoA carboxylase is unusual in Geraniaceae because it is only the second angiosperm family where both prokaryotic and eukaryotic ACCases functionally coexist in the plastid.

MitoSuite: a graphical tool for human mitochondrial genome profiling in massive parallel sequencing.

Recent rapid advances in high-throughput, next-generation sequencing (NGS) technologies have promoted mitochondrial genome studies in the fields of human evolution, medical genetics, and forensic casework. However, scientists unfamiliar with computer programming often find it difficult to handle the massive volumes of data that are generated by NGS. To address this limitation, we developed MitoSuite, a user-friendly graphical tool for analysis of data from high-throughput sequencing of the human mitochondrial genome. MitoSuite generates a visual report on NGS data with simple mouse operations. Moreover, it analyzes high-coverage sequencing data but runs on a stand-alone computer, without the need for file upload. Therefore, MitoSuite offers outstanding usability for handling massive NGS data, and is ideal for evolutionary, clinical, and forensic studies on the human mitochondrial genome variations. It is freely available for download from the website https://mitosuite.com.

Reducing the information gap on Loricarioidei (Siluriformes) mitochondrial genomics

BackgroundThe genetic diversity of Neotropical fish fauna is underrepresented in public databases. This distortion is evident for the order Siluriformes, in which the suborders Siluroidei and Loricarioidei share equivalent proportion of species, although far less is known about the genetics of the latter clade, endemic to the Neotropical Region. Recently, this information gap was evident in a study about the structural diversity of fish mitochondrial genomes, and hampered a precise chronological resolution of Siluriformes. It has also prevented molecular ecology investigations about these catfishes, their interactions with the environment, responses to anthropogenic changes and potential uses.ResultsUsing high-throughput sequencing, we provide the nearly complete mitochondrial genomes for 26 Loricariidae and one Callichthyidae species. Structural features were highly conserved. A notable exception was identified in the monophyletic clade comprising species of the Hemiancistrus, Hypostomini and Peckoltia-clades, a ~60 nucleotide-long deletion encompassing the seven nucleotides at the 3′ end of the Conserved Sequence Block (CSB) D of the control region. The expression of mitochondrial genes followed the usual punctuation pattern. Heteroplasmic sites were identified in most species. The retrieved phylogeny strongly corroborates the currently accepted tree, although bringing to debate the relationship between Schizolecis guntheri and Pareiorhaphis garbei, and highlighting the low genetic variability within the Peckoltia-clade, an eco-morphologically diverse and taxonomically problematic group.ConclusionsHerein we have launched the use of high-throughput mitochondrial genomics in the studies of the Loricarioidei species. The new genomic resources reduce the information gap on the molecular diversity of Neotropical fish fauna, impacting the capacity to investigate a variety of aspects of the molecular ecology and evolution of these fishes. Additionally, the species showing the partial CSB-D are candidate models to study the replication and transcription of vertebrate mitochondrial genome.

Mitochondrial genome sequences uncover evolutionary relationships of two Sargassum subgenera, Bactrophycus and Sargassum

To elucidate the evolution of mitochondrial genomic diversity between two Sargassum subgenera, Bactrophycus and Sargassum, we sequenced four Sargassum genomes in subgenus Sargassum, including Sargassum polycystum C. Agardh, S. spinuligerum Sonder, S. ilicifolium (Turner) C. Agardh, and S. aquifolium (Turner) C. Agardh. Mitogenome sizes of these four species ranging from 34,761 to 34,925 bp are longer than those in subgenus Bactrophycus (34,606 to 34,748 bp), and the content of non-coding regions (4.68–5.25%) is higher than that in Bactrophycus (4.29–4.65%). The evolutionary traits of single mitochondrial genes show apparent inconsistency between the two Sargassum subgenera. Mitogenome sequence identities are from 92.4 to 99.1% in subgenus Sargassum and from 87.6 to 92.7% in subgenus Bactrophycus. Based on the whole mitogenome dataset, ten Sargassum species are clustered into two subclades representing two subgenera, Sargassum and Bactrophycus. Only four individual single-gene phylogenies (cox2, nad6, rpl5, and rps3) show that the ten Sargassum species could be strongly clustered and divided into two subgenera with high values (ML/NJ/BI ≥70%). The study indicates that the two subgenera, Sargassum and Bactrophycus, are distinct evolutionary entities, and mitogenomic traits provide novel insights into Sargassum deep-level relationships.

The contribution of the mitochondrial genome to sex‐specific fitness variance

Maternal inheritance of mitochondrial DNA (mtDNA) facilitates the evolutionary accumulation of mutations with sex-biased fitness effects. Whereas maternal inheritance closely aligns mtDNA evolution with natural selection in females, it makes it indifferent to evolutionary changes that exclusively benefit males. The constrained response of mtDNA to selection in males can lead to asymmetries in the relative contributions of mitochondrial genes to female versus male fitness variation. Here, we examine the impact of genetic drift and the distribution of fitness effects (DFE) among mutations-including the correlation of mutant fitness effects between the sexes-on mitochondrial genetic variation for fitness. We show how drift, genetic correlations, and skewness of the DFE determine the relative contributions of mitochondrial genes to male versus female fitness variance. When mutant fitness effects are weakly correlated between the sexes, and the effective population size is large, mitochondrial genes should contribute much more to male than to female fitness variance. In contrast, high fitness correlations and small population sizes tend to equalize the contributions of mitochondrial genes to female versus male variance. We discuss implications of these results for the evolution of mitochondrial genome diversity and the genetic architecture of female and male fitness.

The complete mitochondrial genome of a threatened loach (Beaufortia kweichowensis) and its phylogeny

The Beaufortia kweichowensis is a threatened and native fish in China. In present study, the complete mitochondrial genome of B. kweichowensis was determined using the next-generation sequencing. The circular mitochondrial genome was 16543 bp in length, and contained 13 protein-coding genes, two ribosomal RNA genes, 22 transfer RNA genes, a putative displacement loop locus and an origin of replication on the light-strand. The overall nucleotide composition was 29.1% A, 25.0% T, 28.7% C, 17.2% G, with 54.1% AT, respectively. Phylogenetic analyses using a nucleotide dataset of cytochrome c oxidase subunit I gene with two different methods (Maximum likelihood and Bayesian analysis) both highly supported the close relationship of B. kweichowensis, Beaufortia szechuanensis and Beaufortia liui, consistent with previous classifications based on morphological and molecular studies. Furthermore, the topology demonstrated that the Balitoridae can be classified into two subfamilies, and the B. kweichowensis belongs to the subfamily Gastromyzoninae. These data provide useful information for a better understanding of the mitochondrial genomic diversities and evolution in fish as well as novel genetic markers for studying population genetics and species identification.

Capturing goats: documenting two hundred years of mitochondrial DNA diversity among goat populations from Britain and Ireland.

The domestic goat (Capra hircus) plays a key role in global agriculture, being especially prized in regions of marginal pasture. However, the advent of industrialized breeding has seen a dramatic reduction in genetic diversity within commercial populations, while high extinction rates among feral herds have further depleted the reservoir of genetic variation available. Here, we present the first survey of whole mitochondrial genomic variation among the modern and historical goat populations of Britain and Ireland using a combination of mtDNA enrichment and high throughput sequencing. Fifteen historical taxidermy samples, representing the indigenous 'Old Goat' populations of the islands, were sequenced alongside five modern Irish dairy goats and four feral samples from endangered populations in western Ireland. Phylogenetic and network analyses of European mitochondrial variation revealed distinct groupings dominated by historical British and Irish samples, which demonstrate a degree of maternal genetic structure between the goats of insular and continental Europe. Several Irish modern feral samples also fall within these clusters, suggesting continuity between these dwindling populations and the ancestral 'Old Goats' of Ireland and Britain.

Aboriginal Australian mitochondrial genome variation \u2013 an increased understanding of population antiquity and diversity

Aboriginal Australians represent one of the oldest continuous cultures outside Africa, with evidence indicating that their ancestors arrived in the ancient landmass of Sahul (present-day New Guinea and Australia) ~55 thousand years ago. Genetic studies, though limited, have demonstrated both the uniqueness and antiquity of Aboriginal Australian genomes. We have further resolved known Aboriginal Australian mitochondrial haplogroups and discovered novel indigenous lineages by sequencing the mitogenomes of 127 contemporary Aboriginal Australians. In particular, the more common haplogroups observed in our dataset included M42a, M42c, S, P5 and P12, followed by rarer haplogroups M15, M16, N13, O, P3, P6 and P8. We propose some major phylogenetic rearrangements, such as in haplogroup P where we delinked P4a and P4b and redefined them as P4 (New Guinean) and P11 (Australian), respectively. Haplogroup P2b was identified as a novel clade potentially restricted to Torres Strait Islanders. Nearly all Aboriginal Australian mitochondrial haplogroups detected appear to be ancient, with no evidence of later introgression during the Holocene. Our findings greatly increase knowledge about the geographic distribution and phylogenetic structure of mitochondrial lineages that have survived in contemporary descendants of Australia’s first settlers.

Genetic variation architecture of mitochondrial genome reveals the differentiation in Korean landrace and weedy rice

Mitochondrial genome variations have been detected despite the overall conservation of this gene content, which has been valuable for plant population genetics and evolutionary studies. Here, we describe mitochondrial variation architecture and our performance of a phylogenetic dissection of Korean landrace and weedy rice. A total of 4,717 variations across the mitochondrial genome were identified adjunct with 10 wild rice. Genetic diversity assessment revealed that wild rice has higher nucleotide diversity than landrace and/or weedy, and landrace rice has higher diversity than weedy rice. Genetic distance was suggestive of a high level of breeding between landrace and weedy rice, and the landrace showing a closer association with wild rice than weedy rice. Population structure and principal component analyses showed no obvious difference in the genetic backgrounds of landrace and weedy rice in mitochondrial genome level. Phylogenetic, population split, and haplotype network evaluations were suggestive of independent origins of the indica and japonica varieties. The origin of weedy rice is supposed to be more likely from cultivated rice rather than from wild rice in mitochondrial genome level.

The phylogenetic relationships of known mosquito (Diptera: Culicidae) mitogenomes

The known mosquito mitogenomes, containing a total of 34 species, which belong to five genera, were collected from GenBank, and the practicality and effectiveness of the variation in the complete mitochondrial DNA genome and portions of mitochondrial COI gene were assessed to reconstruct the phylogeny of mosquitoes. Phylogenetic trees were reconstructed on the basis of parsimony, maximum likelihood, and Bayesian (BI) methods. It is concluded that: (1) Both mitogenomes and COI gene support the monophly of following taxa: Subgenus Nyssorhynchus, Subgenus Cellia, Anopheles albitarsis complex, Anopheles gambiae complex, and Anopheles punctulatus group; (2) Genus Aedes is not monophyletic relative to Ochlerotatus vigilax; (3) The mitogenome results indicate a close relationship between Anopheles epiroticus and Anopheles gambiae complex, Anopheles dirus complex and Anopheles punctulatus group, respectively; (4) The Bayesian posterior probability (BPP) within phylogenetic tree reconstructed by mitogenomes is higher than COI tree. The results show that phylogenetic relationships reconstructed using the mitogenomes were more similar to those based on morphological data.

Mitochondrial Genome Variation after Hybridization and Differences in the First and Second Generation Hybrids of Bream Fishes.

Hybridization plays an important role in fish breeding. Bream fishes contribute a lot to aquaculture in China due to their economically valuable characteristics and the present study included five bream species, Megalobrama amblycephala, Megalobrama skolkovii, Megalobrama pellegrini, Megalobrama terminalis and Parabramis pekinensis. As maternal inheritance of mitochondrial genome (mitogenome) involves species specific regulation, we aimed to investigate in which way the inheritance of mitogenome is affected by hybridization in these fish species. With complete mitogenomes of 7 hybrid groups of bream species being firstly reported in the present study, a comparative analysis of 17 mitogenomes was conducted, including representatives of these 5 bream species, 6 first generation hybrids and 6 second generation hybrids. The results showed that these 17 mitogenomes shared the same gene arrangement, and had similar gene size and base composition. According to the phylogenetic analyses, all mitogenomes of the hybrids were consistent with a maternal inheritance. However, a certain number of variable sites were detected in all F1 hybrid groups compared to their female parents, especially in the group of M. terminalis (♀) × M. amblycephala (♂) (MT×MA), with a total of 86 variable sites between MT×MA and its female parent. Among the mitogenomes genes, the protein-coding gene nd5 displayed the highest variability. The number of variation sites was found to be related to phylogenetic relationship of the parents: the closer they are, the lower amount of variation sites their hybrids have. The second generation hybrids showed less mitogenome variation than that of first generation hybrids. The non-synonymous and synonymous substitution rates (dN/dS) were calculated between all the hybrids with their own female parents and the results indicated that most PCGs were under negative selection.

Inter‐Strain Variation in Mouse Mitochondrial Genome and Effects of Oxidative Stress

Reactive oxygen species contribute to the pathogenesis of many acute and chronic pulmonary disorders, including bronchopulmonary dysplasia (BPD), a respiratory condition affecting preterm infants. BPD treatment often involves respiratory support with high O2, and oxidative stress is an adverse effect associated with vascular damage and impaired lung development and function in a subset of infants. Genetic polymorphisms in a few candidate genes have been associated with BPD susceptibility, however the genetic basis of differential susceptibility remains poorly understood. Understanding the role of genetics is critical to improving treatment strategies and reducing oxidant injury in developing lungs. We developed a neonatal mouse model to mimic many features of BPD, and utilized genome‐wide association (GWA) mapping of quantitative phenotypes to identify susceptibility genes for neonatal hyperoxic lung injury. One day after birth, neonatal mice from 29 inbred strains were exposed for 72 hr to normoxia (room air, 20% O2) or hyperoxia (&gt;95% O2). Hyperoxia induced phenotypes (inflammatory cells/histopathology) that are similar to BPD when compared to normal postnatal lung development in normoxia. We also measured hyperoxia‐induced lesions in nuclear (nuc) and mitochondrial (mt) DNA, and mitochondrial copy number from lung homogenates. Significant inter‐strain variation was found for mtDNA and nucDNA lesions after normoxia and hyperoxia. GWA mapping identified significant quantitative trait loci for mtDNA lesions, nucDNA lesions, and mitochondrial copy number after normoxia and for hyperoxia. We ultra‐deep sequenced neonatal lung mtDNA from mice exposed to normoxia and hyperoxia and found 385 sequence variations in wild‐derived PWD/PhJ inbred mice compared to reference C57BL/6J mice. Higher variation frequency (1/32 bases) was found in the D‐loop region compared to the rest of the mitochondrial genome (1/42 bases). There was also more heteroplasmy in PWD/PhJ mice compared to C57BL/6J. We found five haplotype groups among 27 strains that were sequenced, with classical inbred strains in haplotype 1, NZB and NZO mice in haplotype 2, and PWD/PhJ and PWK/PhJ mice in haplotype 3. Wild derived strains had more variation than classical inbred strains. We conclude that exposure to low (20%) and high (&gt;95%) concentrations of oxygen early in life cause lesions in mouse lung mtDNA and nucDNA that are strain dependent. Ultra‐deep sequencing identified mtDNA sequence variation and differences in heteroplasmy and indels across inbred mouse strains that associate with disease phenotypes. Through these combined approaches, we have identified novel candidate susceptibility genes that may improve our understanding of neonatal lung injury and development.Support or Funding InformationSupport by the NIEHS Intramural Program