A genetic atlas for the butterflies of continental Canada and United States.

Multi-locus genetic data for phylogeographic studies is generally limited in geographic and taxonomic scope as most studies only examine a few related species. The strong adoption of DNA barcoding has generated large datasets of mtDNA COI sequences. This work examines the butterfly fauna of Canada and United States based on 13,236 COI barcode records derived from 619 species. It compiles i) geographic maps depicting the spatial distribution of haplotypes, ii) haplotype networks (minimum spanning trees), and iii) standard indices of genetic diversity such as nucleotide diversity (π), haplotype richness (H), and a measure of spatial genetic structure (GST). High intraspecific genetic diversity and marked spatial structure were observed in the northwestern and southern North America, as well as in proximity to mountain chains. While species generally displayed concordance between genetic diversity and spatial structure, some revealed incongruence between these two metrics. Interestingly, most species falling in this category shared their barcode sequences with one at least other species. Aside from revealing large-scale phylogeographic patterns and shedding light on the processes underlying these patterns, this work also exposed cases of potential synonymy and hybridization.

Identification and characterization of a new pathologic mutation in a large Leber hereditary optic neuropathy pedigree.

BACKGROUND: Most patients suffering from Leber hereditary optic neuropathy carry one of the three classic pathologic mutations, but not all individuals with these genetic alterations develop the disease. There are different risk factors that modify the penetrance of these mutations. The remaining patients carry one of a set of very rare genetic variants and, it appears that, some of the risk factors that modify the penetrance of the classical pathologic mutations may also affect the phenotype of these other rare mutations. RESULTS: We describe a large family including 95 maternally related individuals, showing 30 patients with Leber hereditary optic neuropathy. The mutation responsible for the phenotype is a novel transition, m.3734A > G, in the mitochondrial gene encoding the ND1 subunit of respiratory complex I. Molecular-genetic, biochemical and cellular studies corroborate the pathogenicity of this genetic change. CONCLUSIONS: With the study of this family, we confirm that, also for this very rare mutation, sex and age are important factors modifying penetrance. Moreover, this pedigree offers an excellent opportunity to search for other genetic or environmental factors that additionally contribute to modify penetrance.

Phylogenetics and Population Genetics of the Asian House Shrew, Suncus murinus-S. montanus Species Complex, Inferred From Whole-Genome and Mitochondrial DNA Sequences, with Special Reference to the Ryukyu Archipelago, Japan.

The house shrew (Suncus murinus-S. montanus species complex) colonized regions across southern Asia and the Indian Ocean following human activity. The house shrew is distributed on islands of the Ryukyu Archipelago, the southernmost part of Japan, but the evolutionary history of the shrew on those islands and possible associations between these populations and humans remain unknown. In this study, we conducted phylogenetic and population genetic analyses based on both nuclear and mitochondrial genome sequences of house shrews. Phylogenetic analyses based on mitochondrial cytochrome b (cytb) sequences revealed that shrews from the Ryukyu Archipelago showed strong genetic affinity to Vietnamese and southern Chinese shrews. Demographic analyses of cytb sequences indicated a rapid population expansion event affecting the haplotype group in Vietnam, southern China, and the Ryukyu Archipelago 3300-7900 years ago. Furthermore, gene flow between Ryukyu (Yonaguni Island) and Taiwan and between Ryukyu and Vietnam inferred from f4 statistics of the nuclear genomes suggested repeated immigration to Ryukyu in recent years. The present study demonstrates that the Nagasaki population has a different origin from the Ryukyu population. These findings elucidate the complex pattern of genetic admixture in house shrews and provide insights into their evolutionary history.

Phylogeographic History of Endangered Hokuriku Salamander, Hynobius takedai (Amphibia: Caudata).

Knowledge of the phylogeographic history of organisms is valuable for understanding their evolutionary processes. To the best of our knowledge, the phylogeographic structure of Hokuriku salamander, Hynobius takedai, an endangered species, remains unclear. This study aimed to elucidate the phylogeographic history of H. takedai, which is expected to be strongly influenced by paleogeographic events. Phylogenetic analysis based on partial sequences of the mitochondrial DNA cytochrome b gene confirmed the genetic independence of H. takedai, and the divergence time with closely related species was estimated to be from the Late Pliocene to the Early Pleistocene. In the phylogenetic tree, two clades were identified within H. takedai, and their haplotypes were found in samples collected from the west and east of the distribution range. These intraspecific divergences were strongly influenced by geohistorical subdivisions of the current major distribution areas in the Middle Pleistocene. One clade was further subdivided and its formation may have been influenced by sea level changes in the Late Pleistocene.

Enhanced ROS Production in Mitochondria from Prematurely Aging mtDNA Mutator Mice.

An increase in mitochondrial DNA (mtDNA) mutations and an ensuing increase in mitochondrial reactive oxygen species (ROS) production have been suggested to be a cause of the aging process ("the mitochondrial hypothesis of aging"). In agreement with this, mtDNA-mutator mice accumulate a large amount of mtDNA mutations, giving rise to defective mitochondria and an accelerated aging phenotype. However, incongruously, the rates of ROS production in mtDNA mutator mitochondria have generally earlier been reported to be lower - not higher - than in wildtype, thus apparently invalidating the "mitochondrial hypothesis of aging". We have here re-examined ROS production rates in mtDNA-mutator mice mitochondria. Using traditional conditions for measuring ROS (succinate in the absence of rotenone), we indeed found lower ROS in the mtDNA-mutator mitochondria compared to wildtype. This ROS mainly results from reverse electron flow driven by the membrane potential, but the membrane potential reached in the isolated mtDNA-mutator mitochondria was 33 mV lower than that in wildtype mitochondria, due to the feedback inhibition of succinate oxidation by oxaloacetate, and to a lower oxidative capacity in the mtDNA-mutator mice, explaining the lower ROS production. In contrast, in normal forward electron flow systems (pyruvate (or glutamate) + malate or palmitoyl-CoA + carnitine), mitochondrial ROS production was higher in the mtDNA-mutator mitochondria. Particularly, even during active oxidative phosphorylation (as would be ongoing physiologically), higher ROS rates were seen in the mtDNA-mutator mitochondria than in wildtype. Thus, when examined under physiological conditions, mitochondrial ROS production rates are indeed increased in mtDNA-mutator mitochondria. While this does not prove the validity of the mitochondrial hypothesis of aging, it may no longer be said to be negated in this respect. This paper is dedicated to the memory of Professor Vladimir P. Skulachev.

Revision of the 'Acanthephyra purpurea' species complex (Crustacea: Decapoda), with an emphasis on species diversification in the Atlantic.

We inventoried all nine species of the 'Acanthephyra purpurea' complex, one of the most abundant and cosmopolitan group of mesopelagic shrimps. We used 119 specimens at hand and genetic data for 124 specimens from GenBank and BOLD. Phylogenetic analysis of four genes (COI, 16S, NaK, and enolase) showed that the 'Acanthephyra purpurea' complex is polyphyletic and encompasses two species groups, 'A. purpurea' (mostly Atlantic) and 'A. smithi' (Indo-West Pacific). The 'A. purpurea' species group consists of two major molecular clades A. pelagica and A. kingsleyi - A. purpurea - A. quadrispinosa. Molecular data suggest that hitherto accepted species A. acanthitelsonis, A. pelagica, and A. sica should be considered as synonyms. The Atlantic is inhabited by at least two cryptic genetic lineages of A. pelagica and A. quadrispinosa. Morphological analyses of qualitative and quantitative (900 measurements) characters resulted in a tabular key to species and in a finding of four evolutionary traits. Atlantic species showed various scenarios of diversification visible on mitochondrial gene level, nuclear gene level, and morphological level. We recorded and discussed similar phylogeographic trends in diversification and in distribution of genetic lineages within two different clades: A. pelagica and A. kingsleyi - A. purpurea - A. quadrispinosa.

Assembly and comparative analysis of the initial complete mitochondrial genome of Primulina hunanensis (Gesneriaceae): a cave-dwelling endangered plant.

BACKGROUND: Primulina hunanensis, a troglobitic plant within the Primulina genus of Gesneriaceae family, exhibits robust resilience to arid conditions and holds great horticultural potential as an ornamental plant. The work of chloroplast genome (cpDNA) has been recently accomplished, however, the mitochondrial genome (mtDNA) that is crucial for plant evolution has not been reported. RESULTS: In this study, we sequenced and assembled the P. hunanensis complete mtDNA, and elucidated its evolutionary and phylogenetic relationships. The assembled mtDNA spans 575,242 bp with 43.54% GC content, encompassing 60 genes, including 37 protein-coding genes (PCGs), 20 tRNA genes, and 3 rRNA genes. Notably, high number of repetitive sequences in the mtDNA and substantial sequence translocation from chloroplasts to mitochondria were observed. To determine the evolutionary and taxonomic positioning of P. hunanensis, a phylogenetic tree was constructed using mitochondrial PCGs from P. hunanensis and 32 other taxa. Furthermore, an exploration of PCGs relative synonymous codon usage, identification of RNA editing events, and an investigation of collinearity with closely related species were conducted. CONCLUSIONS: This study reports the initial assembly and annotation of P. hunanensis mtDNA, contributing to the limited mtDNA repository for Gesneriaceae plants and advancing our understanding of their evolution for improved utilization and conservation.

Leveraging new methods for comprehensive characterization of mitochondrial DNA in esophageal squamous cell carcinoma.

BACKGROUND: Mitochondria play essential roles in tumorigenesis; however, little is known about the contribution of mitochondrial DNA (mtDNA) to esophageal squamous cell carcinoma (ESCC). Whole-genome sequencing (WGS) is by far the most efficient technology to fully characterize the molecular features of mtDNA; however, due to the high redundancy and heterogeneity of mtDNA in regular WGS data, methods for mtDNA analysis are far from satisfactory. METHODS: Here, we developed a likelihood-based method dMTLV to identify low-heteroplasmic mtDNA variants. In addition, we described fNUMT, which can simultaneously detect non-reference nuclear sequences of mitochondrial origin (non-ref NUMTs) and their derived artifacts. Using these new methods, we explored the contribution of mtDNA to ESCC utilizing the multi-omics data of 663 paired tumor-normal samples. RESULTS: dMTLV outperformed the existing methods in sensitivity without sacrificing specificity. The verification using Nanopore long-read sequencing data showed that fNUMT has superior specificity and more accurate breakpoint identification than the current methods. Leveraging the new method, we identified a significant association between the ESCC overall survival and the ratio of mtDNA copy number of paired tumor-normal samples, which could be potentially explained by the differential expression of genes enriched in pathways related to metabolism, DNA damage repair, and cell cycle checkpoint. Additionally, we observed that the expression of CBWD1 was downregulated by the non-ref NUMTs inserted into its intron region, which might provide precursor conditions for the tumor cells to adapt to a hypoxic environment. Moreover, we identified a strong positive relationship between the number of mtDNA truncating mutations and the contribution of signatures linked to tumorigenesis and treatment response. CONCLUSIONS: Our new frameworks promote the characterization of mtDNA features, which enables the elucidation of the landscapes and roles of mtDNA in ESCC essential for extending the current understanding of ESCC etiology. dMTLV and fNUMT are freely available from https://github.com/sunnyzxh/dMTLV and https://github.com/sunnyzxh/fNUMT , respectively.

Mitochondrial DNA as a target for analyzing the biodistribution of cell therapy products.

Biodistribution tests are crucial for evaluating the safety of cell therapy (CT) products in order to prevent unwanted organ homing of these products in patients. Quantitative polymerase chain reaction (qPCR) using intronic Alu is a popular method for biodistribution testing owing to its ability to detect donor cells without modifying CT products and low detection limit. However, Alu-qPCR may generate inaccurate information owing to background signals caused by the mixing of human genomic DNA with that of experimental animals. The aim of this study was to develop a test method that is more specific and sensitive than Alu-qPCR, targeting the mitochondrial DNA (mtDNA) sequence that varies substantially between humans and experimental animals. We designed primers for 12S, 16S, and cytochrome B in mtDNA regions, assessed their specificity and sensitivity, and selected primers and probes for the 12S region. Human adipose-derived stem cells, used as CT products, were injected into the tail vein of athymic NCr-nu/nu mice and detected, 7 d after administration, in their lungs at an average concentration of 2.22 ± 0.69 pg/µg mouse DNA, whereas Alu was not detected. Therefore, mtDNA is more specific and sensitive than Alu and is a useful target for evaluating CT product biodistribution.

Genetic diversity and phylogeographic patterns of the peacock jewel-damselfly, Rhinocypha fenestrella (Rambur, 1842).

Despite is known to have widespread distribution and the most active species of the family Chlorocyphidae, the molecular data of Rhinocypha fenestrella (Rambur, 1842) are relatively scarce. The present study is the first that examined the genetic diversity and phylogeographic pattern of the peacock jewel-damselfly R. fenestrella by sequencing the cytochrome C oxidase I (cox1) and 16S rRNA gene regions from 147 individuals representing eight populations in Malaysia. A total of 26 and 10 unique haplotypes were revealed by the cox1 and 16S rRNA genes, respectively, and 32 haplotypes were recovered by the concatenated sequences of cox1+16S. Analyses indicated that haplotype AB2 was the most frequent and the most widespread haplotype in Malaysia while haplotype AB1 was suggested as the common ancestor haplotype of the R. fenestrella that may arose from the Negeri Sembilan as discovered from cox1+16S haplotype network analysis. Overall haplotype and nucleotide diversities of the concatenated sequences were Hd = 0.8937 and Pi = 0.0028, respectively, with great genetic differentiation (FST = 0.6387) and low gene flow (Nm = 0.14). Population from Pahang presented the highest genetic diversity (Hd = 0.8889, Pi = 0.0022, Nh = 9), whereas Kedah population demonstrated the lowest diversity (Hd = 0.2842, Pi = 0.0003, Nh = 4). The concatenated sequences of cox1+16S showed genetic divergence ranging from 0.09% to 0.97%, whereas the genetic divergence for cox1 and 16S rRNA genes were 0.16% to 1.63% and 0.01% to 0.75% respectively. This study provides for the first-time insights on the intraspecific genetic diversity, phylogeographic pattern and ancestral haplotype of Rhinocypha fenestrella. The understanding of molecular data especially phylogeographic pattern can enhance the knowledge about insect origin, their diversity, and capability to disperse in particular environments.

Ancestral allele of DNA polymerase gamma modifies antiviral tolerance.

Mitochondria are critical modulators of antiviral tolerance through the release of mitochondrial RNA and DNA (mtDNA and mtRNA) fragments into the cytoplasm after infection, activating virus sensors and type-I interferon (IFN-I) response1-4. The relevance of these mechanisms for mitochondrial diseases remains understudied. Here we investigated mitochondrial recessive ataxia syndrome (MIRAS), which is caused by a common European founder mutation in DNA polymerase gamma (POLG1)5. Patients homozygous for the MIRAS variant p.W748S show exceptionally variable ages of onset and symptoms5, indicating that unknown modifying factors contribute to disease manifestation. We report that the mtDNA replicase POLG1 has a role in antiviral defence mechanisms to double-stranded DNA and positive-strand RNA virus infections (HSV-1, TBEV and SARS-CoV-2), and its p.W748S variant dampens innate immune responses. Our patient and knock-in mouse data show that p.W748S compromises mtDNA replisome stability, causing mtDNA depletion, aggravated by virus infection. Low mtDNA and mtRNA release into the cytoplasm and a slow IFN response in MIRAS offer viruses an early replicative advantage, leading to an augmented pro-inflammatory response, a subacute loss of GABAergic neurons and liver inflammation and necrosis. A population databank of around 300,000 Finnish individuals6 demonstrates enrichment of immunodeficient traits in carriers of the POLG1 p.W748S mutation. Our evidence suggests that POLG1 defects compromise antiviral tolerance, triggering epilepsy and liver disease. The finding has important implications for the mitochondrial disease spectrum, including epilepsy, ataxia and parkinsonism.

Zebrafish polg2 knock-out recapitulates human POLG-disorders; implications for drug treatment.

The human mitochondrial DNA polymerase gamma is a holoenzyme, involved in mitochondrial DNA (mtDNA) replication and maintenance, composed of a catalytic subunit (POLG) and a dimeric accessory subunit (POLG2) conferring processivity. Mutations in POLG or POLG2 cause POLG-related diseases in humans, leading to a subset of Mendelian-inherited mitochondrial disorders characterized by mtDNA depletion (MDD) or accumulation of multiple deletions, presenting multi-organ defects and often leading to premature death at a young age. Considering the paucity of POLG2 models, we have generated a stable zebrafish polg2 mutant line (polg2ia304) by CRISPR/Cas9 technology, carrying a 10-nucleotide deletion with frameshift mutation and premature stop codon. Zebrafish polg2 homozygous mutants present slower development and decreased viability compared to wild type siblings, dying before the juvenile stage. Mutants display a set of POLG-related phenotypes comparable to the symptoms of human patients affected by POLG-related diseases, including remarkable MDD, altered mitochondrial network and dynamics, and reduced mitochondrial respiration. Histological analyses detected morphological alterations in high-energy demanding tissues, along with a significant disorganization of skeletal muscle fibres. Consistent with the last finding, locomotor assays highlighted a decreased larval motility. Of note, treatment with the Clofilium tosylate drug, previously shown to be effective in POLG models, could partially rescue MDD in Polg2 mutant animals. Altogether, our results point at zebrafish as an effective model to study the etiopathology of human POLG-related disorders linked to POLG2, and a suitable platform to screen the efficacy of POLG-directed drugs in POLG2-associated forms.

iSCNT embryo culture system for restoration of Cervus nippon hortulorum, presumed to be sika deer in the Korean Peninsula.

Sika deer inhabiting South Korea became extinct when the last individual was captured on Jeju Island in Korea in 1920 owing to the Japanese seawater relief business, but it is believed that the same subspecies (Cervus nippon hortulorum) inhabits North Korea and the Russian Primorskaya state. In our study, mt-DNA was used to analyze the genetic resources of sika deer in the vicinity of the Korean Peninsula to restore the extinct species of continental deer on the Korean Peninsula. In addition, iSCNT was performed using cells to analyze the potential for restoration of extinct species. The somatic cells of sika deer came from tissues of individuals presumed to be Korean Peninsula sika deer inhabiting the neighboring areas of the Primorskaya state and North Korea. After sequencing 5 deer samples through mt-DNA isolation and PCR, BLAST analysis showed high matching rates for Cervus nippon hortulorum. This shows that the sika deer found near the Russian Primorsky Territory, inhabiting the region adjacent to the Korean Peninsula, can be classified as a subspecies of Cervus nippon hortulorum. The method for producing cloned embryos for species restoration confirmed that iSCNT-embryos developed smoothly when using porcine oocytes. In addition, the stimulation of endometrial cells and progesterone in the IVC system expanded the blastocyst cavity and enabled stable development of energy metabolism and morphological changes in the blastocyst. Our results confirmed that the individual presumed to be a continental deer in the Korean Peninsula had the same genotype as Cervus nippon hortulorum, and securing the individual's cell-line could restore the species through replication and produce a stable iSCNT embryo.

A challenging differential diagnosis - Leber's Hereditary Optic Neuropathy.

Leber's hereditary optic neuropathy (LHON) is the most common maternally inherited disease linked to mitochondrial DNA (mtDNA). The patients present with subacute asymmetric bilateral vision loss. Approximately 95% of the LHON cases are caused by m.3460G>A (MTND1), m.11778G>A (MTND4), and m.14484T>C (MTND6) mutations. The hallmark of hereditary optic neuropathies determined by mitochondrial dysfunction is the vulnerability and degeneration of retinal ganglion cells (RGC). We present the case of a 28-year-old man who came to our clinic complaining of a subacute decrease in visual acuity of his left eye. From his medical history, we found out that one month before he had the same symptoms in the right eye. From the family history, we noted that an uncle has had vision problems since childhood. We carried out complete blood tests, including specific antibodies for autoimmune and infectious diseases. Laboratory tests and MRI were within normal limits. A blood test of the mtDNA showed the presence of 11778 G>A mutation on the mtND6 gene. The medical history, the fundus appearance, the OCT, and the paraclinical investigations, made us diagnose our patient with Leber's hereditary optic neuropathy. As soon as possible, we began the treatment with systemic idebenone, 900 mg/day. We examined the patient 2, 6, and 10 weeks after initiating the treatment. Abbreviations: LHON = Leber's Hereditary Optic Neuropathy, mtDNA = mitochondrial DNA, VA = visual acuity, RE = right eye, LE = left eye, OCT = Optical coherence tomography, pRNFL = peripapillary retinal nerve fiber layer, GCL = retinal ganglion cells layer, MRI = magnetic resonance imaging, VEP = visual evoked potentials, VEP IT = VEP implicit time, VEP A = VEP amplitude.

Unravelling the maternal evolutionary history of the African leopard (Panthera pardus pardus).

The African leopard (Panthera pardus pardus) has lost a significant proportion of its historical range, notably in north-western Africa and South Africa. Recent studies have explored the genetic diversity and population structure of African leopards across the continent. A notable genetic observation is the presence of two divergent mitochondrial lineages, PAR-I and PAR-II. Both lineages appeared to be distributed widely, with PAR-II frequently found in southern Africa. Until now, no study has attempted to date the emergence of either lineage, assess haplotype distribution, or explore their evolutionary histories in any detail. To investigate these underappreciated questions, we compiled the largest and most geographically representative leopard data set of the mitochondrial NADH-5 gene to date. We combined samples (n = 33) collected in an altitudinal transect across the Mpumalanga province of South Africa, where two populations of leopard are known to be in genetic contact, with previously published sequences of African leopard (n = 211). We estimate that the maternal PAR-I and PAR-II lineages diverged approximately 0.7051 (0.4477-0.9632) million years ago (Ma). Through spatial and demographic analyses, we show that while PAR-I underwent a mid-Pleistocene population expansion resulting in several closely related haplotypes with little geographic structure across much of its range, PAR-II remained at constant size and may even have declined slightly in the last 0.1 Ma. The higher genetic drift experienced within PAR-II drove a greater degree of structure with little haplotype sharing and unique haplotypes in central Africa, the Cape, KwaZulu-Natal and the South African Highveld. The phylogeographic structure of PAR-II, with its increasing frequency southward and its exclusive occurrence in south-eastern South Africa, suggests that this lineage may have been isolated in South Africa during the mid-Pleistocene. This hypothesis is supported by historical changes in paleoclimate that promoted intense aridification around the Limpopo Basin between 1.0-0.6 Ma, potentially reducing gene flow and promoting genetic drift. Interestingly, we ascertained that the two nuclear DNA populations identified by a previous study as East and West Mpumalanga correspond to PAR-I and PAR-II, respectively, and that they have come into secondary contact in the Lowveld region of South Africa. Our results suggest a subdivision of African leopard mtDNA into two clades, with one occurring almost exclusively in South Africa, and we identify the potential environmental drivers of this observed structure. We caution that our results are based on a single mtDNA locus, but it nevertheless provides a hypothesis that can be further tested with a dense sample of nuclear DNA data, preferably whole genomes. If our interpretation holds true, it would provide the first genetic explanation for the smaller observed size of leopards at the southernmost end of their range in Africa.

FUS unveiled in mitochondrial DNA repair and targeted ligase-1 expression rescues repair-defects in FUS-linked motor neuron disease.

This study establishes the physiological role of Fused in Sarcoma (FUS) in mitochondrial DNA (mtDNA) repair and highlights its implications to the pathogenesis of FUS-associated neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Endogenous FUS interacts with and recruits mtDNA Ligase IIIα (mtLig3) to DNA damage sites within mitochondria, a relationship essential for maintaining mtDNA repair and integrity in healthy cells. Using ALS patient-derived FUS mutant cell lines, a transgenic mouse model, and human autopsy samples, we discovered that compromised FUS functionality hinders mtLig3's repair role, resulting in increased mtDNA damage and mutations. These alterations cause various manifestations of mitochondrial dysfunction, particularly under stress conditions relevant to disease pathology. Importantly, rectifying FUS mutations in patient-derived induced pluripotent cells (iPSCs) preserves mtDNA integrity. Similarly, targeted introduction of human DNA Ligase 1 restores repair mechanisms and mitochondrial activity in FUS mutant cells, suggesting a potential therapeutic approach. Our findings unveil FUS's critical role in mitochondrial health and mtDNA repair, offering valuable insights into the mechanisms underlying mitochondrial dysfunction in FUS-associated motor neuron disease.

Genetic Contributions to Recovery following Brain Trauma: A Narrative Review.

Traumatic brain injury (TBI) is a frequently encountered form of injury that can have lifelong implications. Despite advances in prevention, diagnosis, monitoring, and treatment, the degree of recovery can vary widely between patients. Much of this is explained by differences in severity of impact and patient-specific comorbidities; however, even among nearly identical patients, stark disparities can arise. Researchers have looked to genetics in recent years as a means of explaining this phenomenon. It has been hypothesized that individual genetic factors can influence initial inflammatory responses, recovery mechanisms, and overall prognoses. In this review, we focus on cytokine polymorphisms, mitochondrial DNA (mtDNA) haplotypes, immune cells, and gene therapy given their associated influx of novel research and magnitude of potential. This discussion is prefaced by a thorough background on TBI pathophysiology to better understand where each mechanism fits within the disease process. Cytokine polymorphisms causing unfavorable regulation of genes encoding IL-1ß, IL-RA, and TNF-α have been linked to poor TBI outcomes like disability and death. mtDNA haplotype H has been correlated with deleterious effects on TBI recovery time, whereas haplotypes K, T, and J have been depicted as protective with faster recovery times. Immune cell genetics such as microglial differentially expressed genes (DEGs), monocyte receptor genes, and regulatory factors can be both detrimental and beneficial to TBI recovery. Gene therapy in the form of gene modification, inactivation, and editing show promise in improving post-TBI memory, cognition, and neuromotor function. Limitations of this study include a large proportion of cited literature being focused on pre-clinical murine models. Nevertheless, favorable evidence on the role of genetics in TBI recovery continues to grow. We aim for this work to inform interested parties on the current landscape of research, highlight promising targets for gene therapy, and galvanize translation of findings into clinical trials.

The Relationship between Mitochondrial Genome Mutations in Monocytes and the Development of Obesity and Coronary Heart Disease.

BACKGROUND: Metabolic disorders, including obesity, are often accompanied by an increased risk of cardiovascular complications. Monocytes are the common link between obesity and cardiovascular diseases (CVDs). The bias of innate cellular immunity towards pro-inflammatory activation stimulates the development of diseases associated with chronic inflammation, in particular metabolic disorders, including obesity, as well as CVDs. Disorders in the functional state of monocytes and activation of inflammation may be associated with mitochondrial dysfunction. Mutations accumulating in mitochondrial DNA with age may lead to mitochondrial dysfunction and may be considered a potential marker for developing chronic inflammatory diseases. METHODS: The present study aimed to study the relationship between mitochondrial heteroplasmy in CD14+ monocytes and cardiovascular risk factors in 22 patients with obesity and coronary heart disease (CHD) by comparing them to 22 healthy subjects. RESULTS: It was found that single-nucleotide variations (SNV) A11467G have a negative correlation with total cholesterol (r = -0.82, p < 0.05), low density lipoproteins (LDL) (r = -0.82, p < 0.05), with age (r = -0.57, p < 0.05) and with mean carotid intima-media thickness (cIMT) (r = -0.43, p < 0.05) and a positive correlation with HDL level (r = 0.71, p < 0.05). SNV 576insC positively correlated with body mass index (BMI) (r = 0.60, p < 0.001) and LDL level (r = 0.43, p < 0.05). SNV A1811G positively correlated with mean cIMT (r = 0.60, p < 0.05). CONCLUSIONS: It was revealed that some variants of mitochondrial DNA (mtDNA) heteroplasmy are associated with CVD risk factors. The results demonstrate the potential for using these molecular genetic markers to develop personalized CVD and metabolic disorder treatments.

A Two-Genome Portrayal of Mitochondrial Disorders: A Review with Clinical Presentations.

Disorders of mitochondrial function are responsible for many inherited neuromuscular and metabolic diseases. Their combination of high mortality, multi-systemic involvement, and economic burden cause devastating effects on patients and their families. Molecular diagnostic tools are becoming increasingly important in providing earlier diagnoses and guiding more precise therapeutic treatments for patients suffering from mitochondrial disorders. This review addresses fundamental molecular concepts relating to the pathogenesis of mitochondrial dysfunction and disorders. A series of short cases highlights the various clinical presentations, inheritance patterns, and pathogenic mutations in nuclear and mitochondrial genes that cause mitochondrial diseases. Graphical and tabular representations of the results are presented to guide the understanding of the important concepts related to mitochondrial molecular genetics and pathology. Emerging technology is incorporating preimplantation genetic testing for mtDNA disorders, while mitochondrial replacement shows promise in significantly decreasing the transfer of diseased mitochondrial DNA (mtDNA) to embryos. Medical professionals must maintain an in-depth understanding of the gene mutations and molecular mechanisms underlying mitochondrial disorders. Continued diagnostic advances and comprehensive management of patients with mitochondrial disorders are essential to achieve robust clinical impacts from comprehensive genomic testing. This is especially true when supported by non-genetic tests such as biochemical analysis, histochemical stains, and imaging studies. Such a multi-pronged investigation should improve the management of mitochondrial disorders by providing accurate and timely diagnoses to reduce disease burden and improve the lives of patients and their families.

The completed mitochondrial genomes of Globodera vulgaris reveals new insights into the genus Globodera phylogeny.

Due to the highly conserved structure, animal mitochondrial genome (mtDNA) is widely used in classification, evolution, phylogeny, population genetic structure and other fields. We reported on the five circle multipartite mtDNAs of a newly described species of Globodera, Globodera vulgaris (Gv) from potatoes in China. The results showed that the mtDNA of Gv was obtained through second- and third-generation sequencing, with a total length of 42,995 bp. It contained 12 protein-coding genes, two rRNA genes and 17 tRNA genes, which were distributed in different subgenomic circles. Comparison of the differences in mtDNA among Gv, G. rostochiensis, G. pallida and G. ellingtonae showed that the size and arrangement of the genes in the mtDNA of the genus Globodera were variable and not conserved. The codon usage bias of the mitochondrial protein-coding gene of Gv showed that Gv might have originated from locally and more primitive group of existing Globodera. Based on the cytochrome c oxidase subunits I genes (COX1) and the nicotinamide adenine dinucleotide dehydrogenase subunits I genes (ND1), and the results showed that Gv was clustered with Globodera spp. according to the COX1 and ND1 in scmtDNA-V, while Gv was clustered with Meloidogyne spp. according to ND1 in scmtDNA-III. The results of this study provided a new basis for understanding the multipartite structure of mtDNA as a phylogenetic and taxonomic feature of the genus Globodera. The number of subgenomic circles is a diagnostic feature of species and the arrangement order and size of mitochondrial protein-coding genes also have important application value in species identification within the genus.