Mitochondrial Haplogroups Research Articles

Результаты определения гаплогрупп Y-ДНК и мтДНК для средневекового славянского захоронения XII в. в окрестностях посёлка Загорянский на Верхней Клязьме (Московская область). Часть II

The study aims at determining Y-DNA and mtDNA haplogroups of two early medieval Slavic burials at Bolshevo-1 burial ground (near Zagoryansky settlement) on the Klyazma River to consider their possible analogs in other samples of medieval Slavic DNA and to give a historical, archaeological and anthropological interpretation of the result. The comparison of the skulls from Bolshevo-1 with the craniological Slavic series has shown their proximity to the Serbian and West Slavic series. The belonging of Individuals 5666 and 5672 to Y-DNA haplogroups E1b1b and J2a1 suggests the Danube component in the ethnogenesis of this group of the Krivichi tribe, which came from the Upper Volga and the Novgorod-Smolensk border. The mitochondrial haplogroup of Individual 5666 H1e1b allows considering the Baltic branch of the ethnogenesis of this group.

ANTHROPOLOGY AND ARCHAEOGENETICS OF THE PREHISTORIC POPULATION OF UKRAINE: COORDINATION OF RESULTS

The process of the prehistoric population formation in the territory of Ukraine has become the object of archaeogenetic research in the context of studying the genomic history of Southeast Europe. The work was carried out in the framework of scientific cooperation with the genetic laboratories of Grand Valley State University (USA), Harvard Medical School (USA), Universities of Uppsala (Sweden) and Copenhagen (Denmark). The study of the ancient genome of the Ukrainian population has already yielded results for the Late Mesolithic and Neolithic groups of the Middle and Lower Dnieper, the population of the Trypillia culture of Volhynia (Verteba Cave), as well as for the carriers of Yamna (Pit Grave) Culture and some more late groups of the North Pontic Region (Nikitin, Potekhina et al. 2012; 2017; Potekhina et al. 2013; Krzewińska et al. 2018; Matheison et al. 2018; Potekhina 2016; 2018; 2019; Nikitin 2020). Analysis of mitochondrial DNA from Mariupol-type cemeteries showed the dominance of mitochondrial haplogroup U, which indicates a genetic links with the Mesolithic populations of Scandinavia and the forest belt of Eastern Europe. In some cases, mitochondrial haplogroups H and C have been identified here. The existence of the latter in the Dnieper basin is still difficult to explain, as it is characteristic of eastern Eurasian groups. Genetic studies of the population of the Trypillia culture were carried out on samples dated to 3900—3500 cal BC from the Verteba cave in Volhynia. The majority of its inhabitants were carriers of the Mt haplogroup H, which connects the people of Trypillia with the Anatolian and Balkan early farmers. This haplogroup was also characteristic of farming cultures of the Central European Neolithic, but its frequency in Verteba is twice as high. The Mt haplogroup U found in one resident of Verteba may indicate contacts with hunters of the steppe Dnieper Region. Genetic polymorphism is also analyzed in the bearers of the Yamna (Pit grave) Culture of the North Pontic Region, which opens a perspective in the context of the Indo-European studies. The research has shown that among the Late Neolithic populations of the proto-European anthropological type with the dominant Mt haplogroup U, and in the early Eneolithic populations of the region, carriers of haplogroup H of the Mediterranean anthropological type appear as a result of contacts with Trypillian groups, which gradually moved in the eastern direction. The same genetic lines in different proportions are preserved in the anthropologically heterogeneous North Pontic population of Yamna Culture. Expanding the analysis of genetic markers of ancient craniological complexes will facilitate the interpretation of the results of archaeogenetic research. Given the historical and anthropological context, they are promising for the study of intercultural contacts and migrations in the early history of the population of Ukraine.

Mitochondrial DNA haplogroups affect physical performances in Han older adults: an 8-year follow-up prospective cohort study.

The objective of this study was to explore the association between mitochondrial DNA (mtDNA) haplogroups and physical performances in Han older adults. This study was an 8-year follow-up prospective cohort study. A total of 104 Han older adults completed the measurements of the 6-min walk test, grip strength and mitochondrial DNA sequencing. The mtDNA haplogroups were classified by using HaploGrep2 software. We used the mixed model to analyze the longitudinal effect of mtDNA haplogroups on physical performance tests among three waves of data. The mean age at wave 3 among men and women were 78.3 and 77.2 years, respectively. The overall proportions of mtDNA haplogroups in this study population was 26.9% F, 21.2% M, 15.4% R, 14.4% D, 8.7% B and others. After adjusted for age, sex, ethnicity, body mass index and exercise, the interaction of mtDNA haplogroup M and waves significantly affected the 6-min walk distance. Notably, the adjusted mean of the 6-min walk distance among the group of mtDNA haplogroup M was significantly lower than other haplogroups at wave 3. The adjusted mean of grip strength among the group of mtDNA haplogroup R was significantly higher than other haplogroups at wave 3. This finding suggests that mtDNA haplogroups might have effects on the 6-min walk test and grip strength in Han older adults, although studies of the physical performance of older adults with larger sample sizes are necessary to further substantiate these findings. Geriatr Gerontol Int 2021; 21: 166-171.

Mitochondrial ND1 T4216C and ND2 C5178A mutations are associated with maternally transmitted diabetes mellitus

Mutations in mitochondrial DNA (mtDNA) are important causes for type 2 diabetes mellitus (T2DM). To investigate the association between mtDNA mutations/variants and diabetes, we reported here clinical, genetic and biochemical characterization of a Chinese pedigree with maternally transmitted T2DM. Using PCR and direct sequencing analysis of mitochondrial genomes from the matrilineal relatives, we identified two potential pathogenic mutations, m.T4216C (p.Y304H) and m.C5178A (p.L237M) in the ND1 and ND2 genes, respectively, together with a set of genetic polymorphisms belonging to the human mitochondrial haplogroup D4b. Moreover, by isolating and analyzing polymononuclear leukocytes generated from the T2DM patients and controls, we identified lower levels of mitochondrial membrane potential and ATP production in T2DM patients than in the controls, in contrast, a significantly higher level of reactive oxygen species was observed in the T2DM patients carrying both of the m.T4216C and m.C5178A mutations (p < 0.05 for all). In addition, the plasma levels of malondialdehyde and 8-hydroxydeoxyguanosine in the T2DM patients markedly increased, while the level of superoxide dismutase decreased (p < 0.05 for all). Taken together, our data indicated that the ND1 T4216C and ND2 C5178A mutations may lead to oxidative stress and impair the mitochondrial function, and this, in turn, might have been involved in the pathogenesis and progression of T2DM in this pedigree. Thus, our study provides novel insight into the pathophysiology of T2DM that is manifested by mitochondrial dysfunction.

Asthma and its relationship to mitochondrial copy number: Results from the Asthma Translational Genomics Collaborative (ATGC) of the Trans-Omics for Precision Medicine (TOPMed) program.

BackgroundMitochondria support critical cellular functions, such as energy production through oxidative phosphorylation, regulation of reactive oxygen species, apoptosis, and calcium homeostasis.ObjectiveGiven the heightened level of cellular activity in patients with asthma, we sought to determine whether mitochondrial DNA (mtDNA) copy number measured in peripheral blood differed between individuals with and without asthma.MethodsWhole genome sequence data was generated as part of the Trans-Omics for Precision Medicine (TOPMed) Program on participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) and the Study of African Americans, Asthma, Genes, & Environment II (SAGE II). We restricted our analysis to individuals who self-identified as African American (3,651 asthma cases and 1,344 controls). Mitochondrial copy number was estimated using the sequencing read depth ratio for the mitochondrial and nuclear genomes. Respiratory complex expression was assessed using RNA-sequencing.ResultsAverage mitochondrial copy number was significantly higher among individuals with asthma when compared with controls (SAPPHIRE: 218.60 vs. 200.47, P<0.001; SAGE II: 235.99 vs. 223.07, P<0.001). Asthma status was significantly associated with mitochondrial copy number after accounting for potential explanatory variables, such as participant age, sex, leukocyte counts, and mitochondrial haplogroup. Despite the consistent relationship between asthma status and mitochondrial copy number, the latter was not associated with time-to-exacerbation or patient-reported asthma control. Mitochondrial respiratory complex gene expression was disproportionately lower in individuals with asthma when compared with individuals without asthma and other protein-encoding genes.ConclusionsWe observed a robust association between asthma and higher mitochondrial copy number. Asthma having an effect on mitochondria function was also supported by lower respiratory complex gene expression in this group.

Mitochondrial DNA haplogroups and weight gain following switch to integrase strand transfer inhibitor-based antiretroviral therapy.

Integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) has been associated with excess weight gain in some adults, which may be influenced by genetic factors. We assessed mitochondrial DNA (mtDNA) haplogroups and weight gain following switch to INSTI-based ART. All AIDS Clinical Trials Group A5001 and A5322 participants with mtDNA genotyping who switched to INSTI were included. mtDNA haplogroups were derived from prior genotyping algorithms. Race/ethnicity-stratified piecewise linear mixed effects models assessed the relationship between mtDNA haplogroup and weight change slope differences before and after switch to INSTI. A total of 291 adults switched to INSTI: 78% male, 50% non-Hispanic White, 28% non-Hispanic Black, and 22% Hispanic. The most common European haplogroups were H [n = 66 (45%)] and UK [32 (22%)]. Non-H European haplogroups had a significant increase in weight slope after the switch. This difference was greatest among non-H clade UK on INSTI-based regimens that included tenofovir alafenamide (TAF) [3.67 (95% confidence interval 1.12, 6.21) kg/year; P = 0.005]. Although small sample size limited analyses among non-Hispanic Black and Hispanic persons, similarly significant weight gain was seen among the most common African haplogroup, L3 [n = 29 (39%); slope difference 4.93 (1.54, 8.32) kg/year, P = 0.005], after switching to TAF-containing INSTI-based ART. Those in European mtDNA haplogroup clade UK and African haplogroup L3 had significantly greater weight gain after switching to INSTI-based ART, especially those receiving TAF. Additional studies in large and diverse populations are needed to clarify the mechanisms and host risk factors for weight gain after switching to INSTI-based ART, with and without TAF.

J or H mtDNA haplogroups in retinal pigment epithelial cells: Effects on cell physiology, cargo in extracellular vesicles, and differential uptake of such vesicles by naïve recipient cells

PurposeExtracellular vesicles (EVs) are predicted to represent the internal state of cells. In polarized RPE monolayers, EVs can mediate long-distance communication, requiring endocytosis via protein-protein interactions. EV uptake from oxidatively stressed donor cells triggers loss in transepithelial resistance (TER) in recipient monolayers mediated by HDAC6. Here, we examine EVs released from RPE cells with identical nuclear genes but different mitochondrial (mt)DNA haplogroups (H, J). J-cybrids produce less ATP, and the J-haplogroup is associated with a higher risk for age-related macular degeneration. MethodsCells were grown as mature monolayers to either collect EVs from apical surfaces or to serve as naïve recipient cells. Transfer assays, transferring EVs to a recipient monolayer were performed, monitoring TER and EV-uptake. The presence of known EV surface proteins was quantified by protein chemistry. ResultsH- and J-cybrids were confirmed to exhibit different levels of TER and energy metabolism. EVs from J-cybrids reduced TER in recipient ARPE-19 cells, whereas EVs from H-cybrids were ineffective. TER reduction was mediated by HDAC6 activity, and EV uptake required interaction between integrin and its ligands and surface proteoglycans. Protein quantifications confirmed elevated levels of fibronectin and annexin A2 on J-cybrid EVs. ConclusionsWe speculate that RPE EVs have a finite set of ligands (membrane proteoglycans and integrins and/or annexin A2) that are elevated in EVs from stressed cells; and that if EVs released by the RPE could be captured from serum, that they might provide a disease biomarker of RPE-dependent diseases.

EPID-10. MITOCHONDRIAL DNA SEQUENCE VARIATION AND RISK OF GLIOMA

Abstract Malignant gliomas are the most common primary adult brain tumors, with poor prognosis and ill-defined etiology. Mitochondrial DNA (mtDNA) sequence variants and haplogroups have been linked with certain cancers, but research on glioma is lacking. We examined the association of germline mtDNA variants and haplogroups with glioma risk in 1,654 glioma cases and 1,065 controls from a US case-control study, and 427 glioma cases and 1,541 controls from the UK Biobank, all genotyped using the UKBiobank array with 276 tiled mtDNA variants. The analysis was restricted to participants of European ancestry, and risk of glioblastoma (GBM) and lower grade glioma (LGG) was examined separately. Distribution of mitochondrial haplogroups (H/HV,I,J,K,R,T,U,V,W,X) were similar in both study populations, with 46.4% and 48.1% of controls in the US and UK studies respectively, identified as H/HV, the most common haplogroup. In the US study there was an inverse association between haplogroup W and glioma (OR=0.43, 95%CI: 0.23–0.79) when compared with the H/HV haplogroup, which was not seen in the UK study (OR=1.10, 95%CI: 0.49–2.49). In the US study, a significant inverse association was observed with the previously reported mtDNA variant m.14798T &amp;gt; C (PMID: 31323957), resulting in the amino acid substitution F18L, for LGG (OR=0.73; 95%CI: 0.53–0.99) though not for GBM (OR=0.86; 95%CI: 0.66–1.11). In the UK study, the F18L substitution was associated with an increased risk of GBM (OR=1.48; 95%CI: 1.07–2.04), and no association was observed for LGG (OR=0.95; 95%CI: 0.53–1.68). Among cases in the US study with isocitrate dehydrogenase 1 (IDH1) status available (747 gliomas), a nonsignificant inverse association of the F18L substitution was observed in glioma cases with wild type (OR=0.72; 95%CI: 0.52–1.01) but not mutant (OR=1.08; 95%CI: 0.70–1.69) IDH1. No other common mtDNA variant (minor allele &amp;gt; 5%) was associated with glioma risk in either study. These associations merit further study.

Mitochondrial DNA haplogroups and risk of attention deficit and hyperactivity disorder in European Americans

Although mitochondrial dysfunction has been implicated in the pathophysiology of attention deficit and hyperactivity disorder ADHD, the role of mitochondrial DNA (mtDNA) has not been extensively investigated. To determine whether mtDNA haplogroups influence risk of ADHD, we performed a case-control study comprising 2076 ADHD cases and 5078 healthy controls, all of whom were European decedents recruited from The Children’s Hospital of Philadelphia (CHOP). Associations between eight major European mtDNA Haplogroups and ADHD risk were assessed in three independent European cohorts. Meta-analysis of the three studies indicated that mtDNA haplogroups K (odds ratio = 0.69, P = 2.24 × 10−4, Pcorrected = 1.79 × 10−3) and U (odds ratio = 0.77, P = 8.88 × 10−4, Pcorrected = 7.11 × 10−3) were significantly associated with reduced risk of ADHD. In contrast, haplogroup HHV* (odds ratio = 1.18, P = 2.32 × 10−3, Pcorrected = 0.019) was significantly associated with increased risk of ADHD. Our results provide novel insight into the genetic basis of ADHD, implicating mitochondrial mechanisms in the pathophysiology of this relatively common psychiatric disorder.

Association of mitochondrial genomic background with risk of Multiple System Atrophy

IntroductionMultiple system atrophy (MSA) is a rare, sporadic, and progressive neurodegenerative disease which is characterized neuropathologically by alpha-synuclein aggregates in oligodendroglia, and clinically by parkinsonism, ataxia, and autonomic dysfunction. Mitochondrial health influences neurodegeneration and defects in mitochondria, particularly in oxidative phosphorylation, are reported in MSA. Mitochondrial DNA (mtDNA) codes for 13 critical OXPHOS proteins, however no study has investigated if mtDNA variation, in the form of mitochondrial haplogroups, influences MSA risk. Therefore, in this study we investigated the association of mtDNA haplogroups with MSA risk in a case-control manner. Methods176 pathologically confirmed MSA cases and 910 neurologically healthy controls from Mayo Clinic Jacksonville were genotyped for 39 unique mtDNA variants using Agena Biosciences MassARRAY iPlex technology. Mitochondrial haplogroups were assigned to mitochondrial phylogeny, and logistic regression models that were adjusted for age and sex were used to assess associations between mitochondrial haplogroups and risk of MSA. ResultsAfter adjusting for multiple testing (P<0.0019 considered significant), no mitochondrial haplogroups were significantly associated with MSA risk. However, several nominally significant (P<0.05) associations were observed; haplogroup I was associated with a decreased risk of MSA (OR=0.09, P=0.021), while an increased risk of MSA was observed for haplogroups H3 (OR=2.43, P=0.017) and T1 and T2 (OR=2.04, P=0.007). ConclusionThis study investigated whether population-specific mtDNA variation is associated with risk of MSA, and our nominally significant findings suggest mitochondrial haplogroup background may influence MSA risk. Validation of these findings and additional meta-analytic studies will be important.

Oxidative Stress Profile in Genetically Confirmed Cases of Leber's Hereditary Optic Neuropathy.

The mechanisms of the complex pathophysiology of Leber's hereditary optic neuropathy (LHON) are still insufficiently clarified. The role of oxidative stress as an etiological factor has been proposed and demonstrated in vitro, but without conclusive data that rely on clinical samples. The aim of the study was to evaluate and characterize the existence of oxidative stress in the plasma of LHON patients and healthy individuals. Whole mitochondrial genome sequencing has been performed in order to identify primary LHON mutations. For the assessment of oxidative stress, the following biomarkers were determined in plasma: total oxidant status (TOS), total antioxidant status (TAS), and oxidative stress index (OSI), while oxidative damage of cellular proteins was estimated by quantifying advanced oxidation protein products (AOPP). All three primary LHON mutations (m.3460G > A, m.11778G > A and m.14484 T > C) were identified as a genetic cause of the disease, where the most prevalent one was m.11778G > A. LHON patients have a highly significant increase of TOS and a marked decrease of TAS levels, which suggests the existence of substantial oxidative stress. OSI is high in LHON patients, which definitely implies the presence of redox imbalance. Elevated level of AOPP in LHON patients refers to the significant deleterious effects of oxidative stress on cellular proteins. Oxidative stress parameters do not significantly differ between LHON individuals with different primary mutations. Both symptomatic and asymptomatic LHON patients have an augmented level of oxidative stress which suggests that primary mutations exhibit a pro-oxidative phenotype. Gender and smoking habit significantly influence examined biochemical parameters when LHON patients are compared with the control group. Different mitochondrial haplogroups are characterized by altered levels of OSI in LHON group. The absence of physiological correlations between redox parameters reflects the deregulation of homeostatic oxidative/antioxidative balance in LHON patients. This is the greatest series of LHON patients that were evaluated for oxidative stress and the first case-controlled study that evaluated TOS, TAS, OSI, and AOPP and their influence on disease phenotype. It is evident that the presence of oxidative stress represents an important pathophysiological event in LHON and that it could potentially serve as a circulatory biomarker for a therapy efficacy understanding.

Mitochondrial DNA Haplogroup M7 Confers Disability in a Chinese Aging Population.

Mitochondrial DNA (mtDNA) haplogroups have been associated with functional impairments (i.e., decreased gait speed and grip strength, frailty), which are risk factors of disability. However, the association between mtDNA haplogroups and ADL disability is still unclear. In this study, we conducted an investigation of 25 mtSNPs defining 17 major mtDNA haplogroups for ADL disability in an aging Chinese population. We found that mtDNA haplogroup M7 was associated with an increased risk of disability (OR = 3.18 [95% CI = 1.29–7.83], P = 0.012). The survival rate of the M7 haplogroup group (6.1%) was lower than that of the non-M7 haplogroup group (9.5%) after a 6-year follow-up. In cellular studies, cytoplasmic hybrid (cybrid) cells with the M7 haplogroup showed distinct mitochondrial functions from the M8 haplogroup. Specifically, the respiratory chain complex capacity was significantly lower in M7 haplogroup cybrids than in M8 haplogroup cybrids. Furthermore, an obvious decreased mitochondrial membrane potential and 40% reduced ATP-linked oxygen consumption were found in M7 haplogroup cybrids compared to M8 haplogroup cybrids. Notably, M7 haplogroup cybrids generated more reactive oxygen species (ROS) than M8 haplogroup cybrids. Therefore, the M7 haplogroup may contribute to the risk of disability via altering mitochondrial function to some extent, leading to decreased oxygen consumption, but increased ROS production, which may activate mitochondrial retrograde signaling pathways to impair cellular and tissue function.

The first reported case of the rare mitochondrial haplotype H4a1 in ancient Egypt

Takabuti, was a female who lived in ancient Egypt during the 25th Dynasty, c.660 BCE. Her mummified remains were brought to Belfast, Northern Ireland, in 1834 and are currently displayed in the Ulster Museum. To gain insight into Takabuti’s ancestry, we used deep sampling of vertebral bone, under X-ray control, to obtain non-contaminated bone tissue from which we extracted ancient DNA (aDNA) using established protocols. We targeted the maternally inherited mitochondrial DNA (mtDNA), known to be highly informative for human ancestry, and identified 38 single nucleotide variants using next generation sequencing. The specific combination of these SNVs suggests that Takabuti belonged to mitochondrial haplogroup H4a1. Neither H4 nor H4a1 have been reported in ancient Egyptian samples, prior to this study. The modern distribution of H4a1 is rare and sporadic and has been identified in areas including the Canary Islands, southern Iberia and the Lebanon. H4a1 has also been reported in ancient samples from Bell Beaker and Unetice contexts in Germany, as well as Bronze Age Bulgaria. We believe that this is an important finding because first, it adds to the depth of knowledge about the distribution of the H4a1 haplogroup in existing mtDNA, thus creating a baseline for future occurrences of this haplogroup in ancient Egyptian remains. Second, it is of great importance for archaeological sciences, since a predominantly European haplogroup has been identified in an Egyptian individual in Southern Egypt, prior to the Roman and Greek influx (332BCE).

Forensic Application of ATP6 Gene Haplogroups in a Cohort of Obese Saudis

Blood samples from 108 obese individuals (73 males and 35 females) and 106 healthy ones (79 males and27 females) were collected from a cohort of Saudis inhabiting Riyadh province. ATP6 mitochondrial genewas amplified and sequenced to identify obesity-related SNPs and the mitochondrial DNA haplogroups forforensic purposes. A novel site (A8660G) was found while C8655T and T9103C were obesity- related sites.The haplogroups H2a and H1a were common as they were found in 70.4% and 66% of obese and non-obeseindividuals, respectively. L2 was recorded in the obese samples only and H21 was recorded in the obesemales only. The J2a haplohroup was more common in obese individuals. Constructing mtDNA database forpeople inhabiting different regions of Saudi Arabia for forensic purpose and to affirm the utility of H21 andL2 in identifiying obesity is necessary.

Mitochondrial haplogroup G is associated with nonalcoholic fatty liver disease, while haplogroup A mitigates the effects of PNPLA3.

ObjectivesMitochondrial dysfunction plays a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We hypothesized that mitochondrial DNA (mtDNA) haplogroups affect the risk of NAFLD in Han Chinese patients and interact with PNPLA3 genotypes.DesignNAFLD and control patients were recruited from a tertiary care centre. The mitochondrial genome was amplified in overlapping segments and sequenced. Mitochondrial haplogroups were determined using Mitomaster. PNPLA3 rs738409 genotyping was performed using restriction fragment length polymorphism analysis.PatientsWe enrolled 655 NAFLD patients and 504 controls.ResultsMore NAFLD patients encoded haplogroup G; odds ratio (OR) 1.85 (95% confidence interval [CI] 1.16, 2.80). Subhaplogroup G3 was present more frequently in NAFLD patients (25.8% vs 6.5%). The PNPLA3 CG genotype resulted in an OR of 1.66 (95% CI 1.25, 2.21), and the GG genotype resulted in an OR of 2.33 (95% CI 1.72, 3.17) for NAFLD. Patients with mitochondrial haplogroup A had a significantly higher frequency of genotype GG. Among patients with haplogroup A, no PNPLA3 genotype was associated with increased NAFLD risk (CG: OR 1.17, 95% CI 0.55, 2.34; GG: OR 1.04 95% CI 0.66, 2.65). Excluding haplogroup A, the OR for CG was 1.58 (95% CI 1.18, 2.12), and the OR for GG was 1.81 (95% CI 1.30, 2.51).ConclusionHaplogroup G was associated with an increased risk of NAFLD PNPLA3 GG genotype was overrepresented among patients encoding haplogroup A and was not associated with NAFLD risk among haplogroup A patients. Mitochondrial genetics influence NAFLD risk and interact with PNPLA3 genotypes.

Differential effects of cisplatin on cybrid cells with varying mitochondrial DNA haplogroups.

BackgroundDrug therapy yields different results depending on its recipient population. Cisplatin, a commonly used chemotherapeutic agent, causes different levels of resistance and side effects for different patients, but the mechanism(s) are presently unknown. It has been assumed that this variation is a consequence of differences in nuclear (n) DNA, epigenetics, or some external factor(s). There is accumulating evidence that an individual’s mitochondrial (mt) DNA may play a role in their response to medications. Variations within mtDNA can be observed, and an individual’s mtDNA can be categorized into haplogroups that are defined by accumulations of single nucleotide polymorphisms (SNPs) representing different ethnic populations.MethodsThe present study was conducted on transmitochondrial cytoplasmic hybrids (cybrids) that possess different maternal-origin haplogroup mtDNA from African (L), Hispanic [A+B], or Asian (D) backgrounds. Cybrids were created by fusing Rho0 ARPE-19 cells (lacking mtDNA) with platelets, which contain numerous mitochondria but no nuclei. These cybrid cells were cultured to passage five, treated with cisplatin, incubated for 48 h, then analyzed for cell metabolic activity (tetrazolium dye (MTT) assay), mitochondrial membrane potential (JC-1 assay), cytotoxicity (lactate dehydrogenase (LDH) assay), and gene expression levels for ALK, BRCA1, EGFR, and ERBB2/HER2.ResultsResults indicated that untreated cybrids with varying mtDNA haplogroups had similar relative metabolic activity before cisplatin treatment. When treated with cisplatin, (1) the decline in metabolic activity was greatest in L (27.4%, p < 0.012) < D (24.86%, p = 0.0001) and [A+B] cybrids (24.67%, p = 0.0285) compared to untreated cybrids; (2) mitochondrial membrane potential remained unchanged in all cybrids (3) LDH production varied between cybrids (L >[A+B], p = 0.0270). (4) The expression levels decreased for ALK in L (p < 0.0001) and [A+B] (p = 0.0001) cybrids but not in D cybrids (p = 0.285); and decreased for EGFR in [A+B] cybrids (p = 0.0246) compared to untreated cybrids.ConclusionOur findings suggest that an individual’s mtDNA background may be associated with variations in their response to cisplatin treatment, thereby affecting the efficiency and the severity of side effects from the treatment.

The Application of Mitochondrial COI Gene-Based Molecular Identification of Forensically Important Scuttle Flies (Diptera: Phoridae) in Korea.

Phoridae are a family of necrophagous flies commonly found in indoor death scene. They account for approximately 19.7% of the entomofauna in human cadavers in Korea. Additionally, this taxon is an indicator of indoor hygiene, and these flies appear in environments where access by other necrophagous insects is difficult, such as enclosed rooms. Thus, they are likely to be used as forensic evidence. Despite their importance in forensic investigations and environmental hygiene, detailed studies on the taxonomy and molecular barcoding for this family are scarce, including in Korea. Because accurate taxonomic information regarding necrophagous insects collected from a death-related scene is essential during medicolegal investigations, molecular barcoding data could be useful as well as reliable. In this paper, full-length nucleotide sequences of genes coding for the cytochrome c oxidase subunit I (COI) in 79 Phoridae larvae collected from 20 medicolegal autopsy cases in Korea were phylogenetically analyzed by comparing their sequences to the foreign barcoding data of Phoridae. Six mitochondrial haplogroups were identified, which two of them matched to foreign Phoridae fly species haplotypes, Megaselia scalaris (Loew, 1866) and M. spiracularis Schmitz 1938. Taxonomies of five other haplogroups, with nucleotide distances ranging from 1.68% to 2.26% from the M. scalaris group, could not be confirmed solely based on the molecular barcoding data. Further research should be performed to determine whether these five haplogroups are diverged conspecifics of M. scalaris or a closely related sister cryptic species of M. scalaris.

Microscopical discrimination of human head hairs sharing a mitochondrial haplogroup.

In forensic analyses, determining the level of consensus among examiners for hair comparison conclusions and ancestry identifications is important for assessing the scientific validity of microscopical hair examinations. Here, we present data from an interlaboratory study on the accuracy of microscopical hair comparisons among a subset of experienced hair examiners currently analyzing hair in forensic laboratories across the United States. We examined how well microscopical analysis of hair can reliably be used to differentiate hair samples, many of which were macroscopically similar. Using cut hair samples, many sharing similar macroscopic and microscopic features, collected from individuals who share the same mitochondrial haplogroup as an indication of genetic relatedness, we tested multiple aspects that could impact hair comparisons. This research tested the extent to which morphological features related to ancestry and hair length influence conclusions. Microscopical hair examinations yielded accurate assessments of inclusion/exclusion relative to the reference samples among 85% of the pairwise comparisons. We found shorter hairs had reduced levels of accuracy and hairs from populations examiners were not familiar with may have impacted their ability to resolve features. The reliability of ancestry determinations is not yet clear, but we found indications that the existing categories are only somewhat related to current ethnic and genetic variation. Our results provide support for the continued utility of microscopical comparison of hairs within forensic laboratories and to advocate for a combined analytical approach using both microscopical analysis and mtDNA data on all forensic analyses of hair.

Associations of mitochondrial genomic variation with corticobasal degeneration, progressive supranuclear palsy, and neuropathological tau measures

Mitochondrial health is important in ageing and dysfunctional oxidative phosphorylation (OXPHOS) accelerates ageing and influences neurodegeneration. Mitochondrial DNA (mtDNA) codes for vital OXPHOS subunits and mtDNA background has been associated with neurodegeneration; however, no study has characterised mtDNA variation in Progressive supranuclear palsy (PSP) or Corticobasal degeneration (CBD) risk or pathogenesis. In this case–control study, 910 (42.6% male) neurologically-healthy controls, 1042 (54.1% male) pathologically-confirmed PSP cases, and 171 (52.0% male) pathologically-confirmed CBD cases were assessed to determine how stable mtDNA polymorphisms, in the form of mtDNA haplogroups, were associated with risk of PSP, risk of CBD, age of PSP onset, PSP disease duration, and neuropathological tau pathology measures for neurofibrillary tangles (NFT), neuropil threads (NT), tufted astrocytes (TA), astrocytic plaques (AP), and oligodendroglial coiled bodies (CB). 764 PSP cases and 150 CBD cases had quantitative tau pathology scores. mtDNA was genotyped for 39 unique SNPs using Agena Bioscience iPlex technologies and mitochondrial haplogroups were defined to mitochondrial phylogeny. After adjustment for multiple testing, we observed an association with risk of CBD for mtDNA sub-haplogroup H4 (OR = 4.51, P = 0.001) and the HV/HV0a haplogroup was associated with a decreased severity of NT tau pathology in PSP cases (P = 0.0023). Our study reports that mitochondrial genomic background may be associated with risk of CBD and may be influencing tau pathology measures in PSP. Replication of these findings will be important.

Modern Northern Domestic Horses Carry Mitochondrial DNA Similar to Przewalski\u2019s Horse

Several recent studies have suggested past gene flow between the Przewalski’s horse and modern domestic horse and questioned the wild origin of the Przewalski’s horse. Mitochondrial DNA has placed representatives of the Przewalski’s horse into three among the eighteen haplogroups detected from the modern horse. Of these, two haplogroups have so far been found exclusively in the Przewalski’s horse, while the one shared with the domestic horse includes captive individuals that have uncertain pedigrees. We recently found five domestic horse individuals of North European horse breeds to carry a mitochondrial haplogroup that was previously confined only to the Przewalski’s horse. These individuals were sequenced for 6039 bp of mitochondrial DNA and used, together with domestic and Przewalski’s horse sequences presenting all horse haplogroups, to examine the phylogenetic relationships and to date the divergence time between Przewalski’s and domestic horse clusters within this haplogroup. The divergence was dated to have likely occurred about 13,300–11,400 years ago, which coincides with the time of the Younger Dryas.