Mitochondrial Haplogroups Research Articles

Nuclear genome-wide associations with mitochondrial heteroplasmy.

The role of the nuclear genome in maintaining the stability of the mitochondrial genome (mtDNA) is incompletely known. mtDNA sequence variants can exist in a state of heteroplasmy, which denotes the coexistence of organellar genomes with different sequences. Heteroplasmic variants that impair mitochondrial capacity cause disease, and the state of heteroplasmy itself is deleterious. However, mitochondrial heteroplasmy may provide an intermediate state in the emergence of novel mitochondrial haplogroups. We used genome-wide genotyping data from 982,072 European ancestry individuals to evaluate variation in mitochondrial heteroplasmy and to identify the regions of the nuclear genome that affect it. Age, sex, and mitochondrial haplogroup were associated with the extent of heteroplasmy. GWAS identified 20 loci for heteroplasmy that exceeded genome-wide significance. This included a region overlapping mitochondrial transcription factor A (TFAM), which has multiple roles in mtDNA packaging, replication, and transcription. These results show that mitochondrial heteroplasmy has a heritable nuclear component.

Traces of Late Bronze and Early Iron Age Mongolian Horse Mitochondrial Lineages in Modern Populations.

The Mongolian horse is one of the most ancient and relatively unmanaged horse breeds. The population history of the Mongolian horse remains poorly understood due to a lack of information on ancient and modern DNA. Here, we report nearly complete mitochondrial genome data obtained from five ancient Mongolian horse samples of the Khereksur and Deer Stone culture (late 2nd to 1st third of the 1st millennium BC) and one ancient horse specimen from the Xiongnu culture (1st century BC to 1st century AD) using target enrichment and high-throughput sequencing methods. Phylogenetic analysis involving ancient, historical, and modern mitogenomes of horses from Mongolia and other regions showed the presence of three mitochondrial haplogroups in the ancient Mongolian horse populations studied here and similar haplotype composition of ancient and modern horse populations of Mongolia. Our results revealed genetic continuity between the Mongolian horse populations of the Khereksur and Deer Stone culture and those of the Xiongnu culture owing to the presence of related mitotypes. Besides, we report close phylogenetic relationships between haplotypes of the Khereksur and Deer Stone horses and the horses of indigenous breeds of the Middle East (Caspian and Iranian), China (Naqu, Yunnan, and Jinjiang), and Italy (Giara) as well as genetic similarity between the Xiongnu Mongolian horses and those of the most ancient breeds of the Middle East (Arabian) and Central Asia (Akhal-Teke). Despite all the migrations of the Mongolian peoples over the past 3000 years, mitochondrial haplogroup composition of Mongolian horse populations remains almost unchanged.

Mitochondrial DNA haplogroups J and T increase the risk of glioma

The presence of different sets of mitochondrial polymorphisms generated by the accumulation of mutations in different maternal lineages has allowed differentiating mitochondrial haplogroups in human populations. These polymorphisms, in turn, may have effects at the phenotypic level, considering a possible contribution of these germinal mutations to the development of certain diseases such as cancer. The main goal of the present study is to establish a possible association between mitochondrial haplogroups and the risk of suffering glioma. Blood samples were obtained from 32 patients from Catalonia (Spain) diagnosed with different grades of glioma (II, III and IV), according to the World Health Organization. The mitochondrial genome was amplified and sequenced using MiSeq 2000 (Illumina). The HaploGrep tool implemented in mtDNA-Server v.1.0.5 was used for the identification of mitochondrial haplogroups. Data obtained in the present study was further pooled with data from previous European studies including glioma patients from Galicia (Spain) and Italy. Results for the Catalonian samples showed an association between individuals with haplogroup J and the increased risk of suffering glioma, with a significant increase of the frequency of individuals with this haplogroup (25%) regarding the general population (7%). Combining different sets of patients with European origin, it appears that individuals with haplogroups J and T have a significantly higher risk of suffering glioma (p < 0.001; OR: 2.407 and p = 0.007; OR: 1.82, respectively). This is the first study that establishes an association between different mitochondrial haplogroups and the risk of suffering glioma, highlighting the role of mitochondrial variants in this disease.

Global DNA hypermethylation pattern and unique gene expression signature in liver cancer from patients with Indigenous American ancestry.

Hepatocellular carcinoma (HCC) usually afflicts individuals in their maturity after a protracted liver disease. Contrasting with this pattern, the age structure of HCC in Andean people displays a bimodal distribution with half of the patients developing HCC in adolescence and early adulthood. To deepen our understanding of the molecular determinants of the disease in this population, we conducted an integrative analysis of gene expression and DNA methylation in HCC developed by 74 Peruvian patients, including 39 adolescents and young adults. While genome-wide hypomethylation is considered as a paradigm in human HCCs, our analysis revealed that Peruvian tumors are associated with a global DNA hypermethylation. Moreover, pathway enrichment analysis of transcriptome data characterized an original combination of signatures. Peruvian HCC forgoes canonical activations of IGF2, Notch, Ras/MAPK, and TGF-β signals to depend instead on Hippo/YAP1, MYC, and Wnt/β-catenin pathways. These signatures delineate a homogeneous subtype of liver tumors at the interface of the proliferative and non-proliferative classes of HCCs. Remarkably, the development of this HCC subtype occurs in patients with one of the four Native American mitochondrial haplogroups A-D. Finally, integrative characterization revealed that Peruvian HCC is apparently controlled by the PRC2 complex that mediates cell reprogramming with massive DNA methylation modulating gene expression and pinpointed retinoid signaling as a potential target for epigenetic therapy.

Relationship Between the Dynamics of Telomere Loss in Peripheral Blood Leukocytes From Knee Osteoarthritis Patients and Mitochondrial DNA Haplogroups.

To evaluate the evolution of telomere length from peripheral blood leukocytes (PBLs) in subjects from the Osteoarthritis Initiative (OAI) cohort in relation to the incidence of osteoarthritis (OA), and to explore its possible interactive influence with the mitochondrial DNA (mtDNA) haplogroup. Dynamics of telomere sequence loss were quantified in PBLs from initially healthy individuals (without symptoms or radiological signs), 78 carrying the mtDNA cluster HV, and 47 with cluster JT, from the OAI, during a 72-month follow-up period. The incidence of knee OA during this period (n = 39) was radiographically established when Kellgren-Lawrence (KL) score increased from < 2 at recruitment, to ≥ 2 at the end of 72 months of follow-up. Multivariate analysis using binary logistic regression was performed to assess PBL telomere loss and mtDNA haplogroups as associated risk factors of incidence of knee OA. Carriers of cluster HV showed knee OA incidence twice that of the JT carriers (n = 30 vs 9). The rate of PBL telomere loss was higher in cluster HV carriers and in individuals with incident knee OA. Multivariate analysis showed that the dynamics of PBL telomere shortening can be a consistent risk marker of knee OA incidence. Subjects with nonincident knee OA showed a slower telomere loss than those with incident knee OA; the difference was more significant in carriers of cluster JT than in HV. An increased rate of telomere loss in PBLs may reflect a systemic accelerated senescence phenotype that could be potentiated by the mitochondrial function, increasing the susceptibility of developing knee OA.

Diversity and Structure of Mitochondrial Gene Pools of Slavs in the Ethnogenetic Aspect

Data on the variability of the nucleotide sequences of whole mitochondrial genomes in populations of Russians, Poles, and Serbs, which represent, respectively, the groups of East, West, and South Slavs, are reviewed in comparison with similar data for other European peoples. It was shown that the results of the analysis of the variability of whole mitogenomes make it possible to substantially detail the ideas about the structure and diversity of mitochondrial gene pools obtained earlier with other approaches, e.g., analysis of the distribution of haplotypes of mtDNA major noncoding region or the frequencies of mitochondrial haplogroups. It has been demonstrated that Bayesian analysis of large data sets on the variability of whole mitogenomes in the Slavs enabled the identification of between-regional differences in the dynamics of the effective population size over time for Europe. The use of a phylogeographic analysis of modern and paleogenomic data on the variability of whole mitogenomes makes it possible to define unique phylogenetic mtDNA clusters specific to certain ethnic groups and their communities. Their common genetic origin, which dates back to the Bronze and Iron Ages, is demonstrated on the example of three ethnic groups of Slavs.

Impact of modular mitochondrial epistatic interactions on the evolution of human subpopulations

Investigation of human mitochondrial (mt) genome variation has been shown to provide insights to the human history and natural selection. By analyzing 24,167 human mt-genome samples, collected for five continents, we have developed a co-mutation network model to investigate characteristic human evolutionary patterns. The analysis highlighted richer co-mutating regions of the mt-genome, suggesting the presence of epistasis. Specifically, a large portion of COX genes was found to co-mutate in Asian and American populations, whereas, in African, European, and Oceanic populations, there was greater co-mutation bias in hypervariable regions. Interestingly, this study demonstrated hierarchical modularity as a crucial agent for these co-mutation networks. More profoundly, our ancestry-based co-mutation module analyses showed that mutations cluster preferentially in known mitochondrial haplogroups. Contemporary human mt-genome nucleotides most closely resembled the ancestral state, and very few of them were found to be ancestral-variants. Overall, these results demonstrated that subpopulation-based biases may favor mitochondrial gene specific epistasis.

The heterogeneity among subgroups of haplogroup J influencing Alzheimer’s disease risk

IntroductionThe impact of mitochondrial haplogroups on Alzheimer’s disease (AD) risk has not been fully elucidated and warrants further investigation at the subgroup level. ObjectivesThe aim of this research is to evaluate the association between mitochondrial haplogroups and AD risk in subgroups level. MethodsIn total, 809 AD Neuroimaging Initiative subjects were assessed using mtDNA sequencing, the AD Assessment Scale-Cognitive Subscale (ADAS-cog), hippocampal volume measurements, the hypometabolic convergence index (HCI), and MCI-to-AD conversion proportion measurements. ResultsThe frequency of haplogroup J was significantly higher than that of other haplogroups in the AD group (p = 0.013). According to the correlation between haplogroup J-specific SNPs and ADAS-cog, haplogroup J was divided into four subgroups harboring exacerbating SNPs, protective SNPs, both exacerbating and protective SNPs, or irrelevant SNPs. The subgroups harboring exacerbating SNPs exhibited higher AD risk represented by the levels of ADAS-cog, hippocampal volume, HCI, and MCI-to-AD conversion proportion than other subgroups. ConclusionHeterogeneity existed among the subgroups of haplogroup J, which suggested that different subgroups exhibited different levels of AD risk. This study provides novel insights into the correlation between mitochondrial haplogroups and AD risk.

Assessment of the impact of mitochondrial genotype upon drug-induced mitochondrial dysfunction in platelets derived from healthy volunteers

Mitochondrial DNA (mtDNA) is highly polymorphic and encodes 13 proteins which are critical to the production of ATP via oxidative phosphorylation. As mtDNA is maternally inherited and undergoes negligible recombination, acquired mutations have subdivided the human population into several discrete haplogroups. Mitochondrial haplogroup has been found to significantly alter mitochondrial function and impact susceptibility to adverse drug reactions. Despite these findings, there are currently limited models to assess the effect of mtDNA variation upon susceptibility to adverse drug reactions. Platelets offer a potential personalised model of this variation, as their anucleate nature offers a source of mtDNA without interference from the nuclear genome. This study, therefore, aimed to determine the effect of mtDNA variation upon mitochondrial function and drug-induced mitochondrial dysfunction in a platelet model. The mtDNA haplogroup of 383 healthy volunteers was determined using next-generation mtDNA sequencing (Illumina MiSeq). Subsequently, 30 of these volunteers from mitochondrial haplogroups H, J, T and U were recalled to donate fresh, whole blood from which platelets were isolated. Platelet mitochondrial function was tested at basal state and upon treatment with compounds associated with both mitochondrial dysfunction and adverse drug reactions, flutamide, 2-hydroxyflutamide and tolcapone (10–250 μM) using extracellular flux analysis. This study has demonstrated that freshly-isolated platelets are a practical, primary cell model, which is amenable to the study of drug-induced mitochondrial dysfunction. Specifically, platelets from donors of haplogroup J have been found to have increased susceptibility to the inhibition of complex I-driven respiration by 2-hydroxyflutamide. At a time when individual susceptibility to adverse drug reactions is not fully understood, this study provides evidence that inter-individual variation in mitochondrial genotype could be a factor in determining sensitivity to mitochondrial toxicants associated with costly adverse drug reactions.

Delineation of Mitochondrial DNA Variants From Exome Sequencing Data and Association of Haplogroups With Obesity in Kuwait.

Background/ObjectivesWhole-exome sequencing is a valuable tool to determine genetic variations that are associated with rare and common health conditions. A limited number of studies demonstrated that mitochondrial DNA can be captured using whole-exome sequencing. Previous studies have suggested that mitochondrial DNA variants and haplogroup lineages are associated with obesity. Therefore, we investigated the role of mitochondrial variants and haplogroups contributing to the risk of obesity in Arabs in Kuwait using exome sequencing data.Subjects/MethodsIndirect mitochondrial genomes were extracted from exome sequencing data from 288 unrelated native Arab individuals from Kuwait. The cohort was divided into obese [body mass index (BMI) ≥ 30 kg/m2] and non-obese (BMI < 30 kg/m2) groups. Mitochondrial variants were identified, and haplogroups were classified and compared with other sequencing technologies. Statistical analysis was performed to determine associations and identify mitochondrial variants and haplogroups affecting obesity.ResultsHaplogroup R showed a protective effect on obesity [odds ratio (OR) = 0.311; P = 0.006], whereas haplogroup L individuals were at high risk of obesity (OR = 2.285; P = 0.046). Significant differences in mitochondrial variants between the obese and non-obese groups were mainly haplogroup-defining mutations and were involved in processes in energy generation. The majority of mitochondrial variants and haplogroups extracted from exome were in agreement with technical replica from Sanger and whole-genome sequencing.ConclusionsThis is the first to utilize whole-exome data to extract entire mitochondrial haplogroups to study its association with obesity in an Arab population.

Association of Mitochondrial DNA Genomic Variation With Risk of Pick Disease.

To determine whether stable polymorphisms that define mitochondrial haplogroups in mitochondrial DNA (mtDNA) are associated with Pick disease risk, we genotyped 52 pathologically confirmed cases of Pick disease and 910 neurologically healthy controls and performed case-control association analysis. Fifty-two pathologically confirmed cases of Pick disease from Mayo Clinic Florida (n = 38) and the University of Pennsylvania (n = 14) and 910 neurologically healthy controls collected from Mayo Clinic Florida were genotyped for unique mtDNA haplogroup-defining variants. Mitochondrial haplogroups were determined, and in a case-control analysis, associations of mtDNA haplogroups with risk of Pick disease were evaluated with logistic regression models that were adjusted for age and sex. No individual mtDNA haplogroups or superhaplogroups were significantly associated with risk of Pick disease after adjustment for multiple testing (p < 0.0021, considered significant). However, nominally significant (p < 0.05) associations toward an increased risk of Pick disease were observed for mtDNA haplogroup W (5.8% cases vs 1.6% controls, odds ratio [OR] 4.78, p = 0.020) and subhaplogroup H4 (5.8% cases vs 1.2% controls, OR 4.82, p = 0.021). Our findings indicate that mtDNA variation is not a disease driver but may influence disease susceptibility. Ongoing genetic assessments in larger cohorts of Pick disease are currently underway.

Ancient mitochondrial genomes from Chinese cave hyenas provide insights into the evolutionary history of the genus Crocuta.

Cave hyenas (genus Crocuta) are extinct bone-cracking carnivores from the family Hyaenidae and are generally split into two taxa that correspond to a European/Eurasian and an (East) Asian lineage. They are close relatives of the extant African spotted hyenas, the only extant member of the genus Crocuta. Cave hyenas inhabited a wide range across Eurasia during the Pleistocene, but became extinct at the end of the Late Pleistocene. Using genetic and genomic datasets, previous studies have proposed different scenarios about the evolutionary history of Crocuta. However, causes of the extinction of cave hyenas are widely speculative and samples from China are severely understudied. In this study, we assembled near-complete mitochondrial genomes from two cave hyenas from northeastern China dating to 20 240 and 20 253 calBP, representing the youngest directly dated fossils of Crocuta in Asia. Phylogenetic analyses suggest a monophyletic clade of these two samples within a deeply diverging mitochondrial haplogroup of Crocuta. Bayesian analyses suggest that the split of this Asian cave hyena mitochondrial lineage from their European and African relatives occurred approximately 1.85 Ma (95% CI 1.62-2.09 Ma), which is broadly concordant with the earliest Eurasian Crocuta fossil dating to approximately 2 Ma. Comparisons of mean genetic distance indicate that cave hyenas harboured higher genetic diversity than extant spotted hyenas, brown hyenas and aardwolves, but this is probably at least partially due to the fact that their mitochondrial lineages do not represent a monophyletic group, although this is also true for extant spotted hyenas. Moreover, the joint female effective population size of Crocuta (both cave hyenas and extant spotted hyenas) has sustained two declines during the Late Pleistocene. Combining this mitochondrial phylogeny, previous nuclear findings and fossil records, we discuss the possible relationship of fossil Crocuta in China and the extinction of cave hyenas.

Spirit Eye Cave: Reestablishing provenience of trafficked prehistoric human remains using a composite collection-based ancient DNA approach

Spirit Eye Cave, located on private land in west Texas near the US/Mexico border, contains as many as four human interments removed by pay-to-dig collectors in the 1950–60 s. The relocated remains provide initial DNA results from a region peripheral to both the Southwest and Plains, and the bone collagen 14C dates are coeval with a period of presumed multiethnic migration. The mitochondrial DNA results from two individuals indicate a maternal relationship between each interment. Considered together, these data indicate both a familiarity with the region and a stability of land use by foraging groups during a period of reputed instability. The identification of the B2a4a1 haplogroup in both individuals ties the region to indigenous groups in present-day Mexico, Texas, and the prehistoric site of Paquimé, in Chihuahua, Mexico. These results demonstrate the utility of a collaborative collection based aDNA approach for looted and heavily collected sheltered sites. Significance statementTwo rediscovered human remains from at Spirit Eye cave in west Texas situated on the US/Mexico border were radiocarbon dated and sampled for mitochondrial DNA. Both burials belong to the same B2a4a1 mitochondrial haplogroup and were dated to a period of dramatic cultural change in the region. Our results indicate a group of related foraging groups repeatedly used the cave as a mortuary site over several generations. This study also illustrates the utility of pursuing collection-based research from heavily impacted archaeological sites.

Association of mitochondrial DNA haplogroups J and K with low response in exercise training among Finnish military conscripts

BackgroundWe have previously suggested that some of the mutations defining mitochondrial DNA (mtDNA) haplogroups J and K produce an uncoupling effect on oxidative phosphorylation and thus are detrimental for elite endurance performance. Here, the association between haplogroups J and K and physical performance was determined in a population-based cohort of 1036 Finnish military conscripts.ResultsFollowing a standard-dose training period, excellence in endurance performance was less frequent among subjects with haplogroups J or K than among subjects with non-JK haplogroups (p = 0.041), and this finding was more apparent among the best-performing subjects (p < 0.001).ConclusionsThese results suggest that mtDNA haplogroups are one of the genetic determinants explaining individual variability in the adaptive response to endurance training, and mtDNA haplogroups J and K are markers of low-responders in exercise training.

Mitochondrial haplogroup J associated with higher risk of obesity in the Qatari population

Obesity, a major risk factor for metabolic disorders, is highly prevalent in Qatari population. Maternal transmission of obesity traits can be significant; for example, X haplogroup is known to be associated with lower BMI and body fat mass in Northern Europeans and T haplogroup which is a sister haplogroup of J is known to be associated with obesity in Caucasian subjects from Austria and Southern Italy. We aimed to delineate the mitochondrial haplogroups and variants associated with obesity in Qatari population. Mitochondrial genomes of 864 Qatari individuals were extracted from whole exome sequencing data with an average coverage of 77X. We distributed the participants into 2 sub-cohorts: obese (BMI ≥ 30) and non-obese (BMI < 30); the mean value of BMI from these two groups were 36.5 ± 5.7 and 26.5 ± 2.6, respectively. Mitochondrial haplogroup profiling followed by uni- and multivariant association tests adjusted for covariates were performed. Qatari individuals with mitochondrial haplogroup J had an increased (twofold) risk of obesity (odds ratio [OR] 1.925; 95% CI 1.234–3.002; P = 0.0038; the Bonferroni adjusted P value threshold is 0.0041), whereas the individuals with haplogroup X were at low risk of obesity (OR 0.387; 95% CI 0.175–0.857; P = 0.019). Further, a set of 38 mitochondrial variants were found to be associated (at P ≤ 0.05) with obesity in models adjusted for age, sex and haplogroup.

Mitochondrial DNA Haplogroups and Three Independent Polymorphisms have no Association with the Risk of Parkinson's Disease in East Indian Population.

Parkinson's disease (PD) is a multifaceted illness affecting ~ 0.3% of the world population. The genetic complexity of PD has not been, fully elucidated. Several studies suggest that mitochondrial DNA variants are associated with PD. Here, we have explored the possibility of genetic association between mitochondrial haplogroups as well as three independent SNPs with PD in a representative east Indian population. The Asian mtDNA haplogroups: M, N, R, B, D, M7, and 3 other SNPs: 4336 T/C, 9055 G/A, 13708 G/A were genotyped in 100 sporadic PD patients and 100 matched controls via conventional PCR-RFLP-sequencing approach. The distribution of mtDNA haplogroups, as well as 3 single polymorphisms, did not show any significant differences (P > 0.05) between patients and controls. This is the first of its kind of study from India that suggests no association of selected mitochondrial DNA variations with PD.

Analysis of Whole Genome of Indian Male Kashmiri Pandit

Remarkable advancement in next generation sequencing technology has made personal genome analysis feasible and affordable. Here we present the whole genome sequence analysis of an individual from the Kashmir region of India who is from the pandit community (IHGP04). The Indian male’s genome was sequenced at 38.6 X coverage with a total of 110 Gb of sequence data generated using the Illumina HiSeq 2000 platform. The variant analysis revealed over 3.6 million single nucleotide variants and 5 46 681 small insertions and deletions including about 2.7 % of novel (unreported) variants. The known variants were analyzed for their health and disease relevance and drug pharmacogenetic profile. The mitochondrial haplogroup (L3e2b1a1) is indicative of maternal ancestors’ arrival to the Indian subcontinent about 70 000 y ago, while the Y-chromosome haplogroup (J) is suggestive of the arrival of paternal ancestors less than 25 000 y ago. The haplogroups also suggest different routes used by the ancestors to arrive on the subcontinent. The analysis and validation of the novel variants and relationship with health and diseases should be the next logical step.

Heterologous Inferential Analysis (HIA) and Other Emerging Concepts: In Understanding Mitochondrial Variation In Pathogenesis: There is no More Low-Hanging Fruit.

Here we summarize our latest efforts to elucidate the role of mtDNA variants affecting the mitochondrial translation machinery, namely variants mapping to the mt-rRNA and mt-tRNA genes. Evidence is accumulating to suggest that the cellular response to interference with mitochondrial translation is different from that occurring as a result ofmutations in genes encodingOXPHOS proteins. As a result, it appears safe to state that a complete view of mitochondrial disease will not be obtained until we understand the effect of mt-rRNA and mt-tRNA variants on mitochondrial protein synthesis. Despite the identification of a large number of potentially pathogenic variants in the mitochondrially encoded rRNA (mt-rRNA) genes, we lack direct methods to firmly establish their pathogenicity. In the absence of such methods, we have devised an indirect approach named heterologous inferential analysis (HIA ) that can be used to make predictions concerning the disruptive potential of a large subset of mt-rRNA variants. We have used HIA to explore the mutational landscape of 12S and 16S mt-rRNA genes. Our HIA studies include a thorough classification of all rare variants reported in the literature as well as others obtained fromstudies performed in collaboration with physicians. HIA has also been used with non-mammalian mt-rRNA genes to elucidate how mitotypes influence the interaction of the individual and the environment. Regarding mt-tRNA variations, rapidly growing evidence shows that the spectrum of mutations causing mitochondrial disease might differ between the different mitochondrial haplogroups seen in human populations.

МУМИФИЦИРОВАННОЕ ПОГРЕБЕНИЕ РЕБЕНКА ИЗ МОГИЛЬНИКА САРЫГ-БУЛУН (ЦЕНТРАЛЬНАЯ ТУВА) В СВЕТЕ ДАННЫХ АРХЕОЛОГИИ, РЕНТГЕНОГРАФИИ, АНТРОПОЛОГИИ И ГЕНЕТИКИ

In 1988 on the right bank of the Yenisei River in Central Tuva, two burial mounds from the Saryg-Bulun burial ground were excavated. Burial № 5 attracted special attention of archaeologists — it contained the partially mummified remains of a child with a rich and unusual inventory (bow, quiver with arrows, a hat, engraving on a wooden handle) in a wooden block. A recent genetic analysis made it possible to establish, contrary to expectations, the female sex of an individual. Over the years, thanks to the development of natural scientific methods, it was possible to gradually obtain new data on the life and death of this girl. The article presents the results of an examination of the mummy by the method of microfocus digital radiography and a new paleogenetic study, which made it possible to determine the child’s mitochondrial haplogroup (D4g2, which is widespread in East and Central Asia). The rich grave goods indicate the high status. Her biological age was determined — 6–7 years. Indicators of physiological stress (Harris lines), the presence of noticeable physical exertion on the belt of the upper extremities during the child’s life, and rickets were revealed. Radiography made it possible to detect artifacts invisible during a superficial examination, for example, a knife that was previously unnoticed in the deck. Genetic data are consistent with observations on the possible horizontal flattening of the girl’s facial skeleton and the spatula-like shape of her upper incisor. The applied methods and the results obtained allow authors to look in a new light at the issues of the genesis of the Aldy-Bel culture and the theme of childhood in the early Scythian time.

Mitochondria: The Retina's Achilles' Heel in AMD.

Strong experimental evidence from studies in human donor retinas and animal models supports the idea that the retinal pathology associated with age-related macular degeneration (AMD) involves mitochondrial dysfunction and consequent altered retinal metabolism. This chapter provides a brief overview of mitochondrial structure and function, summarizes evidence for mitochondrial defects in AMD, and highlights the potential ramifications of these defects on retinal health and function. Discussion of mitochondrial haplogroups and their association with AMD brings to light how mitochondrial genetics can influence disease outcome. As one of the most metabolically active tissues in the human body, there is strong evidence that disruption in key metabolic pathways contributes to AMD pathology. The section on retinal metabolism reviews cell-specific metabolic differences and how the metabolic interdependence of each retinal cell type creates a unique ecosystem that is disrupted in the diseased retina. The final discussion includes strategies for therapeutic interventions that target key mitochondrial pathways as a treatment for AMD.