Mitochondrial Genome Variation Research Articles

Study on the Mitochondrial Genome of Variants Carrying mt.3243A>G from Type-2 Diabetes Mellitus and Cataract Patients in Indonesia

The association of type-2 diabetes mellitus (T2DM) and cataract with mtDNA mutation has been reported before. Despite the high prevalence of DM and cataract in Indonesia, a study of the mtDNA variants in Indonesia in correlation with the two diseases is still limited. MT.3243A>G is one of the hotspots mutations for mitochondrial diseases, but the explanation for its occurrence in patients with pure cataract is still elusive. Therefore, the objective of this study was to analyze the mitochondrial genome variants from T2DM and cataract patients in Indonesia using the direct sequencing method. The homology analysis of the genome to the Cambridge reference sequence resulted in 86 variants, including 20 variants that cause amino acid substitutions. Based on the Mitomap data, 17 of the 20 variants were novel. Upon comparison with the 12 normal variant genomes, 11 of 17 variants were suggested to be associated with T2DM and cataract diseases since they code the protein in complex-I (ND4L, ND5, and ND6), complex-III (cytb), and complex-V (ATP6) of the respiratory complex. Interestingly, MT.3316G>A, for the first time, is shown in a pure cataract patient. In addition, the novel phenotype of MT.5460G>A and MT.10398A>G were revealed, which are T2DM and cataract in one patient. Based on our study, these diseases might be related to the disruption of the ATP metabolism due to the structure and function changes of proteins involved in the respiratory complex. This discovery is expected to offer an understanding of the origins of gene-level clinical differences, particularly in Indonesia.

Genetic structural variation in mitochondrial genomes of four species of Gomphidae and their phylogenetic implications

The Gomphids are the most diverse and important group in the (sub)tropics. Currently, research on Gomphids is mainly focused on fieldwork and morphological classification, however, the molecular-based study is still insufficient. Here, complete mitogenomes of Nihonogomphus semanticus (15,368 bp), Nihonogomphus lieftincki (15,342 bp), Asiagomphus septimus (15,334 bp), and Davidius fruhstorferi (15,682 bp) were obtained by high-throughput sequencing. Of the 37 genes conserved in order and orientation, 9 protein-coding genes (PCGs) and 14 tRNA genes were encoded by heavy strand, while the rest were encoded by light strand. The secondary structures of the protein encoded by 13 PCGs showed a general trend of proportion: α helix > random coil > extended strand > β turn. The trnS1 gene lacked a dihydrouridine arm and was thus reduced to a loop. The 3D structures of the protein encoded by 13 PCGs showed moderate to high levels of consistency among species. Phylogenetic analysis showed that Gomphids were well-supported monophyletic group, both BI and ML tree showed clear phylogenetic relationships in known Gomphidae: ((((D. lunatus + D. fruhstorferi) + A. septimus) + ((N. semanticus + N. lieftincki) + Ophiogomphus cecilia)) + Ictinogomphus sp MT 2014). Our study provides insight into the gene or their protein structure features of the family Gomphidae mitogenomes and lays the foundation for further phylogenetic studies.

Mitochondrial genomes – unity and diversity

The emergence of mitochondria was one of the most important events in the history of life on Earth. The engulfed bacterial cell, transformed into a mitochondrion, retained its genome, which then underwent numerous modifications. Through massive loss and numerous gene transfers into the nuclear genome, the autonomous bacterium eventually evolved into the organelle we know today. As a result of changes taking place independently in different evolutionary lineages, we observe a great diversity of mitochondrial genomes with respect to structure and gene content. In most cases, mitochondrial DNA has a circular shape, but linear molecules of mitochondrial DNA are also observed in some eukaryotes. In extreme cases, such as in reduced mitochondrial-derived organelles, the genome has been completely lost. In this article, we discuss the diversity of mitochondrial genome structures within the largest groups of Eukarya.

Mapping mitonuclear epistasis using a novel recombinant yeast population.

Genetic variation in mitochondrial and nuclear genomes can perturb mitonuclear interactions and lead to phenotypic differences between individuals and populations. Despite their importance to most complex traits, it has been difficult to identify the interacting mitonuclear loci. Here, we present a novel advanced intercrossed population of Saccharomyces cerevisiae yeasts, called the Mitonuclear Recombinant Collection (MNRC), designed explicitly for detecting mitonuclear loci contributing to complex traits. For validation, we focused on mapping genes that contribute to the spontaneous loss of mitochondrial DNA (mtDNA) that leads to the petite phenotype in yeast. We found that rates of petite formation in natural populations are variable and influenced by genetic variation in nuclear DNA, mtDNA and mitonuclear interactions. We mapped nuclear and mitonuclear alleles contributing to mtDNA stability using the MNRC by integrating a term for mitonuclear epistasis into a genome-wide association model. We found that the associated mitonuclear loci play roles in mitotic growth most likely responding to retrograde signals from mitochondria, while the associated nuclear loci with main effects are involved in genome replication. We observed a positive correlation between growth rates and petite frequencies, suggesting a fitness tradeoff between mitotic growth and mtDNA stability. We also found that mtDNA stability was correlated with a mobile mitochondrial GC-cluster that is present in certain populations of yeast and that selection for nuclear alleles that stabilize mtDNA may be rapidly occurring. The MNRC provides a powerful tool for identifying mitonuclear interacting loci that will help us to better understand genotype-phenotype relationships and coevolutionary trajectories.

Mitochondrial genomes in the iconic reindeer lichens: Architecture, variation, and synteny across multiple evolutionary scales

ABSTRACT Variation in mitochondrial genome composition across intraspecific, interspecific, and higher taxonomic scales has been little studied in lichen obligate symbioses. Cladonia is one of the most diverse and ecologically important lichen genera, with over 500 species representing an array of unique morphologies and chemical profiles. Here, we assess mitochondrial genome diversity and variation in this flagship genus, with focused sampling of two clades of the “true” reindeer lichens, Cladonia subgenus Cladina, and additional genomes from nine outgroup taxa. We describe composition and architecture at the gene and the genome scale, examining patterns in organellar genome size in larger taxonomic groups in Ascomycota. Mitochondrial genomes of Cladonia, Pilophorus, and Stereocaulon were consistently larger than those of Lepraria and contained more introns, suggesting a selective pressure in asexual morphology in Lepraria driving it toward genomic simplification. Collectively, lichen mitochondrial genomes were larger than most other fungal life strategies, reaffirming the notion that coevolutionary streamlining does not correlate to genome size reductions. Genomes from Cladonia ravenelii and Stereocaulon pileatum exhibited ATP9 duplication, bearing paralogs that may still be functional. Homing endonuclease genes (HEGs), though scarce in Lepraria, were diverse and abundant in Cladonia, exhibiting variable evolutionary histories that were sometimes independent of the mitochondrial evolutionary history. Intraspecific HEG diversity was also high, with C. rangiferina especially bearing a range of HEGs with one unique to the species. This study reveals a rich history of events that have transformed mitochondrial genomes of Cladonia and related genera, allowing future study alongside a wealth of assembled genomes.

A Genetically Heterogeneous Rat Model with Divergent MitochondrialGenomes.

We generated a genetically heterogenous rat model by a 4-way cross strategy using 4 inbred strains (Brown Norway [BN], Fischer 344 [F344], Lewis [LEW], and Wistar Kyoto [KY]) to provide investigators with a highly genetically diverse rat model from commercially available inbred rats. We made reciprocal crosses between males and females from the 2 F1 hybrids to generate genetically heterogeneous rats with mitochondrial genomes from either the BN (OKC-HETB, a.k.a "B" genotype) or WKY (OKC-HETW a.k.a "W" genotype) parental strains. These two mitochondrial genomes differ at 94 nucleotides, more akin to human mitochondrial genome diversity than that available in classical laboratory mouse strains. Body weights of the B and W genotypes were similar. However, mitochondrial genotype antagonistically affected grip strength and treadmill endurance in females only. In addition, mitochondrial genotype significantly affected multiple responses to a high-fat diet (HFD) and treatment with 17α-estradiol. Contrary to findings in mice in which males only are affected by 17α-estradiol supplementation, female rats fed a HFD beneficially responded to 17α-estradiol treatment as evidenced by declines in body mass, adiposity, and liver mass. Male rats, by contrast, differed in a mitochondrial genotype-specific manner, with only B males responding to 17α-estradiol treatment. Mitochondrial genotype and sex differences were also observed in features of brain-specific antioxidant response to a HFD and 17α-estradiol as shown by hippocampal levels of Sod2 acetylation, JNK, and FoxO3a. These results emphasize the importance of mitochondrial genotype in assessing responses to putative interventions in aging processes.

Mitonuclear Interactions and the Origin of Macaque Societies.

In most eukaryotes, aerobic respiration requires interactions between autosomally encoded genes (Ninteract genes) and mitochondrial DNA, RNA, and protein. In species where females are philopatric, contrasting distributions of genetic variation in mitochondrial and nuclear genomes create variation in mitonuclear interactions that may be subject to natural selection. To test this expectation, we turned to a group with extreme female philopatry: the macaque monkeys. We examined four genomic data sets from (1) wild caught and (2) captive populations of rhesus macaque, which is the most widely distributed nonhuman primate, and (3) the stump-tailed macaque and (4) a subspecies of longtail macaque, both of whose mitochondrial DNA is introgressed from a highly diverged ancestor. We identified atypically long runs of homozygosity, low polymorphism, high differentiation, and/or rapid protein evolution associated with Ninteract genes compared with non-Ninteract genes. These metrics suggest a subset of Ninteract genes were independently subject to atypically pervasive natural selection in multiple species. These findings suggest that natural selection on mitonuclear interactions could have influenced several aspects of macaque societies including species diversity, ecological breadth, female-biased adult sex ratio and demography, sexual dimorphism, and mitonuclear phylogenomics.

Long-read sequencing characterizes mitochondrial and plastid genome variants in Arabidopsis msh1 mutants.

The abundant repeats in plant mitochondrial genomes can cause rapid genome rearrangements and are also a major obstacle in short-read sequencing studies. Nuclear-encoded proteins such as MSH1 are known to suppress the generation of repeat-associated mitochondrial genome variants, but our understanding of these mechanisms has been constrained by the limitations of short-read technologies. Here, we used highly accurate long-read sequencing (PacBio HiFi) to characterize mitochondrial and plastid genome variants in Arabidopsis thaliana msh1 mutant individuals. The HiFi reads provided a global view of recombination dynamics with detailed quantification of parental and crossover recombination products for both large and small repeats. We found that recombination breakpoints were distributed relatively evenly across the length of repeated sequences and detected widespread internal exchanges of sequence variants between pairs of imperfect repeats in the mitochondrial genome of msh1 mutants. Long-read assemblies of mitochondrial genomes from seven other A. thaliana wild-type accessions differed by repeat-mediated structural rearrangements similar to those observed in msh1 mutants, but they were all in a simple low-heteroplasmy state. The Arabidopsis plastid genome generally lacks small repeats and exhibited a very different pattern of variant accumulation in msh1 mutants compared with the mitochondrial genome. Our data illustrate the power of HiFi technology in studying repeat-mediated recombination in plant organellar genomes and improved the sequence resolution for recombinational processes suppressed by MSH1. Plant organellar genomes can undergo rapid rearrangements. Long-read sequencing provides a detailed and quantitative view of mitochondrial and plastid genome variants normally suppressed by MSH1, advancing our understanding of plant organellar genome dynamics.

Mitochondrial Genome Variants as a Cause of Mitochondrial Cardiomyopathy.

Mitochondria are small double-membraned organelles responsible for the generation of energy used in the body in the form of ATP. Mitochondria are unique in that they contain their own circular mitochondrial genome termed mtDNA. mtDNA codes for 37 genes, and together with the nuclear genome (nDNA), dictate mitochondrial structure and function. Not surprisingly, pathogenic variants in the mtDNA or nDNA can result in mitochondrial disease. Mitochondrial disease primarily impacts tissues with high energy demands, including the heart. Mitochondrial cardiomyopathy is characterized by the abnormal structure or function of the myocardium secondary to genetic defects in either the nDNA or mtDNA. Mitochondrial cardiomyopathy can be isolated or part of a syndromic mitochondrial disease. Common manifestations of mitochondrial cardiomyopathy are a phenocopy of hypertrophic cardiomyopathy, dilated cardiomyopathy, and cardiac conduction defects. The underlying pathophysiology of mitochondrial cardiomyopathy is complex and likely involves multiple abnormal processes in the cell, stemming from deficient oxidative phosphorylation and ATP depletion. Possible pathophysiology includes the activation of alternative metabolic pathways, the accumulation of reactive oxygen species, dysfunctional mitochondrial dynamics, abnormal calcium homeostasis, and mitochondrial iron overload. Here, we highlight the clinical assessment of mtDNA-related mitochondrial cardiomyopathy and offer a novel hypothesis of a possible integrated, multivariable pathophysiology of disease.

Implications of mitochondrial DNA variants in pediatric B-cell acute lymphoblastic leukemia

BackgroundResearch on the role of variations in the mitochondrial genome in pathogenesis of acute lymphoblastic leukemia (ALL) has been unfolding at a rapid rate. Our laboratory has previously described higher number of copies of the mitochondrial genomes per cell in pediatric ALL patients as compared to the healthy controls. In the current study, we evaluated the pattern of mitochondrial genome variations in 20 de-novo pediatric B-ALL cases and seven controls. Quantitative real-time Polymerase Chain Reaction was used for estimation of mitochondrial genomes’ copy number in bone marrow samples of each ALL patient and peripheral blood samples of controls. The complete mitochondrial genomes of all samples were sequenced using the Illumina platform.ResultsSequencing data analysis using multiple mitochondrial genome databases revealed 325 variants in all 27 samples, out of which 221 variants were previously known while 104 were unassigned, new variants. The 325 variants consisted of 7 loss-of-function variants, 131 synonymous variants, 75 missense variants, and 112 non-coding variants. New, missense variants (n = 21) were identified in genes encoding the electron transport chain complexes with most of them encoding ND4, ND5 of complex I. Missense and loss-of-function variants were found to be deleterious by many predictor databases of pathogenicity. MuTect2 identified true somatic variants present only in tumors between patient-sibling pairs and showed overlap with missense and loss-of-function variants. Online MtDNA-server showed heteroplasmic and homoplasmic variants in mitochondrial genome.ConclusionsThe data suggest that some of these variations might have a deleterious impact on the expression of mitochondrial encoded genes with a possible functional relevance in leukemia.

Mitochondrial genomic variation in dementia with Lewy bodies: association with disease risk and neuropathological measures

Dementia with Lewy bodies (DLB) is clinically diagnosed when patients develop dementia less than a year after parkinsonism onset. Age is the primary risk factor for DLB and mitochondrial health influences ageing through effective oxidative phosphorylation (OXPHOS). Patterns of stable polymorphisms in the mitochondrial genome (mtDNA) alter OXPHOS efficiency and define individuals to specific mtDNA haplogroups. This study investigates if mtDNA haplogroup background affects clinical DLB risk and neuropathological disease severity. 360 clinical DLB cases, 446 neuropathologically confirmed Lewy body disease (LBD) cases with a high likelihood of having DLB (LBD-hDLB), and 910 neurologically normal controls had European mtDNA haplogroups defined using Agena Biosciences MassARRAY iPlex technology. 39 unique mtDNA variants were genotyped and mtDNA haplogroups were assigned to mitochondrial phylogeny. Striatal dopaminergic degeneration, neuronal loss, and Lewy body counts were also assessed in different brain regions in LBD-hDLB cases. Logistic regression models adjusted for age and sex were used to assess associations between mtDNA haplogroups and risk of DLB or LBD-hDLB versus controls in a case-control analysis. Additional appropriate regression models, adjusted for age at death and sex, assessed associations of haplogroups with each different neuropathological outcome measure. No mtDNA haplogroups were significantly associated with DLB or LBD-hDLB risk after Bonferroni correction.Haplogroup H suggests a nominally significant reduced risk of DLB (OR=0.61, P=0.006) but no association of LBD-hDLB (OR=0.87, P=0.34). The haplogroup H observation in DLB was consistent after additionally adjusting for the number of APOE ε4 alleles (OR=0.59, P=0.004). Haplogroup H also showed a suggestive association with reduced ventrolateral substantia nigra neuronal loss (OR=0.44, P=0.033). Mitochondrial haplogroup H may be protective against DLB risk and neuronal loss in substantia nigra regions in LBD-hDLB cases but further validation is warranted.

Variation in mitochondrial DNA affects locomotor activity and sleep in Drosophila melanogaster

Mitochondria are organelles that produce cellular energy in the form of ATP through oxidative phosphorylation, and this primary function is conserved among many taxa. Locomotion is a trait that is highly reliant on metabolic function and expected to be greatly affected by disruptions to mitochondrial performance. To this end, we aimed to examine how activity and sleep vary between Drosophila melanogaster strains with different geographic origins, how these patterns are affected by mitochondrial DNA (mtDNA) variation, and how breaking up co-evolved mito-nuclear gene combinations affect the studied activity traits. Our results demonstrate that Drosophila strains from different locations differ in sleep and activity, and that females are generally more active than males. By comparing activity and sleep of mtDNA variants introgressed onto a common nuclear background in cytoplasmic hybrid (cybrid) strains, we were able to quantify the among-line variance attributable to mitochondrial DNA, and we establish that mtDNA variation affects both activity and sleep, in a sex-specific manner. Altogether our study highlights the important role that mitochondrial genome variation plays on organismal physiology and behaviour.

Mitochondrial genome variations, mitochondrial-nuclear compatibility, and their association with metabolic diseases.

Two genomes regulate the energy metabolism of eukaryotic cells: the nuclear genome, which codes for most cellular proteins, and the mitochondrial genome, which, together with the nuclear genome, coregulates cellular bioenergetics. Therefore, mitochondrial genome variations can affect, directly or indirectly, all energy-dependent cellular processes and shape the metabolic state of the organism. This review provides a current and up-to-date overview on how codependent these two genomes are, how they appear to have coevolved, and how variations within the mitochondrial genome might be associated with the manifestation of metabolic diseases. This review summarizes and structures results obtained from epidemiological studies that identified links between mitochondrial haplogroups and individual risks for developing obesity and diabetes. This is complemented by findings on the compatibility of mitochondrial and nuclear genomes and cellular bioenergetic fitness, which have been acquired from well-controlled studies in conplastic animal models. These elucidate, more mechanistically, how single-nucleotide variants can influence cellular metabolism and physiology. Overall, it seems that certain mitochondrial genome variations negatively affect mitochondrial-nuclear compatibility and are statistically linked with the onset of metabolic diseases, whereas, for others, greater uncertainty exists, and additional research into this exciting field is required.

Potential Use of Multiple Sclerosis-Associated Mitochondrial Genome Variants to Predict the Development of Multiple Sclerosis

Potential Use of Multiple Sclerosis-Associated Mitochondrial Genome Variants to Predict the Development of Multiple Sclerosis

Refinements and considerations for trio whole-genome sequence analysis when investigating Mendelian diseases presenting in early childhood

SummaryTo facilitate early deployment of whole-genome sequencing (WGS) for severely ill children, a standardized pipeline for WGS analysis with timely turnaround and primary care pediatric uptake is needed. We developed a bioinformatics pipeline for comprehensive gene-agnostic trio WGS analysis of children suspected of having an undiagnosed monogenic disease that included detection and interpretation of primary genetic mechanisms of disease, including SNVs/indels, CNVs/SVs, uniparental disomy (UPD), imprinted genes, short tandem repeat expansions, mobile element insertions, SMN1/2 copy number calling, and mitochondrial genome variants. We assessed primary care practitioner experience and competence in a large cohort of 521 families (comprising 90% WGS trios). Children were identified by primary practitioners for recruitment, and we used the UK index of multiple deprivation to confirm lack of patient socio-economic status ascertainment bias. Of the 521 children sequenced, 176 (34%) received molecular diagnoses, with rates as high as 45% for neurology clinics. Twenty-three of the diagnosed cases (13%) required bespoke methods beyond routine SNV/CNV analysis. In our multidisciplinary clinician user experience assessment, both pediatricians and clinical geneticists expressed strong support for rapid WGS early in the care pathway, but requested further training in determining patient selection, consenting, and variant interpretation. Rapid trio WGS provides an efficacious single-pass screening test for children when deployed by primary practitioners in clinical settings that carry high a priori risk for rare pediatric disease presentations.

Examining the Association between Mitochondrial Genome Variation and Coronary Artery Disease.

Large-scale genome-wide association studies have identified hundreds of single-nucleotide variants (SNVs) significantly associated with coronary artery disease (CAD). However, collectively, these explain <20% of the heritability. Hypothesis: Here, we hypothesize that mitochondrial (MT)-SNVs might present one potential source of this “missing heritability”. Methods: We analyzed 265 MT-SNVs in ~500,000 UK Biobank individuals, exploring two different CAD definitions: a more stringent (myocardial infarction and/or revascularization; HARD = 20,405), and a more inclusive (angina and chronic ischemic heart disease; SOFT = 34,782). Results: In HARD cases, the most significant (p < 0.05) associations were for m.295C>T (control region) and m.12612A>G (ND5), found more frequently in cases (OR = 1.05), potentially related to reduced cardiorespiratory fitness in response to exercise, as well as for m.12372G>A (ND5) and m.11467A>G (ND4), present more frequently in controls (OR = 0.97), previously associated with lower ROS production rate. In SOFT cases, four MT-SNVs survived multiple testing corrections (at FDR < 5%), all potentially conferring increased CAD risk. Of those, m.11251A>G (ND4) and m.15452C>A (CYB) have previously shown significant associations with body height. In line with this, we observed that CAD cases were slightly less physically active, and their average body height was ~2.00 cm lower compared to controls; both traits are known to be related to increased CAD risk. Gene-based tests identified CO2 associated with HARD/SOFT CAD, whereas ND3 and CYB associated with SOFT cases (p < 0.05), dysfunction of which has been related to MT oxidative stress, obesity/T2D (CO2), BMI (ND3), and angina/exercise intolerance (CYB). Finally, we observed that macro-haplogroup I was significantly (p < 0.05) more frequent in HARD cases vs. controls (3.35% vs. 3.08%), potentially associated with response to exercise. Conclusions: We found only spurious associations between MT genome variation and HARD/SOFT CAD and conclude that more MT-SNV data in even larger study cohorts may be needed to conclusively determine the role of MT DNA in CAD.

Complete mitochondrial genome of Conuslischkeanus Weinkauff, 1875 (Neogastropoda, Conidae) and phylogenetic implications of the evolutionary diversification of dietary types of Conus species.

The family Conidae, commonly known as cone snails, is one of the most intriguing gastropod groups owing to their diverse array of feeding behaviors (diets) and toxin peptides (conotoxins). Conuslischkeanus Weinkauff, 1875 is a worm-hunting species widely distributed from Africa to the Northwest Pacific. In this study, we report the mitochondrial genome sequence of C.lischkeanus and inferred its phylogenetic relationship with other Conus species. Its mitochondrial genome is a circular DNA molecule (16,120 bp in size) composed of 37 genes: 13 protein-coding genes (PCGs), 22 transfer RNA genes, and two ribosomal RNA genes. Phylogenetic analyses of concatenated nucleotide sequences of 13 PCGs and two ribosomal RNA genes showed that C.lischkeanus belongs to the subgenus Lividoconus group, which is grouped with species of the subgenus Virgiconus, and a member of the largest assemblage of worm-hunting (vermivorous) species at the most basal position in this group. Mitochondrial genome phylogeny supports the previous hypothesis that the ancestral diet of cone snails was worm-hunting, and that other dietary types (molluscivous or piscivorous) have secondarily evolved multiple times from different origins. This new, complete mitochondrial genome information provides valuable insights into the mitochondrial genome diversity and molecular phylogeny of Conus species.

EP337: Rapid Genome Sequencing (rGS) as first tier test for critically ill children with suspected genetic etiology

Clinicians are constantly faced with the challenging dilemma to choose the best diagnostic tools when diagnostic yield and turnaround time (TAT) are both very important for clinical management of critically ill children with a suspected genetic etiology. Compared to various genetic tests genome sequencing with rapid processing and analysis can provide the most comprehensive “all in one” solution by interrogating not only small nucleotide variations (SNV), but also copy number variations (CNV), short tandem repeats (STR), and mitochondrial genome variations (mtDNA).

Conflicting nuclear and mitogenome phylogenies reveal ancient mitochondrial replacement between two North American species of collared lemmings (Dicrostonyx groenlandicus, D. hudsonius)

Collared lemmings (Dicrostonyx) are cold adapted rodents, keystone animals in the tundra communities and the model taxa in studies of Arctic genetic diversity and Quaternary paleontology. We examined mitochondrial and nuclear genomic variation to reconstruct phylogenetic relationships among the Eurasian D. torquatus and North American D. groenlandicus, D. hudsonius and evaluate biogeographic hypothesis of the two colonization events of North America from Eurasia based on morphological variation in dental traits. The nuclear and mitogenome phylogenies support reciprocal monophyly of each species but reveal conflicting relationships among species. The mitogenome tree likely reflects ancient mitochondrial replacement between currently isolated D. groenlandicus and D. hudsonius. The nuclear genome phylogeny reveals species cladogenesis and supports the hypothesis that D. hudsonius with primitive and distinct molar morphology represents a relic of the first migration event from Eurasia to North America. Species widely distributed in the North American Arctic, D. groenlandicus, with advanced dental morphology originated from a later colonization event across the Bering Land Bridge. This study shows ancient mitochondrial capture between two Arctic species and emphasizes the importance of multilocus approaches for phylogenetic inference.

Nucleotide-based genetic networks: Methods and applications

Genomic variations have been acclaimed as among the key players in understanding the biological mechanisms behind migration, evolution, and adaptation to extreme conditions. Due to stochastic evolutionary forces, the frequency of polymorphisms is affected by changes in the frequency of nearby polymorphisms in the same DNA sample, making them connected in terms of evolution. This article presents all the ingredients to understand the cumulative effects and complex behaviors of genetic variations in the human mitochondrial genome by analyzing co-occurrence networks of nucleotides, and shows key results obtained from such analyses. The article emphasizes recent investigations of these co-occurrence networks, describing the role of interactions between nucleotides in fundamental processes of human migration and viral evolution. The corresponding co-mutation-based genetic networks revealed genetic signatures of human adaptation in extreme environments. This article provides the methods of constructing such networks in detail, along with their graph-theoretical properties, and applications of the genomic networks in understanding the role of nucleotide co-evolution in evolution of the whole genome.