20 years of human mtDNA pathologic point mutations: Carefully reading the pathogenicity criteria

Despite the strong purifying selection that occurs during embryonic development, the particular location and features of mitochondrial DNA make it especially susceptible to accumulating point mutations, giving rise to a large number of mitochondrial DNA variants. Many of these will have moderate or no phenotypic effects but others will be the cause of very dramatic diseases, usually known as mitochondriopathies. Because of the abundance of different mitochondrial DNA variants, it is not easy to determine whether a new mutation is pathogenic. To facilitate this task, different criteria have been proposed, but they are often either too severely or too loosely applied. Citing examples from the literature, in this paper we discuss some critical aspects of these criteria.     

A possible role for mitochondrial dysfunction in migraine

Migraine is a common neurological disorder characterised by debilitating head pain and an assortment of additional symptoms which can include nausea, emesis, photophobia, phonophobia and occasionally visual sensory disturbances. Migraine is a complex disease caused by an interplay between predisposing genetic variants and environmental factors. It affects approximately 12?% of studied Caucasian populations with affected individuals being predominantly female. Genes involved in neurological, vascular or hormonal pathways have all been implicated in predisposition towards developing migraine. All of these are nuclear encoded genes, but given the role of mitochondria in a number of neurological disorders and in energy production it is possible that mitochondrial variants may play a role in the pathogenesis of this disease. Mitochondrial DNA has been a useful tool for studying population genetics and human genetic diseases due to the clear inheritance shown through successive generations. Given the clear gender bias found in migraine patients it may be important to investigate X-linked inheritance and mitochondrial-related variants in this disorder. This paper explores the possibility that mitochondrial DNA changes may play a role in migraine. Few variants in the mitochondrial genome have so far been investigated in migraine and new studies should be aimed towards investigating the role of mitochondrial DNA in this common disorder.     

Regular bottlenecks and restrictions to somatic fusion prevent the accumulation of mitochondrial defects in Neurospora

The replication and segregation of multi-copy mitochondrial DNA (mtDNA) are not under strict control of the nuclear DNA. Within-cell selection may thus favour variants with an intracellular selective advantage but a detrimental effect on cell fitness. High relatedness among the mtDNA variants of an individual is predicted to disfavour such deleterious selfish genetic elements, but experimental evidence for this hypothesis is scarce. We studied the effect of mtDNA relatedness on the opportunities for suppressive mtDNA variants in the fungus Neurospora carrying the mitochondrial mutator plasmid pKALILO. During growth, this plasmid integrates into the mitochondrial genome, generating suppressive mtDNA variants. These mtDNA variants gradually replace the wild-type mtDNA, ultimately culminating in growth arrest and death. We show that regular sequestration of mtDNA variation is required for effective selection against suppressive mtDNA variants. First, bottlenecks in the number of mtDNA copies from which a ‘Kalilo’ culture started significantly increased the maximum lifespan and variation in lifespan among cultures. Second, restrictions to somatic fusion among fungal individuals, either by using anastomosis-deficient mutants or by generating allotype diversity, prevented the accumulation of suppressive mtDNA variants. We discuss the implications of these results for the somatic accumulation of mitochondrial defects during ageing.     

MitoScape: A big-data,machine-learning platform for obtaining mitochondrial DNA from next-generation sequencing data

The growing number of next-generation sequencing (NGS) data presents a unique opportunity to study the combined impact of mitochondrial and nuclear-encoded genetic variation in complex disease. Mitochondrial DNA variants and in particular, heteroplasmic variants, are critical for determining human disease severity. While there are approaches for obtaining mitochondrial DNA variants from NGS data, these software do not account for the unique characteristics of mitochondrial genetics and can be inaccurate even for homoplasmic variants. We introduce MitoScape, a novel, big-data, software for extracting mitochondrial DNA sequences from NGS. MitoScape adopts a novel departure from other algorithms by using machine learning to model the unique characteristics of mitochondrial genetics. We also employ a novel approach of using rho-zero (mitochondrial DNA-depleted) data to model nuclear-encoded mitochondrial sequences. We showed that MitoScape produces accurate heteroplasmy estimates using gold-standard mitochondrial DNA data. We provide a comprehensive comparison of the most common tools for obtaining mtDNA variants from NGS and showed that MitoScape had superior performance to compared tools in every statistically category we compared, including false positives and false negatives. By applying MitoScape to common disease examples, we illustrate how MitoScape facilitates important heteroplasmy-disease association discoveries by expanding upon a reported association between hypertrophic cardiomyopathy and mitochondrial haplogroup T in men (adjusted p-value = 0.003). The improved accuracy of mitochondrial DNA variants produced by MitoScape will be instrumental in diagnosing disease in the context of personalized medicine and clinical diagnostics.     

The linkage disequilibrium between chloroplast DNA and mitochondrial DNA haplotypes in Beta vulgaris ssp. maritima (L.): the usefulness of both genomes for population genetic studies

The structure and evolution of the plant mitochondrial genome may allow recurrent appearance of the same mitochondrial variants in different populations. Whether the same mitochondrial variant is distributed by migration or appears recurrently by mutation (creating homoplasy) in different populations is an important question with regard to the use of these markers for population genetic analyses. The genetic association observed between chloroplasts and mitochondria (i.e. two maternally inherited cytoplasmic genomes) may indicate whether or not homoplasy occurs in the mitochondrial genome. Four-hundred and fourteen individuals sampled in wild populations of beets from France and Spain were screened for their mitochondrial and chloroplast polymorphisms. Mitochondrial DNA (mtDNA) polymorphism was investigated with restriction fragment length polymorphism (RFLP) and chloroplast DNA (cpDNA) polymorphism was investigated with polymerase chain reaction PCR-RFLP, using universal primers for the amplification. Twenty and 13 variants for mtDNA and cpDNA were observed, respectively. Most exhibited a widespread geographical distribution. As a very strong linkage disequilibrium was estimated between mtDNA and cpDNA haplotypes, a high rate of recurrent mutation was excluded for the mitochondrial genome of beets. Identical mitochondrial variants found in populations of different regions probably occurred as a result of migration. We concluded from this study that mtDNA is a tool as valuable as cpDNA when a maternal marker is needed for population genetics analyses in beet on a large regional scale.     

Genetic polymorphism of enzymes of alcohol metabolism and susceptibility to alcoholic liver disease

Differences in the pharmacokinetics of alcohol absorption and elimination are, in part, genetically determined. There are polymorphic variants of the two main enzymes responsible for ethanol oxidation in liver, alcohol dehydrogenase and aldehyde dehydrogenase. The frequency of occurrence of these variants, which have been shown to display strikingly different catalytic properties, differs among different racial populations. Since the activity of alcohol dehydrogenase in liver is a rate-limiting factor for ethanol metabolism in experimental animals, it is likely that the type and content of the polymorphic isoenzyme subunit encoded at ADH2, beta-subunit, and at ADH3, the gamma-subunit, are contributing factors to the genetic variability in ethanol elimination rate. The recent development of methods for genotyping individuals at these loci using white cell DNA will allow us to test this hypothesis as well as any relationship between ADH genotype and the susceptibility to alcoholism or alcohol-related pathology. A polymorphic variant of human liver mitochondrial aldehyde dehydrogenase, ADLH2, which has little or no acetaldehyde oxidizing activity has been identified. Individuals with the deficient ALDH2 phenotype do not have altered ethanol elimination rates but they do exhibit high blood acetaldehyde levels and dysphoric symptoms such as facial flushing, nausea and tachycardia, after drinking alcohol. Because acetaldehyde is so reactive, it binds to free amino groups of proteins including a 37 kilodalton hepatic protein-acetaldehyde adduct and may elicit an antibody response. We would predict that individuals who have low ALDH2 activity because of liver disease or because they have the inactive ALDH2 variant isoenzyme might form more protein-acetaldehyde adducts and elicit a greater immune response. These adducts may represent good biological markers of alcohol abuse and may also play a role in liver injury due to chronic alcohol consumption.     

Mitochondrial diabetes in children: seek and you will find it

Maternally Inherited Diabetes and Deafness (MIDD) is a rare form of diabetes due to defects in mitochondrial DNA (mtDNA). 3243 A>G is the mutation most frequently associated with this condition, but other mtDNA variants have been linked with a diabetic phenotype suggestive of MIDD. From 1989 to 2009, we clinically diagnosed mitochondrial diabetes in 11 diabetic children. Diagnosis was based on the presence of one or more of the following criteria: 1) maculopathy; 2) hearing impairment; 3) maternal heritability of diabetes/impaired fasting glucose and/or hearing impairment and/or maculopathy in three consecutive generations (or in two generations if 2 or 3 members of a family were affected). We sequenced the mtDNA in the 11 probands, in their mothers and in 80 controls. We identified 33 diabetes-suspected mutations, 1/33 was 3243A>G. Most patients (91%) and their mothers had mutations in complex I and/or IV of the respiratory chain. We measured the activity of these two enzymes and found that they were less active in mutated patients and their mothers than in the healthy control pool. The prevalence of hearing loss (36% vs 75-98%) and macular dystrophy (54% vs 86%) was lower in our mitochondrial diabetic adolescents than reported in adults. Moreover, we found a hitherto unknown association between mitochondrial diabetes and celiac disease. In conclusion, mitochondrial diabetes should be considered a complex syndrome with several phenotypic variants. Moreover, deafness is not an essential component of the disease in children. The whole mtDNA should be screened because the 3243A>G variant is not as frequent in children as in adults. In fact, 91% of our patients were mutated in the complex I and/or IV genes. The enzymatic assay may be a useful tool with which to confirm the pathogenic significance of detected variants.     

Recent Mitochondrial DNA Mutations Increase the Risk of Developing Common Late-Onset Human Diseases

Mitochondrial DNA (mtDNA) is highly polymorphic at the population level, and specific mtDNA variants affect mitochondrial function. With emerging evidence that mitochondrial mechanisms are central to common human diseases, it is plausible that mtDNA variants contribute to the “missing heritability” of several complex traits. Given the central role of mtDNA genes in oxidative phosphorylation, the same genetic variants would be expected to alter the risk of developing several different disorders, but this has not been shown to date. Here we studied 38,638 individuals with 11 major diseases, and 17,483 healthy controls. Imputing missing variants from 7,729 complete mitochondrial genomes, we captured 40.41% of European mtDNA variation. We show that mtDNA variants modifying the risk of developing one disease also modify the risk of developing other diseases, thus providing independent replication of a disease association in different case and control cohorts. High-risk alleles were more common than protective alleles, indicating that mtDNA is not at equilibrium in the human population, and that recent mutations interact with nuclear loci to modify the risk of developing multiple common diseases.     

Variation in mitochondrial genotype has substantial lifespan effects which may be modulated by nuclear background

Mitochondria are thought to play a central role in aging. In humans, specific naturally occurring mitochondrial genetic variants are overrepresented among centenarians, but only in certain populations; therefore, we cannot tell whether this effect is due solely to mitochondrial genetics or to nuclear-mitochondrial gene complexes, nor do we know the magnitude of the effect in terms we can relate to, such as mean lifespan differences. To examine the effects of natural mitochondrial DNA (mtDNA) variation on lifespan, we need to vary the mitochondrial genotype while controlling the nuclear genotype. Here, nuclear genome replacement is achieved using strains of Drosophila melanogaster bearing multiply inverted 'balancer' chromosomes that suppress recombination, and an isogenic donor strain, thus forcing replacement of entire chromosomes in a single cross while suppressing recombination. Lifespans of wild-type mtDNA variants on the chromosome replacement background vary substantially, and sequencing of the entire protein coding mitochondrial genomes indicates that these lifespan differences are sometimes associated with single amino acid differences. On other nuclear genetic backgrounds, the magnitude and direction of these lifespan effects can change dramatically, and this can be due to changes in baseline mortality risk, rate of aging and/or time of onset of aging. The limited mtDNA variation in D. melanogaster makes it an ideal organism for biochemical studies to link genotype and aging phenotype.     

Induction of the cytoplasmic 'petite' mutation by chemical and physical agents in Saccharomyces cerevisiae.

A range of physical and chemical agents induce the mitochondrial 'petite' mutation in the yeast Saccharomyces cerevisiae. DNA intercalating agents as well as chemicals which can interfere with DNA synthesis induce this mutation, but only in growing cells. Many chemical or physical agents that produce a DNA lesion which is not simply reversed can induce various levels of the petite mutation, and may be more effective in non-growing cells. A limited number of chemicals act like ethidium bromide, inducing a high frequency of petites which is partially reversible with increasing concentration or time. The ability of a specific compound to be transported into mitochondria or its affinity for AT base pairs in DNA may determine whether it acts primarily as a nuclear or mitochondrial mutagen. In mammalian cells, some neoplastic changes occur at the mitochondrial level. Analogies between yeast and mammalian mitochondria suggest that agents which increase petite mutagenesis in yeast may have some carcinogenic potential. Although some types of petite inducer may have potential as antitumour drugs, those which are very effective antimitochondrial agents appear to be too toxic for therapeutic use. A process comparable to early stages in petite mutagensis occurs in human degenerative diseases and it seems possible that a consequence of exposure to petite mutagens could be an increase in the rate of degenerative diseases or of the aging process.     

Differential Nuclear and Mitochondrial DNA Preservation in Post-Mortem Teeth with Implications for Forensic and Ancient DNA Studies

Major advances in genetic analysis of skeletal remains have been made over the last decade, primarily due to improvements in post-DNA-extraction techniques. Despite this, a key challenge for DNA analysis of skeletal remains is the limited yield of DNA recovered from these poorly preserved samples. Enhanced DNA recovery by improved sampling and extraction techniques would allow further advancements. However, little is known about the post-mortem kinetics of DNA degradation and whether the rate of degradation varies between nuclear and mitochondrial DNA or across different skeletal tissues. This knowledge, along with information regarding ante-mortem DNA distribution within skeletal elements, would inform sampling protocols facilitating development of improved extraction processes. Here we present a combined genetic and histological examination of DNA content and rates of DNA degradation in the different tooth tissues of 150 human molars over short-medium post-mortem intervals. DNA was extracted from coronal dentine, root dentine, cementum and pulp of 114 teeth via a silica column method and the remaining 36 teeth were examined histologically. Real time quantification assays based on two nuclear DNA fragments (67 bp and 156 bp) and one mitochondrial DNA fragment (77 bp) showed nuclear and mitochondrial DNA degraded exponentially, but at different rates, depending on post-mortem interval and soil temperature. In contrast to previous studies, we identified differential survival of nuclear and mtDNA in different tooth tissues. Futhermore histological examination showed pulp and dentine were rapidly affected by loss of structural integrity, and pulp was completely destroyed in a relatively short time period. Conversely, cementum showed little structural change over the same time period. Finally, we confirm that targeted sampling of cementum from teeth buried for up to 16 months can provide a reliable source of nuclear DNA for STR-based genotyping using standard extraction methods, without the need for specialised equipment or large-volume demineralisation steps.     

Mitochondrial DNA sequences of human schistosomes: the current status

Sequences generated from the mitochondrial genome provide useful molecular markers for defining population groups, for tracing the genetic history of an individual or a particular group of related individuals, and for constructing deep-branch taxonomic phylogenies. There is every reason to believe that the mitochondrial genome will be as valuable in studies on flatworms, such as the human schistosomes, as it has been for other taxa. To date, however, our knowledge of mitochondrial genomes of flatworms remains limited, and this review summarises the currently available information. In particular, details of the recent sequence obtained for cloned Schistosoma mansoni mitochondrial DNA fragments spanning over half of the mitochondrial genome of this species are emphasised. This and other information, available as a result of the Schistosome Genome Project, provide the basis for obtaining the complete mitochondrial DNA sequence and gene order of S. mansoni and the other human schistosomes. The availability of complete mitochondrial DNA sequences from the different species will facilitate much more in-depth study of genetic diversity and host specificity in schistosomes and the interrelationships between the various forms infecting humans and between these and other flatworms.     

Complete mitochondrial genome sequencing reveals novel haplotypes in a Polynesian population

The high risk of metabolic disease traits in Polynesians may be partly explained by elevated prevalence of genetic variants involved in energy metabolism. The genetics of Polynesian populations has been shaped by island hoping migration events which have possibly favoured thrifty genes. The aim of this study was to sequence the mitochondrial genome in a group of Maoris in an effort to characterise genome variation in this Polynesian population for use in future disease association studies. We sequenced the complete mitochondrial genomes of 20 non-admixed Maori subjects using Affymetrix technology. DNA diversity analyses showed the Maori group exhibited reduced mitochondrial genome diversity compared to other worldwide populations, which is consistent with historical bottleneck and founder effects. Global phylogenetic analysis positioned these Maori subjects specifically within mitochondrial haplogroup--B4a1a1. Interestingly, we identified several novel variants that collectively form new and unique Maori motifs--B4a1a1c, B4a1a1a3 and B4a1a1a5. Compared to ancestral populations we observed an increased frequency of non-synonymous coding variants of several mitochondrial genes in the Maori group, which may be a result of positive selection and/or genetic drift effects. In conclusion, this study reports the first complete mitochondrial genome sequence data for a Maori population. Overall, these new data reveal novel mitochondrial genome signatures in this Polynesian population and enhance the phylogenetic picture of maternal ancestry in Oceania. The increased frequency of several mitochondrial coding variants makes them good candidates for future studies aimed at assessment of metabolic disease risk in Polynesian populations.     

Transkinetoplastidy—A Novel Phenomenon Involving Bulk Alterations of Mitochondrion-Kinetoplast DNA of a Trypanosomatid Protozoan1,2

ABSTRACT. Dramatic and consistent changes of mitochondrial or kinetoplast DNA (kDNA) were observed in certain variants of Leishmania amazonensis (A variants) selected in vitro for arsenite-resistance. This was found initially by comparing different lots of wild-type cells and their respective A variants resistant to 30 μM arsenite. The kDNAs isolated from these two groups had different restriction patterns and hybridized poorly to each other, whereas those from different lots within each of the two groups were identical. Hybridization data showed an overall identity of less than 10^?3 between total kDNAs of the two groups. This difference was further examined in three independent series of variants, which were selected from three different clones for resistance to graded concentrations of arsenite (5–30 μM). In all three series, their kDNAs were found to change abruptly in an identical pattern at a late step of the selection process, i.e. A variants resistant to 15 μM or 30 μM arsenite. There was no apparent loss of kDNA in the process. Most of the changes observed appear to involve a shift in either the dominance or the copy number of different minicircle subclasses. Surprisingly, the kDNAs of tunicamycin-resistant variants (T variants) were also found to undergo similar changes. Genetic changes previously described in both A and T variants are limited to their nuclei. Namely, different chromosomal regions are amplified to produce large DNA circles which are responsible for the drug-resistant phenotypes. Interestingly, other arsenite-resistant clones without such chromosomal DNA amplification (A'variants) had kDNA of the wild-type pattern. The profound changes of kDNA observed are unprecedented. We propose the term “transkinetoplastidy” for this phenomenon to distinguish it from dyskinetoplastidy or the loss of kDNA described previously in trypanosomatid protozoa. This phenomenon is discussed with respect to the possible mechanisms of its generation, regulation and relation to the drug-resistant phenotypes.     

Molecular characterization of relatedness among colour variants of Asian Arowana (Scleropages formosus)

Morphological identification of fish taxa can sometimes prove difficult because phenotypic variation is either being affected by environmental factors, phenotypic characters are highly conserved or marker selection has been inappropriate. DNA based markers especially neutral mitochondrial DNA (mtDNA) have been used widely in recent times to provide better resolution of systematic relationships among vertebrate taxa. The Asian Arowana (Scleropages formosus) is a high value ornamental fish belonging to the family Osteoglossidae with a number of different colour variants distributed geographically across different locations around Southeast Asia. Systematic relationships among colour variants still remain unresolved. Partial sequences of the Cytochrome B (Cyt B) and DNA barcoding gene, Cytochrome C Oxidase I (COI) were used here to assess genetic relationships among colour variants and as a tool for molecular identification for differentiating among colour variants in this species. Results of the study show that in general, colour pattern shows no relationship with extent of COI or Cyt B mtDNA differentiation and so cannot be used to identify taxa. Partial sequences of the mtDNA genes were sufficient however, to identify S. formosus from a closely related species within the order Osteoglossidae.     

Persistence Criteria for Susceptibility Genes for Schizophrenia: a Discussion from an Evolutionary Viewpoint

Background

The central paradox of schizophrenia genetics is that susceptibility genes are preserved in the human gene-pool against a strong negative selection pressure. Substantial evidence of epidemiology suggests that nuclear susceptibility genes, if present, should be sustained by mutation-selection balance without heterozygote advantage. Therefore, putative nuclear susceptibility genes for schizophrenia should meet special conditions for the persistence of the disease as well as the condition of bearing a positive association with the disease.

Methodology/Principal Findings

We deduced two criteria that every nuclear susceptibility gene for schizophrenia should fulfill for the persistence of the disease under general assumptions of the multifactorial threshold model. The first criterion demands an upper limit of the case-control difference of the allele frequencies, which is determined by the mutation rate at the locus, and the prevalence and the selection coefficient of the disease. The second criterion demands an upper limit of odds ratio for a given allele frequency in the unaffected population. When we examined the top 30 genes at SZGene and the recently reported common variants on chromosome 6p with the criteria using the epidemiological data in a large-sampled Finnish cohort study, it was suggested that most of these are unlikely to confer susceptibility to schizophrenia. The criteria predict that the common disease/common variant hypothesis is unlikely to fit schizophrenia and that nuclear susceptibility genes of moderate effects for schizophrenia, if present, are limited to ‘rare variants’, ‘very common variants’, or variants with exceptionally high mutation rates.

Conclusions/Significance

If we assume the nuclear DNA model for schizophrenia, it should have many susceptibility genes of exceptionally high mutation rates; alternatively, it should have many disease-associated resistance genes of standard mutation rates on different chromosomes. On the other hand, the epidemiological data show that pathogenic genes, if located in the mitochondrial DNA, could persist through sex-related mechanisms.     

Were inefficient mitochondrial haplogroups selected during migrations of modern humans? A test using modular kinetic analysis of coupling in mitochondria from cybrid cell lines

We introduce a general test of the bioenergetic importance of mtDNA (mitochondrial DNA) variants: modular kinetic analysis of oxidative phosphorylation in mitochondria from cybrid cells with constant nuclear DNA but different mtDNA. We have applied this test to the hypothesis [Ruiz-Pesini, Mishmar, Brandon, Procaccio and Wallace (2004) Science 303, 223-226] that particular mtDNA haplogroups (specific combinations of polymorphisms) that cause lowered coupling efficiency, leading to generation of less ATP and more heat, were positively selected during radiations of modern humans into colder climates. Contrary to the predictions of this hypothesis, mitochondria from Arctic haplogroups had similar or even greater coupling efficiency than mitochondria from tropical haplogroups.     

Gimap3 regulates tissue-specific mitochondrial DNA segregation

Mitochondrial DNA (mtDNA) sequence variants segregate in mutation and tissue-specific manners, but the mechanisms remain unknown. The segregation pattern of pathogenic mtDNA mutations is a major determinant of the onset and severity of disease. Using a heteroplasmic mouse model, we demonstrate that Gimap3, an outer mitochondrial membrane GTPase, is a critical regulator of this process in leukocytes. Gimap3 is important for T cell development and survival, suggesting that leukocyte survival may be a key factor in the genetic regulation of mtDNA sequence variants and in modulating human mitochondrial diseases.     

New insights into molecular evolution: prospects from the Barcode of Life Initiative (BOLI)

Geographic and temporal patterns of morphological and behavioral diversifications among species stimulated Darwin to propose a mechanism for evolutionary change through natural selection. Scientific developments have revealed an even more fundamental level of biological complexity: sequence variation in DNA. While genome projects yield spectacular insights into molecular evolution, they have targeted only a few species. In contrast, the Barcode of Life Initiative (BOLI) proposes a horizontal approach to genomics, examining short, standardized genome segments across the sweep of eukaryotic life, all 10 million species. BOLI will extend our understanding of evolution and speciation in varied ways. It will facilitate quantification of biological diversity by disclosing cryptic species and enabling a rapid survey of taxon diversity in groups that have hitherto received scant morphological examination. It will facilitate assignment of life history stages to known species and provide a first estimate of species ages. It will also reveal key features of the mitochondrial genome, because the evolutionary properties of barcodes relate to those in the mitochondrial genome as a whole, acting to flag taxonomic groups or species with unusual nucleotide composition or evolutionary rates. The growing volume of barcode records has revealed that sequence variability within species is generally much lower than divergence among species (barcoding gap), a pattern that occurs in diverse lineages, suggesting a pervasive evolutionary process. Low variability may reflect recurrent selective sweeps of favored mitochondrial variants propagating as single linkage units across species. If this hypothesis is substantiated, the implications are significant, particularly for our understanding of molecular evolution of mitochondrial DNA and its relationship with species delineation.     

A reassessment of explanations for discordant introgressions of mitochondrial and nuclear genomes

Hybridization is increasingly recognized as a significant evolutionary process, in particular because it can lead to introgression of genes from one species to another. A striking pattern of discordance in the amount of introgression between mitochondrial and nuclear markers exists such that substantial mitochondrial introgression is often found in combination with no or little nuclear introgression. Multiple mechanisms have been proposed to explain this discordance, including positive selection for introgressing mitochondrial variants, several types of sex‐biases, drift, negative selection against introgression in the nuclear genome, and spatial expansion. Most of these hypotheses are verbal, and have not been quantitatively evaluated so far. We use individual‐based, multilocus, computer simulations of secondary contact under a wide range of demographic and genetic scenarios to evaluate the ability of the different mechanisms to produce discordant introgression. Sex‐biases and spatial expansions fail to produce substantial mito‐nuclear discordance. Drift and nuclear selection can produce strong discordance, but only under a limited range of conditions. In contrast, selection on the mitochondrial genome produces strong discordance, particularly when dispersal rates are low. However, commonly used statistical tests have little power to detect this selection. Altogether, these results dismiss several popular hypotheses, and provide support for adaptive mitochondrial introgression.