Selective sweeps of mitochondrial DNA can drive the evolution of uniparental inheritance

Although the uniparental (or maternal) inheritance of mitochondrial DNA (mtDNA) is widespread, the reasons for its evolution remain unclear. Two main hypotheses have been proposed: selection against individuals containing different mtDNAs (heteroplasmy) and selection against “selfish” mtDNA mutations. Recently, uniparental inheritance was shown to promote adaptive evolution in mtDNA, potentially providing a third hypothesis for its evolution. Here, we explore this hypothesis theoretically and ask if the accumulation of beneficial mutations provides a sufficient fitness advantage for uniparental inheritance to invade a population in which mtDNA is inherited biparentally. In a deterministic model, uniparental inheritance increases in frequency but cannot replace biparental inheritance if only a single beneficial mtDNA mutation sweeps through the population. When we allow successive selective sweeps of mtDNA, however, uniparental inheritance can replace biparental inheritance. Using a stochastic model, we show that a combination of selection and drift facilitates the fixation of uniparental inheritance (compared to a neutral trait) when there is only a single selective mtDNA sweep. When we consider multiple mtDNA sweeps in a stochastic model, uniparental inheritance becomes even more likely to replace biparental inheritance. Our findings thus suggest that selective sweeps of beneficial mtDNA haplotypes can drive the evolution of uniparental inheritance.     

The Effects of Natural Hybridization on the Regulation of Doubly Uniparental Mtdna Inheritance in Blue Mussels (Mytilus Spp.)

Blue mussels in the Mytilus edulis species complex have a doubly uniparental mode of mtDNA inheritance with separate maternal and paternal mtDNA lineages. Female mussels inherit their mtDNA solely from their mother, while males inherit mtDNA from both parents. In the male gonad the paternal mtDNA is preferentially replicated so that only paternal mtDNA is transmitted from fathers to sons. Hybridization is common among differentiated blue mussel taxa; whenever it involves M. trossulus, doubly uniparental mtDNA inheritance is disrupted. We have found high frequencies of males without and females with paternal mtDNA among hybrid mussels produced by interspecific matings between M. galloprovincialis and M. trossulus. In contrast, hybridization between M. galloprovincialis and M. edulis does not affect doubly uniparental inheritance, indicating a difference in the divergence of the mechanisms regulating mtDNA inheritance among the three blue mussel taxa. Our data indicate a high frequency of disrupted mtDNA transmission in F(1) hybrids and suggest that two separate mechanisms, one regulating the transmission of paternal mtDNA to males and another inhibiting the establishment of paternal mtDNA in females, act to regulate doubly uniparental inheritance. We propose a model for the regulation of doubly uniparental inheritance that is consistent with these observations.     

Paternal inheritance of mitochondria in Chlamydomonas

To analyze mitochondrial DNA (mtDNA) inheritance, differences in mtDNA between Chlamydomonas reinhardtii and Chlamydomonas smithii, respiration deficiency and antibiotic resistance were used to distinguish mtDNA origins. The analyses indicated paternal inheritance. However, these experiments raised questions regarding whether paternal inheritance occurred normally. Mitochondrial nucleoids were observed in living zygotes from mating until 3 days after mating and then until progeny formation. However, selective disappearance of nucleoids was not observed. Subsequently, experimental serial backcrosses between the two strains demonstrated strict paternal inheritance. The fate of mt+ and mt− mtDNA was followed using the differences in mtDNA between the two strains. The slow elimination of mt+ mtDNA through zygote maturation in darkness was observed, and later the disappearance of mt+ mtDNA was observed at the beginning of meiosis. To explain the different fates of mtDNA, methylation status was investigated; however, no methylation was detected. Variously constructed diploid cells showed biparental inheritance. Thus, when the mating process occurs normally, paternal inheritance occurs. Mutations disrupting mtDNA inheritance have not yet been isolated. Mutations that disrupt maternal inheritance of chloroplast DNA (cpDNA) do not disrupt inheritance of mtDNA. The genes responsible for mtDNA inheritance are different from those of chloroplasts.     

Sequence and functional analyses of mtDNA in a maternally inherited family with bipolar disorder and depression

Recent studies suggest that mutations/polymorphisms of mitochondrial DNA (mtDNA) are associated with neuropsychiatric diseases. We identified a patient with major depression and epilepsy. Some family members in the pedigree of the proband had bipolar disorder, depression, suicide, or psychotic disorder not otherwise specified. The mode of inheritance was compatible with maternal inheritance with low penetration. We assumed that the mental disorder in this family might be associated with maternally inherited mitochondrial DNA (mtDNA) mutation. We sequenced the entire mtDNA of the proband. Among the 34 base substitutions detected in the proband, two homoplasmic, nonsynonymous single substitutions of mtDNA, T3394C in MT-ND1 and A9115G in MT-ATP6, were suspected to cause functional impairment, because the former was reported to be disease-related and the latter is vary rare. To study the functional outcome of these substitutions, we examined mitochondrial membrane potential and the activity of mitochondrial ATP synthesis in the transmitochondrial cybrids, but no significant impairment was detected. The data did not support our hypothesis that these disorders in this family are caused by mtDNA mutation(s).     

The organization and inheritance of the mitochondrial genome

Mitochondrial DNA (mtDNA) encodes essential components of the cellular energy-producing apparatus, and lesions in mtDNA and mitochondrial dysfunction contribute to numerous human diseases. Understanding mtDNA organization and inheritance is therefore an important goal. Recent studies have revealed that mitochondria use diverse metabolic enzymes to organize and protect mtDNA, drive the segregation of the organellar genome, and couple the inheritance of mtDNA with cellular metabolism. In addition, components of a membrane-associated mtDNA segregation apparatus that might link mtDNA transmission to mitochondrial movements are beginning to be identified. These findings provide new insights into the mechanisms of mtDNA maintenance and inheritance.     

A novel mitochondrial DNA missense mutation at G3421A in a family with maternally inherited diabetes and deafness

OBJECTIVE: Mutations in mtDNA are thought to be responsible for the pathogenesis of maternally inherited diabetes. Here, we report a family with maternally inherited diabetes and deafness whose members did not harbour the mtDNA A3243G mutation, the most frequent point mutation in mitochondrial diabetic patients. This study aimed to investigate a possible other mtDNA mutation and its prevalence in type 2 diabetic patients. METHODS: Height, body weight, waistline, and hip circumference were measured and serum biochemical marks determined in all members of the family. In addition, a 75 g oral glucose tolerance test and electric listening test were conducted in these members. Genomic DNA was prepared from peripheral leukocytes. Direct sequencing of PCR products was used to detect the mtDNA mutation in this family. The prevalence of mtDNA G3421A nucleotide substitutions was investigated by restriction fragment length polymorphism analysis in 1350 unrelated type 2 diabetic patients recruited by random cluster sampling from the central city area of Shanghai, China. RESULTS: (1) A new missense homoplasmic mutation of mtDNA G3421A was found in a maternally inherited diabetic family and existed neither in 1350 unrelated type 2 diabetic patients nor in 50 non-diabetic individuals. (2) The mode of mutation and diabetes transmission was typical maternal inheritance in this family. (3) All diabetic family members were found to have an onset at 35-42 years of age, accompanied by deafness of varying degrees. CONCLUSION: mtDNA G3421A (Val39Ile) found in a family with maternally inherited diabetes and deafness is a novel missense mutation. Whether this is a diabetogenic mutation and its effect on mitochondrial function needs to be further studied.     

Revealing the hidden complexities of mtDNA inheritance

Mitochondrial DNA (mtDNA) is a pivotal tool in molecular ecology, evolutionary and population genetics. The power of mtDNA analyses derives from a relatively high mutation rate and the apparent simplicity of mitochondrial inheritance (maternal, without recombination), which has simplified modelling population history compared to the analysis of nuclear DNA. However, in biology things are seldom simple, and advances in DNA sequencing and polymorphism detection technology have documented a growing list of exceptions to the central tenets of mitochondrial inheritance, with paternal leakage, heteroplasmy and recombination now all documented in multiple systems. The presence of paternal leakage, recombination and heteroplasmy can have substantial impact on analyses based on mtDNA, affecting phylogenetic and population genetic analyses, estimates of the coalescent and the myriad of other parameters that are dependent on such estimates. Here, we review our understanding of mtDNA inheritance, discuss how recent findings mean that established ideas may need to be re‐evaluated, and we assess the implications of these new‐found complications for molecular ecologists who have relied for decades on the assumption of a simpler mode of inheritance. We show how it is possible to account for recombination and heteroplasmy in evolutionary and population analyses, but that accurate estimates of the frequencies of biparental inheritance and recombination are needed. We also suggest how nonclonal inheritance of mtDNA could be exploited, to increase the ways in which mtDNA can be used in analyses.     

Paternal inheritance of mitochondrial DNA in the sheep (Ovine aries)

Paternal inheritance of mitochondria DNA in sheep was discovered by examination of 152 sheep from 38 hybrid families for mtDNA D-loop polymorphisms using PCR-RFLP, amplification of repeated sequence somain, and PCR-SSCP of the D-loop 5' end region of a 253 bp fragment. Our findings have provided the first evidence of paternal inheritance of mtDNA in sheep and possible mechanisms of paternal inheritance were discussed.     

A patient with type 2 diabetes mellitus associated with mutations in calcium sensing receptor gene and mitochondrial DNA

A 44-year-old female with familial hypocalciuric hypercalcemia (FHH) due to a homozygous missense mutation (Pro40Ala) in calcium sensing receptor (CaSR) gene has type 2 diabetes mellitus. The identical heterozygous mutation of CaSR gene was observed in consanguineous parents and all other family members examined except her two sisters. Many subjects with abnormal glucose tolerance were observed in this family, which is compatible with maternal inheritance. Mitochondrial function of complex I (NADH-coenzyme Q reductase) activity in cybrid cells between mitochondrial DNA (mtDNA)-deleted (rho(0)) HeLa cells and mtDNA from the proband was decreased by 35%. The proband has eight substitutions and among these 4833 A/G is a missense substitution in NADH dehydrogenase 2 gene and may probably be a major pathogenic mutation of impaired complex I activity. These results suggest that coexistence of nuclear gene and mtDNA mutations may have caused or modified the development of abnormal glucose tolerance in this family.     

The a2 Mating-Type Locus Genes lga2 and rga2 Direct Uniparental Mitochondrial DNA (mtDNA) Inheritance and Constrain mtDNA Recombination During Sexual Development of Ustilago maydis

Uniparental inheritance of mitochondria dominates among sexual eukaryotes. However, little is known about the mechanisms and genetic determinants. We have investigated the role of the plant pathogen Ustilago maydis genes lga2 and rga2 in uniparental mitochondrial DNA (mtDNA) inheritance during sexual development. The lga2 and rga2 genes are specific to the a2 mating-type locus and encode small mitochondrial proteins. On the basis of identified sequence polymorphisms due to variable intron numbers in mitochondrial genotypes, we could demonstrate that lga2 and rga2 decisively influence mtDNA inheritance in matings between a1 and a2 strains. Deletion of lga2 favored biparental inheritance and generation of recombinant mtDNA molecules in combinations in which inheritance of mtDNA of the a2 partner dominated. Conversely, deletion of rga2 resulted in predominant loss of a2-specific mtDNA and favored inheritance of the a1 mtDNA. Furthermore, expression of rga2 in the a1 partner protected the associated mtDNA from elimination. Our results indicate that Lga2 in conjunction with Rga2 directs uniparental mtDNA inheritance by mediating loss of the a1-associated mtDNA. This study shows for the first time an interplay of mitochondrial proteins in regulating uniparental mtDNA inheritance.     

Paternal inheritance of mitochondrial DNA in the sheep (Ovine aries)

Paternal inheritance of mitochondria DNA in sheep was discovered by examination of 152 sheep from 38 hybrid families for mtDNA D-loop polymorphisms using PCR-RFLP, amplification of repeated sequence somain, and PCR-SSCP of the D-loop 5′ end region of a 253 bp fragment. Our findings have provided the first evidence of paternal inheritance of mtDNA in sheep and possible mechanisms of paternal inheritance were discussed.     

Paternal inheritance of mitochondrial DNA in the sheep ( Ovine aries )

Paternal inheritance of mitochondria DNA in sheep was discovered by examination of 152 sheep from 38 hybrid families for mtDNA D-loop polymorphisms using PCR-RFLP, amplification of repeated sequence somain, and PCR-SSCP of the D-loop 5′ end region of a 253 bp fragment. Our findings have provided the first evidence of paternal inheritance of mtDNA in sheep and possible mechanisms of paternal inheritance were discussed.     

动物线粒体DNA重组的研究进展

动物线粒体DNA作为遗传标记广泛用于从种内到高级阶元的许多生物学领域,这些应用是建立在线粒体DNA的严格母系遗传方式和不发生重组的基础上的。近年来的研究提出了一些能够证明动物mtDNA发生重组的直接和间接证据。动物mtDNA重组可能主要通过两条途径发生,一条途径是母系mtDNA与核基因组中mtDNA假基因间发生重组;另一条途径是通过父系渗漏引起的不同单倍型的双亲mtDNA间发生重组。父系渗漏是最可能的途径。如果动物界广泛存在线粒体DNA重组,将会对以mtDNA严格母系遗传为基础的许多应用领域产生重要影响。     

Familial mitochondrial encephalomyopathy (MERRF): genetic, pathophysiological, and biochemical characterization of a mitochondrial DNA disease

A large MERRF pedigree permitted the direct testing of the predictions for a mitochondrial DNA (mtDNA) mutation. A mtDNA mutation was demonstrated by proving maternal inheritance and by identifying specific deficiencies in muscle energetics and mitochondrial respiratory complexes I and IV. mtDNA heteroplasmy (a mixture of mutant and wild-type mtDNAs) was demonstrated by showing variation in the mitochondrial energetic capacity between family members. The phenotypic consequences of differential tissue-specific reliance on mitochondrial ATP was shown by correlating individual respiratory deficiency with the nature and severity of patients' clinical manifestations. The observed spectrum of clinical manifestations resulting from this heteroplasmic mtDNA mutation implies that mtDNA disease may be much more prevalent than previously anticipated.     

Biparental mitochondrial DNA inheritance in the parasitic trematode Schistosoma mansoni

The maternal inheritance of mitochondrial DNA (mtDNA) in eukaryotic organisms occurs because of the selective destruction of paternal mtDNA molecules that may be present in the zygote. The elimination of sperm mtDNA is less efficient in interspecific crosses, and biparental inheritance of mtDNA has been observed in a variety of species. Because interspecific crosses are likely to be extremely rare in nature, parental inheritance of mtDNA has been deemed of little relevance to population genetics. The mtDNA of the parasitic trematode Schistosoma mansoni was examined for its utility in addressing epidemiological questions related to the transmission and spread of schistosomiasis. Prior to embarking on such experiments, we sought to confirm the mode of inheritance of this molecule using the highly polymorphic mtDNA minisatellite as a marker. In 3 separate crosses, mtDNA apparently identical to paternal DNA was observed in some individuals of the F2 and F3 generations. These observations thus suggest the intraspecific paternal inheritance of mtDNA across multiple generations in Schistosoma mansoni.     

Inheritance of organelle DNA in rye (Secale cereale L.) and wheat (x Triticale Thch.) hybrids

The mode of inheritance of chloroplast and mitochondrial DNA (mtDNA) in rye x triticale intergeneric hybrids has been studied with the use of specific PCR markers for loci 18S/5S and 3'rbcL in organelle DNA. In rye x triticale BC1, mtDNA copies of two types, paternal and maternal, have been found; in BC2 plants, only paternal mtDNA and chloroplast DNA (cpDNA) have been detected. Mechanisms determining the inheritance and/or differential amplification of organelles of a specific type are discussed.     

Evidence for multi-copy Mega-NUMTs in the human genome

The maternal mode of mitochondrial DNA (mtDNA) inheritance is central to human genetics. Recently, evidence for bi-parental inheritance of mtDNA was claimed for individuals of three pedigrees that suffered mitochondrial disorders. We sequenced mtDNA using both direct Sanger and Massively Parallel Sequencing in several tissues of eleven maternally related and other affiliated healthy individuals of a family pedigree and observed mixed mitotypes in eight individuals. Cells without nuclear DNA, i.e. thrombocytes and hair shafts, only showed the mitotype of haplogroup (hg) V. Skin biopsies were prepared to generate ρ° cells void of mtDNA, sequencing of which resulted in a hg U4c1 mitotype. The position of the Mega-NUMT sequence was determined by fluorescence in situ hybridization and two different quantitative PCR assays were used to determine the number of contributing mtDNA copies. Thus, evidence for the presence of repetitive, full mitogenome Mega-NUMTs matching haplogroup U4c1 in various tissues of eight maternally related individuals was provided. Multi-copy Mega-NUMTs mimic mixtures of mtDNA that cannot be experimentally avoided and thus may appear in diverse fields of mtDNA research and diagnostics. We demonstrate that hair shaft mtDNA sequencing provides a simple but reliable approach to exclude NUMTs as source of misleading results.     

Further studies on types A and B rat mtDNAs: cleavage maps and evidence for cytoplasmic inheritance in mammals.

We present here the cleavage maps of A and B rat mtDNA, examining particularly the legitimacy of two small recently reported EcoRI fragments. We find that the 0.13-kb fragment belongs in the map whereas the 0.09-kb fragment is of nonmitochondrial origin. A comparison of the types A and B maps shows that no major rearrangements have occurred since the time of the evolutionary segregation of the two DNAs. These data plus fragment patterns from other restriction enzyme digests, including those from additional enzymes which display differences between the two DNA types, provide no evidence for microheterogeneity in either of the mtDNA types, and also permit an estimate of 0.94 to 1.80% for the extent of sequence divergence of the two types. Nine enzymes yielded fragments all of which could be accurately sized leading to a reasonably accurate estimate of 15.85 kb for the size of rat liver mtDNA of either type. In a test of whether cytoplasmic inheritance is operative in mammals, reciprocal cross experiments with the two DNAs showed that only the female parental mtDNA was inherited with no evidence for the persistence of the male parental mtDNA in any of three tissues examined.