Exclusive Maternal Inheritance Research Articles

Autosomal recessive Leber hereditary optic neuropathy, a new neuro-ophthalmo-genetic paradigm.

Leber Hereditary Optic Neuropathy (LHON) is a primary inherited neurodegenerative disorder of the optic nerve. It has been ascribed to variants in the mitochondrial genome, mainly the m.3460G > A, m.11778G > A and m.14484T > C mutations in ND1, ND4 and ND6 respectively. Nonetheless, inconclusive molecular diagnosis is not uncommon. Recently, biallelic mutations in the NDUFS2, DNAJC30, MCAT and NDUFA12 nuclear genes have been identified in unresolved LHON cases, identifying an autosomal recessive LHON (arLHON, OMIM:619382). The clinical presentation of arLHON copies that of typical mtLHON, with an acute phase of sudden and severe vision loss, telangiectatic and tortuous vessels around the optic nerve, and swelling of the retinal nerve fiber layer (RNFL). This is followed by a chronic phase of RNFL loss, but eventually, affected individuals recovered partial or full visual acuity. Idebenone treatment significantly improved vision recovery in DNAJC30-associated patients. As mtLHON, arLHON predominantly affected male as compared to female carriers. The discovery of arLHON cases breaks with the dogma of exclusive maternal inheritance. It defines a new neuro-ophthalmo-genetic paradigm which should be considered in individuals manifesting a LHON phenotype, but inconclusive molecular diagnosis. NDUFS2, DNAJC30, MCAT and NDUFA12 should be investigated in these individuals, knowing that other arLHON genes might exist.

Induction of meiotic gynogenesis in yellow drum (Nibea albiflora, Sciaenidae) using heterologous sperm and evidence for female homogametic sex determination

The yellow drum (Nibea albiflora) is one of the most important species for commercial fisheries and a promising candidate for aquaculture in China. This fish exhibits significant sexually dimorphic growth and the efficiency and profitability of its aquaculture could be maximized by all-female production. Consequently, we developed an effective protocol to induce meiotic gynogenesis using heterologous sperm and defined the sex determination system in yellow drum. Spermatozoa from the rock bream (Oplegnathus fasciatus) were used, and the optimal UV-irradiation dose for genetically inactivating the spermatozoa was determined to be 45mJ/cm2. Cold-shock temperature, duration and time of initiation were optimized, and the best yield of gynogens was obtained with a cold-shock at 4°C for a period of 8min, initiated 2min after fertilization. The DNA ploidy test by flow cytometry showed that the gynogenetic larvae were diploids. The analysis of microsatellite loci revealed an exclusive maternal inheritance in all the gynogens tested, further confirming the success of the diploid gynogenesis using the protocol that we established. All the juvenile gynogens examined by histology were female, supporting the assumption of female homogametic sex determination in the yellow drum. In conclusion, we have developed an effective and reliable method to induce meiotic gynogenesis of yellow drum. Our approach could be potentially applied to produce monosex yellow drum on a large scale to meet the demands of the aquaculture industry.

Constitutional delay of puberty: presentation and inheritance pattern in 48 familial cases.

BackgroundThe mechanism that initiates the onset of puberty is largely unknown but the age of onset is mainly under genetic control and influenced by environmental factors including nutrition. Familial forms of constitutional delay of puberty (CDP) suggest the involvement of genetic factors. The purpose of this study is to describe the presentation and the mode of inheritance of CDP in a series of familial cases.MethodsA retrospective, single center study was carried out over 10 years on 48 probands (14 girls and 34 boys) from 48 families seen for CDP with a familial component.ResultsOf the 48 probands, 46 (96 %) had at least one affected 1st degree relatives and 2 (4 %, 2 boys) had only 2nd degree relatives affected.In girls, 11 families (79 %) exhibited exclusive maternal inheritance, 1 (7 %) paternal inheritance and 2 (14 %) both maternal and paternal inheritance. In boys, 14 families (41 %) exhibited exclusive maternal inheritance, 12 (35 %) paternal inheritance and 8 (24 %) both maternal and paternal inheritance.In the boys with bilineal inheritance, the ages at onset of puberty (16 ± 1.41 years) and at evaluation (16.05 ± 2.47 years) were higher than in those with unilineal inheritance (15.25 ± 0.35 and 15.1 ± 0.42 years respectively), but the difference was not significant.ConclusionsIn girls exclusive maternal inheritance seems to be the major mode of inheritance whereas for boys the mode of inheritance was almost equally maternal, paternal or bilineal. Clinical phenotype of boys with bilineal inheritance seems to be more severe, but the difference did not reach statistical significance, perhaps because of the small sample size. This greater severity of the phenotype in boys with bilineal inheritance is likely due to inheriting different puberty timing genes from each parent. Future research should be directed at identifying such genes.

Development of Microsatellite Markers for Miiuy Croaker, Miichthys miiuy (Sciaenidae), and Their Application in Verifying Gynogenesis of Large Yellow Croaker, Pseudosciaena crocea , Induced with M. miiuy Sperm

A total of 30 microsatellite markers were isolated from miiuy croaker, Miichthys miiuy, and characterized. Of these, 24 were polymorphic with an average of 4.33 alleles per locus (range: 2–8). The observed (Ho) and expected (He) heterozygosities ranged from 0.0667 to 1.0000 (mean: 0.6361) and 0.3828 to 0.8139 (mean: 0.6443), respectively. The mean polymorphism information content (PIC) value was 0.576, ranging from 0.348 to 0.823. Eight loci deviated significantly from the Hardy–Weinberg equilibrium (HWE). Twelve of the 30 primer pairs amplified DNA sequences of large yellow croaker, Pseudosciaena crocea, and 10 were polymorphic. Except for MM007, sequence alignments of microsatellite flanking regions of the other 11 loci were highly similar between the two species. The gynogenetic P. crocea induced by the sperm of M. miiuy were verified using four cross-amplified primer pairs. No specific paternal bands were found in the offspring, indicating exclusive maternal inheritance.

No recombination of mtDNA after heteroplasmy for 50 generations in the mouse maternal germline

Variants of mitochondrial DNA (mtDNA) are commonly used as markers to track human evolution because of the high sequence divergence and exclusive maternal inheritance. It is assumed that the inheritance is clonal, i.e. that mtDNA is transmitted between generations without germline recombination. In contrast to this assumption, a number of studies have reported the presence of recombinant mtDNA molecules in cell lines and animal tissues, including humans. If germline recombination of mtDNA is frequent, it would strongly impact phylogenetic and population studies by altering estimates of coalescent time and branch lengths in phylogenetic trees. Unfortunately, this whole area is controversial and the experimental approaches have been widely criticized as they often depend on polymerase chain reaction (PCR) amplification of mtDNA and/or involve studies of transformed cell lines. In this study, we used an in vivo mouse model that has had germline heteroplasmy for a defined set of mtDNA mutations for more than 50 generations. To assess recombination, we adapted and validated a method based on cloning of single mtDNA molecules in the λ phage, without prior PCR amplification, followed by subsequent mutation analysis. We screened 2922 mtDNA molecules and found no germline recombination after transmission of mtDNA under genetically and evolutionary relevant conditions in mammals.

Molecular phylogeny of Pakistani riverine buffalo based on genetic variability of mitochondrial cytochrome b gene

Mitochondrial cytochrome b gene is considered to be one of the best markers for breed characterization as well as studying the ancestry in the vertebrates due to its exclusive maternal inheritance. DNA fingerprinting by single nucleotide polymorphism is most reliable and widely used molecular technique in modern forensics and is being considered in this study. Partial sequencing of 1,061 bp of aforementioned gene from 14580 to 15643 was conducted in two famous Pakistani buffalo breeds named Nili-Ravi and Kundi. In which we explore seven haplotypes within earlier and none in the latter breed. Nili-Ravi is polymorphic at four codons of this gene, and the protein translation is also different from the reference sample while monomorphic at three codons with no amino acid replacement. Haplotypes frequency distribution of these four haplotypes named NR3, NR4, NR5, NR7 revealed that the prevalence of each haplotype is 0.04 % in the Pakistani buffalo population of this Nili-Ravi breed while complete homoplasmy was observed in the Kundi breed population. Nili-Ravi breed of buffalo is genetically more variable than the Kundi breed as far as the gene in subject is concerned. It means later breed has spent more time to propagate its wild type haplotype which make this breed more ancestral as compare to Nili-Ravi. Secondly both breeds share their common ancestors with regional water buffalo rather than the swamp one.

Induction of meiotic gynogenesis in paddlefish (Polyodon spathula) and its confirmation using microsatellite markers

A protocol for gynogenesis of P. spathula was developed in order to produce inbred lines and to develop a technique to preserve the endangered Chinese paddlefish (Psephurus gladius). Diploid gynogenesis was induced in P. spathula using ultraviolet (UV)-irradiated Amur sturgeon (Acipenser schrenckii) sperm for 4.5-min, 5-min or 5.5-min and subsequent heat shock treatment. UV irradiation of sperm for 5 min at a UV intensity (254 nm) of 863 μw cm−2 was the optimum dose to achieve diploid gynogenesis on the basis of observations on hatching rate of eggs. Three microsatellite loci were used to monitor exclusive maternal inheritance of gynogenetic progenies. The results showed all maternal genome among offspring with no paternal genome. The cytogenetic analysis showed that meiotic gynogenetic diploids possessed 120 chromosomes in metaphase plates, while haploid control groups N1–3 possessed 60 chromosomes.

Gynogenesis and sex determination in large-scale loach Paramisgurnus dabryanus (Sauvage)

Gynogenesis was induced using heterologous sperms in large-scale loach, Paramisgurnus dabryanus (Sauvage), in which a ZW/ZZ sex determination was previously proposed. Three microsatellite loci were used to monitor exclusive maternal inheritance of gynogenetic progenies. The results showed that high percentages of meiogynogens were produced at 4 min post-fertilization and mitogynogens were produced at 18 min post-fertilization by heat shocks, while meiotic gynogenesis was induced by cold shocks within a wide period and high heterozygosity was even observed in gynogens produced at 24 min post-fertilization. The sex ratios of the F1 progenies in three gynogenetic families were significantly deviated from 1:1 expectation with a female bias in two families and a male bias in one family (P < 0.05), and the other four gynogenetic families showed approximate 1:1 sex ratios. Moreover, the self-mating between gynogenetic F1 progenies and mating between gynogenetic F1 progenies and normal individuals produced all-female progenies or identical proportions of females and males. The data of sex ratios generally confirmed that the sex determination in large-scale loach was determined by the putative ZW/ZZ system, and the possible reasons causing the biased sex ratios are discussed.

Growth and gonadal development of gynogenetic diploid Scophthalmus maximus

The survival, growth, gonadal development and sex ratios of gynogenetic diploid turbot Scophthalmus maximus between 9 and 36 months of age were investigated. Gynogenesis was induced by activation of freshly collected eggs with diluted (1 : 10 with Ringer) and UV‐irradiated (30000 erg mm−2) sperm, followed by a cold shock at −1 to 0° C for 25 min, starting at 6·5 min after fertilization. The exclusive maternal inheritance of the resulting gynogenetic diploids was confirmed in all individuals used in the experiment by microsatellite markers. Mean total length and mass throughout the experiment was higher in the controls than in the gynogenetics. The gonadal development in gynogenetic males proceeded normally, and in gynogenetic females it was delayed during the first sexual maturation but was normal during the second one. The sex ratio was 1 male (M) : 1 female (F) in the controls, as expected, but 1 M : 3 F in the gynogenetics. In a second, independent experiment, carried out with fish originating from different broodstock, however, the sex ratio was 1 M : 1 F in the controls and 0 M : 1 F (i.e. 100% females) in the gynogenetics. Together, these results suggested that the main sex‐determining genetic component in turbot fits well to female homogamety, in accordance with data from other flatfishes. These results indicate that it will be possible to obtain near or all‐female turbot stocks through induced gynogenesis or by crosses involving hormonally sex‐reversed fish.

WOLBACHIA INTERACTIONS THAT DETERMINE DROSOPHILA MELANOGASTER SURVIVAL

We have recently described a mutualistic symbiosis in which Wolbachia bacteria were shown to improve the fitness of some Drosophila melanogaster stocks. Wolbachia did not extend longevity in all Drosophila genotypes, even though 16s rDNA sequences indicated that our Drosophila stocks were infected with the same Wolbachia strain. Here, we use reciprocal hybrid crosses between two Drosophila strains, one that lived longer with Wolbachia (Z53) and one that did not (Z2), to investigate the inheritance of the survival phenotype and its dependence on the host genotype, sex, and mating conditions. Wolbachia's positive effects were more apparent in hybrid flies than in parental flies, ruling out exclusive maternal inheritance or the dependence of the survival phenotype on Wolbachia strain differences. The Wolbachia survival effects were more apparent in single-sex cages, where courtship and mating were not permitted. In these cages, nearly all flies with Wolbachia lived longer than uninfected flies, even though strain Z2 showed no Wolbachia effect in mixed-sex mating cages. We used comparisons between single- and mixed-sex cages to estimate the cost of reproduction for both sexes. Our data suggest that Wolbachia infection may increase the inferred cost of reproduction, particularly in males. Wolbachia can even produce a positive survival effect almost as large as the negative survival effect associated with reproduction. We discuss the implications of our experiments for the study of insect symbioses.

As deficiências auditivas relacionadas às alterações do DNA mitocondrial.

A deficiência auditiva é sintoma comum que pode apresentar várias etiologias, entre elas as causadas por alterações genéticas. As mutações genéticas podem ocorrer em genes nucleares e mitocondriais. A mitocôndria, uma organela intracelular, tem o seu próprio genoma (DNA), que é uma molécula circular e é transmitido exclusivamente pela mãe. As mutações do DNA mitocondrial são transmitidas pela linhagem materna, mas podem ocorrer mutações espontâneas. O fenótipo, ou expressão clínica, da mutação mitocondrial vai depender da quantidade de DNA mitocondrial mutante existente na célula, situação conhecida como heteroplasmia. A mitocôndria tem a função de disponibilizar energia para as células sob a forma de ATP (trifosfato de adenosina). Os órgãos que requerem grande quantidade de energia são mais comumente acometidos em casos de mutações do DNA mitocondrial, como células nervosas, musculares, endócrinas, ópticas e auditivas. Como a cóclea é grande consumidora de energia, uma mutação no DNA mitocondrial de células ciliadas causa deficiência auditiva do tipo neurossensorial, bilateral, simétrica e progressiva. As deficiências auditivas causadas por mutações no DNA mitocondrial correspondem a 0,5% a 1% de todas as deficiências auditivas de origem genética. Foi realizada uma extensa revisão bibliográfica, a fim de estudar as deficiências auditivas causadas por alterações no DNA mitocondrial. A deficiência auditiva pode se apresentar na forma isolada (forma não sindrômica), como nos casos de hiper-sensibilidade aos antibióticos aminoglicosídeos e presbiacusia, ou associada a outras doenças (forma sindrômica), como na síndrome de Kearns-Sayre e diabete e surdez de herança materna.

Evaluation of Parental Mitochondrial Inheritance in Neonates Born after Intracytoplasmic Sperm Injection

Intracytoplasmic sperm injection (ICSI) is now used when severe male-factor infertility has been documented. Since defective mitochondrial functions may result in male hypofertility, it is of prime importance to evaluate the risk of paternal transmission of an mtDNA defect to neonates. DNA samples from the blood of 21 infertile couples and their 27 neonates born after ICSI were studied. The highly polymorphic mtDNA D-loop region was analyzed by four PCR-based approaches. With denaturing gradient gel electrophoresis (DGGE), which allows 2% of a minor mtDNA species to be detected, the 27 newborns had a DGGE pattern identical to that of their mother but different from that of their father. Heteroplasmy documented in several parents and children supported an exclusive maternal inheritance of mtDNA. The parental origin of the children's mtDNA molecules also was studied by more-sensitive assays: restriction-endonuclease analysis (REA) of alpha[32P]-radiolabeled PCR products; paternal-specific PCR assay; and depletion of maternal mtDNA, followed by REA. We did not detect paternal mtDNA in nine neonates, with a sensitivity level of 0.01% in five children, 0.1% in two children, and 1% in two children. The estimated ratio of sperm-to-oocyte mtDNA molecules in humans is 0.1%-1.5%. Thus, we conclude that, in these families, the ICSI procedure performed with mature spermatozoa did not alter the uniparental pattern of inheritance of mtDNA.

No Evidence for Significant Linkage between Bipolar Affective Disorder and Chromosome 18 Pericentromeric Markers in a Large Series of Multiplex Extended Pedigrees

Bipolar affective disorder (BP) is a major neuropsychiatric disorder with high heritability and complex inheritance. Previously reported linkage between BP and DNA markers in the pericentromeric region of chromosome 18, with a parent-of-origin effect (linkage was present in pedigrees with paternal transmission and absent in pedigrees with exclusive maternal inheritance), has been a focus of interest in human genetics. We reexamined the evidence in one of the largest samples reported to date (1,013 genotyped individuals in 53 unilineal multiplex pedigrees), using 10 highly polymorphic markers and a range of parametric and nonparametric analyses. There was no evidence for significant linkage between BP and chromosome 18 pericentromeric markers in the sample as a whole, nor was there evidence for significant parent-of-origin effect (pedigrees with paternal transmission were not differentially linked to the implicated chromosomal region). Two-point LOD scores and single-locus sib-pair results gave some support for suggestive linkage, but this was not substantiated by multilocus analysis, and the results were further tempered by multiple test effects. We conclude that there is no compelling evidence for linkage between BP and chromosome 18 pericentromeric markers in this sample.