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Mitochondrial inheritance is delayed in Saccharomyces cerevisiae cells lacking the serine/threonine phosphatase PTC1.

In wild-type yeast mitochondrial inheritance occurs early in the cell cycle concomitant with bud emergence. Cells lacking the PTC1 gene initially produce buds without a mitochondrial compartment; however, these buds later receive part of the mitochondrial network from the mother cell. Thus, the loss of PTC1 causes a delay, but not a complete block, in mitochondrial transport. PTC1 encodes a serine/threonine phosphatase in the high-osmolarity glycerol response (HOG) pathway. The mitochondrial inheritance delay in the ptc1 mutant is not attributable to changes in intracellular glycerol concentrations or defects in the organization of the actin cytoskeleton. Moreover, epistasis experiments with ptc1delta and mutations in HOG pathway kinases reveal that PTC1 is not acting through the HOG pathway to control the timing of mitochondrial inheritance. Instead, PTC1 may be acting either directly or through a different signaling pathway to affect the mitochondrial transport machinery in the cell. These studies indicate that the timing of mitochondrial transport in wild-type cells is genetically controlled and provide new evidence that mitochondrial inheritance does not depend on a physical link between the mitochondrial network and the incipient bud site.

Actins

Inherited prion disease with an alanine to valine mutation at codon 117 in the prion protein gene.

A large English family with autosomal dominant segregation of presenile dementia, ataxia and other neuropsychiatric features is described. Diagnoses of demyelinating disease, Alzheimer's disease, Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker syndrome have been attributed to particular individuals at different times. An Irish family, likely to be part of the same kindred, is also described, in which diagnoses of multiple sclerosis, dementia, corticobasal degeneration and new variant CJD have been considered in affected individuals. Molecular genetic studies have enabled the classification of this disease at the molecular level as one of the group of inherited prion diseases, with the substitution of valine for alanine at codon 117 of the prion protein gene (PRNP). Only three other kindreds have been described world-wide with this mutation and only limited phenotypic information has been reported. Here we describe the phenotypic spectrum of inherited prion disease (PrPA117V). The diversity of phenotypic expression seen in this kindred emphasizes the logic of molecular classification of the inherited prion diseases rather than classification by specific clinicopathological syndrome. Indeed, inherited prion disease should be excluded by PRNP analysis in any individual presenting with atypical presenile dementia or neuropsychiatric features and ataxia, including suspected cases of new variant CJD.

Adult

Evidence for mitochondrial DNA polymorphism and uniparental inheritance in the cellular slime mold Polysphondylium pallidum: effect of intraspecies mating on mitochondrial DNA transmission.

Restriction fragment length polymorphisms (RFLPs) were used as markers to monitor mitochondrial inheritance in the cellular slime mold, Polysphondylium pallidum. When two opposite mating types (mat1 and mat2) of closely related strains were crossed, all the haploid progeny regardless of mating type inherited their mitochondrial DNA from the mat2 parent only. When opposite mating types from more distantly related strains were crossed, most of the progeny also inherited their mitochondrial DNA from the mat2 parent, but some inherited their mitochondrial DNA from the mat1 parent. In both cases however, the transmission of mitochondrial DNA was uniparental, since in every individual progeny only one type of mitochondrial DNA exists. Moreover, in crosses involving more distantly related strains all the progeny of a single macrocyst were shown to contain the same type of mitochondrial DNA. These findings are discussed in regard to mechanisms of transmission and the possible involvement of nuclear genes in the control of transmission of mitochondrial DNA in Polysphondylium.

Crosses, Genetic

Uniparental inheritance and replacement of mitochondrial DNA in Neurospora tetrasperma.

This study tested mechanisms proposed for maternal uniparental mitochondrial inheritance in Neurospora: (1) exclusion of conidial mitochondria by the specialized female reproductive structure, trichogyne, due to mating locus heterokaryon incompatibility and (2) mitochondrial input bias favoring the larger trichogyne over the smaller conidium. These mechanisms were tested by determining the modes of mitochondrial DNA (mtDNA) inheritance and transmission in the absence of mating locus heterokaryon incompatibility following crosses of uninucleate strains of Neurospora tetrasperma with trichogyne (trichogyne inoculated by conidia) and without trichogyne (hyphal fusion). Maternal uniparental mitochondrial inheritance was observed in 136 single ascospore progeny following both mating with and without trichogyne using mtDNA restriction fragment length polymorphisms to distinguish parental types. This suggests that maternal mitochondrial inheritance following hyphal fusions is due to some mechanism other than those that implicate the trichogyne. Following hyphal fusion, mutually exclusive nuclear migration permitted investigation of reciprocal interactions. Regardless of which strain accepted nuclei following seven replicate hyphal fusion matings, acceptor mtDNA was the only type detected in 34 hyphal plug and tip samples taken from the contact and acceptor zones. No intracellular mtDNA mixtures were detected. Surprisingly, 3 days following hyphal fusion, acceptor mtDNA replaced donor mtDNA throughout the entire colony. To our knowledge, this is the first report of complete mitochondrial replacement during mating in a filamentous fungus.

Cell Nucleus

Effective sizes and dynamics of uniparentally and diparentally inherited genes.

Models to determine the temporal dynamics and spatial heterogeneity for maternally and paternally inherited genes were derived for populations that may or may not exhibit spatial subdivision. Results were compared to those for diparentally inherited genes. The models permit definition of parameters for mean and variance of litter sizes, breeding group (subpopulation) sizes, and numbers of female mates per male, dispersal rates, and multiple paternity. Exact solutions for asymptotic effective size and spatial divergence (FLS) for maternal and paternal genes are derived. It is shown that solutions for effective size and FLS are transformations of the same quadratic equation. When compared to values for diparentally inherited genes, it is shown that effective sizes for maternal genes may be considerably higher when female dispersal is low as in many mammalian taxa. Likewise, effective sizes for paternal genes may be higher than for diparentally inherited traits when male dispersal is relatively low, as in many species of birds. The traditional assumption that the effective size for maternal genes is approximately equal to the number of females is seldom realized. Spatial heterogeneity and temporal dynamics of genes are inextricably linked as is shown by the interdependency of effective size and spatial heterogeneity.

Animals

Uniparental inheritance of mitochondrial genes in yeast: dependence on input bias of mitochondrial DNA and preliminary investigations of the mechanism.

In Saccharomyces cerevisiae, previous studies on the inheritance of mitochondrial genes controlling antibiotic resistance have shown that some crosses produce a substantial number of uniparental zygotes, which transmit to their diploid progeny mitochondrial alleles from only one parent. In this paper, we show that uniparental zygotes are formed especially when one parent (majority parent) contributes substantially more mitochondrial DNA molecules to the zygote than does the other (minority) parent. Cellular contents of mitochondrial DNA (mtDNA) are increased in these experiments by treatment with cycloheximide, alpha-factor, or the uvsp5 nuclear mutation. In such a biased cross, some zygotes are uniparental for mitochondrial alleles from the majority parent, and the frequency of such zygotes increases with increasing bias. In two- and three-factor crosses the cap1, ery1, and oli1 loci behave coordinately, rather than independently; minority markers tend to be transmitted or lost as a unit, suggesting that the uniparental mechanism acts on entire mtDNA molecules rather than on individual loci. This rules out the possibility that uniparental inheritance can be explained by the conversion of minority markers to the majority alleles during recombination. Exceptions to the coordinate behavior of different loci can be explained by marker rescue via recombination. Uniparental inheritance is largely independent of the position of buds on the zygote. We conclude that it is due to the failure of minority markers to replicate in some zygotes, possibly involving the rapid enzymatic destruction of such markers. We have considered two general classes of mechanisms: (1) random selection of molecules for replication, as for example by competition for replicating sites on a membrane; and (2) differential marking of mtDNA molecules in the two parents, possibly by modification enzymes, followed by a mechanism that "counts" molecules and replicates only the majority type. These classes of models are distinguished genetically by the fact that the first predicts that the output frequency of a given allele among the progeny of a large number of zygotes will approximately equal the average input frequency of that allele, while the second class predicts that any input bias will be amplified in the output. The data suggest that bias amplification does occur. We hypothesize that maternal inheritance of mitochondrial or chloroplast genes in many organisms may depend upon a biased input of organelle DNA molecules, which usually favors the maternal parent, followed by failure of the minority (paternal) molecules to replicate in many or all zygotes.

Alleles

Determining the mode of inheritance of pesticide resistance with backcross experiments.

The most widely used method for evaluating the mode of inheritance of pesticide resistance is based on bioassays of individuals from a backcross between F1 (hybrid of resistant and susceptible strains) and parental resistant or susceptible strains. Monte Carlo simulations of the standard backcross method showed that the probability of incorrectly rejecting the null hypothesis of monogenic inheritance (Type I error) was generally more than double the conventional value of P = 0.05. Conversely, the null hypothesis of monogenic inheritance was likely to be accepted in a relatively large proportion of cases in which resistance is controlled by two or more loci. Expected differences in mortality of backcross offspring between monogenic and additive polygenic models approached zero as dose approached extremely low values, extremely high values, and the LD50 of the backcross generation. Thus, the effectiveness of the backcross method depended strongly on dose. The power of the standard backcross method to correctly reject the null hypothesis of monogenic inheritance increased as number of loci, slope of parental dose-mortality lines, magnitude of resistance, and sample size increased. Guidelines for improving the design and interpretation of backcross experiments are presented.

Animals

The inclusion of an assay for inherited congenital malformations in the assessment of mutagenicity.

A number of national guidelines and regulations on the mutagenicity of chemical substances mandate the assessment of inherited genetic effects. While inherited congenital malformations represent a major component of genetically-based adverse human health effects, tests for such effects are not used by regulatory agencies to evaluate inherited genetic effects. This paper is intended to highlight some of the salient characteristics of inherited congenital malformations which promote a rationale for their use in a regulatory context.

Abnormalities, Drug-Induced

Autosomal recessive inheritance of goiter in Dutch goats.

The inheritance of congenital goiter due to a thyroglobulin synthesis defect in a strain of Dutch goats has been studied by Mendelian and biochemical methods. Mendelian analysis of 301 matings, resulting in 591 kids, showed an autosomal recessive mode of inheritance. A restriction fragment length polymorphism (RFLP) in the thyroglobulin gene also was used to confirm the recessive mode of inheritance of the defect. In a pedigree consisting of 27 goats, spanning four generations, the genotype determined by RFLP study was in accordance with the observed phenotype and the autosomal inheritance of the defect. Although phenotypically no differences were detected between normal and heterozygous animals, the use of RFLPs allowed the diagnosis of the three genotypes.

Animals

Cytoplasmic male sterility in sunflower: origin, inheritance, and frequency in natural populations.

Cytoplasmic male sterility (CMS) in commercial sunflower hybrids is thought to be derived from a related wild species, Helianthus petiolaris, yet CMS lines are known to carry the chloroplast DNA genotype of H. annuus. To clarify the origin of sunflower CMS, we developed a polymerase chain reaction-based strategy for detecting CMS in sunflower and surveyed more than 1,200 plants representing 55 accessions of H. annuus and 26 accessions of H. petiolaris. We also tested 160 progeny from three crosses for strict maternal inheritance of organelle DNAs to determine if the apparent discrepancy in the species donor of the mitochondrial DNA and chloroplast DNA genotypes in CMS lines might result from low-frequency maternal or biparental inheritance of either organelle. No CMS cytotypes were observed in natural populations of either H. annuus or H. petiolaris, and strict maternal inheritance of organelle DNA was observed. These data provide little insight, therefore, into the origin and population genetics of CMS in natural populations of sunflower, except that the evidence for strict maternal inheritance of organelles in sunflower makes it unlikely that the mtDNA and cpDNA genotypes in CMS lines were derived from different species. Nonetheless, the primers developed for assaying organelle DNA variation in sunflower may be useful tools for plant breeding programs, cytotype identification, and systematic and evolutionary studies in the domesticated sunflower and its relatives.

Base Sequence

A polygenic model of inherited predisposition to cancer.

Polygenic inheritance of predisposition to cancer is demonstrated in experimental animals for different tumor types. Genetic susceptibility to hepatocarcinogenesis, lung tumorigenesis, skin and intestine carcinogenesis, and plasmacytomagenesis is determined by inheritance of multiple cancer predisposition and resistance alleles, whose chromosomal locations have been found by genetic linkage analysis. In some of these experimental models, genetic heterogeneity has also been reported. In humans, increased risk of lung cancer associated with multiple genes coding for drug metabolizing enzymes, increased risk of cancer in relatives of cancer patients, and genetic heterogeneity are compatible with polygenic inheritance of cancer predisposition. Polygenic inheritance based on the combination of multiple alleles that give predisposition and resistance to cancer would predict a very high risk of cancer in carrier individuals and a marginal increase in the relative risk of cancer in the progeny of the cancer patients. Therefore, predisposition to cancer may be genetically determined even in the absence of familial clustering of cases.

Animals

Mitochondrial DNA inherited variants are associated with successful aging and longevity in humans.

Mitochondrial DNA (mtDNA) is characterized by high variability, maternal inheritance, and absence of recombination. Studies of human populations have revealed ancestral associated polymorphisms whose combination defines groups of mtDNA types (haplogroups) that are currently used to reconstruct human evolution lineages. We used such inherited mtDNA markers to compare mtDNA population pools between a sample of individuals selected for successful aging and longevity (212 subjects older than 100 years and in good clinical condition) and a sample of 275 younger individuals (median age 38 years) carefully matched as to sex and geographic origin (northern and southern Italy). All nine haplogroups that are typical of Europeans were found in both samples, but male centenarians emerged in northern Italy as a particular sample: 1) mtDNA haplogroup frequency distribution was different between centenarians and younger individuals (P=0.017 by permutation tests); and 2) the frequency of the J haplogroup was notably higher in centenarians than in younger individuals (P=0.0052 by Fisher exact test). Since haplogroups are defined on the basis of inherited variants, these data show that mtDNA inherited variability could play a role in successful aging and longevity.

Adult

Inheritance of the equine Tf F3 allele.

The inheritance of the equine Tf F3 allele was examined in 39 parent-offspring combinations. For 26 of the cases the allele inherited by the offspring from the heterozygous parent could be determined. The proportion of individuals that inherited the F3 variant compared to the alternative allele was exactly 1:1. In five cases the parental phenotype was identical to that of the offspring. For the remaining eight cases the parent was homozygous for the F3 allele and all offspring had the F3 allele. The results were consistent with Mendelian inheritance.

Alleles

The family history and inherited thrombophilia.

The role of the family history as a tool for the diagnosis of inherited thrombophilia has not been established. Several authors have indicated that a positive family history is not a good predictor of inherited abnormalities such as antithrombin III deficiency, or deficiencies of protein C or protein S. We have tried to approach the family history in a quantitative way. To this end we used the cumulative incidence data of thrombosis in the general population and also in a population of protein C deficient families to estimate the expected number of symptomatic subjects in a family under both the hypothesis of inherited thrombophilia and the null-hypothesis. Although a number of assumptions underlying our calculations need to be verified and probably adjusted before any truly quantitative meaning can be assigned to this approach, we feel that the family history is a useful diagnostic test for inherited thrombophilia if it is used in a critical way.

Adolescent

Correlation between magnitude of CAG repeat length alterations and length of the paternal repeat in paternally inherited Huntington's disease.

An increasing number of diseases are being found to be due to elongation of specific trinucleotide repeat sequences. Inverse correlation between the age at onset and the length of the repeat has been found in most of these. The elongated CAG repeat causing Huntington's disease is highly unstable when inherited from an affected father. In this study we found an average parent-to-offspring difference of +0.08 repeat units in maternally inherited repeats, significantly less than the average difference of +2.92 repeat units with paternal transmission. Large repeat expansions, of more than 5 repeat units, were seen only in paternally inherited cases. With paternal transmission the magnitude of repeat length alterations was directly correlated to increasing paternal repeat length. Increasing variation in repeat length among siblings was correlated to increasing average repeat length in the sibship in both maternally and paternally inherited HD. Comparison of the magnitude of repeat length alterations to parental age at the time of birth of the offspring showed no correlation.

Fathers

Inheritance of histiocytosis in Bernese mountain dogs.

One hundred and twenty-seven cases of histiocytosis in Bernese mountain dogs (BMD) were evaluated to determine if the tumour is inherited. Family data ruled out autosomal recessive, autosomal dominant and sex-linked modes of inheritance. The trait was determined to be inherited with a polygenic mode of inheritance. The salient points permitting this conclusion are: pedigrees developed from independently selected propositi link up allowing the tracing of all cases through several generations; multiple cases occur in the same litter; multiple cases have been produced by given dams and sires; there is a higher frequency of the disease among offspring of affected parents when compared to offspring of normal parents that produced histiocytosis and all offspring in the general population of BMDs; the fact that histiocytosis is common in BMDs and rare in eight other breeds and accounts for 25.4 per cent of the 500 tumours studied in this breed. The heritability of this trait was calculated to be 0.298.

Animals

Inherited resistance to Corynebacterium kutscheri in mice.

An analysis of the factors responsible for inherited resistance to Corynebacterium kutscheri was undertaken. Various inbred mouse strains were examined; these included the Swiss Lynch and C57Bl/l mice, their F1 and F2 progeny, and the progeny of the F1 backcrossed to each parent strain. Two modes of inherited resistance are described. An examination suggested that resistance as measured by the mean lethal dose of C. kutscheri was under polygenic control and was inherited continuously. However, the efficiency with which C. kutscheri was eliminated by the mononuclear phagocyte cells of the liver over 3 days differed markedly among strains. A genetic analysis of this mononuclear phagocyte microbicidal efficiency (MPME) in Swiss Lynch and C57Bl/6 mice was undertaken. The trait, MPME, was present, but did not segregate, in the F1 progeny or in the progeny of the backcross to the resistant C57Bl/6 parent; this was clear evidence of dominance. Moreover, MPME segregated in a ratio of 1:1 in the progeny of the backcross to the sensitive Swiss Lynch parent and in a ratio of 3:1 in the F2 progeny. It was concluded that MPME was inherited discontinuously and was controlled by a single dominant autosomal gene (or closely linked group); the recessive allele was assigned the gene symbol ack. Linkage experiments showed there to be no association between the ack locus and any of the immune-response genes.

Animals

Lack of influence of non-inherited maternal HLA-DR alleles on susceptibility to rheumatoid arthritis.

OBJECTIVE: To reproduce findings from previous reports that non-inherited maternal HLA class II antigens might contribute to rheumatoid arthritis (RA) susceptibility in the offspring. METHODS: Families were recruited from the Arthritis and Rheumatism Council's National Repository of RA families and HLA-DRB1 alleles were examined in these individuals and their first degree relatives using DNA typing methods. RESULTS: There was no evidence of an increase in either non-inherited maternal HLA-DR4 or the HLA-DRB1 shared epitope as a whole compared with the frequency expected using the non-inherited paternal antigens as controls. CONCLUSIONS: The numbers of probands who were shared epitope negative were small, but we are unable to confirm in these families the findings that non-inherited maternal HLA contributes an additional susceptibility factor to rheumatoid arthritis.

Alleles