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The mechanism of centrosome inheritance during parthenogenetic development has long been an outstanding mystery of cell biology. New observations of centrosome inheritance in hymenopterans have provided our first direct insights into this enigmatic process.
BACKGROUND: The association between DNA methylation and gene silencing has long been recognized; however, signals that initiate de novo methylation are largely unknown. In plants, recognition of RNAs that are inducers of posttranscriptional gene silencing (PTGS) can result in sequence-specific DNA methylation, and the aim of this work was to investigate whether heritable epigenetic changes can occur by this mechanism and if the Met1 methyltransferase is required. RESULTS: RNA-directed DNA methylation (RdDM) was initiated in 35S-GFP transgenic plants following infection with plant RNA viruses modified to carry portions of either the 35S promoter or the GFP coding region. Targeting of the promoter sequence resulted in both methylation and transcriptional gene silencing (TGS) that was inherited independently of the RNA trigger. Targeting the coding region also resulted in methylation; however, this was not inherited. Expression of Met1 was suppressed in order to investigate its role in initiation and maintenance of RdDM. Initiation of RdDM was found to be Met1-independent, whereas maintenance of methylation and TGS in the subsequent generations in the absence of the RNA trigger was Met1-dependent. Maintenance of methylation associated with systemic PTGS was also found to be Met1-independent. CONCLUSIONS: RNA-triggered events can lead to heritable changes in gene expression, and it is possible that initiation of other epigenetic phenomena such as trans-silencing and paramutation may have an RNA component.
Respiratory metabolism depends on mitochondrial DNA, yet the mechanisms that ensure the inheritance of the mitochondrial genome are largely obscure. Recent studies with Saccharomyces cerevisiae suggest that distinct factors mediate the active segregation of mitochondrial DNA during mitotic growth. The identification of the proteins required for the maintenance of the mitochondrial genome provides clues to the mechanisms of, and molecular machinery involved in, mitochondrial DNA inheritance.
Mitochondrial disorders are heterogeneous systemic ailments that are most often caused by maternal inheritance of a variety of mutations of the mitochondrial (mt) DNA. Paternal inheritance and somatic mutation are rare. The disorders are well recognized not only for the genotypic heterogeneity, but also the phenotypic variation among the affected members of a single family. The genotype-phenotype correlation of the diversity of the syndromic and non-syndromic features of mitochondrial disorders are discussed. Some aspects of the molecular mechanisms of this heterogeneity, and the histopathologic findings are highlighted.
Familial risk of colorectal cancer is very common. The high-risk inherited syndromes are well described and much is known about the genetics and the effectiveness of registration, endoscopic surveillance, and appropriate intervention in these patients. The inherited syndromes, however, are extremely rare. There is a large group of patients in our population who can benefit from risk stratification based on the number of their relatives with colon cancer or adenomas and the age at which those relatives developed neoplasm. The GI endoscopist has a vital role in recommending and providing colonoscopic screening for this large group of patients.
BACKGROUND: Mannose-binding lectin (MBL), an acute-phase serum protein of hepatic origin, plays an essential protective role in host innate immunity in targeting microbial pathogens for destruction via opsonization, enhancement of phagocytosis and complement activation. MBL deficiency, characterized by low serum MBL, has been attributed to genetic mutations in both structural and promoter regions of the gene coding for the protein. Concomitant MBL deficiency in patients with chronic immunologic disease has been associated with increased susceptibility to complicating infections that may hasten disease progression. OBJECTIVE: Few cases of inherited MBL deficiency in adults and possible associations with recurrent infection have been reported. To address this issue, we investigated the MBL profile of four generations within a single adult family whose members have experienced a variety of persistent infections. METHODS: MBL serum levels and MBL genotypes of each participating family member were ascertained by enzyme-linked immunoadsorbent assay and reverse transcriptase-polymerase chain reaction, respectively. MBL complement activation, as measured by C4b deposition against mannan-coated wells, was assayed using an enzyme-linked immunoadsorbent assay. Routine immunologic and cellular tests were carried out to evaluate the immunologic status of each family member. RESULTS: Six of the 7 family members screened carried one or more of the variant MBL alleles in their genotype and had correspondingly low serum MBL and reduced ability to affect C4b opsonization. Medical histories of the participating family members revealed an array of mild to severe recurrent infections despite no apparent immunodeficiency. CONCLUSIONS: Our studies show that MBL deficiency is an inherited characteristic and may be a crucial factor in maintaining immunologic health.
The function of the retina is to detect light and to send appropriate signals to the brain in response. Inherited diseases that cause the retina to degenerate, leading to either partial or total blindness, affect approximately 1 in 3000 people. Rapid progress is being made in identifying the genetic causes of common, inherited retinal diseases, such as retinitis pigmentosa and macular degeneration, as well as some of the rare forms of retinal disease. Linkage studies of large families and candidate-gene screening of known retinal genes have already identified 59 independent genetic loci that can cause retinal degeneration. The astounding genetic and clinical heterogeneity that is being revealed is a 'nightmare' for those interested in molecular diagnostics but, at the same time, provides great insight into functional aspects of the normal retina.
Polymorphisms of the size of heterochromatic centromeric regions of chromosomes have been well documented in the human. They appear to have no phenotypic effects in the carriers. However, they appear to be over-represented in infertile couples and those with repeated miscarriages, and there is now growing evidence that they are involved in meiotic pairing, spindle fibre attachment and chromosome movement. Here an analysis of inheritance is reported for a couple presenting with repeated IVF failure in which several embryos were identified as carriers of a polymorphism of the centromeric region of chromosome 16 (16qh-) following aneuploidy screening by sequential fluorescence in-situ hybridization (FISH), using probes for chromosomes 13, 16, 18, 21, 22, X and Y. Detailed cytogenetic analysis by high-resolution banding and FISH of both parents and grandparents established that the polymorphism was familial and inherited from the maternal grandfather. Furthermore, complete analysis of all embryonic nuclei from carrier embryos and others rejected for transfer because of aneuploidy revealed no abnormalities in the segregation pattern of chromosome 16.
The most common causes of inherited thrombophilia, the factor V Leiden and the factor II A20210 mutations, confer a higher risk of venous thromboembolism. Moreover, several studies have suggested that they can have a role in the occurrence of gestational vascular complications in otherwise unexplained recurrent fetal losses, hypertensive disorders of pregnancy and fetal growth restriction. Observational and case-control studies addressing these issues are available in literature. However, longitudinal, perspective studies are lacking. Mild hyperhomocysteinaemia can be due partly to inherited susceptibility--as the homozygous carriership of the T677 variant in the gene encoding 5,10-methylenetetrahydrofolate reductase (MTHFR). Case-control studies have been carried out on a possible association between unexplained fetal losses and mild hyperhomocysteinaemia. Although case-control and perspective studies are available on hyperhomocysteinaemia and other gestational vascular complications the data are conflicting.Intervention studies have been carried out to prevent adverse obstetric outcomes in women with factor V Leiden or factor II A20210 mutations and previous adverse outcomes. Although these are not randomized controlled trials, all have found significantly better outcomes in treated pregnancies compared to those of untreated pregnancies in the same women.
The inherited polyposis syndromes are a group of conditions in which multiple gastrointestinal polyps occur in the lumen of the gastrointestinal tract, most exhibit an increased risk of colon cancer. Benign and malignant extraintestinal tumors might also be observed. Recent elucidation of the underlying gene mutations has contributed to our understanding of the cell biology and molecular mechanisms associated with gastrointestinal tumorigenesis. Developments have also allowed genetic testing to become an integral component in accurate diagnosis, categorization, and management of inherited polyposis syndromes. In this review, we will focus on familial adenomatous polyposis, mutY human homologue-associated polyposis, Peutz-Jeghers syndrome, juvenile polyposis, and Cowden syndrome. It is essential that both physician and patient understand the benefits and limitations of genetic testing before submission of samples to the laboratory. There are many issues accompanying molecular diagnosis of cancer syndromes, and genetic counseling is an essential prelude to genetic testing.
By means of complex segregation analysis we studied the inheritance of litter size in two large pedigrees of captive-bred colonies of the Brazilian grass mouse Akodon cursor. Genetic analysis has revealed a highly significant influence of genetic factors on the variation of litter size (heritability, h2, was estimated as 0.44). The inheritance followed the classical polygene model: neither the major-gene model nor the polygene with unequal contribution model described the data significantly better.
A series of multivariate mixed-inheritance models is fitted to the data from an outbred-line pig cross commercially used in Norway. Each model accommodates information on polygenic (co)variances between F2 individuals and their F1 parents across the five traits through incorporation of a random animal effect. Considered traits relate to meat quality and are chosen following up the results from a previous evaluation, in which a putative quantitative trait locus (QTL) was identified on chromosome six that affects the amount of intramuscular fat (IMF), meat percentage, meat tenderness and smell intensity (Grindflek et al., 2001). An additional trait included in the model, based on results of other studies, is the backfat thickness. The analysed material comprises data scored for 305 F2 individuals, whereas marker information is available for F1 and F2 generations. Based on the results of the multivariate analysis with the mixed-inheritance model, it was possible to conclude that the evidence for QTLs for meat percentage, meat tenderness and smell intensity in the study of Grindflek et al. (2001) do not represent separate QTLs, but is caused by the fact that the applied pre-adjustment of trait values for polygenic effects failed properly to remove the polygenic variation. The QTL effect on IMF on chromosome six was confirmed.
In this research we estimated the contribution of a major-gene effect to the control of litter size in hybrids between two local populations of the house musk shrew (Suncus murinus). Segregation analysis was performed on the basis of a mixed polygene and major-gene model. The model presumes that two parental populations may differ from each other in gene frequencies and in the values of polygenic effects but not in the major-gene contribution of the trait. Moreover, the peculiarity of the trait--litter size--is taken into account. This trait is not an individual attribute. It characterizes the parental couple and may depend on the genotypes of both parents. Results of segregation analysis of a large hybrid pedigree of Suncus murinus indicate that the parental populations differ in the allele frequency of the major gene (one population is homozygous, while the other contains the two alleles in approximately equal proportions) and in the values of average polygenic effects. Both major-gene and polygenic components are necessary for the correct description of litter size inheritance in interracial hybrids of S murinus, inasmuch as the exclusion of either of them leads to a significant drop in likelihood. The Elston-Stewart criterion also confirms the Mendelian inheritance of the major gene.
Inherited bleeding disorders are frequently considered an absolute contraindication to tonsillectomy and other ENT procedures. Over a 15-year period we have performed ten elective tonsillectomies and five bilateral myringotomies on children with inherited bleeding disorders. All procedures were carried out with the close co-operation of the Haematology Department in the hospital. All patients underwent uneventful surgery. One patient returned after tonsillectomy with a secondary haemorrhage which did not require surgical intervention. We present our team approach to the management of these children and demonstrate that necessary surgical intervention can be undertaken safely in this select group of patients.
Genetic differences in mice influence both the pathological and immunological responses to schistosomiasis mansoni. We have investigated the nature of the genetic factors influencing these responses by crossing two different pairs of strains of mice which vary in their response to infection, and measuring responses in the F1 hybrid and backcross offspring. The two pairs of parental strains differed with respect to faecal egg excretion, accumulation of eggs in the tissues, splenomegaly and pattern of antibody response. The numbers of adult worms which establish do not differ between strains. The inheritance of the responses measured was different in the two pairs of strains. The F1 hybrid from the C57BL/6/0la X BALB/c cross resembled the low-responding parental strain (C57BL/6/0la) with respect to faecal egg excretion, accumulation of eggs in the tissues and splenomegaly, and was intermediate in its pattern of antibody response. The F1 hybrid mice from the NIH X CBA/Ca cross resembled the high-responding strain (CBA/Ca) with respect to faecal egg excretion, accumulation of eggs in the tissues and splenomegaly, and had an earlier and greater antibody response than either parental strain. No evidence of single gene influence on any of these responses was seen in the backcross offspring. The differing patterns of inheritance and the absence of a bimodal distribution of responses in the backcross offspring indicate that each of these responses is influenced by multiple genes. The pattern of antibody response did not correlate between strains with any of the pathological responses. The positive correlation of egg accumulation in the tissues and faecal egg excretion suggests that there are genetic influences on the fecundity of the worms.
Lung flukes, Paragonimus ohirai, from Kinosaki, Japan, characterized by 3 electrophoretic variants, FF, FS and SS, of glutamic-oxaloacetic transaminase (GOT: EC 2.6.1.1) were crossed in the laboratory. In the case of a cross between FS and SS, a parent, FS, produced 9 SS and 16 FS clones in the offspring, numbers not significantly different from that expected (1:1) from Mendelian inheritance. From the other cross FS X FF, 20 clones originating from the respective 20 miracidia were obtained from a parent FS. The phenotype segregation ratio was 6 FF and 14 FS, which is not significantly different from Mendelian inheritance expectation. Only 3 clones were obtained from the other parent FF, but these segregated in a ratio of 2 FS: 1 FF. These breeding data indicate that the GOT isozymes of P. ohirai are controlled by 2 codominant alleles, GotF and GotS at a single locus whose products aggregate randomly, forming a dimer.
The classification of Charcot-Marie-Tooth disease and related hereditary motor and sensory neuropathies has evolved to incorporate clinical, electrophysiological and burgeoning molecular genetic information that characterize the many disorders. For several inherited neuropathies, the gene product abnormality is known and for others, candidate genes have been identified. Genetic testing can pinpoint a specific inherited neuropathy for many patients. However, clinical and electrophysiological assessments continue to be essential tools for diagnosis and management of this disease group. This article reviews clinical, electrophysiological, pathological and molecular aspects of hereditary motor and sensory neuropathies.
Epidermolysis bullosa (EB) and associated skin-fragility syndromes are a group of inherited skin diseases characterised by trauma-induced blistering of the skin and mucous membranes. Mutations in at least 14 distinct genes encoding molecular components of the epidermis or the dermal-epidermal junction (DEJ) can cause blistering skin diseases that differ by clinical presentation and severity of the symptoms. Despite great advances in discerning the genetic basis of this group of diseases, the molecular pathways leading to symptoms are not yet fully understood. Unravelling these pathways by molecular analysis of the structure and in vitro assessment of functional properties of the human proteins involved, combined with genetic models in lower organisms, should pave the way for specific cures for inherited skin fragility.