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PubMed1990

The impact of phenotypic variation on genetic analysis: application to X-linkage in manic-depressive illness.

Genetic linkage studies have opened new vistas for behavioral and psychiatric genetics. However, phenotypic diversity and diagnostic uncertainties can lead to spurious linkage findings. A method of analysis is proposed that takes these factors into account. When applied to manic-depressive disease, the results indicate that previous evidence for a major gene localized on the distal long arm of the X-chromosome cannot be ascribed to phenotypic uncertainties and misclassifications, i.e., a type I error. Although the lod score (the logarithm of odds) favoring linkage is reduced with the more restrictive clinical definitions of the phenotype, it remains significant nonetheless. Thus, the linkage finding is robust over a range of phenotypic patterns and presumed phenocopy frequencies. The results also suggest that the X-linked phenotype is a particularly severe form of manic depression characterized by early onset, high familial prevalence of the bipolar form, and high recurrence rate of major depression. These findings may have important implications for the design and interpretation of genetic linkage studies and for refining diagnostic techniques in mental disorders.

Adolescent↗
PubMed2000

Genetic analysis of the influence of pertussis toxin on experimental allergic encephalomyelitis susceptibility: an environmental agent can override genetic checkpoints.

Pertussis toxin (PTX) is a potent ancillary adjuvant used to elicit several different autoimmune diseases, including experimental allergic encephalomyelitis (EAE). To delineate the genetics of PTX effect in EAE, we mapped EAE-modifying (eae-m) loci in cohorts of backcross mice immunized with and without PTX. In this study, we analyzed the genetic basis of EAE susceptibility and severity and the intermediate phenotypes of mononuclear cell infiltration, suppuration, and demyelination. In animals immunized with PTX, one major locus, eae9, controls disease susceptibility and severity. Eae9 also regulates the extent of mononuclear cell infiltration of the spinal cord in male mice. Without PTX, five eae-m loci were noted, including three new loci in intervals on chromosomes 8 (eae14), 10 (eae17), and 18 (eae18). Taken together, these results suggest that eae9 controls the effects of PTX in EAE susceptibility, and is capable of overriding the other genetic checkpoints in the pathogenesis of this disease.

Animals↗
PubMed1989

Genetic analysis of inducible sexual agglutination ability in the yeast Saccharomyces cerevisiae.

Genetic regulation of the inducibility of sexual agglutination ability in the yeast Saccharomyces cerevisiae was studied. Detailed analysis of the degree of sexual agglutination was carried out; it showed that a greater number of genes are involved in the regulation of inducible sexual agglutination in strain H1-0 than previously assumed. Although dominancy of inducible phenotype over constitutive was confirmed, the effectiveness of one gene changing the constitutive phenotype to the inducible seemed to be somewhat low. Quantity per cell of agglutination substances responsible for sexual agglutination increased as the agglutination ability became greater.

Agglutination↗
PubMed2003

Genetic analysis of mitochondrial complex II subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma susceptibility.

BACKGROUND: Germline mutations in three subunits of mitochondrial complex II (SDHB, SDHC and SDHD) may be associated with susceptibility to phaeochromocytoma (PC) and/or head and neck paraganglioma (HNPGL). METHODS: To further define the role of SDH subunit mutations in these disorders, we analysed a series of 22 probands with PC and evidence of genetic susceptibility (seven with familial PC only, one with familial PC and HNPGL, 10 sporadic cases with multiple PC and four cases of isolated paediatric onset PC) for germline SDHB, SDHC and SDHD mutations. In addition, we analysed 34 cases of HNPGL (30 isolated cases with single tumours, three isolated cases with multiple tumours and one familial case with multiple tumours) for somatic and germline mutations in SDHB, SDHC and SDHD. RESULTS: We identified four germline mutations (three SDHB and one SDHD, three novel) in the 22 PC probands. Combining these results with our previous series, we have detected germline SDHB or SDHD mutations in 2/12 (17%) of familial PC only kindreds, 4/5 (80%) of familial PC and HNPGL cases, 1/10 of sporadic multiple PC cases and 2/4 (50%) of paediatric PCs. No somatic mutations were detected in the HNPGL tumours, but four cases with multiple HNPGL had the common P81L germline SDHD mutation. Intriguingly a silent SNP (c.204C > T) in SDHD was significantly more common in HNPGL cases (6/34) than in controls (1/100, P = 0.0011). Combining our results with those from two other large studies in which both SDHB and SDHD have been analysed, SDHB mutations were most commonly associated with phaeochromocytoma susceptibility and SDHD with the development of HNPGL (P = 0.025). However, germline SDHB and SDHD mutations demonstrate considerable phenotypic variability and genotype-phenotype correlations are complex. CONCLUSION: The significantly lower frequency (P = 0.028) of germline SDH subunit mutations in familial PC only cases compared to those with familial PC and HNPGL suggests that further PC susceptibility gene(s) remain to be identified.

Adolescent↗
PubMed2000

Fear-potentiated startle response in mice: genetic analysis of the C57BL/6J and DBA/2J intercross.

The role of genetic factors in the fear-potentiated startle (FPS) response was examined in the inbred C57BL/6J (B6) and DBA/2J (D2) mouse strains. Mice in the D2 strain displayed a significant potentiation in the acoustic startle response (ASR) when presented with a visual condition stimulus (CS) previously paired with an aversive unconditioned stimulus (US). The maximal FPS response was observed following 20 conditioning trials but a near maximal response was noted following as few as five trials. Forty conditioning trials produced a significant reduction in the FPS response that may be related to overtraining. The FPS response in the B6 strain was significantly lower than the D2 strain, regardless of the number of conditioning trials. The contrasting FPS responses were not related to differences in auditory sensitivity known to exist between these strains. Analysis of a full Mendelian cross formed from the B6 and D2 strains found that the FPS response was a highly heritable trait, best described by a simple additive model of inheritance and with a broad-sense heritability of 0.46. The distribution of the FPS response in F2 hybrids formed from the intercross of the D2 and B6 strains was continuous which suggests a multigenic substrate. The light + noise and noise-alone trial types were highly correlated, but no association was detected between the baseline ASR amplitude and the FPS response. Mice from the phenotypic extremes of the F2 distribution displayed FPS responses that were more extreme than either of the progenitor strains. However, both baseline startle amplitude and the salience of auditory stimuli did not differ in these groups. The results of this study confirm an early report by Falls et al. (1997), and provide additional quantitative genetics information necessary for the eventual mapping of the chromosomal regions or genes associated with the FPS response in mice.

Acoustic Stimulation↗
PubMed1990

[Molecular genetic analysis of neurologic diseases].

With the recent progress in molecular genetics, our understanding of neurologic diseases on molecular basis has improved tremendously. Molecular analyses of gene mutations in hereditary neurologic diseases bring us not only the identification of mutations but also better understanding of molecular mechanisms involved in the neurologic diseases. We have identified a missense mutation (444Leu----Pro) in glucocerebrosidase gene of a type 2 Gaucher patient. The mutant glucocerebrosidase carrying 444Pro is unstable and degraded rapidly before the mutant protein is targetted to lysosomes. Detailed analysis on the 444Leu----Pro mutations among three phenotypes (types 1, 2 and 3) of Gaucher disease, it has been demonstrated that patients homozygous for the mutation frequently have the neurologic involvement (types 1 and 2). Very recently we have identified a mutation in tRNA(Lys) gene of mitochondrial genome of patients with myoclonus epilepsy associated with ragged-red fibers. The pathophysiologic mechanism with the tRNA(Lys) mutation is considered to be based on the impaired function of tRNA(Lys).

Amino Acid Sequence↗
PubMed2000

Genetic analysis and conservation of 31 surviving individuals of a rare New Zealand tree, Metrosideros bartlettii (Myrtaceae).

Metrosideros bartlettii (Myrtaceae) is a distinctive and extremely rare tree, endemic to New Zealand, first discovered in 1975. Prior to this study, a total of 19 adult individuals of the species had been reported; these are located in three small forest remnants in the far north of the North Island of New Zealand. Here we describe a total of 31 adult M. bartlettii at the three sites, including 12 individuals newly discovered by us. We analyse the genetic diversity of the species, using microsatellites to examine the chloroplast genome and amplified fragment length polymorphisms (AFLPs) to monitor nuclear variation. The results clearly demonstrate that M. bartlettii is a unique species, distinct from its two closest relatives M. robusta and M. excelsa. Analysis of genetic diversity within the 31 remaining individuals of M. bartlettii showed an average heterozygosity (< H >) of 0.18 and a proportion of polymorphic genes (< P >) of 0.44. Population structure, as shown by 286 AFLP loci, varied between the three geographical sites; the site with fewest individuals, containing two trees, showed some separation from the populations at the other two locations. These two latter sites, by contrast, had highly overlapping AFLP population diversity profiles. The implications of these results for conservation of the species are discussed.

Conservation of Natural Resources↗
PubMedDate not supplied

Molecular population genetic analysis of emerged bacterial pathogens: selected insights.

Research in bacterial population genetics has increased in the last 10 years. Population genetic theory and tools and related strategies have been used to investigate bacterial pathogens that have contributed to recent episodes of temporal variation in disease frequency and severity. A common theme demonstrated by these analyses is that distinct bacterial clones are responsible for disease outbreaks and increases in infection frequency. Many of these clones are characterized by unique combinations of virulence genes or alleles of virulence genes. Because substantial interclonal variance exists in relative virulence, molecular population genetic studies have led to the concept that the unit of bacterial pathogenicity is the clone or cell line. Continued new insights into host parasite interactions at the molecular level will be achieved by combining clonal analysis of bacterial pathogens with large-scale comparative sequencing of virulence genes.

Bacteria↗
PubMed2004

[Molecular genetic analysis of congenital lipoid adrenal hyperplasia].

OBJECTIVE: Congenital lipoid adrenal hyperplasia (CLAH) is an autosomal recessive inherited disorder, characterized by deficiency of adrenal and gonadal steroid hormones. Recent studies have shown that mutations in the gene for steroidogenic acute regulatory protein (StAR) cause this most severe genetic disorder in steroid hormone biosynthesis. StAR is a mitochondrial protein promotes cholesterol transfer from outer mitochondrial membrane to the inner mitochondrial membrane, where the cholesterol serves as a substrate for P450scc and initiates steroidogenesis. So far, more than 30 different mutations in the StAR gene have been found in the patients with CLAH from various ethnic groups. None of CLAH patients in the Chinese population has been previously reported. In the present study we analyzed the StAR gene in a Chinese patient with CLAH. METHODS: The patient who was a 19-yr-old phenotypic female, has a 46, XY karyotype. Endocrinological evaluation was performed. Genomic DNA samples were abstracted from the bloods of the patient and his parents. Polymerase chain reaction (PCR), direct DNA sequencing, family analysis and restriction enzyme digestion analysis were used to detect and confirm the mutations of StAR gene. RESULTS: Endocrine evaluation of the patient showed extremely elevated basal concentrations of serum ACTH and gonadotropin and minimal concentration of gonadal steroids. An ACTH stimulation test indicated basal serum dehydroepiandrosterone and 17-hydroxyprogesterone were lower than normal detectable range and had no obvious increase after the ACTH stimulation. Automatic sequencing of 7 exons of the StAR gene with the polymerase chain reaction products of the genomic DNA revealed compound heterozygous for a novel nonsense mutation Q77X in exon 3 and the frameshift mutation 838delA in exon 6. The father carried Q77X mutation and the mother carried 838delA mutation. The restriction enzyme site of the Q77X mutation was examined by endonucleotidase BfaI. Furthermore, this mutation was not found in a series of 20 alleles of normal individuals. CONCLUSION: Q77X is the novel mutation found in the patient with CLAH. Q77X and 838delA compound mutations could inactivate the StAR function and give rise to clinically manifest CLAH. This case is the first Chinese patient with CLAH identified by molecular genetic analysis. DNA-based analysis of StAR gene will be helpful for the diagnosis of CLAH.

Adrenal Hyperplasia, Congenital↗
PubMed2000

Genetic analysis of Holstein cattle populations in Brazil and the United States.

Genetic relationships between Brazilian and US Holstein cattle populations were studied using first-lactation records of 305-d mature equivalent (ME) yields of milk and fat of daughters of 705 sires in Brazil and 701 sires in the United States, 358 of which had progeny in both countries. Components of(co)variance and genetic parameters were estimated from all data and from within herd-year standard deviation for milk (HYSD) data files using bivariate and multivariate sire models and DFREML procedures distinguishing the two countries. Sire (residual) variances from all data for milk yield were 51 to 59% (58 to 101%) as large in Brazil as those obtained from half-sisters in the average US herd. Corresponding proportions of the US variance in fat yield that were found in Brazil were 30 to 41% for the sire component of variance and 48 to 80% for the residual. Heritabilities for milk and fat yields from multivariate analysis of all the data were 0.25 and 0.22 in Brazil, and 0.34 and 0.35 in the United States. Genetic correlations between milk and fat were 0.79 in Brazil and 0.62 in the United States. Genetic correlations between countries were 0.85 for milk, 0.88 for fat, 0.55 for milk in Brazil and fat in the US, and 0.67 for fat in Brazil and milk in the United States. Correlated responses in Brazil from sire selection based on the US information increased with average HYSD in Brazil. Largest daughter yield response was predicted from information from half-sisters in low HYSD US herds (0.75 kg/kg for milk; 0.63 kg/kg for fat), which was 14% to 17% greater than estimates from all US herds because the scaling effects were less severe from heterogeneous variances. Unequal daughter response from unequal genetic (co)variances under restrictive Brazilian conditions is evidence for the interaction of genotype and environment. The smaller and variable yield expectations of daughters of US sires in Brazilian environments suggest the need for specific genetic improvement strategies in Brazilian Holstein herds. A US data file restricting daughter information to low HYSD US environments would be a wise choice for across-country evaluation. Procedures to incorporate such foreign evaluations should be explored to improve the accuracy of genetic evaluations for the Brazilian Holstein population.

Animals↗
PubMed2006

Genetic analysis of human Orc2 reveals specific domains that are required in vivo for assembly and nuclear localization of the origin recognition complex.

Eukaryotic DNA replication begins with the binding of a six subunit origin recognition complex (ORC) to DNA. To study the assembly and function of mammalian ORC proteins in their native environment, HeLa cells were constructed that constitutively expressed an epitope-tagged, recombinant human Orc2 subunit that had been genetically altered. Analysis of these cell lines revealed that Orc2 contains a single ORC assembly domain that is required in vivo for interaction with all other ORC subunits, as well as two nuclear localization signals (NLSs) that are required for ORC accumulation in the nucleus. The recombinant Orc2 existed in the nucleus either as an ORC-(2-5) or ORC-(1-5) complex; no other combinations of ORC subunits were detected. Moreover, only ORC-(1-5) was bound to the chromatin fraction, suggesting that Orc1 is required in vivo to load ORC-(2-5) onto chromatin. Surprisingly, recombinant Orc2 suppressed expression of endogenous Orc2, revealing that mammalian cells limit the intracellular level of Orc2, and thereby limit the amount of ORC-(2-5) in the nucleus. Because this suppression required only the ORC assembly and NLS domains, these domains appear to constitute the functional domain of Orc2.

Cell Line↗
PubMedDate not supplied

Quantitative genetic analysis of brain copper and zinc in BXD recombinant inbred mice.

Copper and zinc are trace nutrients essential for normal brain function, yet an excess of these elements can be toxic. It is important therefore that these metals be closely regulated. We recently conducted a quantitative trait loci (QTL) analysis to identify chromosomal regions in the mouse containing possible regulatory genes. The animals came from 15 strains of the BXD/Ty recombinant inbred (RI) strain panel and the brain regions analyzed were frontal cortex, caudate-putamen, nucleus accumbens and ventral midbrain. Several QTL were identified for copper and/or zinc, most notably on chromosomes 1, 8, 16 and 17. Genetic correlational analysis also revealed associations between these metals and dopamine, cocaine responses, saccharine preference, immune response and seizure susceptibility. Notably, the QTL on chromosome 17 is also associated with seizure susceptibility and contains the histocompatibility H2 complex. This work shows that regulation of zinc and copper is under polygenic influence and is intimately related to CNS function. Future work will reveal genes underlying the QTL and how they interact with other genes and the environment. More importantly, revelation of the genetic underpinnings of copper and zinc brain homeostasis will aid our understanding of neurological diseases that are related to copper and zinc imbalance.

Animals↗
PubMed2006

Longitudinal genetic analysis of plasma lipids.

The consensus from published studies is that plasma lipids are each influenced by genetic factors, and that this contributes to genetic variation in risk of cardiovascular disease. Heritability estimates for lipids and lipoproteins are in the range .48 to .87, when measured once per study participant. However, this ignores the confounding effects of biological variation measurement error and ageing, and a truer assessment of genetic effects on cardiovascular risk may be obtained from analysis of longitudinal twin or family data. We have analyzed information on plasma high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol, and triglycerides, from 415 adult twins who provided blood on two to five occasions over 10 to 17 years. Multivariate modeling of genetic and environmental contributions to variation within and across occasions was used to assess the extent to which genetic and environmental factors have long-term effects on plasma lipids. Results indicated that more than one genetic factor influenced HDL and LDL components of cholesterol, and triglycerides over time in all studies. Nonshared environmental factors did not have significant long-term effects except for HDL. We conclude that when heritability of lipid risk factors is estimated on only one occasion, the existence of biological variation and measurement errors leads to underestimation of the importance of genetic factors as a cause of variation in long-term risk within the population. In addition our data suggest that different genes may affect the risk profile at different ages.

Adolescent↗
PubMed1991

Genetic analysis of chromosome region 63 of Drosophila melanogaster.

The salivary chromosome region including cytological division 63 of Drosophila melanogaster was genetically analyzed in order to (1) characterize this previously unstudied region and (2) attempt to isolate mutations in the hsp82 gene. Seven deletions which span this region were isolated, including four which remove the hsp82 gene. A Minute mutation was mapped to this region and this Minute was used to isolate duplications in the 63 region. These duplications map the Minute to 63B8-C1. F2 screens were initiated using deletions which remove the hsp82 gene. Over 15,000 chromosomes were screened, yielding 40 lethal mutations which comprise 14 complementation groups. Several of these mutations map outside the 63 region and appear to give second site interaction with the Minute locus. Four loci, including the Minute gene, are candidates for hsp82 mutations by cytogenetic mapping. These loci were tested for complementation with a P element carrying the hsp82 gene. However, none of the mutations was rescued.

Animals↗
PubMed2002

Genetic analysis of Pseudomonas aeruginosa isolates from the sputa of Australian adult cystic fibrosis patients.

Genetic investigations were carried out with 50 phenotypically selected strains of Pseudomonas aeruginosa from 18 patients attending an Australian cystic fibrosis (CF) center. The isolates were analyzed by restriction fragment length polymorphism (RFLP) analysis by pulsed-field gel electrophoresis (PFGE). Phylogenetic analysis of the macrorestriction patterns showed rates of genetic similarity ranging from 76 to 100%; 24 (48%) of the strains from 11 patients had greater than 90% similarity. A dominant strain emerged: 15 isolates from seven patients had identical PFGE patterns, and 4 other isolates were very closely related. The 50 isolates were grouped into 21 pulsotypes on the basis of visual delineation of a three-band difference. Ten of the 18 (56%) patients were infected with clonal or subclonal strains. Sequence analysis of PCR products derived from the mucA gene showed 20 mutations, with the number of mutations in individual isolates ranging from 1 to 4; 19 of these changes are reported here for the first time. Potentially functional changes were found in 22 (44%) isolates. Eight changes (five transversions and three single base deletions) led to premature stop codons, providing support for the presence of mucA mutations as one pathway to mucoidy. There was a trend toward an association between the dominant strain and lack of potentially functional mucA mutations (P = 0.09 by the chi(2) test) but no relationship between genotype and phenotype. This is the first study of genetic variation in P. aeruginosa isolates from adult Australian CF patients. The findings highlight the need for further investigations on the transmissibility of P. aeruginosa in CF patients.

Adult↗
PubMed2026

Clinicopathological and genetic analysis of primary intraosseous carcinoma not otherwise specified (PIOC NOS).

BACKGROUND: Primary intraosseous carcinoma not otherwise specified (PIOC NOS) is an extremely rare jawbone cancer, accounting for approximately 1-2% of all oral cancers. Considering its rarity, no established standard treatment exists for postoperative recurrence or metastasis. This study aimed to analyse the clinical manifestations of this disease and identify novel genomic abnormalities to aid identification of potential treatment strategies. METHODS: We examined the clinical information of 14 PIOC NOS cases treated at our institution in recent years and compared it with previous reports. Genomic analysis was conducted on seven formalin-fixed paraffin-embedded surgical specimens, assessing 523 DNA and 55 RNA cancer-related genes using next-generation sequencing. RESULTS: Our findings, along with previous literature, revealed the posterior mandible as the primary site in most cases, though this was rarely identified at the time of initial diagnosis. Recurrence within two years of surgery was common. Hotspot mutations in PIK3CA were observed in 60% of cases. Additionally, one patient had high TMB status. CONCLUSIONS: Given the challenges in diagnosis and the potential for rapid recurrence or metastasis, early detection is crucial. Comprehensive genomic profiling is highly desirable, as genomic analysis may direct the development of targeted therapeutic agents to treat relapse.

Humans↗