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A combined segregation, linkage, and association analysis using the program COMBIN was performed on the simulated pedigree data prepared for the Second Genetic Analysis Workshop. The model used in COMBIN is described and the presented results illustrate its effectiveness in the analysis of such data. Linkage analysis was performed and maps for each linkage group are presented.
The process and results of genetic analysis of the short-stem rye populations (Secale cereale L.) for the trait "plant height" are described. The analysis has been performed with the joint scaling test using data of estimation of the parental and hybrid populations developed in the cyclic reciprocal crosses between four initial populations. Monogenic, digenic, and trigenic differences between parental rye populations for two genes of incomplete dominance and one multiallelic gene with additive allelic interaction were determined.
The inbred mouse strains BALB/cBy (C) and C57BL/6By (B6) differed significantly in their susceptibility to seizures induced by the benzodiazepine inverse agonist methyl beta-carboline-3-carboxylate (beta-CCM). Following a 5 mg/kg injection of beta-CCM, 74% of C (n = 35) and 13% of B6 (n = 40) mice exhibited a convulsion. No sex difference was found. Analysis of the reciprocal F1s failed to show either maternal environmental and/or heterosomal effects. A genetic analysis of the strain difference in susceptibility to beta-CCM-induced seizures using recombinant inbred strains (RIS) was performed. The strain distribution for the RIS showed a two group partition. Statistical analysis showed that, although a one-segregating-unit model could not be rejected to explain the strain difference in beta-CCM-induced seizures, some of the evidence weakened the one-segregating-unit hypothesis.
The atypical structure and behavior of dinoflagellate chromosomes suggests that the genetics of these organisms might show comparable peculiarities. We have begun genetic analysis of the neritic, marine heterotroph Crypthecodinium (Gyrodinium) cohnii by means of motility mutants that show complementation shortly after zygote formation, permitting identification of heterozygotes. Six mutations, conferring four microscopically distinguishable phenotypes, have been isolated and investigated. These "genes" were found to complement in double heterozygotes in all pairwise combinations, indicating that the lesions are recessive and non-allelic. Clones of all possible combinations of these factors have been established and each complements only those combinations expected on the assumption that there are six independent recessive mutant "genes." Tetrad analysis following isolation of over 200 complementing zygotes showed: (1) regular segregation with recovery of parental phenotypes and genotypes; (2) independent assortment, with one possible exception; (3) segregations that were always 1:1, that is, in all tetrads showing recombination, only the two reciprocal recombinant genotypes were found; there were no tetratypes. This behavior could result from centromere linkage or the absence of crossing over in an otherwise conventional meiosis, or it could result from an unusual one-division "meiosis." Some evidence is provided that favors the latter hypothesis.
PURPOSE: Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) is a rare eye genetic disorder caused by mutations in the FOXL2 gene located at chromosome 3q23. The purpose of the present study was to carry out genetic analysis of BPES in a five-generation Indian family. METHODS: Peripheral blood samples were obtained from individuals for genomic DNA isolation. To determine the linkage of this family to the FOXL2 locus, haplotype analysis was carried out using microsatellite markers from the BPES candidate region. Five overlapping sets of primers were used to amplify the entire coding region of the FOXL2 gene for mutation detection. Allele-specific oligonucleotide hybridization (ASOH) analysis was carried out to determine segregation of the mutation in the family and to also determine if the mutation was present in 100 ethnically matched normal control chromosomes. RESULTS: Pedigree analysis suggested that BPES segregated in this family as an autosomal dominant trait. Cytogenetic analysis in one patient did not reveal any rearrangement. Haplotype analysis suggested that this family was linked to the FOXL2 locus on chromosome 3q23. DNA sequence analysis showed that the BPES phenotype in this family was caused by a novel missense mutation, c.881A->G (p.Y215C). CONCLUSIONS: This study reports for the first time a novel missense mutation in a five-generation Indian family with BPES. A review of the literature showed that the total number of mutations in the FOXL2 gene described to date is 42.
We propose the mixed model or multilevel model as a general alternative approach to existing behavior genetic analysis-an alternative to correlation analysis, the DeFries-Fulker analysis, and structural equation modeling. The mixed or multilevel model handles readily families of behavioral genetic data, which include paired sibling data (e.g., pairs of MZ and DZ twins) and clustered sibling data (e.g., a family of more than two biological siblings) as special cases. Not only can a family of behavioral genetic data have more than two siblings, it can also contain multiple types of siblings (e.g., a pair of MZ twins, a pair of DZ twins, a full sibling, and a half sibling). In contrast to the traditional approaches, the mixed or multilevel model is insensitive to the order of the siblings in a sibling cluster. We apply our approach to a large, nationally representative behavior genetic sample collected recently by the Add Health Study. We demonstrate the approach through several applications using both clustered and family complex behavioral genetic data: conventional variance decomposition analysis, analysis of interactions between genetic and environmental influences, and analysis of the possible genetic basis for friendship selection. We compare results from the mixed or multilevel model, Pearson's correlation analysis, and the structural equation model.
Evidentiary items sometimes contain an insufficient quantity of DNA for routine forensic genetic analysis. These so-called low copy number DNA samples (< 100 pg of genomic DNA) often fall below the sensitivity limitations of routine DNA analysis methods. Theoretically, one way of making such intractable samples amenable to analysis would be to increase the number of starting genomes available for subsequent STR (short tandem repeat) analysis by a whole genome amplification strategy (WGA). Although numerous studies employing WGA have focused primarily on clinical applications, few in-depth studies have been conducted to evaluate the potential usefulness of these methods in forensic casework. After an initial evaluation of existing methods, a modified WGA strategy was developed that appears to have utility for low copy number forensic casework specimens. The method employs a slight, but important, modification of the "improved primer extension preamplification PCR" method (I-PEP-PCR), which we term mIPEP (modified-I-PEP-PCR). Complete autosomal STR and Y-STR (Y chromosome short tandem repeat) profiles were routinely obtained with 5 pg of template DNA, which is equivalent to 1-2 diploid cells. Remarkably, partial Y- and autosomal STR profiles were obtained from mIPEP-treated DNA recovered from bloodstains exposed to the outside environment for 1 year whereas non-mIPEP-treated samples did not produce profiles. STR profiles were obtained from contact DNA from single dermal ridge fingerprints when the DNA was subjected to prior mIPEP amplification but not when the mIPEP step was omitted.
This review will examine the application of genetic analysis to cytological specimens obtained by fine-needle aspiration biopsy in the management of thyroid tumours. In particular, it will consider the use of polymerase chain reaction-based techniques in the diagnosis of the micrometastasis of differentiated thyroid carcinoma to cervical lymph nodes, as well as in the detection of oncogenic alterations in solid thyroid nodules.
Contemporary molecular genetic analysis methods have not been used to study large samples of carriage isolates of group A Streptococcus. To determine the emm types causing asymptomatic carriage and pharyngitis in a closed population, we analyzed 675 isolates recovered from a population-based surveillance study of 10,634 recruits at Lackland Air Force Base, Texas, during 4 months in 1993-1994. Strains with emm1 and emm6 alleles accounted for only 22% of the isolates recovered from asymptomatic recruits at entrance to training. However, these 2 emm types caused 69% of the pharyngitis cases identified during training and represented 51% of the isolates recovered from the throat on exit from training. Sequence analysis of the hypervariable sic gene documented that distinct emm1 subclones disseminated in specific training groups called flights. The preferential increase in the prevalence of emm1 and emm6 isolates during the 6-week training period indicates an enhanced ability of these strains to disseminate and cause disease in this population.
The analysis of how human cancers evade chemotherapy has revealed a rich variety of cell-based genetic changes resulting in drug resistance. One of the best studied of these genetic alterations is increased expression of an ATP-dependent plasma membrane transport system, known as P-glycoprotein, or the multidrug transporter. This transporter actively effluxes a large number of natural product, hydrophobic, cytotoxic drugs, including many important anticancer agents. This review focuses on the genetic and molecular genetic analysis of the human multidrug transporter, including structure-function analysis, pre- and posttranslational regulation of expression, the role of gene amplification in increased expression, and the properties of transgenic and "knock-out" mice. One important feature of the MDR gene is its potential for the development of new selectable vectors for human gene therapy.
The mld mutation is a complex genetic lesion affecting the myelin basic protein (MBP) locus in the mouse. The mutation consists of a variety of DNA rearrangements including: tandem duplication of the MBP structural gene, partial inversion of the 3' end of the upstream gene copy, duplication of a region flanking the rearrangement junction in the upstream copy and insertion between the two gene copies of a segment of extraneous DNA not associated with the wild-type MBP locus. The net result of the mutation is a dysfunctional MBP locus. Homozygous mld/mld mice produce very little MBP and consequently very little myelin. They exhibit a clinical phenotype characteristic of hypomyelination (shaking, convulsions). We have discovered a revertant mld mouse which does not exhibit clinical symptoms of hypomyelination. Genetic analysis indicates that the reversion is allelic to mld. We have designated the revertant locus mldr. Restriction analysis of mldr genomic DNA indicates that there is a single intact MBP gene. Analysis of various junction regions using the polymerase chain reaction indicates that the single MBP gene in mldr is derived by recombination from the 5' end of the upstream gene and the 3' end of the downstream gene. Studies on MBP expression in mldr mice indicate that the developmental regulation, level of expression and pattern of post-transcriptional processing of MBP gene products in mldr are similar to wild type. These results indicate that the recombinant MBP gene in mldr is fully functional. From this we infer that the MBP-deficient phenotype of the original mld mutant is attributable to the complex rearrangements in the upstream gene copy which render the locus dysfunctional.(ABSTRACT TRUNCATED AT 250 WORDS)
We analyzed disease-marker associations in Problem 3 for the Genetic Analysis Workshop II, using PAP for segregation analysis and LIPED for linkage analysis. In this report we present aspects of our analyses that are not reported in the summary [MacCluer et al, 1984]. Certain features that we added to the running of LIPED to facilitate the analysis are discussed. Furthermore, we tested for Mendelian transmission in the hypothetical trait locus and we calculated modified relative risks for marker-trait genotypes. Some of the problems involved in analyzing complex associations among loci are discussed.
Molecular genetic analysis of polymorphism of the factor VIII gene at loci HindIII (intron 19) and (CA)-repeats (intron 13) was performed in seven ethnic groups of the Volga-Ural region (Bashkirs, Tatars, Chuvashes, Maris, Mordovians, Udmurts, and Komis). The allelic frequency of the HindIII locus was shown to be similar in these ethnic groups. The ethnic groups were more heterogeneous with regard to the genotype and allele frequencies of (CA)-repeats, which indicates that this polymorphic system can be used to characterize the genetic structure of the Volga-Ural human populations.
The ambulatory and rearing responses to d-amphetamine were studied in a battery of recombinant inbred strains and in three closely related strains: C57BL/6J, C57BL/10J, and C57BL/6By. Differences in the increase of ambulation (stimulation) caused by d-amphetamine were seen between C57BL/6By and the other two C57BL strains. Analysis of F1 and backcross matings suggests a one-gene model. A mutation at the genetic locus that affects the response to d-amphetamine seems to have taken place in the C57BL/6By strain. Strain differences in the decrease of rearing behavior (inhibition) produced by the drug were observed in recombinant inbred strains. Although the genetic analysis is not conclusive, it appears to be compatible with regulation by a single major gene. The two single-gene models reported here (one affecting the stimulatory response and the other the inhibitory response to d-amphetamine) may be useful in the study of neural mechanisms involved in stimulation and inhibition of behavior by d-amphetamine.
When normal nontumorigenic cells are fused with tumorigenic cells some of the resulting hybrids are nontumorigenic in respect to their ability to grow in immune-deficient nude mice. Comparison of the chromosome content of nontumorigenic with tumorigenic hybrids, as well as with the cells of tumors which develop from the latter, reveals that in normal human x tumorigenic Chinese hamster hybrid crosses, two specific human chromosomes of the nontumorigenic parental line are very likely responsible for the suppressive effect. In some other hybrid crosses these and additional human chromosomes also seem to cause suppression. These findings suggest that a tumorigenic cell has lost at least two and possibly more gene functions which determine normal growth responses. The chromosomes from a normal cell can apparently correct these defects, although it is not yet clear if this is true genetic complementation or due to introduction of other genes which control cell growth or a cell's response to environmental growth regulatory stimuli. These findings led support to the view that genetic alterations are important in the process of malignant transformation and allow the development of a working hypothesis for the possible mechanisms involved. Some findings of other workers in this area also suggest that malignant cells may be producing some cell membrane proteins which are different from those of nontumorigenic cells. If this turns out to be true then it may ultimately be possible to develop immunotherapeutic procedures, i.e., to produce tumor cell specific antisera.
Mutants of the yeast Saccaromyces cerevisiae which can grow on glycerol medium in the presence of 0.05% D (+) glucosamine have been isolated. Genetic analysis of 13 of these glucosamine resistant (GR) mutants demonstrated two modes of inheritance. One group of mutants (GR 5, 6, 7, 8, 9 and 10) gave results characteristic of non-Mendelian inheritance and it is suggested that these mutants represent one or more new mitochondial loci. Four of the remaining mutants showed clear-cut Mendelian inheritance. These mutants fell into two complementation groups and subsequent mapping experiments demonstrated that two independent loci, gay 1 and gay 2, unlinked to each other or to the centromeres of chromosomes I, II, IV, VIII or IX, were responsible for conferring glucosamine resistance in these mutants.
BACKGROUND: Haemophilias are the most common hereditary severe disorders of blood clotting. In families afflicted with heamophilia, genetic analysis provides opportunities to prevent recurrence of the disease. This study establishes a diagnostical strategy for carriership determination and prenatal diagnostics of haemophilia A in Bulgarian haemophilic population. METHODS: A diagnostical strategy consisting of screening for most common mutations in the factor VIII gene and analysis of a panel of eight linked to the factor VIII gene locus polymorphisms was established. RESULTS: Polymorphic analysis for carrier status determination of haemophilia A was successful in 30 families out of 32 (94%). Carrier status was determined in 25 of a total of 28 women at risk (89%). Fourteen prenatal diagnoses in women at high risk of having a haemophilia A - affected child were performed, resulting in 6 healthy boys and 5 girls. CONCLUSION: The compound approach proves to be a highly informative and cost-effective strategy for prevention of recurrence of haemophilia A in Bulgaria. DNA analysis facilitates carriership determination and subsequent prenatal diagnosis in the majority of Bulgarian families affected by haemophilia A.
Moderately dense maps of single-nucleotide polymorphism (SNP) markers across the human genome for both the simulated data set and data from the Collaborative Study of the Genetics of Alcoholism were available at Genetic Analysis Workshop 14 for the first time. This allowed examination of various novel and existing methods for haplotype analyses. Three contributors applied Mantel statistics in different ways for both linkage and association analysis by using the shared length between two haplotypes at a marker locus as a measure of genetic similarity. The results indicate that haplotype-sharing based on Mantel statistics can be a powerful approach and needs further methodological evaluation. Four contributors investigated haplotype-tagging SNP (htSNP) selection procedures, two contributors examined the use of multilocus haplotypes compared to single loci in association tests, and two contributors compared the accuracy of various methods for reconstructing haplotypes and estimating haplotype frequencies for both pedigree data and data from unrelated individuals. For all three different tasks, software packages and procedures gave similar results in regions of high linkage disequilibrium (LD). However, they were not as consistent in regions of moderate to low LD. One coalescence-based approach for estimating haplotype frequencies, coupled with a Markov chain Monte Carlo technique, outperformed the other haplotype frequency estimation methods in regions of low LD. In conclusion, regardless of the task, results were similar in chromosomal regions of high LD. However, based on the differing results observed here, methodological improvements are required for chromosomal regions of low to moderate LD.