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PubMed2004

An unusual mosaic structure of the PIM gene of Theileria parva and its relationship to allelic diversity.

Genetic diversity and structural organisation of the polymorphic immunodominant molecule (PIM) gene of the protozoan parasite Theileria parva was studied in isolates from sympatric and allopatric areas. The analyses revealed a mosaic structure consisting of highly conserved regions shared among some of the isolates from geographically different areas and homologous sequence runs shared among isolates from one area. The specific pattern of diversity in which large insertions and deletions were observed, giving a mosaic structure to the PIM locus, is quite exceptional for single-locus genes. The polymorphic middle region of the gene was characterised by large deletions or insertions in many isolates. There was no correlation between the copy number of the tetrapeptide repeats in this region and the total length of the sequence. The gene was highly polymorphic when compared with sequences from other known T. parva antigenic regions. The findings support the concept that as yet unidentified mechanisms are generating extensive diversity and shaping the PIM locus. The relevance of this finding for diagnosis and the relationship between these mechanisms and the possible role of this protein in host immune responses is discussed.

Alleles↗

PubMed1997

Complex segregation analysis of schizophrenia in Santiago, Chile.

Genetic epidemiologic studies have provided evidence that genetic factors contribute to familial aggregation of schizophrenia. However, the precise mode of inheritance has not been elucidated. The majority of such studies have been carried out in Caucasian populations. The present study was performed in Santiago, Chile, whose population stems from the admixture of Amerindians with Spaniards. The sample consisted of 44 randomly ascertained schizophrenic probands (22 males and 22 females) with ages ranging between 20 and 48 years. The diagnosis was made according to DSM-III-R criteria. Both probands and relatives were interviewed using a structured interview (CIDI) and the DSM-III-R checklist. Complex segregation analysis was carried out using the computer program POINTER. The non-transmission model (Q = H = 0) was rejected as well as the recessive single locus (H = 0, Z = 1). The multifactorial, the single codominant, the non-major locus component, the non-polygenic component transmission model and the non-transmission of a major effect could not be rejected. The model that best fits the data of the present study is that of a mixed model with a great environmental component (93.12%). The frequency of the major gene was estimated at 0.000155. Our results are similar to previous reports in ethnically different populations.

Adult↗

PubMed1997

Partial characterization of a fatty acid desaturase gene in Drosophila melanogaster.

The open reading frame of a gene encoding a protein homologous to vertebrate fatty acid desaturases has been characterized in Drosophila melanogaster. This is the first description of a desaturase sequence in insects. Two cDNAs were cloned: the combined 1.5 kb nucleotide sequences indicate that the gene encodes a polypeptide of 383 amino acid residues with a high sequence similarity to the well defined delta 9 desaturases from rat and yeast and desaturases from carp and tick. The Drosophila protein contains two histidine cluster motifs (HXXHH) and two hydrophobic regions which are conserved among all desaturases, whereas the amino and carboxy ends look more variable. The desaturase gene seems to be expressed in adults at a low level, with a greater prevalence in females than in males. Two genomic sequences have been amplified by polymerase chain reaction (PCR), and have a very similar open reading frame but a different organization; one with three introns and the other without introns. Both seem to correspond to two distinct genes and have been named "desat locus". They are localized to a single locus, 87C, on the right arm of the third chromosome. The possible involvement of the desat product in the biosynthesis of D. melanogaster contact pheromones is discussed.

Amino Acid Sequence↗

PubMed2002

Power and sample sizes for linkage with extreme sampling under an oligogenic model for quantitative traits.

Extreme sampling of sibling pairs has been shown to be efficient in terms of statistical power and sample sizes (in number of sibling pairs needed to genotype) to detect a quantitative trait locus (QTL) when the residual distribution is normal. In the present study, the efficiency of extreme sampling strategies to detect each locus under an oligogenic model is analytically explored with a test statistic based on identical-by-descent (IBD) statuses of independent sibling pairs. In the oligogenic model, the joint effect of oligogenes is the sum of the effects of each locus. Under this model, detecting each single locus will depend, in part, on the allele frequencies and magnitudes of effect of the other loci. Effects of two QTLs with different magnitudes of displacement and acting nonepistatically are considered. Three types of extreme sampling-that is, extreme concordant high (ECH), extreme concordant low (ECL), and extreme discordant (ED)-are primarily considered herein. Among these, ED sampling under the oligogenic model is shown to be most efficient in most situations considered here in terms of allele frequency and mode of inheritance. Differences in results between ECH and ECL sampling are purely arbitrary, brought up mostly by the directions of displacement effects. However, power to detect a locus with the lesser (in magnitude) displacement effect does not necessarily increase with extremity of sampling. Combinations of extreme discordant and extreme concordant sibling pairs are briefly discussed.

Alleles↗

PubMed1999

Single-copy transgenic wheat generated through the resolution of complex integration patterns.

Genetic transformation of plants often results in multiple copies of the introduced DNA at a single locus. To ensure that only a single copy of a foreign gene resides in the plant genome, we used a strategy based on site-specific recombination. The transformation vector consists of a transgene flanked by recombination sites in an inverted orientation. Regardless of the number of copies integrated between the outermost transgenes, recombination between the outermost sites resolves the integrated molecules into a single copy. An example of this strategy has been demonstrated with wheat transformation, where four of four multiple-copy loci were resolved successfully into single-copy transgenes.

Chimera↗

PubMed1991

CAL1, a gene required for activity of chitin synthase 3 in Saccharomyces cerevisiae.

The CAL1 gene was cloned by complementation of the defect in Calcofluor-resistant calR1 mutants of Saccharomyces cerevisiae. Transformation of the mutants with a plasmid carrying the appropriate insert restored Calcofluor sensitivity, wild-type chitin levels and normal spore maturation. Southern blots using the DNA fragment as a probe showed hybridization to a single locus. Allelic tests indicated that the cloned gene corresponded to the calR1 locus. The DNA insert contains a single open-reading frame encoding a protein of 1,099 amino acids with a molecular mass of 124 kD. The predicted amino acid sequence shows several regions of homology with those of chitin synthases 1 and 2 from S. cerevisiae and chitin synthase 1 from Candida albicans. calR1 mutants have been found to be defective in chitin synthase 3, a trypsin-independent synthase. Transformation of the mutants with a plasmid carrying CAL1 restored chitin synthase 3 activity; however, overexpression of the enzyme was not achieved even with a high copy number plasmid. Since Calcofluor-resistance mutations different from calR1 also result in reduced levels of chitin synthase 3, it is postulated that the products of some of these CAL genes may be limiting for expression of the enzymatic activity. Disruption of the CAL1 gene was not lethal, indicating that chitin synthase 3 is not an essential enzyme for S. cerevisiae.

Amino Acid Sequence↗

PubMed1992

Novel human endogenous sequences related to human immunodeficiency virus type 1.

Endogenous retrovirus-related sequences exist within the normal genomic DNA of all eukaryotes, and these endogenous sequences have been shown to be important to the nature and biology of related exogenous retroviruses and may also play a role in cellular functions. To date, no endogenous sequences related to human immunodeficiency virus type 1 (HIV-1) have been reported. Herein we describe the first report of the presence of nucleotide sequences related to HIV-1 in human, chimpanzee, and rhesus monkey DNAs from normal uninfected individuals. We also present the isolation and characterization of two of these endogenous HIV-1-related sequences, EHS-1 and EHS-2. With use of low-stringency Southern blot hybridization, complex banding patterns were detected in human DNA with 5' and 3' HIV-1-derived probes. When an HIV-1 env region probe was used, we detected a less complex, conserved banding pattern in human DNA as well as a related but distinct banding pattern in chimpanzee and rhesus monkey DNAs. EHS-1 and -2 were cloned from normal human genomic DNA libraries by using the env region probe. Clone EHS-1 shows sequence similarity with the domain of the envelope cellular protease cleavage site of HIV-1, while EHS-2 has sequence similarity to the overlapping reading frame for Rev and gp41. Stringent hybridization of EHS-1 back to primate genomic DNA indicates two distinct EHS-1 loci in normal human DNA, an identical band pattern in chimpanzee DNA, and a single locus in rhesus monkey DNA. Likewise, EHS-2 is present as a single highly conserved locus in all three species. An oligonucleotide derived from EHS-2 across a region of near identity to HIV-1 detects a complex banding pattern in all primates tested similar to that seen with the 3' HIV-1 probe. These data suggest that most of the HIV-1-related sequences identified in primate DNA share a common core of nucleic acid sequence found in both EHS-2 and rev and that some of these HIV-1-related sequences have additional larger regions of sequence similarity to HIV-1.

Amino Acid Sequence↗

PubMed1990

Genetic imprinting in clinical genetics.

Genetic, and indeed genomic, imprinting does occur in humans. This is manifest at the level of the genome, the individual chromosome, subchromosomal region or fragile site, or the single locus. The best evidence at the single gene level comes from a consideration of familial tumour syndromes. Chromosomal imprinting effects are revealed when uniparental disomy occurs, as in the Prader-Willi syndrome and doubtless other sporadic, congenital anomaly syndromes. Genomic imprinting is manifest in the developmental defects of hydatidiform mole, teratoma and triploidy. Fragile (X) mental retardation shows an unusual pattern of inheritance, and imprinting can account for these effects. Future work in clinical genetics may identify congenital anomalies and growth disorders caused by imprinting: the identification of imprinting effects for specific chromosomal regions in mice will allow the examination of the homologous chromosomal region in humans.

Animals↗

PubMed1987

Synchronous occurrence of spontaneous localized calcium release from the sarcoplasmic reticulum generates action potentials in rat cardiac ventricular myocytes at normal resting membrane potential.

Under certain conditions, spontaneous release of Ca2+ from the sarcoplasmic reticulum occurs in resting mammalian myocardium. In single rat ventricular myocytes, such spontaneous Ca2+ release appears localized rather than homogeneous. When the increase in cytosolic Ca2+ is present in a single locus within a cell, it causes a small depolarization, which, at the normal resting potential, is subthreshold for generating an action potential. However, when spontaneous Ca2+ release occurs simultaneously at more than a single discrete locus, the resultant sarcolemmal depolarization is augmented to levels that can induce an action potential, even when this depolarization begins at the normal resting membrane potential. Thus, the synchronous occurrence of multifocal localized increases in cytosolic Ca2+ due to spontaneous Ca2+ release from the sarcoplasmic reticulum within ventricular myocytes is a mechanism for "abnormal automaticity."

Action Potentials↗

PubMed2000

Linkage analysis of sex determination in Bracon sp. near hebetor (Hymenoptera: Braconidae).

To test whether sex determination in the parasitic wasp Bracon sp. near hebetor (Hymenoptera: Braconidae) is based upon a single locus or multiple loci, a linkage map was constructed using random amplified polymorphic DNA (RAPD) markers. The map includes 71 RAPD markers and one phenotypic marker, blonde. Sex was scored in a manner consistent with segregation of a single "sex locus" under complementary sex determination (CSD), which is common in haplodiploid Hymenoptera. Under haplodiploidy, males arise from unfertilized haploid eggs and females develop from fertilized diploid eggs. With CSD, females are heterozygous at the sex locus; diploids that are homozygous at the sex locus become diploid males, which are usually inviable or sterile. Ten linkage groups were formed at a minimum LOD of 3.0, with one small linkage group that included the sex locus. To locate other putative quantitative trait loci (QTL) for sex determination, sex was also treated as a binary threshold character. Several QTL were found after conducting permutation tests on the data, including one on linkage group I that corresponds to the major sex locus. One other QTL of smaller effect had a segregation pattern opposite to that expected under CSD, while another putative QTL showed a female-specific pattern consistent with either a sex-differentiating gene or a sex-specific deleterious mutation. Comparisons are made between this study and the in-depth studies on sex determination and sex differentiation in the closely related B. hebetor.

Animals↗

PubMed1989

Genetic determination of plasma apolipoprotein AI in a population-based sample.

Apolipoprotein AI (apo AI) is the major protein of high-density lipoprotein (HDL). Using radioimmunoassay, we measured plasma apo AI levels in 1,880 individuals in 283 pedigrees randomly selected from the population with respect to disease status and risk factors for coronary artery disease. Apo AI levels were first adjusted for date of assay (6.8% of apo AI variation) and then adjusted for variability in age and body mass index (an additional 6.6%, 20.4%, and 23.0% of apo AI variations for males, females not using exogenous hormones, and females using exogenous hormones, respectively). A mixture of two normal distributions fit the adjusted data better than did a single normal distribution. Genetic and environmental models that could explain the mixture of normal distributions were investigated using complex segregation analysis. Heterogeneous etiologies for individual differences in adjusted apo AI levels were suggested by the data in the 283 pedigrees. In a subset of 126 pedigrees, there is evidence for the major effect of a nontransmitted environmental factor that explains the mixture of distributions as well as polygenic loci that influence apo AI levels within each distribution. The environmental factor and polygenic loci account for 32% and 65% of the adjusted variation, respectively. In the other 157 pedigrees there is strong support for a single locus with a major effect that accounts for 27% of the adjusted variation. The effect of the polygenic loci is not different from zero in these 157 pedigrees. This is the first study to present evidence for the segregation of a single unmeasured locus with a major effect on levels of apo AI in a population-based sample of pedigrees.

Adolescent↗

PubMed1982

Power of the affected-sib-pair method to defect disease susceptibility loci of small effect: an application to multiple sclerosis.

The distribution of marker locus identity-by-descent scores in affected sib pairs provides a powerful tool for detecting the presence of a linked non-Mendelian disease susceptibility locus. This basic approach is here extended to include a trio of sibs. A special type of sib trio consisting of two affected and one unaffected sib is investigated. It is shown that compared to affected-sib-pairs, trios with the above configuration are less efficient in detecting the presence of a linked disease susceptibility locus. When the generalized two-allele single locus model is fitted to sib pairs affected with multiple sclerosis, an estimate of the recombination fraction of 0.21 between the putative disease susceptibility locus and the HLA complex is obtained. However, this transmission model is deemed inadequate since a recombination fraction this large is inconsistent with the variety of HLA associations observed at the population level.

Chromosome Mapping↗

PubMed2005

Focal not widespread grafts induce novel dyskinetic behavior in parkinsonian rats.

Dyskinesias are a common consequence of dopaminergic therapy in patients with Parkinson's disease. Little is known about the influence of cellular replacement strategies upon drug-induced dyskinesias. In the current study, we employed parkinsonian rats to test whether the distribution of dopamine neuron grafts could differentially alter striatal circuitry and levodopa-induced dyskinesias. Specifically, we compared behavioral and neurochemical consequences of dopamine reinnervation restricted to a focal region of the striatum to innervation encompassing the majority of the striatum by distributing the same number of cells into single locus or multiple locations. Both the single-site and widespread grafts reduced pregraft dyskinesias and normalized FosB/DeltaFosB in the dorsal two-thirds of the lateral striatum. However, single-site DA graft recipients developed a robust, novel forelimb-facial stereotypy and upregulated FosB/DeltaFosB expression in the ventrolateral striatum, an area associated with movements of tongue and forelimbs. The onset of forelimb-facial stereotypy correlated with measures of increased graft function.

Animals↗

PubMed1999

Commentary on Annett, Yeo et al., Klar, Saugstad and Orr: cerebral asymmetry, language and psychosis--the case for a Homo sapiens-specific sex-linked gene for brain growth.

Annett, Yeo et al. and Klar have each proposed theories that relate the genetics of cerebral lateralization to predisposition to psychosis. These theories are considered in relation to the central paradox that psychosis is associated with a substantial biological disadvantage. Annett's heterozygote advantage hypothesis critically identified lateralization as a major determinant of ability, but it appears that what is inherited is degrees (as suggested by Yeo et al.) rather than (or as well as) direction of lateralization. Relative hand skill has been shown (Crow, T.J., Crow, L.R., Done, D.J., Leask, S.J., 1998. Relative hand skill predicts academic ability: global deficits at the point of hemispheric indecision. Neuropsychologia 36, 1275-1282.) to be a powerful predictor (interacting with sex) of academic ability but the greatest region of vulnerability (that includes reading disability and predisposition to psychosis) is close to the point of equal hand skill ('hemispheric indecision'). In contrast with Annett's single locus, Yeo's polygenic and Klar's strand-segregation hypotheses, each of which postulates an autosomal locus or loci, the hypothesis of a single gene for asymmetry located in a sex-specific region of homology on both X and Y chromosomes can account for sex differences, as observed in age of onset, and premorbid precursors of psychosis, as well as differences in the general population in relation to degrees of hand skill, verbal ability and cerebral asymmetry. The evolutionarily recent transposition to, and subsequent paracentric inversion in, the Y chromosome short arm of a 4-Mb block from Xq21.3 (the proximal long arm of the X) are candidates for speciation events in the lineage that led to Homo sapiens. A gene associated with a range of variation (that may be due to a high mutation site, or perhaps to epigenetic modification) on the Y that overlaps with, but differs quantitatively from, that on the X may explain the sex differences associated with psychosis, and may be relevant to its persistence. Such a gene could be the principal determinant in Man of the rate of brain growth, as suggested by Saugstad and by the findings of a recent study of adolescent onset psychosis (James, A., Crow, T.J., Renowden, S., Wardell, M., Smith, D.M., Anslow, P., in press. Is the course of brain development in schizophrenia delayed? Evidence from onsets in adolescence. Schizophr. Res.).

Biological Evolution↗

PubMed2002

New strategies for identifying gene-gene interactions in hypertension.

Essential hypertension is a common disease that has a complex multifactorial etiology. For this reason, it is not surprising that studies of the effects of single genes on hypertension have often failed to replicate the original findings. We propose, as a working hypothesis, that the failure to replicate some single locus results is because the impact of single alleles on the risk of hypertension is dependent on genetic variations at other loci (i.e. gene-gene interactions) and on environmental factors (i.e. gene-environment interactions). Thus, studies that do not consider the appropriate genetic and/or environmental contexts may not identify important susceptibility loci. The identification and characterization of such gene-gene and gene-environment interactions have been limited by a lack of powerful statistical methods and/or a lack of large enough sample sizes. Here, we review the general problem of identifying gene-gene interactions and describe several traditional and several newer methods that are being used to assess complex genetic interactions in essential hypertension.

Gene Frequency↗

PubMed1995

Transcription and processing of the rodent ID repeat family in germline and somatic cells.

ID elements comprise a rodent SINE (short interspersed DNA repetitive element) family that has amplified by retroposition of a few master genes. In order to understand the important factors of SINE amplification, we investigated the transcription of rat ID elements. Three different size classes of ID transcripts, BC1, BC2 and T3, have been detected in various rat tissues, including brain and testes. We have analysed the nucleotide sequences of testes- and brain-derived ID transcripts isolated by size-fractionation, C-tailing and RACE. Nucleotide sequence variation of testes ID transcripts demonstrated derivation from different loci. However, the transcripts represent a preferred set of ID elements that closely match the subfamily consensus sequences. The small ID transcripts, T3, are not comprised of primary transcripts, but are instead processed polyA-transcripts generated from many different loci. These truncated transcripts would be expected to be retroposition-incompetent forms. Therefore, the amplification of ID elements is likely to be regulated at multiple steps of retroposition, which include transcription and processing. Although brain ID transcripts showed a similar pattern, with the addition of very high levels of transcription from the BC1 locus, we also found evidence that a single locus dominated the production of brain BC2 RNA species. BC1 RNA is highly stable in both germ line and brain cells, based on the low level of detection of the processing product, T3. This stability of BC1 RNA might have been a contributing factor in its role as a master gene for ID amplification.

Animals↗

PubMed1990

Genetic systems of red cell blood groups in goats.

Evidence is presented for six genetic systems of goat red cell blood groups. The A system presently consists of one specificity, two alleles, two phenotypes (A1 and no-A1) and appears to be homologous to the A system of sheep. The B system, like its homologue in sheep, is very complex. Fourteen of 21 specificities detected in the present study, i.e. B2, B3, B4, B5, B7, B8, B9, B10, B11, B14, B15, B16, B17 and B20, belong to the B system which involves a large number of phenogroups (31 different B phenogroups identified in 26 sires). Because of their homology with sheep C and R systems, two other genetic systems of goat blood groups are named C and R respectively. Each of the two goat systems is presently a one blood group specificity, two phenotype (C12 and no-C12; R and no-R detectable on the red cells) two allele system. Two specificities, namely E6 and E18, belong to a genetic system called E in which four phenotypes are under the control of two alleles codominant and one recessive at a single locus. The F system involves but a single pair of alleles and two phenotypes (F19 and no-F19). Because of its low frequency in the goats tested, the X13 specificity remains unassigned.

Alleles↗

PubMed2001

Relationship between monokaryotic growth rate and mating type in the edible basidiomycete Pleurotus ostreatus.

The edible fungus Pleurotus ostreatus (oyster mushroom) is an industrially produced heterothallic homobasidiomycete whose mating is controlled by a bifactorial tetrapolar genetic system. Two mating loci (matA and matB) control different steps of hyphal fusion, nuclear migration, and nuclear sorting during the onset and progress of the dikaryotic growth. Previous studies have shown that the segregation of the alleles present at the matB locus differs from that expected for a single locus because (i) new nonparental B alleles appeared in the progeny and (ii) there was a distortion in the segregation of the genomic regions close to this mating locus. In this study, we pursued these observations by using a genetic approach based on the identification of molecular markers linked to the matB locus that allowed us to dissect it into two genetically linked subunits (matBalpha and matBbeta) and to correlate the presence of specific matBalpha and matA alleles with differences in monokaryotic growth rate. The availability of these molecular markers and the mating type dependence of growth rate in monokaryons can be helpful for marker-assisted selection of fast-growing monokaryons to be used in the construction of dikaryons able to colonize the substrate faster than the competitors responsible for reductions in the industrial yield of this fungus.

Alleles↗