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PubMedDate not supplied

[Genomic imprinting and human pathology. 2].

Genetic imprinting does occur in humans. This is manifest at the level of the genome, the individual chromosome or subcromosomal region, and the single locus. Genomic imprinting is manifest in the developmental defects of hydatiform mole, teratoma and triploidy. Chromosomal imprinting effects are revealed when uniparental disomy or deletion occur as costitutional aberration or in tumural tissues. Evidence at the single gene level comes from an increasing number of autosomal dominant genetic diseases. This part of the paper will briefly review the importance of imprinting in the contest of human genetic diseases.

Adult↗
PubMed1987

Assignment of human tryptophan hydroxylase locus to chromosome 11: gene duplication and translocation in evolution of aromatic amino acid hydroxylases.

A cDNA clone for rabbit tryptophan hydroxylase was used as a probe to identify human tryptophan hydroxylase gene fragments in a panel of hamster-human somatic cell hybrids and determine its chromosomal location in man. A single locus was identified for tryptophan hydroxylase on chromosome 11. Tryptophan hydroxylase is a member of the superfamily of pterin-dependent aromatic amino acid hydroxylases which includes tyrosine hydroxylase, located at 11p15.5-p15, and phenylalanine hydroxylase, located at 12q22-q24.1 in human. The locations of these genes and the evolutionary distance between their sequences suggest that at least three distinct genetic events have occurred during the evolution of the aromatic amino acid hydroxylase superfamily: two sequential gene duplications giving rise to the three distinct hydroxylase loci, and a translocation which separated the tryptophan and tyrosine hydroxylase loci on chromosome 11 from the phenylalanine hydroxylase locus on chromosome 12.

Animals↗
PubMed1999

Assignment of chromosomal locus and evidence for alternatively spliced mRNAs of a human sperm membrane protein (hSMP-1).

The gene (HSD-1) coding a human sperm membrane protein (hSMP-1) was isolated from a human testis cDNA expression library using antibodies found in the serum of an infertile woman. HSD-1 was localized to a single locus on chromosome 9 and assigned to band 9p12-p13 by fluorescent in situ hybridization (FISH) mapping and DAPI (4,6-diamidino-2-phenylindole) banding, using rat/human somatic cell hybrids and metaphase chromosomes of human lymphocytes. In rescreening a testis lambdagt10 cDNA expression library, the full-length cDNA (HSD-1) and several truncated cDNAs with heterologous regions were isolated from positive clones. The heterology consisted of deletion, insertion and alteration of the 5'-end. These heterologous truncated fragments may be produced by alternative splicing of mRNAs. Two recombinant prokaryotic expression vectors were constructed with one of the heterologous fragment (clone #26) with and without the alternative 5'-end. Escherichia coli transfected with the construct containing the alternative 5'-end failed to produce the recombinant product, whereas those transfected with the vector lacking the 5'-end produced hSMP-1. DNASIS analysis of the structure of #26 mRNA suggests that the 5'-end has a stable secondary configuration that may maintain the mRNA in an inactivated state, whereby hindering its translation and preventing the expression of the gene.

Amino Acid Sequence↗
PubMed1993

Joint linkage of multiple loci for a complex disorder.

Many investigators who have been searching for linkage to complex diseases have by now accumulated a drawer full of negative results. If disease is actually caused by genes at several loci, these data might contain multiple-locus system (MLS) information that the investigator does not realize. Trying to obtain this information formally, through the MLS likelihood, leads to severe computational and statistical difficulties. Therefore, we propose a scheme of inference based on single-locus (SL) statistics, considered jointly. By simulation, we find that the MLS lod score is closely approximated by the sum of SL lod scores. However, we also find that for moderately large systems, say three of four loci, both MLS and SL lod scores are likely to be inconclusive. Nonetheless, MLS can often be detected through the correlation of individual pedigree SL lod scores. Significant correlation is itself evidence of an MLS, because, in the absence of linkage, false-positive lod scores are necessarily random. Under epistasis SL lod scores tend to be positively correlated among pedigrees, while under independent action SL lod scores from high-density samples tend to be negatively correlated.

Chi-Square Distribution↗
PubMed1993

Two-trait-locus linkage analysis: a powerful strategy for mapping complex genetic traits.

Recent advances in molecular biology have provided geneticists with ever-increasing numbers of highly polymorphic genetic markers that have made possible linkage mapping of loci responsible for many human diseases. However, nearly all diseases mapped to date follow clear Mendelian, single-locus segregation patterns. In contrast, many common familial diseases such as diabetes, psoriasis, several forms of cancer, and schizophrenia are familial and appear to have a genetic component but do not exhibit simple Mendelian transmission. More complex models are required to explain the genetics of these important diseases. In this paper, we explore two-trait-locus, two-marker-locus linkage analysis in which two trait loci are mapped simultaneously to separate genetic markers. We compare the utility of this approach to standard one-trait-locus, one-marker-locus linkage analysis with and without allowance for heterogeneity. We also compare the utility of the two-trait-locus, two-marker-locus analysis to two-trait-locus, one-marker-locus linkage analysis. For common diseases, pedigrees are often bilineal, with disease genes entering via two or more unrelated pedigree members. Since such pedigrees often are avoided in linkage studies, we also investigate the relative information content of unilineal and bilineal pedigrees. For the dominant-or-recessive and threshold models that we consider, we find that two-trait-locus, two-marker-locus linkage analysis can provide substantially more linkage information, as measured by expected maximum lod score, than standard one-trait-locus, one-marker-locus methods, even allowing for heterogeneity, while, for a dominant-or-dominant generating model, one-locus models that allow for heterogeneity extract essentially as much information as the two-trait-locus methods. For these three models, we also find that bilineal pedigrees provide sufficient linkage information to warrant their inclusion in such studies. We also discuss strategies for assessing the significance of the two linkages assumed in two-trait-locus, two-marker-locus models.

Chromosome Mapping↗
PubMed2001

A centuries-long epidemic of scrapie in British sheep?

The apparent persistence of scrapie in British sheep for more than 250 years is difficult to explain. Susceptibility to scrapie is associated with particular alleles at a single locus, the PrP gene. As the only known effect of these alleles is to confer susceptibility to a fatal disease, natural selection is expected to reduce their frequency, as has been observed in practice during scrapie outbreaks in single sheep flocks. Susceptibility alleles, and hence scrapie itself, are therefore expected to become rare, yet the disease remains widespread. We suggest that the paradox of scrapie's persistence can be explained by the exceptionally long time-scales inherent in the epidemiology of the disease. It is proposed that scrapie should be regarded as epidemic in British sheep but, unlike more familiar epidemics, which have time-scales of months or years, the scrapie epidemic has a time-scale of centuries. This interpretation implies that scrapie should eventually disappear from the sheep population.

Animals↗
PubMed2006

A clarification of the Hardy-Weinberg law.

C. C. Li showed that Hardy-Weinberg proportions (HWP) can be maintained in a large population by nonrandom mating as well as random mating. In particular he gave the mating matrix for the symmetric case in the most general form possible. Thus Li showed that, once HWP are attained, the same proportions can be maintained by what he called pseudorandom mating. This article shows that, starting from any genotypic distribution at a single locus with two alleles, the same in each sex, HWP can be reached in one round of nonrandom mating with no change in allele frequency. In the model that demonstrates this fact, random mating is represented by a single point in a continuum of nonrandom possibilities.

Alleles↗
PubMed1999

The Caenorhabditis elegans unc-49 locus encodes multiple subunits of a heteromultimeric GABA receptor.

Ionotropic GABA receptors generally require the products of three subunit genes. By contrast, the GABA receptor needed for locomotion in Caenorhabditis elegans requires only the unc-49 gene. We cloned unc-49 and demonstrated that it possesses an unusual overlapping gene structure. unc-49 contains a single copy of a GABA receptor N terminus, followed by three tandem copies of a GABA receptor C terminus. Using a single promoter, unc-49 generates three distinct GABAA receptor-like subunits by splicing the N terminus to each of the three C-terminal repeats. This organization suggests that the three UNC-49 subunits (UNC-49A, UNC-49B, and UNC-49C) are coordinately rescued and therefore might coassemble to form a heteromultimeric GABA receptor. Surprisingly, only UNC-49B and UNC-49C are expressed at high levels, whereas UNC-49A expression is barely detectable. Green fluorescent protein-tagged UNC-49B and UNC-49C subunits are coexpressed in muscle cells and are colocalized to synaptic regions. UNC-49B and UNC-49C also coassemble efficiently in Xenopus oocytes and HEK-293 cells to form a heteromeric GABA receptor. Together these data argue that UNC-49B and UNC-49C coassemble at the C. elegans neuromuscular junction. Thus, C. elegans is able to encode a heteromeric GABA receptor with a single locus.

Alternative Splicing↗
PubMed1993

Complex segregation analysis of antibodies to thyroid peroxidase in Old Order Amish families.

Autoimmune thyroid disease (AITD) may be characterized by the measurement in serum of antibodies to thyroid peroxidase. A population of Old Order Amish individuals and families was investigated to determine the prevalence of these antibodies and to examine hypotheses about the mode of transmission of thyroid antibodies. Complex segregation analyses were performed on 4 large multigenerational Old Order Amish families composed of 26 nuclear families containing 199 first degree relatives. Several alternative hypotheses of genetic transmission were examined. Hypotheses of no transmission, polygenic inheritance, single locus transmission, and mixed inheritance were compared. The analyses incorporated population prevalences obtained from a random sample of individuals. Results suggest that the pattern of transmission of thyroid antibodies in these families is consistent with a mixed model in which the major gene is transmitted in an autosomal dominant pattern. The mixed model postulates that there is a single gene of major effect as well as a polygenic component that can act separately and/or together to confer susceptibility for this phenotype. The parameter estimates for the major locus are: gene frequency (q), 0.16 +/- 0.01; maximum male penetrance, 0.35; and maximum female penetrance, 0.70. The heritability of the polygenic background is estimated at 0.41.

Adolescent↗
PubMed2001

Genetic variation in beta-adrenergic receptors and their relationship to susceptibility for asthma and therapeutic response.

Our early work focused on quantitative variation in traits related to beta-adrenergic signaling: lymphocyte levels of cAMP and the binding properties of the beta-adrenergic receptor. We confirmed the work of others that the major histocompatibility locus had an effect on cAMP levels in mice and in man. The latter result was presumably due to the influence of beta-adrenergic receptors, since it was the isoproterenol-stimulated lymphocyte cAMP level that was studied. We went on to directly study beta-adrenergic receptor levels in mouse hepatic plasma membranes using dihydroalprenolol binding. We discovered a strain variation, apparently controlled by a single locus, which determined a magnesium influence on measurable levels of dihydroalprenolol binding. More recently, our group's work has focused on the human single nucleotide polymorphisms (SNPs) in the human beta2-adrenergic receptor. We found that variation at amino acid position 16 had a very marked effect on the response of subjects to albuterol. Similar trends were observed for asthmatic and nonasthmatic children, and the results were independent of baseline lung function. Our results, and those of other groups relating SNPs in the beta-adrenergic receptor to a number of responses, mostly related to asthma, are reviewed in this article.

Animals↗
PubMed2002

Expression of mRNA and functional alpha(1)-adrenoceptors that suppress the GIRK conductance in adult rat locus coeruleus neurons.

1. Locus coeruleus neurons in adult rats express binding sites and mRNA for alpha(1)-adrenoceptors even though the depolarizing effect of alpha(1)-adrenoceptor agonists on neonatal neurons disappears during development. 2. In this study intracellular microelectrodes were used to record from locus coeruleus neurons in brain slices of adult rats and reverse transcription-polymerase chain reaction (RT - PCR) was used to investigate the mRNA expression of alpha(1)- and alpha(2)-adrenoceptors in juvenile and adult rats. 3. The alpha(1)-adrenoceptor agonist phenylephrine had no effect on the membrane conductance of locus coeruleus neurons (V(hold) -60 mV) but decreased the G protein coupled, inward rectifier potassium (GIRK) conductance induced by alpha(2)-adrenoceptor or mu-opioid agonists. The GIRK conductance induced by noradrenaline was increased in amplitude when alpha(1)-adrenoceptors were blocked with prazosin. 4. RT - PCR of total cellular RNA isolated from microdissected locus coeruleus tissue demonstrated strong mRNA expression of alpha(1a)-, alpha(1b)- and alpha(1d)-adrenoceptors in both juvenile and adult rats. However, only mRNA transcripts for the alpha(1b)-adrenoceptors were consistently detected in cytoplasmic samples taken from single locus coeruleus neurons of juvenile rats, suggesting that this subtype may be responsible for the physiological effects seen in juvenile rats. 5. Juvenile and adult locus coeruleus tissue expressed mRNA for the alpha(2a)- and alpha(2c)-adrenoceptors while the alpha(2b)-adrenoceptor was only weakly expressed in juveniles and was not detected in adults. 6. The results of this study show that alpha(1)-adrenoceptors expressed in adult locus coeruleus neurons function to suppress the GIRK conductance that is activated by mu-opioid and alpha(2)-adrenoceptors.

Action Potentials↗
PubMed2005

Flowering phenology and sexual allocation in single-mutation lineages of Arabidopsis thaliana.

We investigated the relationship between flowering time and sexual allocation in wild-type Arabidopsis thaliana and in genetically similar lineages with single-locus mutations of floral induction genes. We examined whether the mechanisms of growth and development that govern resource investment would permit the independent evolution of reproductive phenology and sexual allocation, or whether constraints, manifested as pleiotropic effects of the single mutations, would link these two life-history traits. Flowering times differed significantly among genotypes, and, as expected, later flowering times were associated with larger vegetative size. Later flowering genotypes produced heavier floral parts (larger petals, in particular), and allocated a significantly lower proportion of biomass to androecia, especially in final allocations that included fruit biomass. At least part of this pleiotropic covariation of flowering time and sexual allocation is likely to be mediated by vegetative size and the rate of resource supply to growing reproductive tissues, because the larger fruits of late-flowering genotypes required the same time, or proportionately less time than the difference in biomass, to mature. Because fruit mass is considered an investment in female function, sexual allocation measured at the end of a growing season tends to be highly female biased in angiosperms. We consider the implications of the pleiotropic association of flowering time, vegetative size, and sexual investment for the theory of sex allocation, and suggest that the idiosyncratic phenology of sexual investment in flowering plants creates a departure from a central assumption of Fisher's seminal sex allocation argument.

Analysis of Variance↗
PubMed1998

Further refinement of the Usher 2A locus at 1q41.

Usher syndrome (USH) is characterised by congenital sensorineural hearing loss and progressive pigmentary retinopathy. All three subtypes (USH1, USH2, and USH3) are inherited as recessive traits. People with Usher type 2 (USH2) have normal vestibular responses and moderate to severe hearing loss. These syndromes have been found to be genetically heterogeneous, with a single locus for USH2 at 1q41 (USH2A), six loci for USH1, and one for USH3. Some USH2 families have been excluded from the 1q41 locus suggesting that a second, as yet unidentified, locus (USH2B) must exist. Linkage studies suggest that around 90% of USH2 families are USH2A. Four USH2 families were analysed for linkage to markers flanking the USH2A locus. In one of these families a recombination event was observed in an affected subject which excludes the USH2A gene from proximal to the marker AFM143XF10 and defines this as the new centromeric flanking marker for the USH2A locus. A further recombination event in another patient from this family confirmed AFM144XF2 as the telomeric flanking marker. The interval between these polymorphic markers is estimated to be 400 kb. This region is completely contained in each of three YACs from the CEPH library: 867g9, 919h3, and 848b9. This refinement more than halves the critical genetic interval and will greatly facilitate positional cloning of the USH2A gene.

Chromosome Mapping↗
PubMedDate not supplied

Statistical power of an exact test of Hardy-Weinberg proportions of genotypic data at a multiallelic locus.

A computer algorithm for numerical evaluation of the statistical power of an exact test of Hardy-Weinberg genotypic proportions (HWP), developed here, indicates that the power is dependent on the number of segregating alleles as well as allele frequencies. While low levels of departure from the null hypothesis are difficult to detect from single-locus data, should such deviation be due to population substructuring, multiple loci, at each of which the number of segregating alleles is large (as seen with hypervariable loci), may easily detect even low levels of departure from HWP. Undetected small levels of departure may still provide conservative estimates of genotype frequencies from allele frequency data, following the current practice in forensic genetics.

Algorithms↗
PubMed1992

Genetic and molecular evidence for a trans-acting regulatory locus controlling glutathione S-transferase-2 expression in Aedes aegypti.

The amount of glutathione S-transferase-2 (GST-2) protein and enzyme activity in a mutant strain (strain GG) of the yellow fever mosquito (Aedes aegypti) is approximately 25-fold higher than in the wild-type (++) strain. The mode of inheritance of the GG phenotype was studied in F1 and backcross progeny using GST enzyme assays, isozyme-specific antisera, and Northern blot analysis. Enzyme assay of parental and F1 progeny showed that the ++ phenotype was dominant to the GG phenotype. This was true for larvae as well as for all tissues examined in adults in both sexes. Immunoblotting experiments showed that, like the ++ strain, F1 larvae and adults express very low levels of GST-2 protein compared with the GG strain. Northern blotting experiments showed that the steady-state levels of GST-2 mRNA in parental and F1 hybrid larvae closely matched the enzyme activity and immunological data. These results suggest the existence of a trans-acting regulatory locus that acts to repress GST-2 mRNA transcription and/or decrease GST-2 mRNA stability in ++ and F1 hybrids. GST enzyme activity in backcross progeny, however, did not segregate into the two distinct phenotypes (low and high) predicted for a single locus, dominant allele model. Backcross progeny expressed a wide range of GST activity and GST-2 protein amount with no apparent fit to simple Mendelian ratios. These backcross data suggest that additional loci are also involved in regulating GST-2 isozyme expression.(ABSTRACT TRUNCATED AT 250 WORDS)

Aedes↗
PubMed1991

Estimating allele frequencies of hypervariable DNA systems.

Several polymorphisms of human DNA have been shown to be hypervariable due to the recurrence of a variable number of tandem repeats (VNTRs) in the lengths of allelic restriction fragments. The recurrence of allelic variants in this novel class of polymorphisms seems to comply well with a model of continuous random variables. Based on this assumption, we have compiled some simple algorithms for classification of continuous data and estimation of classes of relative frequencies and have implemented these routines for the management of databases storing hypervariable single locus DNA genetic systems. The algorithms are compiled in BASIC language and can be incorporated in task-oriented computer programs. Three procedures are discussed, based in turn on: (a) using predetermined, arbitrary classes; (b) point estimations of frequencies for single fragments using error measurements associated with the kilobase value assignment; (c) estimates of phenotype frequencies according to error measurements. Error measurements are obtained from a statistic of values pertaining to several restriction fragments (genomic controls) repeatedly tested in different experiments. Problems related to these approaches are discussed.

Algorithms↗
PubMedDate not supplied

Genetics of the Akp-2 locus for alkaline phosphatase of liver, kidney, bone, and placenta in the mouse. Linkage with the Ahd-1 locus on chromosome 4.

Differences between strains of mice were observed in electrophoretic migration on cellulose acetate plates of alkaline phosphatase in butanol extracts of kidney, bone and placenta. Each strain exhibited a broad band with fast or slow migration. Distribution among strains including recombinant inbred (Rl) strains indicated the variation in these organs to be the same as the previously described in the liver as coded for by the Akp-2 locus. An analysis of Rl strains for the kidney isozyme showed 43 with the faster moving form (AKP-2A), and 43 with the slower moving form (AKP-2B), and thus in the 1:1 ratio expected if a single locus is responsible for the strain differences. Comparisons of Rl strains showed linkage of the Akp-2 locus to two loci on chromosome 4 as follows: centromere-Gpd-1-5.7 +/- 1.9 cM-Akp-2-0.6 +/- 0.4 cM-Ahd-1. These data based on 82 Rl strains typed for both the first and second loci, and 86 for the second and third loci.

Alkaline Phosphatase↗