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PubMed1983

Germline integration of moloney murine leukemia virus at the Mov13 locus leads to recessive lethal mutation and early embryonic death.

Thirteen mouse substrains genetically transmitting the exogenous Moloney murine leukemia virus (M-MuLV) at a single locus (Mov locus) have been derived previously. Experiments were performed to investigate whether homozygosity at the Mov loci would be compatible with normal development. Animals heterozygous at an Mov locus were mated, and the genotype of the offspring was analyzed. From parents heterozygous at the loci Mov1 to Mov12, respectively, homozygous offspring were obtained with the expected Mendelian frequency. In contrast, no homozygous offspring or embryos older than day 15 of gestation were obtained from parents heterozygous at the Mov13 locus. When pregnant Mov13 females at day 13 and day 14 of gestation were analyzed, approximately 25% of the embryos were degenerated. Genotyping revealed that these degenerated embryos were invariably homozygous and the normal appearing embryos were either heterozygous or negative for M-MuLV. These results suggest that integration of M-MuLV at the Mov13 locus leads to insertion mutagenesis, resulting in embryonic arrest between day 12 and day 13 of gestation. It is possible that the Mov13 locus represents a gene or gene complex involved in the early embryonic development of the mouse.

Animals↗

PubMed1976

The evolution of one- and two-locus systems.

Assuming age-independent fertilities and mortalities and random mating, continuous-time models for a monoecious population are investigated for weak selection. A single locus with multiple alleles and two alleles at each of two loci are considered. A slow-selection analysis of diallelic and multiallelic two-locus models with discrete nonoverlapping generations is also presented. The selective differences may be functions of genotypic frequencies, but their rate of change due to their explicit dependence on time (if any) must be at most of the second order in s, (i.e., O(s2), where s is the intensity of natural selection. Then, after several generations have elapsed, in the continuous time models the time-derivative of the deviations from Hardy-Weinberg proportions is of O(s2), and in the two-locus models the rate of change of the linkage disequilibrium is of O(s2). It follows that, if the rate of change of the genotypic fitnesses is smaller than second order in s (i.e., o(s2)), then to O(s2) the rate of change of the mean fitness of the population is equal to the genic variance. For a fixed value of s, however, no matter how small, the genic variance may occasionally be smaller in absolute value than the (possibly negative) lower order terms in the change in fitness, and hence the mean fitness may decrease. This happens if the allelic frequencies are changing extremely slowly, and hence occurs often very close to equilibrium. Some new expressions are derived for the change in mean fitness. It is shown that, with an error of O(s), the genotypic frequencies evolve as if the population were in Hardy-Weinberg proportions and linkage equilibrium. Thus, at least for the deterministic behaviour of one and two loci, deviations from random combination appear to have very little evolutionary significance.

Biological Evolution↗

PubMed1978

Genetic control of the immune response to the H-2Dk private specificity, H-2.32. II. Genetic linkage analysis of a backcross generation.

B10.AKM mice (H-2M) when immunized with H-2k cells showed very low cytotoxic antibody responses to the H-2Dk private specificity H-2.32, whereas AKR.M and (AKR.M X B10.AKM)F1 mice that possess the same H-2m haplotype mounted reasonable anti-H-2.32 antibody responses. The genetic nature of the non-H-2 linked gene(s) controlling the anti-H-2.32 response was analyzed on the backcross progeny raised between (AKR.M X B10.AKM)F1 and B10.AKM mice. The anti-H-2.32 antibody response was found to be predominantly controlled by a single locus. This locus segregated independently of the Ig heavy chain locus, the Ly2 locus, and the Mls locus. Despite the observed difference in antibody production, no significant differences between AKR.M and B10.AKM mice were detected in induction of H-2Dk-specific killer T cells. Thus, the defect in the response of B10.AKM mice to H-2.32 can be detected at the level of B cell function and is controlled by a single non-H-2-linked genetic locus, but is not attributable to genes linked to the major immunoglobulin structural genes nor to the Mls locus.

Animals↗

PubMed1989

Genetic analysis of IDDM: summary of GAW5 IDDM results.

This paper summarizes the analyses by participants in the insulin-dependent diabetes mellitus (IDDM) component of Genetic Analysis Workshop 5 (GAW5). The data were obtained from 94 families with two or more IDDM sibs. Topics treated in the Workshop analysis included the following: methods for detecting associations and linkage, the contribution by HLA-linked and -unlinked loci to IDDM susceptibility, the role of subtypes of the serologically defined HLA specificities, the implications of associated diseases other than IDDM in the families, the significance of antibodies to Coxsackie viruses, and of autoantibodies to pancreatic islet cells and insulin, and the use of genetic models to analyze the inheritance of IDDM. There was agreement that an explanation for the data on multiplex IDDM families must include the following features: 1) There is a susceptibility locus (or loci) in the HLA region. 2) The HLA-linked factor(s) are more complex than a single locus with one disease and one nondisease allele. 3) There is additional familial correlation beyond that explained by HLA-linked susceptibility, which may be genetic and/or environmental. With regard to the third feature, IDDM-GAW5 included data on variation in Gm haplotypes and at the insulin gene, two regions unlinked to HLA. However, there was no direct evidence (i.e., from marker segregation) that the additional factor, if genetic, is linked to either Gm or the insulin gene. Nevertheless, a significant difference was found between "diabetic" and "control" insulin genes with respect to frequency of class 1 alleles for the 5' flanking polymorphism, strongly suggesting linkage.

Data Collection↗

PubMed1982

Genetic regulation of neurotransmitter enzymes and receptors: relationship to the inheritance of psychiatric disorders.

This report begins with a summary of the evidence for genetic involvement in certain major psychiatric syndromes. The relation of these disorders to deficits in central nervous system neurotransmitters is also summarized. These reviews serve as an introduction to our studies on the genetic regulation of neurotransmitters and their enzymes and receptors in inbred mice. The steady-state levels of the adrenal catecholamine biosynthetic enzymes are controlled genetically; not only is each enzyme regulated by a single locus, but also there is statistical evidence that the phenotypic expression of the entire pathway is regulated by a single gene. Studies on the biochemical mechanism of gene action suggest that genetic regulation is exerted on proteolysis of the enzymes, rather than their synthesis. In addition, we have examined the genetic control of dopamine receptors in inbred mice. Dopaminergic receptors in the nigrostriatal and mesolimbic pathways are under genetic control. Preliminary evidence suggests that the pathways are regulated by different genetic systems. If this early speculation proves true, it would have important clinical implications.

Animals↗

PubMed1990

Polymerase chain reaction for detection of the alpha-1-antitrypsin Z allele in chronic liver disease.

The genetic locus for alpha-1-antitrypsin (alpha-AT) is highly polymorphic, but all protein variants are encoded by a single locus on chromosome 14. Periportal hepatocyte granules are described in association with chronic liver disease and the Z variant. A Z-specific point mutation in exon V of the alpha-AT gene, converting amino acid 342 from Glu to Lys, is thought to be responsible for the hepatocyte accumulation. We describe the use of the polymerase chain reaction (PCR) to amplify exon V of the alpha-AT gene and subsequent detection of the wild-type M- and Z-specific sequences by hybridisation to 32P-labelled-allele-specific oligonucleotides. We applied this technique to leucocyte DNA from 37 patients with suspected chronic liver disease, 25 of whom had hepatocyte alpha-AT inclusion granules on liver biopsy. All 25 were homozygous or heterozygous for the Z allele. One patient, phenotyped as PiS, was found to be PiSZ and another phenotyped as PiZ (presumed homozygous), was found to be a Z heterozygote. No Z allele was detected in any of the twelve patients without alpha-AT inclusion granules. This sensitive PCR technique could be used to assess the relative risk of chronic liver disease in PiZ heterozygotes and to determine whether individuals without the Z amino acid 342 substitution can developed periportal alpha-AT granules.

Alleles↗

PubMed1985

Complexity of minor histocompatibility loci.

Allografts can be rejected as a result of major histocompatibility antigen disparity or as a result of differences at any of a number of minor histocompatibility antigens. In many cases, rejection due to multiple minor histoincompatibility is as difficult to control as that induced by major histoincompatibility. Although an understanding of the molecular, biochemical, and functional parameters of the major histocompatibility loci and their products is increasing at an exponential rate, little is known about these same facets of minor histocompatibility loci and their products. It is generally accepted that minor histocompatibility loci in the murine model have a degree of polymorphism similar to that of H-2K or H-2D. This conclusion was based on typing alleles by the classic F1-skin graft test. Based on these allelic assignments, numerous unexpected findings of CTL specificity were made. Therefore, a systematic analysis was made comparing CTL specificity, F1-complementation, and allograft rejection. Based on these three parameters, the data presented using strains of mice that were bred to, and therefore presumed to, differ only at H-3 indicate that the antigen disparity of these congenic strains and the parental B10 strain as defined by CTL specificity and skin graft rejection is much more complex than originally described. One especially interesting chromosomal region is H-3/beta 2-microglobulin in the fifth linkage group of chromosome 2. Using CTL, ten specificities are defined, three of which appear to be specific for beta 2-microglobulin-A, -B, and -C. These findings raise the question of whether any minor histocompatibility locus is polymorphic or is instead a composite of multiple minor H-loci which are masquerading as a single locus.

Alleles↗

PubMed1999

Temporal and spatial genetic variation within and among populations of the mosquito Culex tarsalis (Diptera: Culicidae) from California.

The genetic structure of 11 populations of Culex tarsalis Coquillett from California and 1 population from Nevada was examined at 18 loci using polyacrylamide gel electrophoresis. Six populations from northern and southern California were sampled repeatedly to determine if the genetic structure of Cx. tarsalis changes seasonally. Significant differences in allele frequencies at 13 different loci were seen in 3 populations over time as determined by contingency chi-square tests. Nei's genetic distance coefficients among different sampling dates was consistently < 0.025. The number of alleles per locus in these populations ranged from 1.6 to 2.7, whereas the average heterozygosity ranged from 0.086 to 0.228. No single locus was found to vary in a consistent pattern within all populations that were sampled repeatedly. These results indicate that Cx. tarsalis populations are genetically stable over time and that temporal variation is due to fluctuations in population size or immigration of genetically distinct individuals. In contrast, Cx. tarsalis did exhibit some differences in genetic structure that were related to geographical features including the Sierra Nevada and the Tehachapi Mountains of southern California. Genetically differentiated populations occurred in Nevada, southern and northeastern California, and the Central Valley of California. Little differentiation was observed among populations located in the Central Valley of California and those located at high elevations in the Sierra Nevada. Thus, in the populations examined, mountain ranges or arid conditions that limit the number of larval development sites appeared to be important barriers to the dispersal of Cx. tarsalis.

Animals↗

PubMed1996

Nuclease sensitivity of the human growth hormone-chorionic somatomammotropin locus in pituitary and placenta suggest different mechanisms for tissue-specific regulation.

The five human growth hormone (GH) and chorionic somatomammotropin (CS) genes are located at a single locus on chromosome 17. These genes share extensive nucleotide sequence similarity (approximately 94%) even in their flanking DNA, yet GH-N is expressed efficiently in the pituitary under the control of the pituitary-specific factor GHF-1/Pit-1 and the remaining CS-A, CS-B, CS-L and GH-V genes are transcriptionally active in the placenta. Despite this specificity in vivo, a truncated CS-A promoter can bind GHF-1/Pit-1 and allow CS-A promoter activity in pituitary cells in vitro. With a view to assessing whether the placental genes of the GH/CS locus possess a different chromatin structure in the pituitary and are, thus, less transcriptionally active than the GH-N gene, we have compared the DNAase I sensitivity of GH/CS in isolated pituitary and placenta cell nuclei. Our data indicate that these genes are equally sensitive in isolated human pituitary nuclei. By contrast, the CS-A, CS-B and CS-L genes were significantly (P < 0.05) more sensitive than the GH-N gene in isolated human placenta nuclei. Although just not significant, the GH-V gene was slightly more sensitive than the GH-N gene. This pattern was also seen with nuclei from human choriocarcinoma BeWo and JEG-3 cells, which express low and extremely low levels of CS RNA, respectively, but was distinct from the pattern observed in the non placental human cervical carcinoma HeLa cell line. These data indicate that the inactivity of the CS genes in the pituitary does not correlate with a 'closed' chromatin structure. However, they are consistent with a role for a more 'open' chromatin conformation in placenta-specific expression, but not necessarily high levels of transcriptional activity.

Cell Nucleus↗

PubMed1995

A major locus influencing plasma high-density lipoprotein cholesterol levels in the San Antonio Family Heart Study. Segregation and linkage analyses.

To detect and measure the effects of a single locus on quantitative variation in plasma concentrations of HDL cholesterol (HDL-C), we conducted statistical genetic analyses on data from 526 Mexican American individuals in 25 randomly ascertained pedigrees. By using maximum-likelihood complex segregation analysis, we found evidence for a major locus with a codominant mixture model that included the phenotypic means, standard deviations, relative frequency of a low HDL-C allele, and heritability for plasma HDL-C levels, plus the effects of sex (genotype specific), age-by-sex, age2-by-sex, plasma concentrations of apolipoprotein (apo)AI and triglycerides (genotype specific), exogenous sex hormone use, and menopausal status under an unrestricted general model. Inclusion of the four covariates (in addition to the sex and age-by-sex effects) accounted for nearly 79% of the variance in total plasma HDL-C levels. Of the remaining 21% of the variance, the detected major locus accounted for approximately 55% in men and 21% in women; the total genetic contributions to the variance by genes were approximately 82% in men and 69% in women. Linkage analyses with penetrance parameter estimates from the segregation analysis excluded tight linkage between the detected major locus and markers for the following candidate loci: the apoAI/apoCIII genomic region (P < .05), apoB (P < .01), hepatic lipase (P < .001), lipoprotein lipase (P < .001), and the LDL receptor (P < .001). While not excluding the apoE locus (LOD = -0.348, P < .21), the analysis provided no support for tight linkage between it and the detected major locus.

Adolescent↗

PubMed1999

Simulated data for a complex genetic trait (problem 2 for GAW11): how the model was developed, and why.

This paper describes a simulated data set created as Problem 2 for GAW11. The generating model for Problem 2 involved two different genetic diseases, or "types," in three separate populations. The two-locus (2L) type results from the epistatic interaction of two genetic loci, and the three-allele type, from a single locus with two disease-causing alleles and one normal allele. Each type has two phenotypic forms: Mild and Severe. Both forms are subject to both genetic and environmental influences. The disease occurs in three different hypothetical populations, each with different disease allele frequencies and penetrances. In two populations there is also a fourth locus with an allele that is associated with the 2L type. Misdiagnosis can occur, but only after a family has already been ascertained through > or = 2 "genetically" affected offspring. Finally, the three different populations are studied by four different hypothetical research groups. These groups each have their own ideas about how the disease is inherited and have therefore devised different ascertainment schemes based on those beliefs. Each research group collected 100-family data sets, including data on 300 markers on six chromosomes and measurements on disease status and on the proposed two environmental factors. GAW participants were supplied with 25 random replicates of each data set.

Alleles↗

PubMed1975

A heterozygote for Hb S beta, Hb C beta and Hb G Philadelphia beta in a family presenting evidence for heterogeneity of hemoglobin alpha chain loci.

A child heterozygous for the genes for hemoglobins S, C and G alpha Philadelphia presented with a clinical picture similar to sickle cell anemia. Her hemoglobin electrophoretic pattern contained three components with the mobilities of hemoglobins S (35 per cent), C (47 per cent) and a more slowly migrating hybrid G/C molecule (15 per cent). Seven relatives were heterozygous for Hb G beta and Hb S beta and five were heterozygous only for Hb G alpha. Among the latter, three had approximately 30 per cent and two had 40 per cent of Hb G. These proportions are consistent with the hypothesis that the American Negro genome contains two types of chromosomes bearing structural loci for alpha chains, some possessing one Hb alpha locus, others having two loci. Hb G alpha-Philadelphia presumably arose as a mutation on a chromosome with a single locus. Those heterozygotes having 30 per cent and 40 per cent Hb G presumably have two loci and only one locus, respectively, on the homologous chromosome.

Amino Acid Sequence↗

PubMed1996

Design and synthesis of heterotrimeric collagen peptides with a built-in cystine-knot. Models for collagen catabolism by matrix-metalloproteases.

A heterotrimeric collagen peptide was designed and synthesized which contains the collagenase cleavage site (P4-P'9/10) of type I collagen linked to a C-terminal cystine-knot, and N-terminally extended with (Gly-Pro-Hyp)5 triplets for stabilization of the triple-helical conformation. By employing a newly developed regioselective cysteine pairing strategy based exclusively on thiol disulfide exchange reactions, we succeeded in assembling in high yields and in a reproducible manner the triple-stranded cystine peptide. While the single chains showed no tendency to self-association into triple helices, the heterotrimer (alpha1 alpha2 alpha1') was found to exhibit a typical collagen-like CD spectrum at room temperature and a melting temperature (Tm) of 33 degrees C. This triple-helical collagen-like peptide is cleaved by the full-length human neutrophil collagenase (MMP-8) at a single locus fully confirming the correct raster of the heterotrimer. Its digestion proceeds at rates markedly higher than that of a single alpha1' chain. In contrast, opposite digestion rates were measured with the catalytic Phe79-MMP-8 domain of HNC. Moreover, the full-length enzyme exhibits Km values of 5 microM and 1 mM for the heterotrimer and the single alpha1' chain, respectively, which compare well with those reported for collagen type I (approximately 1 microM), gelatine (approximately 10 microM) and for octapeptides of the cleavage sequence (> or = 1 mM). The high affinity of the MMP-8 for the triple-helical heterotrimer and the fast digestion of this collagenous peptide confirm the decisive role of the hemopexin domain in recognition and possibly, partial unfolding of collagen.

Amino Acid Sequence↗

PubMedDate not supplied

A cGMP-dependent protein kinase gene, foraging, modifies habituation-like response decrement of the giant fiber escape circuit in Drosophila.

The Drosophila giant fiber jump-and-flight escape response is a model for genetic analysis of both the physiology and the plasticity of a sensorimotor behavioral pathway. We previously established the electrically induced giant fiber response in intact tethered flies as a model for habituation, a form of nonassociative learning. Here, we show that the rate of stimulus-dependent response decrement of this neural pathway in a habituation protocol is correlated with PKG (cGMP-Dependent Protein Kinase) activity and foraging behavior. We assayed response decrement for natural and mutant rover and sitter alleles of the foraging (for) gene that encodes a Drosophila PKG. Rover larvae and adults, which have higher PKG activities, travel significantly farther while foraging than sitters with lower PKG activities. Response decrement was most rapid in genotypes previously shown to have low PKG activities and sitter-like foraging behavior. We also found differences in spontaneous recovery (the reversal of response decrement during a rest from stimulation) and a dishabituation-like phenomenon (the reversal of response decrement evoked by a novel stimulus). This electrophysiological study in an intact animal preparation provides one of the first direct demonstrations that PKG can affect plasticity in a simple learning paradigm. It increases our understanding of the complex interplay of factors that can modulate the sensitivity of the giant fiber escape response, and it defines a new adult-stage phenotype of the foraging locus. Finally, these results show that behaviorally relevant neural plasticity in an identified circuit can be influenced by a single-locus genetic polymorphism existing in a natural population of Drosophila.

Animals↗

PubMed2005

[Sex identification from DNA in old teeth].

The sex determination was carried out on 80 fresh and 15 old teeth by amplifying sex chromosome specific sequences with the polymerase chain reaction. The DNA content in the tooth significantly decreases with aging. There was no correlation between days after evulsion and the amounts of DNA extracted from fresh teeth that had been preserved less than 186 days. The sex determination based on fresh teeth was successful using multi locus markers, DYZ-1 and DYZ-3 in combination with DXZ-1. However, amelogenin and pseudoautosomal boundary, both that are single locus markers and specific for both sex chromosomes with different lengths, could not be detected in three samples, of which DNA contents were extremely low. However, the sex determination by amelogenin amplified with fluorescent probes was possible in these three samples. We also determined sexes of 30 old specimens (15 teeth and 15 bones) from 15 human skulls using sex chromosomes locus markers. Prior to molecular sex determination, two forensic specialists determined the sex of the skull morphologically. From the 15 skulls, sex identification using multi locus marker (DYZ-1 or DYZ-3) was possible for 12 of 15 teeth and 7 of 15 bones. The sex was successfully determined from 11 teeth and 9 bones by amplification of the amelogenin locus. However, the coincidence rate of the molecular test with morphological examination was < 20%. In conclusion, sex determination on the fresh tooth would be successful using any sex chromosome marker. However, in cases on samples that have spent considerable years in the ground, pollution and putrefaction, especially, by humicolous, must be considered. Thus, sex determination by DNA testing should be regarded as accurate, when the results from two or more molecular markers are coincident. Hokkaido J Med Sci 80(2), 191-199, 2005

Adolescent↗

PubMed1990

[Possibilities for individual identification of hair roots using DNA probes].

High-molecular weight DNA was extracted from hair roots. The obtained DNA was digested with Hae III and Msp I and transferred to nylon membranes by Southern blotting. The possibility of applying a probe for sex determination (pHY2.1) a "single-locus"-probe (YNH24) as well as a "multi-locus"-probe (M13) was examinated as a function of the amount of hair being supplied. In the laboratory experiment a single hair root was enough for a sex determination or individual identification. Because of methodical difficulties in practice this kind of profiling should only be done with several hair roots.

Adolescent↗

PubMed2006

An analysis paradigm for investigating multi-locus effects in complex disease: examination of three GABA receptor subunit genes on 15q11-q13 as risk factors for autistic disorder.

Gene-gene interactions are likely involved in many complex genetic disorders and new statistical approaches for detecting such interactions are needed. We propose a multi-analytic paradigm, relying on convergence of evidence across multiple analysis tools. Our paradigm tests for main and interactive effects, through allele, genotype and haplotype association. We applied our paradigm to genotype data from three GABAA receptor subunit genes (GABRB3, GABRA5, and GABRG3) on chromosome 15 in 470 Caucasian autism families. Previously implicated in autism, we hypothesized these genes interact to contribute to risk. We detected no evidence of main effects by allelic (PDT, FBAT) or genotypic (genotype-PDT) association at individual markers. However, three two-marker haplotypes in GABRG3 were significant (HBAT). We detected no significant multi-locus associations using genotype-PDT analysis or the EMDR data reduction program. However, consistent with the haplotype findings, the best single locus EMDR model selected a GABRG3 marker. Further, the best pairwise genotype-PDT result involved GABRB3 and GABRG3, and all multi-locus EMDR models also selected GABRB3 and GABRG3 markers. GABA receptor subunit genes do not significantly interact to contribute to autism risk in our overall data set. However, the consistency of results across analyses suggests that we have defined a useful framework for evaluating gene-gene interactions.

Autistic Disorder↗

PubMed1983

Topography of locus ceruleus neurons projecting to the area dentata.

The distribution of locus ceruleus neurons projecting to the dorsal and ventral area dentata was studied using the retrograde transport of horseradish peroxidase (HRP). Furthermore, the possibility that collaterals of single locus ceruleus neurons innervate both the dorsal and ventral area dentata was explored with a retrograde double-label technique using HRP and the fluorescent dye 4',6-diamidino-2-phenylindole 2 HCl (DAPI). Fusiform and multipolar neurons of the pars dorsalis of the locus ceruleus (LCd) were labeled after injection of HRP into the area dentata. The HRP-positive cells were found almost exclusively in the dorsal LCd after dorsal area dentata injections whereas ventral injections labeled neurons throughout the LCd. The highest density of LCd neurons labeled from the ventral area dentata was observed in the dorsal half of the LCd and thus overlapped with the distribution of neurons labeled from dorsal injections. Neurons containing both HRP and DAPI were observed in the dorsal LCd suggesting that the topographic coincidence of neurons labeled from dorsal and ventral area dentata was in part a result of single neurons having terminals in both loci.

Animals↗