Showing papers in "American Journal of Human Genetics in 1980"

Construction of a genetic linkage map in man using restriction fragment length polymorphisms.

Abstract: We describe a new basis for the construction of a genetic linkage map of the human genome. The basic principle of the mapping scheme is to develop, by recombinant DNA techniques, random single-copy DNA probes capable of detecting DNA sequence polymorphisms, when hybridized to restriction digests of an individual's DNA. Each of these probes will define a locus. Loci can be expanded or contracted to include more or less polymorphism by further application of recombinant DNA technology. Suitably polymorphic loci can be tested for linkage relationships in human pedigrees by established methods; and loci can be arranged into linkage groups to form a true genetic map of "DNA marker loci." Pedigrees in which inherited traits are known to be segregating can then be analyzed, making possible the mapping of the gene(s) responsible for the trait with respect to the DNA marker loci, without requiring direct access to a specified gene's DNA. For inherited diseases mapped in this way, linked DNA marker loci can be used predictively for genetic counseling.

Mercaptopurine pharmacogenetics: monogenic inheritance of erythrocyte thiopurine methyltransferase activity.

Abstract: Thiopurine methyltransferase (TPMT) catalyzes thiopurine S-methylation, an important metabolic pathway for drugs such as 6-mercaptopurine. Erythrocyte (RBC) TPMT activity was measured in blood samples from 298 randomly selected subjects. Of the subjects, 88.6% were included in a subgroup with high enzyme activity (13.50 ± 1.86 U, mean ± SD), 11.1% were included in a subgroup with intermediate activity (7.20 ± 1.08 U), and 0.3% had undetectable activity. This distribution conforms to Hardy-Weinberg predictions for the autosomal codominant inheritance of a pair of alleles for low and high TPMT activity, TPMTL and TPMTH, with gene frequencies of .059 and .941, respectively. If RBC TPMT activity is inherited in an autosomal codominant fashion, then subjects homozygous for TPMTH would have high enzyme activity, subjects heterozygous for the two alleles would have intermediate activity, and subjects homozygous for TPMTL would have undetectable activity. The segregation of RBC TPMT activity among 215 first-degree relatives in 50 randomly selected families and among 35 members of two kindreds and one family selected because they included probands with undetectable RBC enzyme activity were also compatible with the autosomal codominant inheritance of RBC TPMT. For example, in eight matings between subjects with intermediate activity (presumed genotype TPMTL TPMTH) and subjects with high activity (presumed genotype TPMTH TPMTH), 47% (8/17) of the offspring had intermediate activity. This value is very similar to the 50% figure expected on the basis of autosomal codominant inheritance (χ2[1] = .059). Further experiments are required to determine whether this genetic polymorphism for an important drug metabolizing enzyme may represent one factor in individual variations in sensitivity to thiopurines.

Population genetic studies of retinitis pigmentosa.

Abstract: A questionnaire survey characterized a sample of 670 probands with retinitis pigmentosa (RP) and allied disorders. Segregation analysis provided some evidence for a small proportion of sporadic cases and for decreased segregation ratios of the dominant and recessive genotypes, which could be attributed to delayed age of onset in some cases. The overall incidence of RP was indirectly calculated to be approximately 1 in 3,700, while the incidence of autosomal recessive RP, including at least two genocopies, was estimated to be about 1 in 4,450. Family data analysis included the calculation of the likelihood that each family represented autosomal recessive, autosomal dominant, and X-linked inheritance patterns. These likelihoods were then converted to relative probabilities and summed over the sample population to yield estimates of the proportions of the three Mendelian types. This large, heterogeneous sample indicated that approximately 84% of the cases in the United States may be autosomal recessive, while about 10% are dominant and 6% X-linked recessive.

Genetics of the apolipoprotein E-system in man

Abstract: The polymorphism of apolipoprotein E (Apo E) in man is controlled by two codominant alleles, Apo En and Apo Ed, at the Apo E-N/D locus and by two alleles, the dominant, Apo E4+, and the recessive, Apo E4o, at the Apo E4 locus. Frequency distribution analysis of Apo E phenotypes demonstrated a highly significant association between both systems (P ~ 1%). The Apo E4-(+) variant was about twice as frequent in phenotype Apo E-N (30.1%) than in phenotype Apo E-ND (16.4%). The phenotypic combination Apo E-D/-E4(+) was not observed. The segregation of Apo E phenotypes in informative matings is consistent with a close linkage of both loci. The results may be explained by different models. On the basis of the present data, these models cannot be distinguished by formal genetic criteria. (1) Haplotypes Apo En/E4+, Apo En/E4o, and Apo Ed/E4o determine the different phenotypes, and a linkage disequilibrium exists of Δ = .0147 between the E-N/D and E4 loci. (2) The fourth haplotype, Apo Ed/E4+, exists, but the gene E4+ is not expressed in coupling with Apo Ed. The four-haplotype model seems more attractive in view of Apo E-N/D polymorphism's quantitative character and of biochemical results, which show that phenotypes Apo E-N and Apo E-D differ in the apparent molecular weight (Mr) of the respective major Apo E polymorphic form. Hence, the Apo E-N/D locus may control structural genes involved in the posttranslational modification of Apo E. (3) Finally, there may exist only one Apo E structural gene locus but with mutations at two sites susceptible to posttranslational modification.

Liver alcohol dehydrogenase and aldehyde dehydrogenase in the Japanese: isozyme variation and its possible role in alcohol intoxication.

Abstract: Forty autopsy livers from Japanese individuals were studied concerning alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) isozymes using electrophoretic and enzyme assay methods. A remarkably high frequency (85%) was found for the atypical ADH phenotype. The gene frequencies of ADH22 and ADH32 were .625 and .05, respectively. The usual ALDH phenotype showed two major isozyme bands, a faster migrating (low Km for acetaldehyde) and a slower migrating isozyme (high Km for acetaldehyde). Fifty-two percent of the specimens had an unusual phenotype of ALDH, which showed only the slower migrating isozyme. The usual phenotype was inhibited about 20%--30% by disulfiram and the unusual type up to 90%. Such a high incidence in the Japanese of the unusual phenotype, which lacks in the low Km isozyme, suggests that the initial intoxicating symptoms after alcohol drinking in these subjects might be due to delayed oxidation of acetaldehyde rather than its higher-than-normal production by typical or atypical ADH.

A cytogenetic study of repeated spontaneous abortions.

Abstract: During a cytogenetic study of spontaneous abortions, successive abortions from 40 couples were karyotyped. The chromosome constitutions of the first and second abortions were found to be highly correlated. In each of 21 instances in which the first abortion was chromosomally normal, the subsequent abortion(s) was normal as well. In nine cases, the two abortions were chromosomally abnormal, and in four of these, both abortions were trisomic. Combined with findings from other studies of consecutive spontaneous abortions, the present data indicate that certain couples are at an increased risk for either repeated chromosomally normal abortions or for repeated trisomic conceptions. The increased risk of trisomy does not seem to be restricted to a particular chromosome, and the magnitude of the risk increase appears to be independent of maternal age.

Leukocyte beta-glucosidase in homozygotes and heterozygotes for Gaucher disease.

Abstract: Human leukocytes contain at least two isozymes of 4-methylumbelliferyl-beta-glucosidase acting optimally at pH 4.0 and 4.8; in Gaucher disease, only the former is deficient. Brief exposure of the leukocyte homogenate to pH 4.0 at room temperature results in irreversible inactivation of the pH 4.8 activity, while the activity at pH 4.0 remains unaffected. The more acidic isozyme is stimulated four- to fivefold by 0.2% sodium taurodeoxycholate (TDC) with a shift in the pH optimum to 5.0. The less acidic isozyme is completely suppressed in the presence of this detergent. Both leukocyte isozymes appear to be membrane-bound since gel filtration of Sephadex G-200 produces only one peak of activity located at the void volume, unlike in liver and kidney where a second peak also can be demonstrated. Heat inactivation analysis indicated that in controls, assayed in the absence of detergent, pH 4.0 activity is more thermostable than pH 4.8 activity. However, in Gaucher disease, the residual beta-glucosidase at pH 4.0 is just as thermolabile as the unaffected pH 4.8 activity. Heat inactivation of the enzyme in the presence of TDC resulted in rapid loss of activity, suggesting a direct effect of the bile salt on the configuration of the enzyme decreasing its thermal stability. In the absence of detergent, acid beta-glucosidase shows two K(m)'s, one at 3.2 mM and another at 0.9 mM. In the presence of detergent, only the higher K(m) at 3.3 mM is obtained. In patients with Gaucher disease and in obligate carriers, the K(m) remains essentially unaffected while the V(max) shows the expected deficiency.A reliable and reproducible selective assay technique has been developed for the diagnosis of Gaucher disease homozygotes and obligate heterozygotes and for the carrier screening of individuals at risk for this inherited disorder. The efficacy of this technique has been demonstrated by studying the activity in 42 controls, 26 patients, 32 obligate heterozygotes, and 23 healthy relatives of patients with Gaucher disease.

Evidence for genetic control of nondisjunction in man.

Abstract: Data on factors associated with the occurrence of Down syndrome in a highly inbred population were evaluated to investigate the presence of a genetic control of nondisjunction in man In Kuwait, close consanguinity occurs in 40% of marriages In its main obstetric hospital, 20 trisomic Down babies out of 11,614 singleton births were delivered over a 12-month period Chi-square analyses indicate the occurrence of Down syndrome to be linked to two independent factors: consanquinity of parents and maternal age The relative risk is approximately four times greater for closely related than for nonrelated parents (P less than 005); a possible explanation for this is the existence of a gene that induces mitotic nondisjunction in the homozygous fertilized ovum An alternative explanation is the existence of an autosomal recessive gene which results in meiotic nondisjunction in the homozygous parents Consanguinity is usually perpetuated in certain families, or sections of the population, and parents in highly inbred families have a higher probability to be homozygotes for that gene

Congenital malformation in twins.

Abstract: Data from the population-based Metropolitan Atlanta Congenital Defects Program (MACDP) show that the overall rate of malformed infants, as well as the incidence of several specific defects, is higher for twins than for singletons. This elevated risk appears limited to same sex twins and, hence, is probably related to monozygosity. In addition to an 18-fold increase in risk of fetal death compared to singletons, twins have almost a 50% greater likelihood of congenital malformation.

Taurodontism, an isolated trait associated with syndromes and X-chromosomal aneuploidy.

Abstract: A review of the literature on teeth with enlarged pulp chambers and apical displacement of the bifurcation or trifurcation of roots (taurodontism) and investigation of the association of this trait with X-chromosomal aneuploidy shows that: (1) Taurodontism is not a rare trait in modern man, as indicated by the majority of recent reports, but occurs in approximately 2.5% of adult Caucasians. (2) Taurodontism occurs in syndromes, particularly in those having an ectodermal defect. (3) Among 12 patients showing taurodontic teeth radiographically, all had normal karyotypes. (4) Among 12 patients showing various combinations of X-chromosomal aneuploidy, 11 had taurodontic molars. (5) Patients with a female habitus and X-chromosomal aneuploidy as well as patients with a male habitus and X-chromosomal states have taurodontic teeth. (6) There is no simple association of the degree of taurodontism and the number of X chromosomes, but, in general, patients with the more severe forms of the trait--meso- or hypertaurodontism--are more likely to have X-chromosomal aneuploidy. While taurodontism may be viewed as an extension of a continuous trait of pulp chamber size, the extreme shape may arise when conditions disturbing the epithelial-derived root sheath produce a generalized amplified instability of development, as has been suggested from tissue culture studies of X-chromosomal aneuploid cells.

47,XXY males: sex chromosomes and tooth size.

Abstract: Permanent tooth crowns of 47,XXY males were found to be generally larger than those of control males and females and their first-degree male and female relatives. These results suggest that tooth-size increase in 47,XXY males is due to a direct genetic effect and support the concept of the presence of a specific growth gene (or genes) in the human X and Y chromosomes. The effect of this gene (or genes) seems to be the promotion of tooth growth, and the Y chromosome is more effective than the X chromosome in this respect.

A genetic study of panic disorder pedigrees.

Abstract: Pedigree analysis is done on 19 kindreds of panic disorder, and the results suggest that this disorder is transmitted as an autosomal dominant trait. Seven of these 19 kindreds were ascertained through a panic disorder proband with mitral valve prolapse. When the analysis is done omitting these seven kindreds, the results also suggest that panic disorder without prolapse is transmitted as an autosomal dominant trait.

Metabolic interference and the + - heterozygote. a hypothetical form of simple inheritance which is neither dominant nor recessive.

Abstract: Another form of simple inheritance is possible which is neither dominant nor recessive and in which the heterozygote alone is affected. In this system, homozygosity for the normal allele AA, and the mutant allele A'A', give a normal phenotype. Only the heterozygous condition AA' (+ − heterozygote) produces an abnormal phenotype because the two alleles, when present together, interact to produce a harmful effect. This metabolic interference may occur because the two allelic genes code for different subunits of a multisubunit enzyme or structural protein. The two genes may interact in other ways and need not be allelic. The various matings result in pedigrees, which in some cases resemble those of dominant or recessive inheritance, and in other cases are unique. Certain unusual pedigrees in the literature are compatible with the predictions of metabolic interference and are difficult to explain by other means. Metabolic interference is most likely to be recognized as: (1) a disorder limited to females, apparently dominant or recessive, especially a disorder passed to affected females through unaffected males; (2) a disorder occurring in all members of a large sibship with normal parents; (3) a disorder occurring in all members of a large sibship with one parent similarly affected; (4) an apparently dominant disorder with females more severely affected than males; (5) an apparently X-linked dominant disorder in which males are not more severely affected; or (6) any autosomal dominant disorder. Examples of possible metabolic interference exist among disorders of animals, and the mechanism could be a factor in speciation. Tissue culture methods could be used to demonstrate metabolic interference.

Permanent tooth sizes in 46,XY females.

Abstract: The teeth of seven Finnish patients with complete testicular-feminization syndrome (46,XY females) were studied to obtain further information about their growth and possible somatic determinants on the Y chromosome. The sizes of the permanent teeth of the 46,XY females were found to be as large as those of control males and definitely larger than those of control females. Testicular feminization is caused by androgen insensitivity, and persons affected are phenotypically females. Hence, these results also indicate the influence of the Y chromosome on dental determination.

Genetic mechanisms of sexual development

Abstract: What do you do to start reading genetic mechanisms of sexual development ? Searching the book that you love to read first or find an interesting book that will make you want to read? Everybody has difference with their reason of reading a book. Actuary, reading habit must be from earlier. Many people may be love to read, but not a book. It's not fault. Someone will be bored to open the thick book with small words to read. In more, this is the real condition. So do happen probably with this genetic mechanisms of sexual development .

A search for protein cores in chromosomes: Is the scaffold an artifact?

Abstract: A protein chromosome scaffold structure has been proposed that acts as a structural framework for attachment of chromosomal DNA There are several troubling aspects of this concept: (1) such structures have not been seen in many previous thin-section and whole-mount electron microscopy studies of metaphase chromosomes, while they are readily seen in leptotene and zygotene chromosomes; (2) such a structure poses problems for sister chromatid exchanges; and (3) the published photographs show a marked variation in the amount of scaffold in different whole-mount preparations An alternative explanation is that the scaffold in whole-mount preparations represents incomplete dispersion of the high concentration of chromatin in the center of chromosomes, and when the histones are removed and the DNA dispersed, the remaining nonhistone proteins (NHPs) aggregate to form a chromosome-shaped structure Two studies were done to determine if the scaffold is real or an artifact: (1) Chinese hamster mitotic cells and isolated chromosomes were examined using two protein stains —EDTA-regressive staining and phosphotungstic acid (PTA) stain The EDTA-regressive stain showed ribonucleoprotein particles at the periphery of the chromosomes but nothing at the center of the chromosomes The PTA stain showed the kinetochore plates but no central structures; and (2) isolated chromosomes were partially dispersed to decrease the high concentration of chromatin in the center of the chromosome, then treated with 4 M ammonium acetate or 2 M NaCl to dehistonize them and disperse the DNA Under these circumstances, no chromosome scaffold was seen We conclude that the scaffold structure is an artifact resulting from incomplete dispersion of central chromatin and aggregation of NHPs in dehistonized chromosomes

Morquio syndrome (mucopolysaccharidosis IV B) associated with beta-galactosidase deficiency. Report of two cases.

Abstract: Two male patients, aged 6 and 25, both with normal intelligence and absence of neurological abnormalities, exhibited dysostosis multiplex, dwarfism, odontoid anomalies, cloudy corneas, exessive excretion of keratan sulfate, and abnormal urinary oligosaccharides. Leukocytes and fibroblasts of both patients were deficient in acid beta-galactosidase (beta-gal) and normal in N-acetylgalactosamine-6-sulfate sulfatase, the deficient enzyme in classical Morquio syndrome. The beta-gal deficiency was not due to an endogenous inhibitor, and the parents exhibited intermediate activities. Deficient beta-gal activity was observed toward p-nitrophenyl-beta-galactoside, 4-methylumbelliferyl-beta-galactoside (4 MU-beta-gal), lactose, GM1 ganglioside, keratan sulfate, and asialofetuin (ASF). Under standard assay conditions, the residual activity was similar for all substrates tested. Toward p-nitrophenyl-beta-glactoside, the mutant enzyme behaved as a Km variant.

Estimating age-of-onset distributions for disorders with variable onset.

Abstract: A necessary item of information in many genetic analysis of complex disorders with late onset is the cumulative probability of onset by a given age. The effect of sample design upon the estimation of age-of-onset probability distribution parameters is discussed. Mathematical descriptions of several common sample designs used to estimate the distribution parameters are developed here. Failure to describe the sample space adequately can lead to erroneous genetic analyses because the cumulative probability of onset is incorrectly estimated. In genetic counseling, the errors would usually result in an underestimate of the true risk.

Heritable fragile sites on human chromosomes. V. A new class of fragile site requiring BrdU for expression.

Abstract: A new fragile site at 10q25 is described, representing a new class of fragile site that requires bromodeoxyuridine (BrdU) in the culture medium for expression. This new fragile site is present in approximately one in 30 of the Australian population; it has only been observed in heterozygotes.

HLA and the inheritance of multiple sclerosis: linkage analysis of 72 pedigrees.

Abstract: Linkage analysis of 72 pedigrees by the maximum-likelihood method provides evidence of linkage between HLA and the hypothesized multiple sclerosis susceptibility gene (MSSG) for both the dominant and recessive models of inheritance and for penetrance values ranging from 5%--65% (or higher). This MSSG, if it exists, is most likely located at 15%--20% recombination units from the HLA complex, probably on the B-D side. The analysis also shows that there is no heterogeneity in the estimates of linkage, and lod scores are not artifically inflated because of the association of multiple sclerosis (MS) with HLA-B7.

Genetic polymorphism of human plasminogen.

Abstract: Using isoelectric focusing (IEF) in polyacrylamide gel of neuraminidase-treated serum or plasma samples and immunofixation or caseinolytic overlay after urokinase activation of gels, a common genetic polymorphism in human plasminogen has been delineated. Two alleles PLGN*A and PLGN*B, were observed with gene frequencies in whites of .69 and .30; in Orientals of .96 and .03; and in blacks of .80 and .18. Several rare alleles were also found. The distribution of phenotypes fits the Hardy-Weinberg equilibrium. Inheritance is autosomal codominant and fits the expectations of Mendelian inheritance. There is fetal synthesis, but no transplacental passage of plasminogen in either direction.

Properties of fetal and adult red blood cell arginase: a possible prenatal diagnostic test for arginase deficiency.

Abstract: Prenatal diagnosis of inborn errors of metabolism has been possible only if the enzyme affected is expressed in amniotic fluid cells grown in culture. Arginase is essentially undetectable in normal human fibroblasts, amniotic fluid, and amniotic fluid cells but is present in high amounts in red blood cells. It is absent in the red blood cells of patients with liver arginase deficiency. The properties of the enzyme in the red cells of healthy children and adults were compared to those of the enzyme obtained from cord blood red cells of 13--20-week fetuses obtained at hysterotomy. The activities, heavy metal requirements, heat stability, pH optimum, kinetic properties, and reaction with anti-arginase antibody were examined. Both enzyme species were either identical or substantially similar by all criteria. The adult and fetal enzymes are, therefore, probably determined by the same structural gene. Fetal red cells obtained during amniocentesis and amnioscopy should then be a suitable tissue to use to make the prenatal diagnosis of arginase deficiency.

Genetically determined asynapsis, spermatogenic degeneration, and infertility in men.

Abstract: We report a family in which azoospermia and infertility affected two sibs whose parents were first cousins once removed. Meiotic cells of the proband, who had the chromosomal complement of a normal male (46,XY), exhibited asynapsis, defective synaptonemal complex (SC) formation, chiasma failure, and degeneration of prophase spermatocytes with asynapsis. Based on these observations, we suggest that the meiotic abnormalities and infertility in this family comprise a trait with an autosomal recessive mode of inheritance. Review of published cases of infertile men with normal chromosomal complements and disturbed meiosis suggests that genetically determined asynapsis and desynapsis similar to that established in plant and insect species also occur in humans. In humans, asynapsis appears to be inherited as an autosomal recessive. The mode of inheritance of desynapsis is not clear; X-linked recessive or autosomal dominant has been suggested in one family. Studies by us and by others reported in the literature suggest that the mode of action of genes that affect synapsis and cause a reduction in the numbers of visible chiasmata at diakinesis is dissimilar to that of the action of genes that cause defective meiotic recombination, defective repair of induced damage to DNA in somatic cells, and chromosome instability.

Genetic markers in human bone marrow transplantation.

Abstract: Blood cell isozymes, red cell antigens, immunoglobulin allotypes, and marker chromosomes are suitable tools to monitor bone marrow engraftment and marrow graft quality. Data on genetic markers from 26 patients who underwent bone marrow transplantation as a treatment for acute leukemia are presented here.

A genetic study of anodontia in X-linked hypohidrotic ectodermal dysplasia.

Abstract: Dental examinations and tooth measurements were conducted on 16 mothers, 10 fathers, and 23 affected males in 15 families with X-linked hypohidrotic ectodermal dysplasia. Small teeth and congenital missing teeth were sufficiently consistent findings in obligate heterozygotes to suggest that carriers can usually be recognized by clinical criteria.