Biomedical subjects

S P Daiger

Publications and source records attributed to S P Daiger.

At least 73 records · Page 4Linked to original sources

PubMed1989

Autosomal dominant retinitis pigmentosa: exclusion of the gene from the short arm of chromosome 1 including the region surrounding the rhesus locus.

Members of a large Irish pedigree exhibiting early-onset autosomal dominant retinitis pigmentosa (ADRP) were typed for the rhesus blood group and nine DNA markers on chromosome 1. Close linkage between the ADRP locus and any of the marker loci was excluded using two-point analysis. With use of the sex-averaged maps of Dracopoli et al. and Donis-Keller et al. and a strategy of rolling multipoint analyses, support was gained for the exclusion of ADRP from a 224-cM region of the chromosome, including almost the entire short arm. The disease locus was significantly excluded from within at least 50 cM of the rhesus locus and, as a loose linkage between these two genes has been suggested by other studies, this result may support the possibility of genetic heterogeneity within the autosomal dominant subgroup of retinitis pigmentosa.

Chromosomes, Human, Pair 1↗

PubMed1989

Haplotype distribution of the human phenylalanine hydroxylase locus in Scotland and Switzerland.

RFLP haplotypes at the phenylalanine hydroxylase (PAH) locus were determined in 45 nuclear Caucasian families from Switzerland and Scotland. The RFLPs at the PAH locus are highly informative, and prenatal diagnosis is possible in 85% of the families studied. The data were combined with the profiles previously observed in the Danish population, in order to study the variation in RFLP haplotype distribution among European populations. A total of 22 different haplotypes were observed in Denmark, Switzerland, and Scotland. Fifteen and 19 haplotypes are associated with the normal (non-PKU) and with the mutant chromosomes, respectively. The haplotype distribution and the allele frequency of normal chromosomes remain constant between Denmark, Switzerland, and Scotland. However, both the haplotype distribution and allele frequencies of mutant chromosomes show significant variation between the three countries. Our results suggest there may be additional mutations in the PAH gene that cause PKU.

Alleles↗

PubMed1989

Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in European families with phenylketonuria (PKU).

DNA haplotype data from the phenylalanine hydroxylase (PAH) locus are available from a number of European populations as a result of RFLP testing for genetic counseling in families with phenylketonuria (PKU). We have analyzed data from Hungary and Czechoslovakia together with published data from five additional countries--Denmark, Switzerland, Scotland, Germany, and France--representing a broad geographic and ethnographic range. The data include 686 complete chromosomal haplotypes for eight RFLP sites assayed in 202 unrelated Caucasian families with PKU. Forty-six distinct RFLP haplotypes have been observed to date, 10 unique to PKU-bearing chromosomes, 12 unique to non-PKU chromosomes, and the remainder found in association with both types. Despite the large number of haplotypes observed (still much less than the theoretical maximum of 384), five haplotypes alone account for more than 76% of normal European chromosomes and four haplotypes alone account for more than 80% of PKU-bearing chromosomes. We evaluated the distribution of haplotypes and alleles within these populations and calculated pairwise disequilibrium values between RFLP sites and between these sites and a hypothetical PKU "locus." These are statistically significant differences between European populations in the frequencies of non-PKU chromosomal haplotypes (P = .025) and PKU chromosomal haplotypes (P much less than .001). Haplotype frequencies of the PKU and non-PKU chromosomes also differ significantly (P much less than .001. Disequilibrium values are consistent with the PAH physical map and support the molecular evidence for multiple, independent PKU mutations in Caucasians. However, the data do not support a single geographic origin for these mutations.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1989

Polymorphic DNA haplotypes at the phenylalanine hydroxylase (PAH) locus in Asian families with phenylketonuria (PKU).

DNA polymorphisms at the phenylalanine hydroxylase (PAH) locus have proved highly effective in linkage diagnosis of phenylketonuria (PKU) in Caucasian families. More than 10 RFLP sites have been reported within the PAH structural locus in Caucasians. With information from affected and unaffected offspring in PKU families it is often possible to reconstruct complete RFLP haplotypes in parents and to use these haplotypes to follow the segregation of PKU within families and to determine the distribution of PKU chromosomes within populations. To establish the utility of these RFLPs in characterizing Asian families with PKU, we typed eight DNA sites in 21 Chinese families and 12 Japanese families with classical PKU. The eight RFLPs were chosen for their informativeness in Caucasians. From these families we reconstructed a total of 91 complete PAH haplotypes, 44 from non-PKU chromosomes and 47 from PKU-bearing chromosomes. Although all eight marker sites are polymorphic in both Chinese and Japanese, there is much less haplotypic variation in Asians than in Caucasians. In particular, one haplotype alone, haplotype 4, accounts for more than 77% of non-PKU chromosomes and for more than 80% of PKU-bearing chromosomes. Haplotype 4 is also relatively common in Caucasians. The next most common Asian haplotype is 10 times less frequent than haplotype 4. By contrast, in many Caucasian populations the sum of the frequencies of the five most common haplotypes is still less than 80%, and several of the most common haplotypes are equally frequent. Even though the extent of haplotypic variation in Asians is severely limited, the few haplotypes that are found often differ at a number of RFLP sites.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗

PubMed1988

Spinocerebellar ataxia: variable age of onset and linkage to human leukocyte antigen in a large kindred.

We studied a seven-generation kindred with autosomal dominant spinocerebellar ataxia (SCA) to assess linkage relationships to multiple human leukocyte antigen (HLA) loci on the short arm of chromosome 6. Age at onset, clinical features, and course of the disease are described. Although the mean age of onset was 34 years in this family, in 6 of 41 affected individuals onset was below 15 years of age and was accompanied by the unique clinical features of mental retardation and rapid progression of disease. Linkage studies were performed on 93 individuals, and the results show strong evidence for linkage of the SCA locus to the HLA loci. A maximum logarithm of the odds score of 5.83 was found at a recombination fraction of 0.12. This is the first documentation of childhood onset in the HLA-linked form of SCA.

Adult↗

PubMed1988

Extensive DNA polymorphism at the factor XIIIa (F13A) locus and linkage to HLA.

A 1,161-bp EcoRI fragment from the 5' end of the cDNA coding for human factor XIIIa (gene symbol F13A) was used to identify RFLPs in human DNAs. Several different RFLPs were identified with 15 different restriction enzymes. Two RFLPs detected with the restriction enzyme BamHI and one multiallelic RFLP detected with BclI were used for further studies. Linkage relationships between these three polymorphisms and the HLA complex were studied in DNA samples from the 40 Centre d'Etude du Polymorphisme Humain families. Combining all of the data to form highly informative haplotypes, we found linkage to HLA with a maximum lod score of 11.44 at a recombination fraction of .25 for males and .35 for females. These three RFLPs at the FXIIIa locus provide a highly informative marker for the short arm of chromosome 6 with an observed heterozygosity of 91%. Using this marker and the HLA locus, one can confirm or exclude the assignment of gene loci to most of chromosome 6p.

Chromosome Mapping↗

PubMed1987

Evolution of nuclear gene families in primates. Copy-number variation in the argininosuccinate synthetase (ASS) pseudogene family and the anonymous DNA sequence, D1S1.

Changes in the copy number of nuclear genes provide the raw material for the creation of new gene functions. To better understand the mechanisms for such events, and their physiologic and evolutionary consequences, it is valuable to study a well characterized and closely related group of species such as primates. Fortuitously, most of the powerful molecular techniques and DNA probes developed for research in humans are equally applicable to non-human primates. We review what is known of copy number variation in primates and describe two informative DNA probes: pAS-1, a cDNA probe to the human urea cycle enzyme argininosuccinate synthetase (ASS), and an anonymous DNA probe, D1S1. In addition to the ASS structural locus on human chromosome 9, pAS-1 detects at least 14 dispersed, processed pseudogenes in humans. The number of pseudogene copies appears to be approximately the same in humans, chimpanzees, gorillas, orangutans and baboons; less in marmosets; and least in some rodents. Chimpanzees and gorillas appear to have all of the human pseudogenes though an Xp copy may be missing from gorillas. The Y pseudogene is apparently absent from orangutans and baboons, and, finally, a comparison of humans and chimpanzees revealed that the number of nucleotide substitutions in the Y chromosome pseudogenes is approximately 1 per 100. D1S1 maps to human chromosome 3 but also detects a high homology copy on chromosome 1. Chimpanzees, gorillas and orangutans all appear to have only the chromosome 3 homolog suggesting that this is the ancestral sequence and that the duplication occurred after separation of humans and the great apes. Both the ASS pseudogene family and the D1S1 system provide valuable information on the evolution of nuclear gene families in primates.

Animals↗

PubMed1987

Polymorphic DNA haplotypes at the human phenylalanine hydroxylase locus and their relationship with phenylketonuria.

Eight polymorphic restriction enzyme sites at the phenylalanine hydroxylase (PAH) locus were analyzed from the parental chromosomes in 33 Danish nuclear families with at least one phenylketonuric (PKU) child. Determination of haplotypes of 66 normal chromosomes and 66 chromosomes bearing mutant allele(s) demonstrated that there are at least two haplotypes which occur predominantly on PKU chromosomes and rarely otherwise. Overall, the relative frequencies of the various haplotypes are significantly different on PKU- and normal-allele bearing chromosomes, even though there is no predominantly occurring unique haplotype which can characterize the PKU chromosomes. In addition, no significant association (linkage disequilibrium) between any single polymorphic site and the mutant allele(s) was observed. The results suggest that either the phenylketonuric mutation was very ancient so that the polymorphic sites and the mutation have reached linkage equilibrium or the mutant allele(s) are the results of multiple mutations in the phenylalanine hydroxylase gene in man. Furthermore, a crude relationship between standardized linkage disequilibria and physical map distances of the polymorphic sites indicates that there is no apparent recombination hot-spot in the human phenylalanine hydroxylase gene, since the recombination rate within the locus appears to be uniform and likely to be occurring at a rate similar to that within the HLA gene cluster. The limitations of this later analysis are discussed in view of the sampling errors of disequilibrium measure used, and the potential utility of the PAH haplotypes for prenatal diagnosis and detection of PKU carriers is established.

Alleles↗

PubMed1987

DNA linkage studies of degenerative retinal diseases.

DNA linkage studies of human genetic diseases have led to rapid characterization of a number of otherwise intractable disease loci. Detection of a linked DNA marker, the first step in "reverse genetics", has permitted cloning of the genes for Duchenne muscular dystrophy, retinoblastoma and chronic granulomatosis disease, among others. Thus, the case for applying these techniques to retinitis pigmentosa and related diseases, and the urgency in capitalizing on molecular developments, is justified and compelling. The first major success regarding RP was in demonstrating linkage of the DNA marker DXS7 (L1.28) to XRP. For autosomal forms of the disease, conventional linkage studies have provided tentative evidence for linkage of ADRP to the Rh blood group on chromosome lp and for linkage of Usher's syndrome to Gc and 4q. These provisional assignments are, at least, an important starting point for DNA analysis. The Support Program for DNA Linkage Studies of Degenerative Retinal Diseases was established to provide access for the scientific community to appropriate families, using the resources of the Human Genetic Mutant Cell Repository to prepare, store and distribute lymphoblast lines. To date, two extensive, well-characterized families are included in the program: the autosomal dominant RP family UCLA-RP01, and the Usher's syndrome families LSU-US01. It is highly likely that rapid progress will be made in mapping and characterizing the inherited retinal dystrophies. We believe the support program will facilitate this progress.

Choroid↗

PubMed1986

Polymorphic DNA haplotypes at the phenylalanine hydroxylase locus in prenatal diagnosis of phenylketonuria.

Restriction fragment length polymorphisms (RFLPs) detected in the human genome by means of a cDNA clone of phenylalanine hydroxylase (PAH) segregate concordantly with phenylketonuria (PKU) in several families. To establish the usefulness of these DNA polymorphisms for prenatal diagnosis of PKU the genotypes and chromosomal haplotypes of eight RFLPs at the PAH locus were determined in 46 families, each with one or more affected children. 34 of these families were informative for linkage analysis, giving a maximum probability of 10(9):1 in favour of tight linkage between PKU and the PAH RFLP haplotypes. Thus the deficiency of hepatic PAH in PKU patients is caused by mutations in the PAH gene itself, and the RFLPs could be used effectively for prenatal diagnosis and carrier detection of PKU in affected families. Use of the PKU haplotypes based on these eight RFLPs would establish disease status in approximately 87% of siblings at risk, although three RFLPs alone (detected with the restriction enzymes Pvu II, Xmn I, and EcoR R) are nearly as effective.

Alleles↗

PubMed1986

The anonymous polymorphic DNA clone D1S1, previously mapped to human chromosome 1p36 by in situ hybridization, is from chromosome 3 and is duplicated on chromosome 1.

D1S1, a human anonymous DNA clone originally called lambda Ch4A-H3 or lambda H3, was mapped by two other laboratories to human chromosome 1p36 by in situ hybridization but its localization was not confirmed using a different mapping method. We used a panel of human-hamster somatic cell hybrids to show that there are copies of D1S1 on both chromosomes 1 and 3. The D1S1 clone itself is from chromosome 3, and part of it is duplicated at least twice on chromosome 1. A high frequency HindIII polymorphism detected by D1S1, believed to be at chromosome 1p36 on the basis of the in situ hybridization data, maps instead to chromosome 3. This finding demonstrates the importance of using two mapping methods to verify the localization of a gene or DNA segment, particularly a polymorphic one which itself may be used in mapping studies. It also raises the question of why in situ hybridization detected a duplicated portion of a clone but not the chromosomal origin of the clone itself.

Animals↗

PubMed1985

The human apolipoprotein B-100 gene: a highly polymorphic gene that maps to the short arm of chromosome 2.

Using a cloned cDNA of apolipoprotein B-100 as hydridization probe, we have found high frequence polymorphisms in the apoB-100 gene involving sites for the restriction enzymes EcoRI, BamHI, and HindIII. The major EcoRI polymorphisms involved a 17 kb vs 15 kb variant. The incidence of the various phenotypes was estimated. In addition, other complex polymorphisms involving MspI and TaqI sites were also noted. [32P]-labeled apoB-100 cDNA was used as a probe in chromosome mapping studies to detect the human apoB-100 structural gene sequence in human-Chinese hamster and human-mouse cell hybrids. Southern blot analysis of 14 hybrids localized the gene to the short arm of human chromosome 2.

Apolipoprotein B-100↗

PubMed1985

Extensive restriction site polymorphism at the human phenylalanine hydroxylase locus and application in prenatal diagnosis of phenylketonuria.

A total of 10 restriction site polymorphisms have been identified at the human phenylalanine hydroxylase locus using a full-length human phenylalanine hydroxylase cDNA clone as a hybridization probe to analyze human genomic DNA. These polymorphic patterns segregate in a Mendelian fashion and concordantly with the disease state in various PKU kindreds. The frequencies of the restriction site polymorphisms at the human phenylalanine hydroxylase locus among Caucasians are such that the observed heterozygosity in the population is 87.5%. Thus, most families with a history of classical phenylketonuria can take advantage of the genetic analysis for prenatal diagnosis and carrier detection of the hereditary disorder.

Female↗

PubMed1984

Increased frequency of coronary heart disease in relatives of wives of myocardial infarct survivors: assortative mating for lifestyle and risk factors?

The frequency of myocardial infarction (MI) and coronary artery disease (CAD) was studied among the first-degree relatives of 126 spouses of male survivors of MI, and compared with the frequency of MI and CAD among relatives of 126 age-matched control subjects. MI and CAD were as frequent among the relatives of the wives as among the relatives of their husbands with MI. MI and CAD were less frequent among the relatives of control subjects. Familial aggregation of CAD, therefore, is not limited to patients' relatives, but also affects the wives' families. This finding can be explained by assortative mating, i.e., marriage partners choose mates with similar lifestyles and risk factors that lead to CAD.

Adult↗

PubMed1984

X-linked, polymorphic genetic variation of thyroxin-binding globulin (TBG) in baboons and screening of additional primates.

X-linked polymorphic variation of thyroxin-binding globulin (TBG) is observed in several human groups. Isoelectric focusing of plasma samples labeled in vitro with [125I]thyroxin, followed by autoradiography, also reveals genetically determined polymorphic electrophoretic variation in baboon TBG. The protein detected by this method in baboon plasma is immunologically similar to human TBG and is distinct from the other thyroxin-binding proteins, albumin and prealbumin. The isoelectric patterns of human and baboon TBG are very similar and both have an isoelectric range of pH 4.1 to 4.5. The baboon TBG polymorphism is inherited in a two-allele X-linked fashion, with a frequency of 72% for the "common" allele and 28% for the "slow" allele. A survey of seven other primate species including African green monkey, bonnet macaque, chimpanzee, crab-eating macaque, gorilla, rhesus monkey, and spider monkey revealed no polymorphic variation in TBG, although isoelectric patterns were similar to the human and baboon patterns. In addition, samples from pregnant chimpanzees demonstrate a pronounced quantitative anodal shift in relative band densities, a shift also observed in pregnant humans. This shift was not observed in samples from pregnant baboons. TBG should prove to be a useful X-linked genetic marker in baboons and provides a model of serum protein changes in pregnancy, at least in humans and chimpanzees.

Animals↗

PubMed1984

Multiple, independent restriction site polymorphisms in human DNA detected with a cDNA probe to argininosuccinate synthetase (AS).

We have used a cDNA clone of the human urea cycle enzyme argininosuccinate synthetase (AS) to screen for restriction fragment length polymorphisms (RFLPs) using a large panel of restriction enzymes. The probe, pAS-1, detects from 15 to 27 human DNA fragments by Southern gel analysis. In addition to the structural locus on chromosome 9, AS-like sequences are found on at least 10 human chromosomes, including the X and Y. This large number of dispersed pseudogenes accounts for the multiplicity of hybridizing fragments detected with pAS-1. Of 37 restriction enzymes tested, 18 produced excellent digest patterns; of these 18 enzymes, three revealed high-frequency, independent RFLPs, testing a minimum of 16 individuals with each enzyme. The enzymes producing high-frequency polymorphisms are Hind III (allele frequencies .30 and .70), Hind II (.13 and .87), and Bam HI (.56 and .44). Most of the polymorphic alleles are found in Caucasians, American blacks, and Orientals. The RFLP detected with Hind III maps to chromosome 9 (9q11-q22), although not to the structural locus; the others are autosomal but otherwise unassigned. Two additional six-base enzymes and a four-base enzyme, Msp I, revealed further individual variation, but these variants have not been shown to segregate in families yet. We observed approximately 0.8% high-frequency RFLPs per cut site per enzyme or a minimum of .05% heterozygosity per nucleotide. pAS-1 should prove useful in assigning high-frequency RFLPs to several human chromosomes.

Adult↗

PubMed1984

Heritability of quantitative variation at the group-specific component (Gc) locus.

Human group-specific component (Gc) is the plasma transport protein for vitamin D; in addition, polymorphic electrophoretic variants of Gc are found in all human populations. Because of its physiologic importance and in view of the extensive genetic variation at the Gc locus, we have determined the heritability of quantitative variation in Gc by comparing a series of monozygotic (MZ) and dizygotic (DZ) twins of known Gc genotype. The series included 31 MZ twin pairs, 13 DZ twin pairs, and 45 unrelated controls. Since Gc concentration is increased by estrogens, pregnant women and women taking oral contraceptives were excluded. We found no age-related differences in Gc concentration or differences between males and females, but the concentrations of Gc in the three electrophoretically determined genotypes were significantly different from each other. Using classical methods of heritability analysis, the overall heritability of variation in Gc concentration is approximately 70%. Heritability in males is greater than in females, probably reflecting the additional environmental effect of estrogens in women. To determine if the differences in Gc concentration between the three genotypes explain the high heritability, a new variance decomposition procedure was developed following classical methods in quantitative genetics. Application of this method suggests that 19% of the total variation in Gc concentration, combining both sexes, is due to electrophoretic differences between individuals (30% in females and 20% in males). Thus, the genetic component of variation in Gc concentration can be decomposed into a major gene component--the result of electrophoretic variation at the structural locus--and a second, unexplained, polygenic component.

Adolescent↗

PubMed1983

Deletion mapping of polymorphic loci by apparent parental exclusion.

Deletion of a chromosome region containing a polymorphic marker may result in apparent parental exclusion at that locus. We present a general method for calculating the probability that deletion at a specific locus would have such an effect. For many autosomal loci this probability is substantial, justifying attempts at deletion mapping in most cases. This method may be especially valuable in assigning DNA restriction fragment polymorphisms to chromosome regions.

Chromosome Deletion↗