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PubMed2000

Fine volumetric analysis of the cerebral ventricular system in schizophrenia: further evidence for multifocal mild to moderate enlargement.

We used traditional volumetric regional analysis and a finer anterior-posterior (AP) profile volumetric analysis to examine the cerebral ventricular system in an all-male, demographically matched sample of schizophrenia patients (n = 73) and normal controls (n = 29) using 2.8-mm-thin coronal T1-weighted magnetic resonance images from a 1.5 tesla scanner. Traditional regional analysis was performed on various regions using absolute volumes after adjusting for intracranial volume (ICV) and age. The fine AP profile analysis was done by intrasubject "stacking" of contiguous coronal cross-sectional volumes (adjusted for ICV and age) across the AP plane, intersubject AP alignment of all slices relative to the mammillary bodies, and plotting of slice volumes along the AP plane with 95 percent t-test-based confidence intervals. Schizophrenia subjects had mild to moderate multifocal ventricular enlargement (overall effect size d = 0.48), which was especially prominent in the right posterior temporal horn and, more generally, in the central to posterior portions of the lateral and third ventricles. Schizophrenia subjects also had milder enlargement in the left frontal horn, but no significant differences were found in the anterior temporal horns and the right frontal horn. Post hoc analyses of demographic, clinical, and neuropsychological variables did not account for much variance in the ventriculomegaly observed in the schizophrenia group. The lack of a single locus in the observed ventricular enlargement, the nonsignificant results from schizophrenia subtypes based on regional distributions, and the strong positive correlations among the ventricular regions for the schizophrenia group suggest that the ventriculomegaly seen in this chronic population reflects a single brainwide disease process leading to a multifocal or patchy loss of integrity in brain structure.

Adult↗

PubMed1986

The use of measured genotype information in the analysis of quantitative phenotypes in man. I. Models and analytical methods.

Improved laboratory methods allow one to investigate the contribution of measured allelic variability at a locus physiologically involved in determining the expression of a quantitative trait. We present statistical methods that incorporate measured genotype information into the analysis of a quantitative phenotype that allows one simultaneously to detect and estimate the effects of a measured single locus and residual polygenic effects. Likelihoods are presented for the joint distribution of the quantitative phenotype and a measured genotype that are appropriate when the data are collected as a sample of unrelated individuals or as a sample of nuclear families. Application of this method to the analysis of serum cholesterol levels and the concentration of the group specific component (Gc) are presented. The analysis of the contribution of the common Gc polymorphism to the determination of quantitative variability in Gc using samples of related and unrelated individuals presents, for the first time, the simultaneous estimation of the frequencies and the effects of the genotypes at a measured locus, and the contribution of residual unmeasured polygenes to phenotypic variability.

Genotype↗

PubMed1994

Retrotransposition of a plant SINE into the wx locus during evolution of rice.

A new type of plant retroposon, p-SINE1, has been found in the wx locus of rice (Oryza sativa). It has some structural characteristics similar to those of mammalian SINEs, such as members of the Alu or B1 family. In order to estimate the time at which the integration of p-SINE1 into a single locus occurred during rice evolution, we examined the distribution of two members of p-SINE1 in several species of the Oryza genus by the polymerase chain reaction (PCR). We found that one member of p-SINE1 (p-SINE1-r2) in the ninth intron of the wx+ gene was present only in two closely related species, O. sativa and O. rufipogon, and was not present in the other species carrying the AA genome within the Oryza genus. This result indicates that p-SINE1-r2 was integrated into the wx locus after O. sativa and O. rufipogon had diverged from other species with the AA genome. In contrast to p-SINE1-r2, another member (p-SINE1-r1) located in the untranslated 5'-region of the wx+ gene was present not only in all species with the AA genome but also in species with a different genome (CCDD). This result suggests that p-SINE1-r1 was integrated into that position prior to the genomic divergence. Thus, it appears that each member of p-SINE1 was retroposed at a specific site at a different time during rice evolution.

Base Sequence↗

PubMed2002

Inheritance of superoxide dismutase ( Sod-1) in a perennial x annual ryegrass cross and its allelic distribution among cultivars.

Identifying annual ryegrass contamination in perennial ryegrass seed lots has been of major interest in seed-testing laboratories and for seed regulatory agencies in the USA for many years. This study was conducted to characterize a superoxide dismutase locus ( Sod-1) and determine its potential to distinguish cultivated ryegrass species. The inheritance of Sod-1 was evaluated in a three-generation annual x perennial ryegrass mapping population and segregation fitted an expected 1:2:1 ratio for a single locus with two alleles. The molecular form of the Sod-1 locus was determined by H(2)O(2) and KCN inhibitor assays which indicated that the Sod-1, and a second independently segregating Sod-2, locus were both Cu/ZnSod enzymes. The common alleles at the Sod-1 locus were scored in 13 annual and 24 perennial ryegrass cultivars to determine the potential of using this locus for species separation. The Sod-1b allele was homozygous in 98% of perennial ryegrass individuals from 24 cultivars, but those not 100% homozygous for Sod-1b were seed lots with unknown contamination from annual ryegrass. These results indicate that the Sod-1b allele in the homozygous condition is a good indicator of perenniality. All eight annual ryegrass cultivars originating in Europe or Asia had a low frequency of Sod-1b homozygous individuals or none at all. The five cultivars originating in the Western Hemisphere, however, had genotype frequencies for homozygous Sod-1b of up to 56%. The potential of the Sod-1 locus to serve as a test to separate the two growth forms depends on the source of the annual-type contamination.

Journal Article↗

PubMed1978

Genetic analysis of the gene for N-acetylglucosaminidase in Dictyostelium discoideum.

Three independent mutations affecting N-acetylglucosaminidase in Dictyostelium discoideum were mapped by the parasexual system and found to lie on linkage group IV. These mutations as well as two others were found to be recessive and noncomplementing in heterozygous diploids. Thus they all appear to affect the nagA locus. Since two of the mutations give rise to thermolabile enzyme, this defines the structural gene for N-acetylglucosaminidase. The enzyme is a homodimer of a 68,000 dalton subunit and thus would be expected to be determined by a single locus. The expression of this gene is regulated by the stages of development; however, it should be mentioned that none of the mutations fell in a separate locus that might determine a specific positive regulatory proteins.

Acetylglucosaminidase↗

PubMed1999

Microsatellite retrieval in lettuce (Lactuca sativa L.).

By using enriched genomic libraries, microsatellite-containing sequences were isolated from lettuce (Lactuca sativa) with high efficiency. With this approach, a sizeable fraction (up to 55%) of the clones contained a microsatellite. In about half of these clones, primers could be designed for PCR amplification of the microsatellite. This yielded 28 primer sets amplifying unambiguously scorable products, of which 26 showed polymorphisms in a test set of six lettuce varieties. Practically all microsatellite-amplifying primer sets yielded products in lettuce's nearest relative, L. serriola, but only half of the primer sets yielded products in the more distant species L. saligna and L. virosa. An average polymorphism information content (PIC) value of 0.55 and an average number of 3.5 alleles per locus were in the normal range for a self-fertilizing species like lettuce. In addition, the incidental cloning of a microsatellite-containing repeat family, apparently specific for Lactuca, is reported and the implications for the efficient retrieval of single-locus microsatellite sequences are discussed. The microsatellite loci isolated will be useful for distinguishing lettuce cultivars and for screening diversity of genetic resources.

Alleles↗

PubMed2006

PedGenie: an analysis approach for genetic association testing in extended pedigrees and genealogies of arbitrary size.

BACKGROUND: We present a general approach to perform association analyses in pedigrees of arbitrary size and structure, which also allows for a mixture of pedigree members and independent individuals to be analyzed together, to test genetic markers and qualitative or quantitative traits. Our software, PedGenie, uses Monte Carlo significance testing to provide a valid test for related individuals that can be applied to any test statistic, including transmission disequilibrium statistics. Single locus at a time, composite genotype tests, and haplotype analyses may all be performed. We illustrate the validity and functionality of PedGenie using simulated and real data sets. For the real data set, we evaluated the role of two tagging-single nucleotide polymorphisms (tSNPs) in the DNA repair gene, NBS1, and their association with female breast cancer in 462 cases and 572 controls selected to be BRCA1/2 mutation negative from 139 high-risk Utah breast cancer families. RESULTS: The results from PedGenie were shown to be valid both for accurate p-value calculations and consideration of pedigree structure in the simulated data set. A nominally significant association with breast cancer was observed with the NBS1 tSNP rs709816 for carriage of the rare allele (OR = 1.61, 95% CI = 1.10-2.35, p = 0.019). CONCLUSION: PedGenie is a flexible and valid statistical tool that is intuitively simple to understand, makes efficient use of all the data available from pedigrees without requiring trimming, and is flexible to the types of tests to which it can be applied. Further, our analyses of real data indicate NBS1 may play a role in the genetic etiology of heritable breast cancer.

Biomarkers, Tumor↗

PubMed1997

A rapid typing system at three STR loci from bloodstains using a simple DNA extraction kit and capillary electrophoresis.

A rapid typing method for STR analysis from bloodstains was devised. DNA from three-year-old bloodstains of six individuals was extracted with a cationic detergent in a newly-released kit. Amounts of DNA extracted by the kit were 16.2 +/- 1.8 ng from 10 microliters of fresh blood samples. DNA was also extracted from bloodstains of three months and three years left at room temperature, and amounts of extracted DNA were estimated at 2.2 +/- 1.0 ng and 0.1 +/- 0.1 ng, respectively. The PCR mixture supplied with the kit, plus three sets of fluorescently labeled primers, were directly added to the tube used for DNA extraction. The amplified products were then analyzed by capillary electrophoresis, and the obtained data were automatically sized and typed using computer software. Three genotypes of all bloodstains except one sample at a single locus were determined correctly as those of freshly collected blood from the same individuals although some stains contained no more than 0.1 ng. Using this typing system, we were able to type three STR loci, HUMTH01, HUMF13A1 and HUMFES/FPS, from a single bloodstain within five hours. This typing is particularly useful for forensic practice.

Blood Stains↗

PubMed1978

Genetic regulation of liver alcohol dehydrogenase in Peromyscus.

Data from genetic crosses of Peromyscus maniculatus and P. polionotus suggests that electrophoretic variants of liver alcohol dehydrogenase are coded by alleles at a single locus. These alleles, designated AdhF, AdhS, and AdhN, determine, respectively, the fast, slow, and not detectable (null) ADH electrophoretic phenotype. Heterozygotes (AdhF/AdhS) exhibit three bands on zymograms, suggesting a dimeric subunit structure for the enzyme. However, AdhF/AdhN and AdhS/AdhN animals exhibit a single band, suggesting that the AdhN allele does not produce a polypeptide subunit capable of dimerizing into an active molecule. Fast and slow electrophoretic phenotypes exhibit multiple bands which can be converted into single major fast and slow bands, respectively, upon treatment with oxidized or reduced NAD. Addition of NAD also stabilizes both the fast and slow enzyme to heat inactivation at 60 C for at least 30 min.

Alcohol Oxidoreductases↗

PubMed2006

Family-based association analysis validates chromosome 3p21 as a putative nasopharyngeal carcinoma susceptibility locus.

PURPOSE: Nasopharyngeal carcinoma (NPC) poses one of the serious health problems in southern Chinese, with an incidence rate ranging from 15 to 50/100,000. In our previously linkage analysis, a locus on 3p21 was identified to link to NPC. In this study, family-based association analysis was performed to test the transmission disequilibrium of chromosome 3p in 18 high-risk nasopharyngeal carcinoma families of Hunan province in southern China. METHODS: Single locus and multi-point of transmission disequilibrium test was performed by Genehunter program package with 15 microsatellite markers on chromosome 3p in 18 nasopharyngeal carcinoma pedigrees. RESULTS: A major transmission disequilibrium peak was observed near D3S1568, which possessed 20 alleles or haplotypes of 6 loci, spanning a 12.4 cM region from D3S1298 to D3S1289 on chromosome 3p21.31-3p21.2, and 3 alleles or haplotypes reached high significantly difference (P < 0.01). CONCLUSION: These results reflected a link disequilibrium between this chromosome region and a nasopharyngeal carcinoma susceptibility locus, and provided further evidence that a novel nasopharyngeal carcinoma susceptibility gene may be located in this chromosome region. These alleles or haplotypes transmitting disequilibrium in nasopharyngeal carcinoma pedigrees may act as the highly risk molecular markers after verified in large population.

Alleles↗

PubMed1997

Inheritance of larval resistance to permethrin in Aedes aegypti and association with sex ratio distortion and life history variation.

The genetic mechanisms that confer larval permethrin resistance were investigated in two strains of Aedes aegypti, vectors of yellow fever and dengue hemorrhagic fever. Larval resistance to permethrin in an Ae. aegypti field-collected resistant Couva (R) strain was associated with the sex-determining locus by analysis of backcrosses to the susceptible Rockefeller (S) strain. The median lethal concentrations (LC50s) of these strains were 23.1 (95% confidence interval = 22.0-24.3) and 2.2 (2.0-2.3) parts/billion of permethrin, respectively. The estimated resistance ratio (RR) for the R strain was 10.8 (10.3-11.4) compared with the S strain. Resistance was inherited as partly recessive (dominance [D] = -0.31) with an estimated RR of 2.3 (2.1-2.4) in the F1 hybrids when the R parent was male. There were also significantly male-biased sex ratios for this cross. In contrast, inheritance was slightly dominant (D = 0.19) with an estimated RR of 4.1 (3.8-4.4) when the R parent was female, and no significant sex ratio bias of progeny was observed. Analysis revealed a strong paternal-strain effect in bioassay mortality, sex ratio, egg hatch, and fecundity. A maternal-strain effect was also evident for bioassay mortality. Similarly, a strong maternal by paternal strain interaction was also evident for sex ratio. Progeny of single-family backcrosses of F1 hybrids to R were statistically homogeneous for sex ratio, duration of oviposition, fecundity, and hatch rate. A significant increase in male bias was found for only one backcross to R, after treatment with permethrin. In contrast, complex patterns of inheritance of life histories were observed among backcrosses to S. Backcrosses to S had greater mean fecundities, shorter mean times to the start of oviposition, and shorter mean oviposition periods than did backcrosses to R. Hatch rates were statistically homogeneous among backcrosses, but all strikingly reduced relative to the parental generation. Times of start and duration of oviposition were highly negatively correlated with fecundity (first gonotropic cycle only) and rate of egg hatch. Females with lower fecundities had lower hatch rates, and there was a threshold of approximately 80 eggs per female, below which no eggs hatched. Generally all backcrosses had higher LC50s than expected from single-locus inheritance. Association between sex bias and inheritance of resistance was apparent, but no single genetic linkage model based on current understanding of sex chromosome genetics was consistent with these observations. These results may have epidemiologic importance considering that permethrin-soaked bed nets are being used in many countries to control the biting activity of disease vectors.

Aedes↗

PubMed2002

A locus for autosomal dominant keratoconus: linkage to 16q22.3-q23.1 in Finnish families.

PURPOSE: The estimated world-wide prevalence of keratoconus is 50 to 230 per 100,000 in the general population. Sporadic keratoconus is the leading cause of corneal transplantation surgery in Western countries. Positive family history has been reported in 6% to 8% of patients. The purpose of this study was to map the disease locus in 20 Finnish families with autosomal dominant keratoconus, each family having two or more affected members and with no other associated genetic disease. METHODS: DNA was extracted from blood samples, collected from 42 affected and 34 unaffected family members. Genomic DNA from patients and their parents, was typed for alleles of 292 polymorphic markers. A genome-wide screening was performed to localize the disease gene. Fluorescent markers were amplified by polymerase chain reaction and separated on an automated sequencer. Allele sizes were assigned to each family member, after which LOD scores were calculated. RESULTS: The disease locus was mapped to chromosome 16q, between the markers D16S2624 and D16S3090, with a maximum parametric multipoint LOD score of 4.10 and corresponding nonparametric score of 3.27 (NPL, P = 0.00006). Evidence from 20 families provided support for the linkage, consistent with a single locus for familial autosomal dominant keratoconus without heterogeneity. CONCLUSIONS: This study is the first genome-wide linkage study to map the keratoconus gene. The results suggest that the causative gene in keratoconus is located within the 16q22.3-q23.1 chromosomal region.

Adolescent↗

PubMed1997

Different mechanisms underlie DNA instability in Huntington disease and colorectal cancer.

Two recent lines of evidence raise the possibility that instability in germ-line or somatic cells arises by a common mechanism that involves defective mismatch repair. Mutations in mismatch-repair proteins are known to cause instability in hereditary nonpolyposis colorectal cancer, instability that is physically similar to germ-line instability observed in Huntington disease (HD). Furthermore, both germ-line and somatic-cell instability are likely to be mitotic defects, the former occurring early in embryogenesis. To test the hypothesis that defective repair is a common prerequisite for instability, we have utilized two disease groups that represent different instability "conditions." Germ-line instability within simple tandem repeats (STR) at 10 loci in 29 HD families were compared with somatic instability at the same loci in 26 colon cancer (CC) patients with identified or suspected defects in mismatch-repair enzymes. HD is known to be caused by expansion within the CAG repeat of the locus, but the extent or pattern of STR instability outside this region has not been examined systematically. We find a distinctly different pattern of STR mutation in the two disease groups, suggesting different mechanisms. Instability in HD is generally confined to a single locus, whereas instability is widespread for the same loci in CC. Our data do not support a causative role for defective mismatch-repair enzymes in instability associated with HD; rather, our data are consistent with a model in which DNA structure may inhibit normal mismatch repair at the expansion site.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMedDate not supplied

Genetic susceptibility factors of Type 1 diabetes in Asians.

Type 1 diabetes is a multifactorial disease in which the insulin producing beta-cells of the pancreas are destroyed by the immune system, a process determined by the activity of major histocompatibility complex (MHC)-restricted T lymphocytes. Progress has been made in elucidating genetic factors involved in Type 1 diabetes in Caucasians, with less data available from Asia. For Asians, the human MHC locus (HLA region), especially the class II region, is the major susceptibility interval. The role of IDDM2, the insulin locus, has been questioned in Asia. In contrast to Caucasians, Asian populations have a very low incidence of Type 1 diabetes (0.4-1.1 cases/year/100 000 individuals). This low incidence rate in the Asian population may be related to the population frequency distribution of susceptible Type 1 diabetes genes, especially of HLA. The overall risk for Type 1 diabetes from HLA DR and DQ is determined by polymorphic residues (alleles) and particular combinations of alleles (haplotypes and genotypes) in a given individual. In Asians, it is very common that a protective DR4 allele is associated with susceptible DQ alleles while neutral/protective DQ alleles are associated with the susceptible DR4 alleles. Our analyses indicate that the counterbalancing between susceptible DRB1 and protective DQB1, and vice versa, is a factor that may contribute to the low incidence of diabetes in Asians. We find that identical HLA DRB1-DQB1 haplotypes of Asians and Caucasians have similar transmission to diabetic children and similar associations with diabetes. Moreover, the association with diabetes and transmission to a diabetic offspring of DR4 haplotypes varies depending on the haplotype borne on the homologous chromosome. This might contribute not only to the synergistic effect of DR3/4, but also to the susceptibility influence of DQB1*0401 haplotypes confined to DR4/X. High-risk DR4 subtypes were predominant in DR4/X, whereas protective DR4 subtypes were observed mainly in the DR3/4 genotype. Since in Asians DQB1*0401 is in linkage disequilibrium (LD) with DRB1*0405, we find more DRB1*0405-DQB1*0401 haplotypes in patients with DR4/X than in patients with DR3/4, suggesting that the contribution of the DRB1 locus may be greater in DR4/X than in DR3/4 genotypes. Several genome scans suggested additional susceptibility intervals and provided supporting evidence for several previously reported linkages. Other studies focused on the confirmation of linkage using multipoint sib-pair analyses with densely spaced markers and multiethnic collection of families. Although significant and consistent linkage evidence was reported for the susceptibility intervals IDDM12 (on 2q33) even in Asia, evidence for most other intervals varies in different data sets. LD mapping has become an increasingly important tool for both confirmation and fine-mapping of susceptibility intervals, as well as identification of etiological mutations. The examination of large and ethnically varied data sets including those of Asia has allowed identification of haplotypes that differ only at a single codon in a single locus. As more data become available, the study of pairs of haplotypes which differ at a single polymorphic site, but have different effects on disease susceptibility, should allow more precise definition of the polymorphisms involved in the disease process.

Asia↗

PubMed1981

A genetic locus responsible for salmonella susceptibility in BSVS mice is not responsible for the limited T-dependent immune responsiveness of BSVS mice.

BSVS mice are known to be highly susceptible to salmonella infection. We have shown that the bulk of the difference in susceptibility between BSVS and salmonella-resistant A/J mice is the result of a genetic difference at a single locus not closely linked to H-2, Igh-C, or Hbb, and not X-linked. We have backcrossed the A/J allele at this locus into BSVS mice for 8 successive generations and have demonstrated that the salmonella resistance afforded by this allele is not the result of a restoration of the generalized poor T-dependent responsiveness of BSVS mice. The salmonella resistance locus we have examined with these 2 strains is probably the same as the Ity locus described by others.

Animals↗

PubMed2005

Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method.

Schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world's population. It is considered a complex inheritance disorder. A number of genes are involved in combination in the etiology of the disorder. Evidence implicates the altered dopaminergic transmission in schizophrenia. In the present study, in order to identify susceptibility genes for schizophrenia in dopaminergic metabolism, we analyzed 59 single nucleotide polymorphisms (SNPs) in 24 genes of the dopaminergic pathway among 82 unrelated patients with schizophrenia and 108 matched normal controls. Considering that traditional single-locus association studies ignore the multigenic nature of complex diseases and do not take into account possible interactions between susceptibility genes, we proposed a multi-locus analysis method, using the posterior probability of morbidity as a measure of absolute disease risk for a multi-locus genotype combination, and developed an algorithm based on perturbation and average to detect the susceptibility multi-locus genotype combinations, as well as to repress noise and avoid false positive results at our best. A three-locus SNP genotype combination involved in the interactions of COMT and ALDH3B1 genes was detected to be significantly susceptible to schizophrenia.

Aldehyde Dehydrogenase↗

PubMed1990

Transmission of a psychometric indicator for liability to schizophrenia in normal families.

The genetic analysis of schizophrenia would be facilitated by identification of a heritable correlate of liability. Deviance on an index of Minnesota Multiphasic Personality Inventory (MMPI) signs is associated with the disease phenotype; the familial aggregation and mode of transmission of this continuous psychometric indicator have yet to be established. In this paper, we examine the indicator through commingling analysis and segregation analysis with both the mixed and unified models on 65 nuclear families containing 211 normal individuals. Evidence for a high degree of familiality is found. Analysis of untransformed data under a conditional likelihood provides evidence for Mendelian transmission of a major gene with commingling of two distributions. The frequency of the "high index score" allele is 0.15, with the gene accounting for 31% of the total population variance; such a locus would be relevant to the study of psychopathology as 28% of the population would carry at least one deviant allele. When power-transformed scores are used to eliminate skewness, there is evidence for one distribution and it is not possible to distinguish single gene from multifactorial (polygenic or cultural) inheritance. While our findings regarding mode of transmission must be interpreted cautiously and confirmation of a single locus requires further study, demonstration of familiality warrants continued investigation of the index as an indicator of liability for schizophrenia.

Adolescent↗

PubMed1988

Analysis of a mutator activity necessary for germline transposition and excision of Tc1 transposable elements in Caenorhabditis elegans.

The Tc1 transposable element family of the nematode Caenorhabditis elegans consists primarily of 1.6-kb size elements. This uniformity of size is in contrast to P in Drosophila and Ac/Ds in maize. Germline transposition and excision of Tc1 are detectable in the Bergerac (BO) strain, but not in the commonly used Bristol (N2) strain. A previous study suggested that multiple genetic components are responsible for the germline Tc1 activity of the BO strain. To analyze further this mutator activity, we derived hybrid strains between the BO strain and the N2 strain. One of the hybrid strains exhibits a single locus of mutator activity, designated mut-4, which maps to LGI. Two additional mutators, mut-5 II and mut-6 IV, arose spontaneously in mut-4 harboring strains. This spontaneous appearance of mutator activity at new sites suggests that the mutator itself transposes. The single mutator-harboring strains with low Tc1 copy number generated in this study should be useful in investigations of the molecular basis of mutator activity. As a first step toward this goal, we examined the Tc1 elements in these low copy number strains for elements consistently co-segregating with mutator activity. Three possible candidates were identified: none was larger than 1.6 kb.

Animals↗