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PubMed2000

Multiplex PCR for detection of trait and virulence factors in enterohemorrhagic Escherichia coli serotypes.

A multiplex PCR assay was developed which allowed the simultaneous detection of five trait genes or virulence markers in enterohemorrhagic Escherichia coli (EHEC) serotypes. A primer pair, designed to detect a single base-pair mutation in the uidA gene, is specific only for the prototypic EHEC of O157:H7 serotype and its toxigenic, non-motile variants. In a similar way, primers to the eaeA gene of the gamma-intimin derivative specifically detects strains in the EHEC 1 clonal group, which consists mostly of O157:H7 and some O55:H7 serotypes. The other three primer pairs, specific for stx1, stx2 and both variants of ehxA genes, will detect the presence of these virulence genes in all EHEC serotypes. Analysis of 34 strains, including various serotypes of EHEC, Shiga toxin-producing E. coli and enteropathogenic E. coli, confirmed that the multiplex PCR assay detected the presence of these genes in a manner consistent with the known genotype of each respective strains.

Bacterial Proteins↗
PubMed2003

Novel approaches to identify low-penetrance cancer susceptibility genes using mouse models.

Studies of cancer predisposition have largely concentrated on the role of high-penetrance susceptibility genes. Less than 10% of the total human tumor burden, however, is accounted for by mutations in these genes. More genetic variation in cancer risk is likely to be due to commoner but lower penetrance alleles. In man, such modifier genes will be difficult to find since they do not segregate as single Mendelian traits. The mouse offers a powerful system for studying polygenic traits such as cancer and has been widely used for this purpose. Novel approaches that might accelerate the identification of these low-penetrance cancer susceptibility genes by using mouse models will be discussed.

Alleles↗
PubMed1983

Family study of congenital limb reduction abnormalities in Hungary 1975-1977.

A family study of 274 index patients with limb reduction malformations born in Hungary from 1975 to 1977 is reported. The majority of 789 first-degree relatives were personally examined. Information was collected on 1094 uncles and aunts and on 1095 cousins, and those affected by limb malformations were examined. Among 789 first-degree relatives six were affected by a similar malformation (radial, ulnar and central ray defects) and 1 by a malformation of a different type; no secondary cases of the same type were found among the relatives of patients with terminal transverse and amniogenic malformations, and with limb malformations which were part of syndromes or unclassifiable associations with other malformations. While a few rare types of limb defects are due to dominant genes, the aetiology of most cases is obscure. There is no evidence of sex-linked inheritance, of multifactorial causation or of environmental factors shared by relatives. These results are similar to those of an earlier study by Birch-Jensen.

Abnormalities, Multiple↗
PubMed2003

Accuracy of marker-assisted selection with auxiliary traits.

Genetic information on molecular markers is increasingly being used in plant and animal improvement programmes particularly as indirect means to improve a metric trait by selection either on an individual basis or on the basis of an index incorporating such information. This paper examines the utility of an index of selection that not only combines phenotypic and molecular information on the trait under improvement but also combines similar information on one or more auxiliary traits. The accuracy of such a selection procedure has been theoretically studied for sufficiently large populations so that the effects of detected quantitative trait loci can be perfectly estimated. The theory is illustrated numerically by considering one auxiliary trait. It is shown that the use of an auxiliary trait improves the selection accuracy; and, hence, the relative efficiency of index selection compared to individual selection which is based on the same intensity of selection. This is particularly so for higher magnitudes of residual genetic correlation and environmental correlation having opposite signs, lower values of the proportion of genetic variation in the main trait associated with the markers, negligible proportion of genetic variation in the auxiliary trait associated with the markers, and lower values of the heritability of the main trait but higher values of the heritability of the auxiliary trait.

Animals↗
PubMed2002

The power and statistical behaviour of allele-sharing statistics when applied to models with two disease loci.

We have evaluated the power for detecting a common trait determined by two loci, using seven statistics, of which five are implemented in the computer program SimWalk2, and two are implemented in GENEHUNTER. Unlike most previous reports which involve evaluations of the power of allele-sharing statistics for a single disease locus, we have used a simulated data set of general pedigrees in which a two-locus disease is segregating and evaluated several nonparametric linkage statistics implemented in the two programs. We found that the power for detecting linkage using the S(all) statistic in GENEHUNTER (GH, version 2.1), implemented as statistic E in SimWalk2 (version 2.82), is different in the two. The P values associated with statistic E output by SimWalk2 are consistently more conservative than those from GENEHUNTER except when the underlying model includes heterogeneity at a level of 50% where the P values output are very comparable. On the other hand, when the thresholds are determined empirically under the null hypothesis, S(all) in GENEHUNTER and statistic E have similar power.

Alleles↗
PubMed1999

The 677T genotype of the common MTHFR thermolabile variant and fasting homocysteine in childhood venous thrombosis.

Controlled data on the association of MTHFR genotypes, hyperhomocysteinaemia and their interaction with factor V G1691A with childhood thrombosis are not yet available. Therefore we conducted a case-control study comparing 141 childhood patients with venous thrombosis with 345 healthy controls. The MTHFR C677T genotypes, FV G1691A and prothrombin G20210A were evaluated; in addition, fasting homocysteine concentrations were measured in a subgroup of 60 children and 80 healthy controls. 10.4% of the healthy control population showed the MTHFR TT genotype, 34.2% the CT genotype and 55.4% the CC variant. MTHFR genotypes account for fasting homocysteine concentrations in healthy controls (CC: 5.5 micromol/l (4-7.2); CT: 7 micromol/l (3.9-9.8); TT: 12.1 micromol/l (7.7-13.3)) with an upper age-specific 95th percentile of 8.3 micromol/l. The following frequencies (patients versus controls), odds ratios (OR) and 95% confidence intervals (CI) were found for single defects: MTHFR 677TT genotype (10.6% vs. 10.4%; OR/CI: 1.02/0.54-1.93; P = 0.99) and CT genotype (43.8% vs. 34.2%; OR/CI: 2.12/1.42-3.16; P = 0.0000). A combination of FV G1691A mutation and MTHFR 677CT genotype was found in 9.9% of patients and in 2.9% of the controls (OR/CI: 3.8/1.64-8.75; P = 0.027). Fasting homocysteine median (range) concentrations in the patient group were significantly higher than in the controls (7 micromol/l (3-23) vs. 5.5 micromol/l (3-8.4): P = 0.0004), and homocysteine concentrations >8.3 micromol/l were found in 40% of patients vs. 2.5% of the controls (OR/CI: 22/2.64-183; P = 0.0003). Conclusion Data of this childhood case-control study suggest that mildly elevated fasting homocysteine concentrations >8.3 micromol/l and the CT genotype of the MTHFR C677T variant are significant risk factors for venous vascular occlusion in children.

Adolescent↗
PubMed2004

SLC22A4 and RUNX1: identification of RA susceptible genes.

Recently we reported that SLC22A4 and RUNX1 are associated with rheumatoid arthritis (RA). SLC22A4 is an organic cation transporter with unknown physiological function, and RUNX1 is a hematological transcriptional regulator that has been shown to be responsible for acute myelogenic leukemia. It is suggested that the association of RUNX1 with RA is due to its regulation of expression of SLC22A4. Because the physiological function of SLC22A4 is still unclear, further investigation is needed into how SLC22A4 affects RA susceptibility. Although the association of RUNX1 with RA was identified as a regulatory factor of SLC22A4, it is possible that RUNX1 is a key molecule in autoimmunity, as it has been reported to be associated with systemic lupus erythematosus and psoriasis, two other autoimmune diseases.

Animals↗
PubMed2003

Loci on chromosomes 2, 4, 9, and 16 for body weight, body length, and adiposity identified in a genome scan of an F2 intercross between the 129P3/J and C57BL/6ByJ mouse strains.

Mice have proved to be a powerful model organism for understanding obesity in humans. Single gene mutants and genetically modified mice have been used to identify obesity genes, and the discovery of loci for polygenic forms of obesity in the mouse is an important next step. To pursue this goal, the inbred mouse strains 129P3/J (129) and C57BL/6ByJ (B6), which differ in body weight, body length, and adiposity, were used in an F2 cross to identify loci affecting these phenotypes. Linkages were determined in a two-phase process. In the first phase, 169 randomly selected F2 mice were genotyped for 134 markers that covered all autosomes and the X Chromosome (Chr). Significant linkages were found for body weight and body length on Chr 2. In addition, we detected several suggestive linkages on Chr 2 (adiposity), 9 (body weight, body length, and adiposity), and 16 (adiposity), as well as two suggestive sex-dependent linkages for body length on Chrs 4 and 9. In the second phase, 288 additional F2 mice were genotyped for markers near these regions of linkage. In the combined set of 457 F2 mice, six significant linkages were found: Chr 2 (Bwq5, body weight and Bdln3, body length), Chr 4 (Bdln6, body length, males only), Chr 9 (Bwq6, body weight and Adip5, adiposity), and Chr 16 (Adip9, adiposity), as well as several suggestive linkages (Adip2, adiposity on Chr 2, Bdln4 and Bdln5, body length on Chr 9). In addition, there was a suggestive linkage to body length in males on Chr 9 (Bdln4). For adiposity, there was evidence for epistatic interactions between loci on Chr 9 (Adip5) and 16 (Adip9). These results reinforce the concept that obesity is a complex trait. Genetic loci and their interactions, in conjunction with sex, age, and diet, determine body size and adiposity in mice.

Animals↗
PubMed2004

A large-sample QTL study in mice: II. Body composition.

Using lines of mice having undergone long-term selection for high and low growth, a large-sample (n = approximately 1,000 F2) experiment was conducted to gain further understanding of the genetic architecture of complex polygenic traits. Composite interval mapping on data from male F2 mice (n = 552) detected 50 QTL on 15 chromosomes impacting weights of various organ and adipose subcomponents of growth, including heart, liver, kidney, spleen, testis, and subcutaneous and epididymal fat depots. Nearly all aggregate growth QTL could be interpreted in terms of the organ and fat subcomponents measured. More than 25% of QTL detected map to MMU2, accentuating the relevance of this chromosome to growth and fatness in the context of this cross. Regions of MMU7, 15, and 17 also emerged as important obesity "hot-spots." Average degrees of directional dominance are close to additivity, matching expectations for body composition traits. A strong QTL congruency is evident among heart, liver, kidney, and spleen weights. Liver and testis are organs whose genetic architectures are, respectively, most and least aligned with that for aggregate body weight. In this study, growth and body weight are interpreted in terms of organ subcomponents underlying the macro aggregate traits, and anchored on the corresponding genomic locations.

Animals↗
PubMed2004

A large-sample QTL study in mice: I. Growth.

By use of long-term selection lines for high and low growth, a large-sample (n = approximately 1,000 F2) experiment was conducted in mice to further understand the genetic architecture of complex polygenic traits. In combination with previous work, we conclude that QTL analysis has reinforced classic polygenic paradigms put in place prior to molecular analysis. Composite interval mapping revealed large numbers of QTL for growth traits with an exponential distribution of magnitudes of effects and validated theoretical expectations regarding gene action. Of particular significance, large effects were detected on Chromosome (Chr) 2. Regions on Chrs 1, 3, 6, 10, 11, and 17 also harbor loci with significant contributions to phenotypic variation for growth. Despite the large sample size, average confidence intervals of approximately 20 cM exhibit the poor resolution for initial estimates of QTL location. Analysis with genome-wide and chromosomal polygenic models revealed that, under certain assumptions, large fractions of the genome may contribute little to phenotypic variation for growth. Only a few epistatic interactions among detected QTL, little statistical support for gender-specific QTL, and significant age effects on genetic architecture were other primary observations from this study.

Animals↗
PubMed2004

Genetic structure of the LXS panel of recombinant inbred mouse strains: a powerful resource for complex trait analysis.

The set of LXS recombinant inbred (RI) strains is a new and exceptionally large mapping panel that is suitable for the analysis of complex traits with comparatively high power. This panel consists of 77 strains-more than twice the size of other RI sets--and will typically provide sufficient statistical power (beta = 0.8) to map quantitative trait loci (QTLs) that account for approximately 25% of genetic variance with a genomewide p < 0.05. To characterize the genetic architecture of this new set of RI strains, we genotyped 330 MIT microsatellite markers distributed on all autosomes and the X Chromosome and assembled error-checked meiotic recombination maps that have an average F2-adjusted marker spacing of approximately 4 cM. The LXS panel has a genetic structure consistent with random segregation and subsequent fixation of alleles, the expected 3-4 x map expansion, a low level of nonsyntenic association among loci, and complete independence among all 77 strains. Although the parental inbred strains-Inbred Long-Sleep (ILS) and Inbred Short-Sleep (ISS)--were derived originally by selection from an 8-way heterogeneous stock selected for differential sensitivity to sedative effects of ethanol, the LXS panel is also segregating for many other traits. Thus, the LXS panel provides a powerful new resource for mapping complex traits across many systems and disciplines and should prove to be of great utility in modeling the genetics of complex diseases in human populations.

Alleles↗
PubMed2004

Quasi-linkage: a confounding factor in linkage analysis of complex diseases?

Human linkage analysis is based on the assumption that unlinked genomic loci, particularly loci located on non-homologous chromosomes, segregate independently during meiosis. An exception to this rule is the phenomenon of quasi-linkage (QL) that describes the non-random segregation of non-homologous chromosomes, which can undermine the basic concept of linkage. Molecular mechanisms of QL are not clear; however, observations in mice and plants suggest a possible affinity between non-homologous chromosomal regions containing repetitive or like sequences. QL has not been investigated in humans. As QL may generate false linkages in genome scans of complex diseases, we sought to determine whether genomic loci detected in such genome scans exhibit QL. A number of individual markers showing linkage to schizophrenia, asthma, multiple sclerosis, inflammatory bowel disease and type-1 diabetes were tested for QL in a pairwise linkage analysis against all other markers exhibiting evidence for linkage in each specific study. The Marshfield genotype dataset of eight CEPH families was used for this purpose. The best QL lod scores generated from the analysis were within the range of the "lukewarm" lod scores reported in the majority of linkage studies for complex disorders. In addition, we performed a genome-wide QL analysis on the Marshfield family database which detected eight QL lod scores >6. The replication of the best Marshfield QL scores was performed using the deCODE families and although none of the eight pairs demonstrated independent evidence for QL, three pairs generated maximal lod scores of 0.11, 0.3, and 1.51. In conclusion, although complex disease relevant markers did not produce high QL lod scores, the general phenomenon of QL in humans cannot be excluded and potentially can be a confounding factor in genetic studies of complex traits.

Asthma↗
PubMed2004

High throughput multiple combination extraction from large scale polymorphism data by exact tree method.

Single nucleotide polymorphisms (SNPs) are increasingly becoming important in clinical settings as useful genetic markers. For the evaluation of genetic risk factors of multifactorial diseases, it is not sufficient to focus on individual SNPs. It is preferable to evaluate combinations of multiple markers, because it allows us to examine the interactions between multiple factors. If all the combinations possible were evaluated round-robin, the number of calculations would rapidly explode as the number of markers analyzed increased. To overcome this limitation, we devised the exact tree method based on decision tree analysis and applied it to 14 SNP data from 68 Japanese stroke patients and 189 healthy controls. From the obtained tree models, we succeeded in extracting multiple statistically significant combinations that elevate the risk of stroke. From this result, we inferred that this method would work more efficiently in the whole genome study, which handles thousands of genetic markers. This exploratory data mining method will facilitate the extraction of combinations from large-scale genetic data and provide a good foothold for further verificatory research.

Adult↗
PubMed1999

Association of diffuse panbronchiolitis with microsatellite polymorphism of the human interleukin 8 (IL-8) gene.

Diffuse panbronchiolitis (DPB) is a distinctive chronic inflammatory lung disease predominantly found in Asian populations. Although its etiology is unknown, DPB is considered to be a multifactorial disease of whose susceptibility is determined by genetic predisposition unique to Asians. We and others have previously reported that the B*5401 allele of the human leukocyte antigen (HLA)-B gene or a closely linked gene in the HLA region on 6p21.3 is one of the major genetic factors in susceptibility to this disease. However, the association with B*5401 is not absolute and the contribution of other genetic or environmental factors should also be considered. Here, four candidate genes that are postulated to play a role in the pathophysiology of DPB, namely, RON-kinase, CYP3A4, motilin, and interleukin (IL)-8, were chosen, and association studies between microsatellite markers at these loci and DPB were conducted. We demonstrated the presence of a specific allele at the IL-8 locus was associated with the disease (c2 = 9.13; P = 0.0025; corrected P [Pc] < 0.05). Although further studies are needed to examine whether neutrophil accumulation in the airways of patients with DPB is controlled by a possible genetic variation of IL-8 or other chemokine genes located in the region 4q12-q13, our data suggest that genes other than those of the HLA system may also contribute to a genetic predisposition to DPB.

Asian People↗
PubMed2026

Advancing genetic evaluation of milk yield and composition using a genomic-polygenic model in smallholder dairy cattle farms in Thailand.

Improving the accuracy of genetic evaluation in smallholder dairy systems is essential for sustainable productivity. However, traditional polygenic models (PM) are often constrained by incomplete pedigree, heterogeneous management, and limited genotyping resources. This study evaluated a genomic-polygenic model (GPM) relative to a PM using data from a multibreed dairy population raised under Thai tropical smallholder conditions. Phenotypic records for 305-day milk yield (MY), fat percentage (FP), protein percentage (PP), and somatic cell count (SCC) from 14,417 first-lactation cows across 1,321 farms were analyzed together with genotypes from 5,479 animals generated using GeneSeek Genomic Profiler (GGP) arrays ranging from 9&#xa0;K to 150&#xa0;K SNPs. Both models included herd-year-season of calving, age at first calving, and heterosis as fixed effects, and additive genetic and residual components treated as random. The GPM yielded higher additive genetic variances and heritability estimates and produced more biologically consistent antagonistic correlations among traits than the PM. Prediction accuracy was improved for all animal groups under the GPM, with the largest gain observed in genotyped young sires (18.36%). Pedigree connectedness analysis indicated that genotyping animals with low to moderate relationships enhances accuracy cost-effectively. Despite persistent challenges associated with heterogeneous management and limited pedigree depth, the results demonstrate the practical value of genomic-polygenic evaluation for smallholder multibreed dairy populations in tropical environments.

Animals↗
PubMed2005

Complex phenotypes and complex genetics: an introduction to genetic studies of complex traits.

There is currently intense interest in the genetic factors contributing to many diseases with cardiovascular complications. Diseases like atherosclerosis, diabetes, and hypertension are referred to as complex traits because multiple genes contribute to the phenotype either individually or through interactions with each other or the environment. Enabled and energized by the striking successes over the past 20 years in identifying genes that are responsible for single gene traits, many geneticists have turned to the investigation of methods that will allow for the dissection of complex traits. There have already been some successes, so there is no reason to consider the problem as inherently intractable. However, it is important to reflect on what conditions are necessary for the identification of genes that operate in complex traits. A recurring theme in this research area has been difficulty in repeating and validating research findings, and this most often can be attributed to limitations in study design. It is also important to consider that any particular research strategy can only hope to describe a portion of factors that contribute to variation in the population; therefore, the genetic approach cannot be a panacea. New efficient technologies for genotyping and public databases describing the fine structure of genetic correlations in the genome should aid many aspects of the gene discovery process.

Genetic Predisposition to Disease↗