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PubMed1981

Segregation and linkage analysis of 40 multiplex multiple sclerosis families.

40 multiplex multiple sclerosis (MS) families were analyzed for evidence of an MS susceptibility gene linked to the HLA region of the sixth chromosome. We assumed that population associations between specific HLA alleles and MS are due to linkage disequilibrium, so preference was given to hypotheses compatible with tight linkage, and explanations were sought for conflicting evidence. The analyses proceeded in two steps: (1) segregation analysis using the computer program POINTER, and (2) linkage analysis using LINKAS, first assuming linkage equilibrium and then allowing for linkage disequilibrium and etiological heterogeneity. The results of the segregation analyses were indeterminate. The results of the linkage analyses suggest that analyses that do not allow for disequilibrium lose substantial evidence on linkage. Of the models that were investigated under linkage disequilibrium, the best fit is with a model of complete linkage (theta= 0.0) in 75% of the pedigrees and no linkage in the remaining pedigrees. We were unable, however, to statistically reject another model involving loose linkage and no heterogeneity.

Chromosomes, Human, 6-12 and X↗
PubMed1985

Segregation and linkage analyses of 72 leprosy pedigrees.

Data on 72 families with multiple cases of leprosy were analyzed for a susceptibility gene linked to the HLA loci. We conducted segregation analysis with the program POINTER and identity of HLA types by descent analysis to determine the most likely mode of inheritance. We then conducted linkage analysis with the program LINKAS, first assuming linkage equilibrium and then allowing for linkage disequilibrium and etiological heterogeneity. Segregation results suggest a recessive mode of inheritance, especially for the tuberculoid forms of leprosy. The linkage results, limited to tuberculoid forms and assuming a recessive model, suggest a hypothesis of loose linkage with no unlinked locus. When an additive model is assumed, the best fit is obtained with a hypothesis of complete linkage (theta = 0.0) with heterogeneity. We currently favor the additive model as the more plausible one.

Disease Susceptibility↗
PubMedDate not supplied

Complex segregation analysis of thyroid autoantibodies: are they inherited as an autosomal dominant trait?

The presence of circulating autoantibodies (Abs) to the thyroid antigens thyroid peroxidase (TPO) and thyroglobulin (Tg) is a marker for autoimmune thyroid disease. Recent studies have suggested that the tendency to produce these Abs is inherited as an autosomal dominant characteristic. In order to confirm or refute these observations, we have carried out a complex segregation analysis using POINTER on Ab data in 86 unselected pedigrees (172 nuclear families). The overall prevalence of TPO Ab was 9.9% in men and 24.1% in women. Tg Ab was found in 11.0% of men and 23.5% of women. There was a marked tendency for both TPO Ab and Tg Ab to cluster in families and complex segregation analysis provided strong evidence for vertical transmission. However, it was not possible to distinguish between a single locus and a multifactorial model for either Ab. In the absence of strong evidence for a single locus, genetic linkage strategies are unlikely to be successful.

Adolescent↗
PubMed1994

Complex segregation analysis provides evidence for a major gene acting on serum triglyceride levels in 55 British families with familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCHL) was first described as an autosomal dominant inherited trait with primary action on triglyceride levels and secondary effects on cholesterol metabolism. This conclusion has since been questioned by several groups despite subsequent supportive biochemical and metabolic studies. To reexplore the genetics of FCHL, we assembled 55 families from the United Kingdom comprising 559 persons ascertained through probands with both hypercholesterolemia and hypertriglyceridemia. The results of univariate complex segregation analysis were consistent with a major gene acting on triglyceride and explaining two thirds of the genetic variability and 20% of the phenotypic variance in triglyceride levels. Univariate analysis did not identify a major genetic component acting on cholesterol levels. Bivariate segregation analysis rejected a major gene model. We also reexamined the original FCHL pedigrees collected by Goldstein et al and obtained results similar to those in the UK families. The prospects for mapping putative major genes determining triglyceride levels in FCHL patients by linkage analysis are discussed.

Family Health↗
PubMed1995

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

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

Adolescent↗
PubMed2000

Conjunctions of colour, luminance and orientation: the role of colour and luminance contrast on saliency and proximity grouping in texture segregation.

To examine whether perceptual grouping on the basis of orientation can be performed simultaneously with or only subsequently to grouping according to colour or luminance, we tested whether subjects are able to segregate arrays of texture elements that differ from surrounding elements by conjunctions of either (i) colour and orientation, or (ii) luminance contrast and orientation, or (iii) luminance contrast polarity and orientation. Subjects were able to use conjunctions between luminance and orientation for segregation but not conjunctions between colour or contrast polarity and orientation. Our results suggest that (i) in agreement with earlier findings, there seem to exist no specific conjunction detectors for colour and orientation or contrast polarity and orientation, and (ii) when orientation defined textures are to be distinguished by virtue of differences in luminance, colour, or contrast polarity, luminance provides a much stronger cue than colour or contrast polarity for saliency-based orientation grouping.

Adaptation, Ocular↗
PubMed1989

Central performance drop on perceptual segregation tasks.

The main concern of this study is the range of the central (foveal) performance drop in perceptual segregation tasks reported by Kehrer (Spatial Vision 2, 247-261, 1987). This effect suggests that parafoveal areas of the retina make a significant contribution to the perceptual segregation of textures. Results showed that: (1) the central performance drop was not due to retinal criterion shifts in the sense of signal detection theory; (2) the central performance drop was not restricted to very short presentation times but could also be observed in 80- or 120-ms presentation times; (3) the retinal area in which maximal segmentation performance was found could be shifted by manipulating the spacing between the elements of the stimulus. This finding suggests that each different area of the retina is linked to the processing of a specific, limited area of the spatial frequency band.

Female↗
PubMed1996

Segregation analysis of physician-diagnosed asthma in Hispanic and non-Hispanic white families. A recessive component?

The inheritance of asthma, evident from its high family concordance, is not well understood. To investigate whether asthma may be inherited through a major gene with two alleles, segregation analyses were conducted in 3,369 individuals from 906 nuclear families enrolled, without selection, in a longitudinal study of respiratory health in Tucson, Arizona. Physician-diagnosed asthma and its age of onset were ascertained for each family member when children were at a mean age of 7 yr. Age of asthma diagnosis was allowed for in analyses, and the impact of the covariate total serum IgE level on age of onset was examined. Segregation analyses were conducted with and without residual family effects, with and without the covariate IgE. The hypothesis of a single two-allele locus for asthma was rejected. However, depending on the method of assessment of the residual familial effects, either a polygenic/multifactorial mode of inheritance alone, or an oligogenic model with some evidence of a recessive component present in the population with the high frequency of 0.67, were compatible with the data. Results were unchanged with the addition of the covariate IgE.

Adult↗
PubMed1999

Familial aggregation and segregation analysis of eosinophil levels.

The number of circulating eosinophils is associated with the risk of asthma in population samples. Therefore, eosinophil levels may be an intermediate phenotype for asthma amenable to genetic analysis. We examined familial aggregation of the number of eosinophils x 10(6) L(-1) and the percentage of eosinophils based on a 300 count differential in 644 Hispanic and non-Hispanic white families, with 2, 097 subjects, enrolled in the Tucson Children's Respiratory Study. Both measures were adjusted for age, season and year at the time blood was drawn, sex, and ethnicity. Segregation analysis was conducted in the 458 non-Hispanic white families, as there were no significant familial correlations in the Hispanic families, and there was significant heterogeneity by ethnic group. Familial correlations (rho) in the non-Hispanic white families were as follows: mother-father, 0.05; mother-child, 0.18 (p < 0.001); father-child, 0.07; sibling-sibling, 0.31 (p < 0.001). Without covariates analyses indicated a polygenic/multifactorial mode of inheritance. After adjusting for current and past asthma an oligogenic mode of inheritance was suggested, plus additional residual familial components that were mainly maternally mediated. This study supports the notion of multiple, relatively common genes interacting to determine genetic susceptibility to asthma. Holberg CJ, Halonen M, Wright AL, Martinez FD. Familial aggregation and segregation analysis of eosinophil levels.

Adult↗
PubMed2005

Effects of segregation on an epidemic Pseudomonas aeruginosa strain in a cystic fibrosis clinic.

The detection of a clonal Pseudomonas aeruginosa strain in 21% of children attending a cystic fibrosis clinic during 1999, which may have led to a worse prognosis, prompted strict infection control measures, including cohort segregation. We determined whether these strategies interrupted cross-infection within the clinic. Patients from 1999 were observed and a cross-sectional study of the 2002 clinic was performed. By 2002, the epidemic strain prevalence had decreased from 21 to 14% (p = 0.03), whereas the proportion of patients with nonepidemic P. aeruginosa strains was unchanged. The age- and sex-adjusted relative risk for epidemic strains among sputum producers in 2002 compared with 1999 was 0.64 (95% confidence interval, 0.47, 0.87; p = 0.004). Increased mortality or transfer to another clinic did not explain this reduction. Although children with epidemic strains may have had increased mortality (adjusted odds ratio, 2.0; 95% confidence interval, 0.6-6.8), they did not demonstrate greater morbidity than those with other P. aeruginosa isolates. Successful infection control measures provided additional indirect evidence for person-to-person transmission of an epidemic strain within the clinic. Further studies are needed to resolve whether cohort segregation completely eliminates cross-infection and if acquisition of epidemic isolates is associated with worse outcomes.

Adolescent↗
PubMed1982

A low-gold dental alloy: structure and segregations.

The structure and concentration gradients were studied in the as-cast state for a low-gold alloy and a conventional Type III gold alloy. A much more lamellar eutectic phase was found at the grain boundaries in the low-gold alloy. TEM investigations showed that the interior of the grains consisted of fine lamellae, which probably were alternating Au-Ag and Au-Cu-rich bands due to the miscibility gap in the solid state. Microprobe analyses, where the beam overlapped several of the observed lamellae, displayed both the interdendritic and grain boundary segregations to be much larger for the low-gold alloy than for the Type III alloy. The lamellae observed in the as-cast state are quickly dissolved at 700 degrees C into one phase, but the relaxation by diffusion of the concentration differences associated with grain boundary segregations required several hours because of the much larger distances involved. Aging at 350 degrees C cause precipitation of ordered fct particles. On the basis of structure and alloy composition, they are most likely AuCu I and may contain some Pd.

Chemical Phenomena↗
PubMed2004

Familial correlations, segregation analysis, and nongenetic correlates of soy isoflavone-metabolizing phenotypes.

Particular intestinal bacteria metabolize the soy isoflavone daidzein to equol and O-desmethylangolensin (O-DMA), metabolites that can be identified in urine. Individuals that harbor bacteria capable of producing equol or O-DMA are known as equol producers (approximately 30%-50% of the population) and O-DMA producers (approximately 80%-90% of the population), respectively. The equol-producer phenotype has been associated with sex hormone-related outcomes in several studies. However, the bacteria responsible for these phenotypes have not yet been identified and factors that influence the manifestation of these phenotypes are not well understood. To evaluate familial clustering of and nongenetic factors associated with these phenotypes, 410 individuals from 112 families participated in phenotyping (3-day soy challenge and Day 4 spot urine collection). In segregation analyses of the equol-producer phenotype, the Mendelian dominant model provided the most parsimonious fit to the data, suggesting that the pattern of inheritance of the equol-producer phenotype is consistent with an autosomal dominant trait. This phenotype was positively associated with education (p trend = 0.01), but not with sex, smoking, or several dietary factors. Results of the segregation analyses of the O-DMA-producer phenotype were inconclusive; no other models provided a more parsimonious fit to the data than the general model. This phenotype was inversely associated with age in a nonlinear model (p = 0.01), positively associated with age- and sex-adjusted height (odds ratio [OR] 10-cm increase = 0.38, 95% confidence interval [CI] = 0.15, 0.95) and body mass index (kg/m(2)) (OR = 0.91, 95% CI = 0.85, 0.96), but not with sex, education, smoking, or several dietary factors. These results suggest the equol-producer phenotype may be under some degree of genetic control and that there are likely other environmental factors not evaluated in the present analysis that contribute to both of these phenotypes. These results provide a foundation for further work to refine our understanding of heritable and environmental determinants of daidzein-metabolizing phenotypes.

Female↗
PubMedDate not supplied

Bayesian segregation analysis of milk flow in Swiss dairy cattle using Gibbs sampling.

Segregation analyses with Gibbs sampling were applied to investigate the mode of inheritance and to estimate the genetic parameters of milk flow of Swiss dairy cattle. The data consisted of 204,397, 655,989 and 40,242 lactation records of milk flow in Brown Swiss, Simmental and Holstein cattle, respectively (4 to 22 years). Separate genetic analyses of first and multiple lactations were carried out for each breed. The results show that genetic parameters especially polygenic variance and heritability of milk flow in the first lactation were very similar under both mixed inheritance (polygenes + major gene) and polygenic models. Segregation analyses yielded very low major gene variances which favour the polygenic determinism of milk flow. Heritabilities and repeatabilities of milk flow in both Brown Swiss and Simmental were high (0.44 to 0.48 and 0.54 to 0.59, respectively). The heritability of milk flow based on scores of milking ability in Holstein was intermediate (0.25). Variance components and heritabilities in the first lactation were slightly larger than those estimates for multiple lactations. The results suggest that milk flow (the quantity of milk per minute of milking) is a relevant measurement to characterise the cows milking ability which is a good candidate trait to be evaluated for a possible inclusion in the selection objectives in dairy cattle.

Animals↗
PubMed2002

Molecular phylogeny of Subtribe Artemisiinae (Asteraceae), including Artemisia and its allied and segregate genera.

BACKGROUND: Subtribe Artemisiinae of Tribe Anthemideae (Asteraceae) is composed of 18 largely Asian genera that include the sagebrushes and mugworts. The subtribe includes the large cosmopolitan, wind-pollinated genus Artemisia, as well as several smaller genera and Seriphidium, that altogether comprise the Artemisia-group. Circumscription and taxonomic boundaries of Artemisia and the placements of these small segregate genera is currently unresolved. RESULTS: We constructed a molecular phylogeny for the subtribe using the internal transcribed spacers (ITS) of nuclear ribosomal DNA analyzed with parsimony, likelihood, and Bayesian criteria. The resulting tree is comprised of three major clades that correspond to the radiate genera (e.g., Arctanthemum and Dendranthema), and two clades of Artemisia species. All three clades have allied and segregate genera embedded within each. CONCLUSIONS: The data support a broad concept of Artemisia s.l. that includes Neopallasia, Crossostephium, Filifolium, Seriphidium, and Sphaeromeria. However, the phylogeny excludes Elachanthemum, Kaschgaria, and Stilnolepis from the Artemisia-group. Additionally, the monophyly of the four subgenera of Artemisia is also not supported, with the exception of subg. Dracunculus. Homogamous, discoid capitula appear to have arisen in parallel four to seven times, with the loss of ray florets. Thus capitular morphology is not a reliable taxonomic character, which traditionally has been one of the defining characters.

Artemisia↗
PubMed2003

Using an age-at-onset phenotype with interval censoring to compare methods of segregation and linkage analysis in a candidate region for elevated systolic blood pressure.

BACKGROUND: Genetic studies of complex disorders such as hypertension often utilize families selected for this outcome, usually with information obtained at a single time point. Since age-at-onset for diagnosed hypertension can vary substantially between individuals, a phenotype based on long-term follow up in unselected families can yield valuable insights into this disorder for the general population. METHODS: Genetic analyses were conducted using 2884 individuals from the largest 330 families of the Framingham Heart Study. A longitudinal phenotype was constructed using the age at an examination when systolic blood pressure (SBP) first exceeds 139 mm Hg. An interval for age-at-onset was created, since the exact time of onset was unknown. Time-fixed (sex, study cohort) and time-varying (body mass index, daily cigarette and alcohol consumption) explanatory variables were included. RESULTS: Segregation analysis for a major gene effect demonstrated that the major gene effect parameter was sensitive to the choice for age-at-onset. Linkage analyses for age-at-onset were conducted using 1537 individuals in 52 families. Evidence for putative genes identified on chromosome 17 in a previous linkage study using a quantitative SBP phenotype for these data was not confirmed. CONCLUSIONS: Interval censoring for age-at-onset should not be ignored. Further research is needed to explain the inconsistent segregation results between the different age-at-onset models (regressive threshold and proportional hazards) as well as the inconsistent linkage results between the longitudinal phenotypes (age-at-onset and quantitative).

Adolescent↗
PubMed2006

Cis-regulatory variations: a study of SNPs around genes showing cis-linkage in segregating mouse populations.

BACKGROUND: Changes in gene expression are known to be responsible for phenotypic variation and susceptibility to diseases. Identification and annotation of the genomic sequence variants that cause gene expression changes is therefore likely to lead to a better understanding of the cause of disease at the molecular level. In this study we investigate the pattern of single nucleotide polymorphisms (SNPs) in genes for which the mRNA levels show cis-genetic linkage (gene expression quantitative trait loci mapping in cis, or cis-eQTLs) in segregating mouse populations. Such genes are expected to have polymorphisms near their physical location (cis-variations) that affect their mRNA levels by altering one or more of the cis-regulatory elements. This led us to characterize the SNPs in promoter (5 Kb upstream) and non-coding gene regions (introns and 5 Kb downstream) (cis-SNPs) and the effects they may have on putative transcription factor binding sites. RESULTS: We demonstrate that the cis-eQTL genes (CEGs) have a significantly higher frequency of cis-SNPs compared to non-CEGs (when both sets are taken from the non-IBD regions, i.e. regions not identical by descent). Most CEGs having cis-SNPs do not contain these SNPs in the phylogenetically conserved regions. In those CEGs that contain cis-SNPs in the phylogenetically conserved regions, enrichment of cis-SNPs occurs both within and outside of the conserved sequences. A higher fraction of CEGs are also seen to harbor cis-SNP that affect predicted transcription factor binding sites, a likely consequence of the higher cis-SNPs density in these genes. CONCLUSION: This present study provides the first genome-wide investigation of the putative cis-regulatory variations in a large set of genes whose levels of expression give rise to cis-linkage in segregating mammalian populations. Our results provide insights into the challenges that exist in identifying polymorphisms regulating gene expression using bioinformatic sequence analysis approaches. The data provided herein should benefit future investigations in this area.

Adipose Tissue↗
PubMed1982

Testing the monogenic theory of schizophrenia: An application of segregation analysis to blind family study data.

Segregation analysis was applied to blind family data concerning schizophrenia to decide if the transmission of schizophrenia could be explained by a single major gene. Our results showed that the Mendelian model was unacceptable. Therefore, the monogenic hypothesis could not account for the transmission of schizophrenia. Since the hypothesis of no parent-child transmission was also not accepted, there was an indication that some form of vertical transmission existed which could be psychosocial, or an interaction between genetic and psychosocial factors. Our results suggest genetic heterogeneity in schizophrenia. Currently available clinical criteria for defining subgroups must be improved in conjunction with detection of biological indicators so that segregation analysis of family data could be effectively used in determining modes of transmission in schizophrenia.

Adult↗