Genetic analysis of total cholesterol and triglycerides in a pedigree of St. Thomas rabbits

A pedigree consisting of 103 New Zealand White hyperlipidemic and normal rabbits was used in a genetic analysis of total cholesterol and triglyceride levels to test for Mendelian control of hyperlipidemia. The founder male of this pedigree was identified through hypercholesterolemia and evidence suggested vertical transmission of a hypercholesterolemic phenotype in this pedigree, although a combined hyperlipidemia phenotype (elevated cholesterol and triglycerides) also occurred in many descendents of the original founders. Segregation analysis of quantitative measures of total cholesterol and triglycerides in this pedigree was employed to test hypotheses about Mendelian control in the presence of substantial inbreeding. A simple Mendelian model was the best explanation for triglycerides in these animals. This best fitting model was essentially co-dominant with genotypic specific variances, where the heterozygote was hypertriglyceridemic and the mutant homozygote showed even more extreme values. The observed distribution of total cholesterol was also compatible with a mixture of distinct genotypic distributions, but there was evidence of non-Mendelian transmission in this pedigree. The observed hypertriglyceridemia in these animals may reflect an abnormality of very low density lipoprotein metabolism described previously. Further studies will be required to elucidate the genetic control of hypercholesterolemia and the associated combined hyperlipidemia in these rabbits.     

Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients.

Plasma levels of two lipoprotein risk factors, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apo A-1), have been shown to be negatively associated with the risk of developing coronary artery disease, and several reports have examined familial factors in HDL-C and apo A-1 levels. A number of studies suggest that shared genes influence familial resemblance of these lipoprotein levels far more than do shared environments. Possible mechanisms for the inheritance of these two risk factors (HDL-C and apo A-1 plasma levels) are explored using data from 390 individuals in 69 families ascertained through probands undergoing diagnostic cardiac catheterization. Segregation analysis was used to test a series of specific models of inheritance. Evidence for single-locus control of apo A-1 levels, with Mendelian transmission of a dominant allele leading to elevated apo A-1 levels, was seen in these families, although there was additional correlation among sibs present. This locus accounted for 48.6% and 37.2% of the total variation in apo A-1 levels in males and females, respectively. Similar evidence of segregation at a single locus controlling HDL-C levels was not seen in these families.     

A common genetic mechanism determines plasma apolipoprotein B levels and dense LDL subfraction distribution in familial combined hyperlipidemia.

Familial combined hyperlipidemia (FCH) is a common lipid disorder characterized by elevations of plasma cholesterol and/or triglyceride in first-degree relatives. A predominance of small, dense LDL particles and elevated apolipoprotein B (apoB) levels is commonly found in members of FCH families. Many studies have investigated the genetic mechanisms determining individuals' lipid levels, in FCH families. Previously, we demonstrated a major gene effect on LDL particle size and codominant Mendelian inheritance involved in determination of apoB levels in a sample of 40 well-defined FCH families. An elevation of apoB levels is associated metabolically with a predominance of small, dense LDL particles in FCH. To establish whether a common gene regulates both traits, we conducted a bivariate genetic analysis to test the hypothesis of a common genetic mechanism. In this study, we found that 66% of the total phenotypic correlation is due to shared genetic components. Further bivariate segregation analysis suggested that both traits share a common major gene plus individual polygenic components. This common major gene explains 37% of the variance of adjusted LDL particle size and 23% of the variance of adjusted apoB levels. Our study suggests that a major gene that has pleiotropic effects on LDL particle size and apoB levels may be the gene underlying FCH in the families we studied.     

Contribution of fungal loline alkaloids to protection from aphids in a grass-endophyte mutualism

Fungal endophytes provide grasses with enhanced protection from herbivory, drought, and pathogens. The loline alkaloids (saturated 1-aminopyrrolizidines with an oxygen bridge) are fungal metabolites often present in grasses with fungal endophytes of the genera Epichlo? or Neotyphodium. We conducted a Mendelian genetic analysis to test for activity of lolines produced in plants against aphids feeding on those plants. Though most loline-producing endophytes are asexual, we found that a recently described sexual endophyte, Epichlo? festucae, had heritable variation for loline alkaloid expression (Lol+) or nonexpression (Lol-). By analyzing segregation of these phenotypes and of linked DNA polymorphisms in crosses, we identified a single genetic locus controlling loline alkaloid expression in those E. festucae parents. We then tested segregating Lol+ and Lol- full-sibling fungal progeny for their ability to protect host plants from two aphid species, and observed that alkaloid expression cosegregated with activity against these insects. The in planta loline alkaloid levels correlated with levels of anti-aphid activity. These results suggested a key role of the loline alkaloids in protection of host plants from certain aphids, and represent, to our knowledge, the first Mendelian analysis demonstrating how a fungal factor contributes protection to plant-fungus mutualism.     

On the evolution of fluctuating segregation distortion

Previous mathematical models of the genetic control by one locus of the segregation at another have all concluded that alleles causing departures from Mendelian segregation should succeed. In this study the segregation ratios induced at the major locus by the modifier locus fluctuate cyclically. It is shown that if initially there is Mendelian segregation and if the rare modifying allele induces symmetric fluctuation about the Mendelian ratios it cannot succeed. It is further proven that if initially there are symmetric fluctuations about Mendelian segregation then an allele reducing the amplitude of the fluctuation will succeed.     

A major susceptibility locus influencing plasma triglyceride concentrations is located on chromosome 15q in Mexican Americans

Although several genetic forms of rare or syndromic hypertriglyceridemia have been reported, little is known about the specific chromosomal regions across the genome harboring susceptibility genes for common forms of hypertriglyceridemia. Therefore, we conducted a genomewide scan for susceptibility genes influencing plasma triglyceride (TG) levels in a Mexican American population. We used both phenotypic and genotypic data from 418 individuals distributed across 27 low-income, extended Mexican American families. For the analyses, TG values were log transformed (ln TG). We used a variance-components technique to conduct multipoint linkage analyses for localizing susceptibility genes that determine variation in TG levels. We used an approximately 10-15-cM map, which was made on the basis of information from 295 microsatellite markers. After accounting for the effects of sex and sex-specific age terms, we found significant evidence for linkage (LOD = 3.88) of ln TG levels to a genetic location between the markers GABRB3 and D15S165 on chromosome 15q. This putative locus explains 39.7+/-7% (P=.000012) of total phenotypic variation in ln TG levels. Suggestive evidence was found for linkage of ln TG levels to two different locations on chromosome 7, which are approximately 85 cM apart from each other. Also, there is some evidence for linkage of high-density lipoprotein cholesterol concentrations to a genetic location near one of the regions on chromosome 7. In conclusion, we found strong evidence for linkage of ln TG levels to a genetic location on chromosome 15q in a Mexican American population, which is prone to disease conditions such as type 2 diabetes and the insulin-resistance syndrome that are associated with hypertriglyceridemia. This putative locus appears to have a major influence on ln TG variation.     

Segregation analysis of alcoholism in families ascertained through a pair of male alcoholics.

To determine the nature of the genetic component controlling liability to alcoholism, complex segregation analysis was performed on 35 multigenerational families each ascertained through a pair of male alcoholics. The results suggest that liability to alcoholism is, in part, controlled by a major effect with or without additional multifactorial effects. Mendelian transmission of this major effect was rejected, as was the hypothesis that the major effect is due to a single major locus. Absence of this major effect, leaving only multifactorial effects, was also rejected. Some sources for the non-Mendelian character of the major effect are suggested, such as a combination of two or more Mendelian loci, the presence of phenocopies, sex-dependent differences in the underlying liability model, or heterogeneity in the alcoholism phenotype. Evidence for and against each is discussed.     

Major genes regulating total serum immunoglobulin E levels in families with asthma

Immunoglobulin E (IgE) has a major role in the pathogenesis of allergic disorders and asthma. Previous data from 92 families, each identified through a proband with asthma, showed evidence for two major genes regulating total serum IgE levels. One of these genes mapped to 5q31-33. In the current study, the segregation analysis was extended by the addition of 108 probands and their families, ascertained in the same manner. A mixed recessive model (i.e., major recessive gene and residual genetic effect) was the best-fitting and most-parsimonious one-locus model of the segregation analysis. A mixed two-major-gene model (i.e., two major genes and residual genetic effect) fit the data significantly better than did the mixed recessive one-major-gene model. The second gene modified the effect of the first recessive gene. Individuals with the genotype aaBB (homozygous high-risk allele at the first gene and homozygous low-risk allele at the second locus) had normal IgE levels (mean 23 IU/ml), and only individuals with genotypes aaBb and aabb had high IgE levels (mean 282 IU/ml). A genomewide screening was performed using variance-component analysis. Significant evidence for linkage was found for a novel locus at 7q, with a multipoint LOD score of 3. 36 (P=.00004). A LOD score of 3.65 (P=.00002) was obtained after genotyping additional markers in this region. Evidence for linkage was also found for two previously reported regions, 5q and 12q, with LOD scores of 2.73 (P=.0002) and 2.46 (P=.0004), respectively. These results suggest that several major genes, plus residual genetic effects, regulate total serum IgE levels.     

Segregation analysis of congenital glaucoma: approach by two differential models.

To determine the mode of inheritance of congenital glaucoma, segregation analysis was performed using two different models: the transmission probability model and the mixed model. Whereas the latter, testing for monogenic inheritance in the presence of both monogenic and polygenic components, results in strong evidence for a major locus, the former, testing for Mendelian segregation at one locus, rejects this hypothesis. The differences in the results of these two models are discussed and are attributed to the underlying structure of each. Genetic heterogeneity of congenital glucoma is proposed.     

凡纳滨对虾微卫星位点在两个选育家系中遗传的初步研究

利用两个选育凡纳滨对虾全同胞家系研究了10个微卫星位点的遗传特征。通过ABI310或3100测序仪检测, 在所观察到的20个基因型比例（genotypic ratios）(10个微卫星位点 X 2个家系)中,有17个基因型比例符合孟德尔遗传。微卫星位点TUMXLv8.220在两个家系中均存在无效等位基因,从而3个不符合孟德尔遗传基因型中2个可由无效等位基因来解释。TUMXLv 3.1在06家系偏离了1：1：1：1的孟德尔预期比。3个微卫星位点（TUMXLv5.66,TUMXLv7.74,TUMXLv8.224）在两个家系中均表现单态。3个微卫星位点（TUMXLv5.45,TUMXLv7.56,TUMXLv8.256）在两个家系均既表现多态又遵循孟德尔共显性遗传, 是亲子鉴定和种群遗传分析的较好选择。结果显示在应用微卫星标记进行遗传分析之前利用全同胞家系进行遗传模式研究是非常必要的。     

Identification and characterization of nuclear microsatellites in Mediterranean cedars (Cedrus sp.)

We developed primers for the amplification of six polymorphic nuclear microsatellites in Mediterranean Cedrus taxa. Microsatellites originated from two Cedrus atlantica genomic libraries enriched for TC (four markers) and TG (two markers) motifs. No distortion from Mendelian segregation was observed. There were up to eight alleles per locus and mean expected heterozygosity was 0.75. Four microsatellites also amplified in the Himalayan cedar. These markers should be helpful for species identification, diversity studies, parentage analysis and genome mapping and to monitor biodiversity in endangered Mediterranean Cedrus forests.     

Two novel quantitative trait loci on mouse chromosomes 6 and 4 independently and synergistically regulate plasma apoB levels

An elevated plasma apolipoprotein B (apoB) level is a strong predictor of atherosclerosis and coronary heart disease. Epidemiologic and family linkage studies have suggested a genetic basis for the wide variations of plasma apoB levels in the general population. Using a human apoB transgenic (HuBTg) mouse model, we have previously shown that hepatic apoB-100 secretion is a major determinant of the high and low plasma human apoB levels in HuBTg mice of the C57BL/6 (B6) and 129/Sv (129) strains, respectively. In the present article, we present the identification of two novel quantitative trait loci (QTL) as major regulators of plasma human apoB levels in the F(2) and N(2) (backcrossed) offspring (n = 572) derived from crosses between the B6 and 129 mouse strains. These loci were designated ApoB regulator genes (Abrg), because the gene products are likely to be involved in the regulation of plasma apoB levels either directly or indirectly. The first locus, designated Abrg1, was mapped to chromosome 6 in 8-week-old male and female mice with a combined logarithm of odds ratio (LOD) score of 14 at the D6Mit55 marker ( approximately 45.9 cM). Abrg1 contributed approximately 35% of the genetic variance. The second locus, designated Abrg2, was mapped to chromosome 4 with an LOD score of 8.6 in 8-week-old male mice but an LOD score of only 2.0 in 8-week-old female mice at the D4Mit27 marker ( approximately 35 cM). Abrg2 contributed approximately 26% of the genetic variance. Epistasis between Abrg1 and Abrg2 was detected and accounted for approximately 12% of the genetic variance. The combination of these two QTL has major effects (>70%) on the regulation of plasma human apoB levels in the tested population. In summary, we have identified two novel loci that have a major role in the regulation of plasma apoB levels and are likely to regulate the secretory pathway of apoB. The human orthologs for the Abrg loci are strong candidates for human disorders characterized by altered plasma apoB levels, such as FCHL and familial hypobetalipoproteinemia.     

On the evolutionary stability of Mendelian segregation

We present a model of a primary locus subject to viability selection and an unlinked locus that causes sex-specific modification of the segregation ratio at the primary locus. If there is a balanced polymorphism at the primary locus, a population undergoing Mendelian segregation can be invaded by modifier alleles that cause sex-specific biases in the segregation ratio. Even though this effect is particularly strong if reciprocal heterozygotes at the primary locus have distinct viabilities, as might occur with genomic imprinting, it also applies if reciprocal heterozygotes have equal viabilities. The expected outcome of the evolution of sex-specific segregation distorters is all-and-none segregation schemes in which one allele at the primary locus undergoes complete drive in spermatogenesis and the other allele undergoes complete drive in oogenesis. All-and-none segregation results in a population in which all individuals are maximally fit heterozygotes. Unlinked modifiers that alter the segregation ratio are unable to invade such a population. These results raise questions about the reasons for the ubiquity of Mendelian segregation.     

Complex segregation analysis of nonsyndromic cleft lip and palate.

This study was undertaken to examine the inheritance pattern of nonsyndromic cleft lip with or without cleft palate (CL/P). Complex segregation analysis using the unified model as in POINTER and the regressive model as in REGD programs were applied to analyze a midwestern U.S. Caucasian population of 79 families ascertained through a proband with CL/F. In REGD, the dominant or codominant Mendelian major locus models of inheritance were the most parsimonious fit. In POINTER, besides the Mendelian major locus model, the multifactorial threshold (MF/T) model and the mixed model were also consistent with the observed data. However, the high heritability parameter of .93 (SD .063) in the MF/T model suggests that any random exogenous factors are unlikely to be the underlying mechanisms, and the mixed model indicates that this high heritability is accounted for by a major dominant locus component. These findings indicate that the best explanation for the etiology of CL/P in this study population is a putative major locus associated with markedly decreased penetrance. Molecular studies may provide further insight into the genetic mechanism underlying CL/P.     

Causal Role of Alcohol Consumption in an Improved Lipid Profile: The Atherosclerosis Risk in Communities (ARIC) Study

Introduction

Health benefits of low-to-moderate alcohol consumption may operate through an improved lipid profile. A Mendelian randomization (MR) approach was used to examine whether alcohol consumption causally affects lipid levels.

Methods

This analysis involved 10,893 European Americans (EA) from the Atherosclerosis Risk in Communities (ARIC) study. Common and rare variants in alcohol dehydrogenase and acetaldehyde dehydrogenase genes were evaluated for MR assumptions. Five variants, residing in the ADH1B, ADH1C, and ADH4 genes, were selected as genetic instruments and were combined into an unweighted genetic score. Triglycerides (TG), total cholesterol, high-density lipoprotein cholesterol (HDL-c) and its subfractions (HDL2-c and HDL3-c), low-density lipoprotein cholesterol (LDL-c), small dense LDL-c (sdLDL-c), apolipoprotein B (apoB), and lipoprotein (a) (Lp(a)) levels were analyzed.

Results

Alcohol consumption significantly increased HDL2-c and reduced TG, total cholesterol, LDL-c, sdLDL-c, and apoB levels. For each of these lipids a non-linear trend was observed. Compared to the first quartile of alcohol consumption, the third quartile had a 12.3% lower level of TG (p < 0.001), a 7.71 mg/dL lower level of total cholesterol (p = 0.007), a 10.3% higher level of HDL2-c (p = 0.007), a 6.87 mg/dL lower level of LDL-c (p = 0.012), a 7.4% lower level of sdLDL-c (p = 0.037), and a 3.5% lower level of apoB (p = 0.058, p_overall = 0.022).

Conclusions

This study supports the causal role of regular low-to-moderate alcohol consumption in increasing HDL2-c, reducing TG, total cholesterol, and LDL-c, and provides evidence for the novel finding that low-to-moderate consumption of alcohol reduces apoB and sdLDL-c levels among EA. However, given the nonlinearity of the effect of alcohol consumption, even within the range of low-to-moderate drinking, increased consumption does not always result in a larger benefit.     

Evidence for two unlinked loci regulating total serum IgE levels.

Studies investigating the genetic control of total serum IgE levels are of major importance in understanding basic pathophysiologic mechanisms in atopy and asthma, since IgE levels predict onset and correlate with the clinical expression of these disorders. Previous analysis of data from 92 families, ascertained through a parent with asthma, showed evidence for recessive inheritance of high IgE levels with linkage to chromosome 5q. Since there was significant residual familial correlation in the one-locus segregation analysis, two-locus segregation and linkage analyses were performed. Segregation analyses provided evidence for a second major locus unlinked to the locus on 5q. Utilization of this two-locus model corroborates the previous evidence for linkage between this trait and markers on 5q31-q33. The LODs for the most informative marker D5S436 increased from 3.00 at 10% recombination to 4.67 at 9% recombination, when the two-locus model was used. Additional linkage studies are needed to map this second locus. These results demonstrate the importance of performing multilocus segregation and linkage analyses for quantitative traits that are related to the phenotype of a complex disorder. This approach has given further insight into the genetics of allergy and asthma by providing evidence for a two-locus model.     

Pedigree and sib-pair linkage analysis suggest the apolipoprotein B gene is not the major gene influencing plasma apolipoprotein B levels.

Previous studies suggest that plasma apolipoprotein B-100 (apoB) level is strongly influenced by genetic factors. Characterizing alleles that influence plasma apoB level would help define genetic risk factors for coronary artery disease. This study examined the role of variability in the apolipoprotein B gene (APOB) in determining plasma apoB level. Twenty-three informative families from the Johns Hopkins Coronary Artery Disease Family Study were studied. Linkage analysis between three polymorphisms in the APOB gene (XbaI at codon 2488, MspI at codon 3611, and EcoRI at codon 4154) and a putative major gene with a codominant allele for elevated apoB levels gave evidence against linkage (LOD score of -7.9 at a recombination fraction of .001). None of the families had a LOD score greater than 0.5, while five families had a LOD score less than -0.5. Sib-pair analysis also showed no relationship between the proportion of genes identical by descent at the APOB locus and either crude or adjusted plasma apoB levels. Thus, in 23 informative families, there was no evidence for the presence, in APOB, of common alleles that influence plasma apoB levels. These results suggest that APOB is not the major locus influencing plasma apoB levels.     

Segregation analysis of restless legs syndrome: possible evidence for a major gene in a family study using blinded diagnoses

OBJECTIVE: The objective of this study was to ascertain the most likely inheritance pattern of restless legs syndrome (RLS) using segregation analysis. METHODS: Probands were RLS patients presenting to the Neurology and Sleep clinics of the Johns-Hopkins Bayview medical center with willing first and second degree relatives. Blinded diagnosis was made in those who exhibited the four diagnostic features of RLS. Analysis was performed on RLS as a dichotomous trait and considering age of onset models on 590 phenotyped subjects from 77 pedigrees. RESULTS: All non-genetic models were rejected considering RLS as a dichotomous trait. A single locus Mendelian dominant model with gender as a covariate had best fit with allele frequency of 0.077 and complete penetrance. RLS frequency in non-carrier subjects was estimated to be 0.14. Two underlying distributions of age of onset, with a possible dichotomy at 26.3 years, were identified. Contrary to the results for RLS as a dichotomous trait, age of onset models did not indicate single major gene inheritance. CONCLUSION: This segregation analysis suggests that the pattern of segregation is consistent with that of a single major locus, when RLS is treated as a dichotomous trait without considering age of onset. The high rate of phenocopies matches known population frequencies and taken with significant residual familial effects and the lack of evidence for a major gene controlling age of onset, indicates that non-genetic causes of RLS may exist and RLS is a complex disorder.     

Highly variable SSR markers in Douglas-fir: Mendelian inheritance and map locations

Twenty-two highly variable SSR markers were developed in Douglas-fir [Pseudotsuga menziesii (Mirb.) Franco] from five SSR-enriched genomic libraries. Fifteen PCR primer pairs amplified a single codominant locus, while seven primer pairs occasionally amplified two loci. The Mendelian inheritance of all 22 SSRs was confirmed via segregation analyses in several Douglas-fir families. The mean observed heterozygosity and the mean number of alleles per locus were 0.855 (SE=0.020) and 23 (SE=1.6), respectively. Twenty markers were used in genetic linkage analysis and mapped to ten known linkage groups. Because of their high polymorphism and unambiguous phenotypes, 15 single-locus markers were selected as the most suitable for DNA fingerprinting and parentage analysis. Only three SSRs were sufficient to achieve an average probability of exclusion from paternity of 0.998 in a Douglas-fir seed orchard block consisting of 59 parents.Communicated by O. Savolainen     

Segregation and linkage analysis for longitudinal measurements of a quantitative trait

We present a method for using slopes and intercepts from a linear regression of a quantitative trait as outcomes in segregation and linkage analyses. We apply the method to the analysis of longitudinal systolic blood pressure (SBP) data from the Framingham Heart Study. A first-stage linear model was fit to each subject's SBP measurements to estimate both their slope over time and an intercept, the latter scaled to represent the mean SBP at the average observed age (53.7 years). The subject-specific intercepts and slopes were then analyzed using segregation and linkage analysis. We describe a method for using the standard errors of the first-stage intercepts and slopes as weights in the genetic analyses. For the intercepts, we found significant evidence of a Mendelian gene in segregation analysis and suggestive linkage results (with LOD scores >or= 1.5) for specific markers on chromosomes 1, 3, 5, 9, 10, and 17. For the slopes, however, the data did not support a Mendelian model, and thus no formal linkage analyses were conducted.