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Selection against genetic defects in conservation schemes while controlling inbreeding.

We studied different genetic models and evaluation systems to select against a genetic disease with additive, recessive or polygenic inheritance in genetic conservation schemes. When using optimum contribution selection with a restriction on the rate of inbreeding (DeltaF) to select against a disease allele, selection directly on DNA-genotypes is, as expected, the most efficient strategy. Selection for BLUP or segregation analysis breeding value estimates both need 1-2 generations more to halve the frequency of the disease allele, while these methods do not require knowledge of the disease mutation at the DNA level. BLUP and segregation analysis methods were equally efficient when selecting against a disease with single gene or complex polygene inheritance, i.e. knowledge about the mode of inheritance of the disease was not needed for efficient selection against the disease. Smaller schemes or schemes with a more stringent restriction on DeltaF needed more generations to halve the frequency of the disease alleles or the fraction of diseased animals. Optimum contribution selection maintained DeltaF at its predefined level, even when selection of females was at random. It is argued that in the investigated small conservation schemes with selection against a genetic defect, control of DeltaF is very important.

Animals↗

Cryptic plasmid pRK2 from Escherichia coli W: sequence analysis and segregational stability.

Cryptic plasmid pRK2 of the strain Escherichia coli W (ATCC 9637), an ancestor of production strains for penicillin G acylase, was sequenced and characterized. Based on the data on replication region and origin (ori sequence AAC, 924-926nt), the plasmid was classified as ColE1-like plasmid. DNA sequence analysis revealed five orfs hypothetical products of which shared a significant sequence similarity with putative proteins encoded by DNA of plasmid pColE1. orf1 codes for protein Rom involved in the control of plasmid replication, orfs 2-5 code for putative mobilization proteins (Mob A-D) that show a high level of similarity with the ones encoded by DNA of plasmids pColE1 and pLG13 (E. coli), pECL18 and pEC01 (Enterobacter cloacae), pSFD10 (Salmonella choleraesuis), and pScol7 (Shigella sonnei). Recombinant plasmids pRS11 (4.91kbp), pRS12 (4.91kbp), pRS2 (2.996kbp), and pRS3 (2.623kbp) that bear the Spectinomycin resistance determinant (Spc(R)) were prepared on the basis of nucleotide sequence of pRK2. These constructs are stably maintained in the population of E. coli cells grown in the absence of the selection pressure for 63 generations. The copy number of Spc(R) constructs in E. coli host grown in antibiotic-free LB medium ranges from 25 to 40 molecules per chromosomal equivalent.

Bacterial Proteins↗

Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families.

Segregation analysis of breast cancer in families can provide the logical basis and the specific genetic models for mapping and identifying genes responsible for human breast cancer. Patterns of breast cancer occurrence in families were investigated by complex segregation analysis. In a sample of 1579 nuclear families ascertained through a population-based series of probands, an autosomal dominant model with a highly penetrant susceptibility allele fully explained disease clustering. From the maximum-likelihood Mendelian model, the frequency of the susceptibility allele was 0.0006 in the general population, and lifetime risk of breast cancer was 0.82 among susceptible women and 0.08 among women without the susceptibility allele. Inherited susceptibility affected only 4% of families in the sample: multiple cases of this relatively common disease occurred in other families by chance. The same genetic models, with higher gene frequency, explained disease clustering in an extended kindred at high risk of breast cancer. Evidence for a highly penetrant, autosomal dominant susceptibility allele for breast cancer in a high-risk family and the general population suggests that high-risk families can serve as models for understanding breast cancer in the population as a whole.

Adult↗

Inheritance of recurrent exertional rhabdomyolysis in thoroughbreds.

OBJECTIVE: To develop a diagnostic test for recurrent exertional rhabdomyolysis (RER) in Thoroughbreds that relied on in vitro contracture of muscle biopsy specimens and determine whether the inheritance pattern of RER diagnosed on the basis of this contracture test was consistent with an autosomal dominant trait. DESIGN: Clinical trial. ANIMALS: 8 adult horses with RER and 16 control adult horses for development of the contracture test; 23 foals for inheritance of RER. PROCEDURE: External intercostal muscle biopsy specimens from the 24 adult horses were tested for contracture in response to halothane and caffeine, and criteria for a positive test result were determined. These criteria were then applied to results for the 23 foals to determine whether they had RER. Simple segregation analysis was performed to determine whether results were consistent with a dominant pattern of inheritance. RESULTS: Results of the contracture test were positive for 5 of the 12 colts and 4 of the 11 fillies. Results of segregation analysis were consistent with an auto-. somal dominant pattern of inheritance. Two sires with RER produced colts with RER, supporting the hypothesis that RER had an autosomal, rather than an X-linked, inheritance pattern. In addition, in 1 instance, an unaffected colt was produced by 2 affected parents, which was not consistent with a recessive mode of inheritance. CONCLUSIONS AND CLINICAL RELEVANCE: Although the expression of the RER trait is influenced by sex, temperament, and diet, among other factors, results from the in vitro muscle contracture test and this breeding trial suggest that RER in Thoroughbreds can be modeled as a genetic trait with an autosomal dominant pattern of inheritance.

Anesthetics, Inhalation↗

Clinical description and mode of inheritance of idiopathic epilepsy in English springer spaniels.

OBJECTIVE: To determine clinical characteristics and mode of inheritance of idiopathic epilepsy (IE) in English Springer Spaniels. DESIGN: Original study. ANIMALS: 45 dogs with IE and 74 siblings and their respective parents. PROCEDURE: IE was diagnosed on the basis of age at the time of seizure onset and results of laboratory testing and neurologic examinations. Simple segregation analysis was performed with the Davie method. RESULTS: Median age at the onset of seizures was 3 years; however, 9 (20%) dogs were between 5 and 6 years old at the time of the onset of seizures. Twenty-one dogs (47%) had generalized seizures, and 24 (53%) had focal onset seizures. Results of segregation analysis were consistent with partially penetrant autosomal recessive or polygenic inheritance. Simulated linkage indicated that there was a 58% chance of obtaining suggestive linkage with the available pedigrees. CONCLUSIONS AND CLINICAL RELEVANCE: Results of the present study suggest that in English Springer Spaniels, IE segregates in a manner that is consistent with partially penetrant autosomal recessive inheritance (ie, a single major locus with modifying genes) or polygenic inheritance. Given enough families with accurate phenotypic information and available DNA, it should be possible to use genetic linkage analysis to identify chromosomal segments containing the causative gene or genes.

Age Factors↗

Genetic analysis of families with nonsmoking lung cancer probands.

As part of a genetic epidemiologic study of lung cancer among nonsmokers, we investigated the role of genetic predisposition in familial aggregation. Cases were identified from the Metropolitan Detroit Cancer Surveillance System. Information on lung cancer occurrence, smoking habits (active or passive), and chronic respiratory diseases in first-degree relatives was obtained for 257 nonsmoking lung cancer probands (71 males, 186 females) diagnosed at ages 40-84 years. Among the 2,021 first-degree relatives, 24 (2.6%) males and 10 (1.1%) females were reported as having lung cancer. The occurrence of lung cancer among smoking and nonsmoking relatives was 4.5% and 1.1% in males and 2.8% and 0.4% in females, respectively. To evaluate the role of a putative Mendelian gene (one locus, two alleles) in the presence of other risk factors, we performed complex segregation analyses on the data using two different regressive model approaches [Segregation Analysis of a Discrete Trait Under a Class A Regressive Logistic Model, V4.0 (REGD) and Segregation Analysis of a Truncated Trait, V2.0, Model 1(REGTL)] as implemented in the Statistical Analysis for Genetic Epidemiology (SAGE) program. Using either approach, an environmental model best explained the observed lung cancer aggregation in families ascertained through nonsmoking probands. Based on our final model, only 0.04% of this population had a very high risk and 4.2% had a moderate risk of lung cancer. The rest of the population had virtually no risk of lung cancer during their lifetime unless they have multiple risk factors. Among the high-risk individuals without any risk factor under study, the estimated risks at ages 40, 60, and 80 years in males were 16.7%, 83.6%, and 95.4%, and in females were 14.0%, 72.2%, and 88.0%, respectively. Among at-moderate-risk smokers the estimated risks at the same age and gender groups were essentially the same as in the high-risk nonsmokers. Our results suggest that the pattern of lung cancer occurrence in families of nonsmoking lung cancer patients differs from that in families of smoking lung cancer patients. Despite the profound effect of smoking on the risk of lung cancer, other environmental and/or genetic risk factors need to be identified.

Adult↗

Close linkage of probe p212 (DXS178) to X-linked agammaglobulinemia.

Segregation analysis was performed in three families affected in X-linked agammaglobulinemia (XLA) with five polymorphic DNA probes linked to the disease locus. In agreement with previous studies, no recombination was observed with either pXG12 (DXS94) or S21 (DXS17). Segregation analysis was also performed with a marker, p212 (DXS178), which has been shown to be closely linked to pXG12 in normal families. No cross-over with XLA was observed in these three families and in five additional families previously analyzed with DXS17 and DXS94 (z = 5.92 at theta = 0). These data provide evidence against genetic heterogeneity in XLA and indicate the value of probe p212 for carrier detection and prenatal diagnosis of XLA. We were able to estimate the carrier status of six females (out of six) in the three previously unreported families.

Agammaglobulinemia↗

Genetic analysis of apolipoprotein A-I in two dietary environments.

Although of great clinical and biological importance, the role of genotype-diet interaction in lipoprotein metabolism and atherosclerosis is still poorly understood. We analyzed serum apolipoprotein A-I (apo A-I) concentrations of approximately 600 pedigreed baboons that were fed two dietary regimens: (1) a basal diet and (2) an atherogenic (high-cholesterol, saturated-fat) diet. Complex segregation analysis was performed separately for apo A-I concentrations in each dietary environment. A major locus model with a recessive allele for high levels of apo A-I and a polygenic component best fit the family data for both diets. Using bivariate segregation analysis, we showed that the major genes detected in the univariate analyses represent two distinct loci that act additively to determine apo A-I concentrations. These two loci accounted for approximately 40% of the total phenotypic variance in apo A-I levels in each dietary environment and were also responsible for 33% of the variation in apo A-I response to the atherogenic diet. Both major loci were influenced by genotype-diet interaction in which the two-locus genotypes exhibited heterogeneous responses to the atherogenic diet. Most genotypes responded to the atherogenic diet with an increase in apo A-I, but two genotypes showed a decrease that can be traced to the effect of one of the major loci. The presence of two major loci and genotype-diet interaction may be responsible for the equivocal results obtained in human pedigree studies of apo A-I.

Animals↗

[Fibrillin-1 gene mutation in Chinese patients with Marfan syndrome and its gene diagnosis by haplotype analysis].

OBJECTIVE: To analyze fibrillin-1 (FBN(1)) gene mutation in Chinese patients with Marfan syndrome(MFS) and to make a gene diagnosis by haplotype analysis for MFS. METHODS: Nine MFS families were analysed with single strand conformation polymorphism(SSCP) and DNA sequencing. With the use of four primers designed in the flanking sequences of each short-sequence tandem-repeat region in FBN(1) gene, the haplotype-segregation analysis for MFS(B) was performed. RESULTS: In MFS(A)II(1), PCR-SSCP detected SSCP band alterations in exon 25 of FBN(1) gene; direct sequencing showed a small 13bp deletion, the deleted sequence being gcctctgcaccca at base 3243-3456 of cDNA. This mutation caused a frame-shift which was never seen in any unaffected members of the family, and it was a heterozygous mutation; neither of them was identified in 100 chromosomes from 50 normal control individuals. Haplotype-segregation analysis suggested that the disease was passed from Subject I(2) to Subject II(2), Subject II(3), Subject II(5) with the same allele in MFS B family, the proband's daughter also inherited the allele. These data indicated that MFS(B) family was linked to FBN(1) gene, the proband's daughter was an asymptomatic patient. CONCLUSION: The combination of mutation analysis and haplotype analysis can provide more evidence for gene diagnosis.

Base Sequence↗

Analyses for the presence of a major gene affecting uterine capacity in unilaterally ovariectomized rabbits.

The presence of a major gene for uterine capacity (UC), ovulation rate (OR), number of implanted embryos (IE), embryo survival (ES), fetal survival (FS), and prenatal survival (PS) was investigated in a population of rabbits divergently selected for UC for 10 generations. Selection was performed on estimated breeding values for UC up to four parities. UC was estimated as litter size in the remaining overcrowded horn of unilaterally ovariectomized does. OR and IE were counted by means of laparoscopy. Bartlett's test, Fain's test, and a complex segregation analysis using Bayesian methods were used to test for the presence of a major gene. All three tests showed that the data appeared consistent with the presence of a major gene affecting UC and IE. The results of the complex segregation analysis suggested the presence of a major gene with large effect on IE and ES (a > 1sigma(p)), at high frequency (p = 0.70 and 0.68, respectively), and with a large contribution to the total variance (R(g) = 0.39 and 0.47, respectively); and the presence of a major gene with moderate effect on each of OR, FS, PS, and UC. The results suggest that the studied reproductive traits are determined genetically by at least one gene of large effect.

Animals↗

Low frequency of MECP2 mutations in mentally retarded males.

A high frequency of mutations in the methyl CpG-binding protein 2 (MECP2) gene has recently been reported in males with nonspecific X-linked mental retardation. The results of this previous study suggested that the frequency of MECP2 mutations in the mentally retarded population was comparable to that of CGG expansions in FMR1. In view of these data, we performed MECP2 mutation analysis in a cohort of 475 mentally retarded males who were negative for FMR1 CGG repeat expansion. Five novel changes, detected in seven patients, were predicted to change the MECP2 coding sequence. Except for one, these changes were not found in a control population. While this result appeared to suggest a high mutation rate, this conclusion was not supported by segregation studies. Indeed, three of the five changes could be traced in unaffected male family members. For another change, segregation analysis in the family was not possible. Only one mutation, a frameshift created by a deletion of two bases, was found to be de novo. This study clearly shows the importance of segregation analysis for low frequency mutations, in order to distinguish them from rare polymorphisms. The true frequency of MECP2 mutations in the mentally retarded has probably been overestimated. Based on our data, the frequency of MECP2 mutations in mentally retarded males is 0.2% (1/475).

Amino Acid Sequence↗

Genetic inheritance of body mass index in African-American and African families.

Numerous studies have shown recessive major gene inheritance of body mass index (BMI) in white populations; few have examined the inheritance of BMI in the African-American population where obesity is more prevalent, nor in African populations where obesity is comparatively rare. To evaluate the inheritance of obesity in two different populations of African origin, we used segregation analysis to determine the transmission of BMI in 95 African-American families and 400 Nigerian families. Probands were selected from participants in the population-based International Collaborative Study on Hypertension in Blacks. Using class D regressive models, results from the segregation analysis of the African-American data showed evidence of a major gene effect on BMI. The Nigerian results were strikingly similar, with comparable estimates for the genotype frequencies and means and strong evidence for a major effect in the transmission of BMI. The high BMI allele frequency estimate of 24% is consistent with estimates in other studies, but the mode of transmission appeared codominant, which differs from studies involving predominantly white populations. In the Nigerian analysis, however, the probability of a high BMI homozygote parent transmitting a low BMI allele to his/her offspring was significantly different from the Mendelian expectation of zero (estimated tau(BB) = 0.45), suggesting that additional complexities exist in the major gene inheritance of BMI in this population. The strong similarity of the genotype frequencies and means obtained from the African-American and Nigerian samples suggests that a common codominant major gene effect may contribute to the variation in BMI in both populations.

Alleles↗

Segregation analyses and a genome-wide linkage search confirm genetic heterogeneity and suggest oligogenic inheritance in some Milroy congenital primary lymphedema families.

We previously described six families with Milroy congenital lymphedema, only one of which showed possible linkage to a candidate locus on chromosome 5 [Witte et al., 1998]. We have now performed a complex segregation analysis of these families, and performed linkage analyses with the other 387 markers used in our genome-wide search. Our results confirm that Milroy lymphedema is generally inherited as a dominant condition. However, this mode of inheritance, as elucidated from the segregation analyses, did not account for all observed familial correlations. The segregation analysis also suggested that shared environmental or additional genetic factors are important in explaining the observed familial aggregation. The finding of linkage to multiple locations in the largest family studied by multipoint parametric mapping (one of which was confirmed by sib-pair non-parametric mapping), suggests that Milroy congenital lymphedema may be oligogenic in this family.

Chromosome Mapping↗

Evidence of major gene control of cortical bone loss in humans.

Cortical index (CI) is the ratio of the combined cortical thickness to the total diameter of the bone. It serves for the assessment of the geometric properties of bone and for indirect evaluation of bone mass. CI is a useful predictor of osteoporosis. The aim of the present study was to test the hypothesis of major gene control of CI variation in a large sample of pedigrees from Chuvashia, Russia. Complex segregation analysis revealed that the major gene model of CI inheritance is the best fitting and most parsimonious for the present data. Parameters of the genotype-gender specific dependence of CI variation on age were estimated simultaneously with other parameters in the segregation analysis. The results of analysis showed that not only the baseline level of CI but also the age at onset of the involutive bone changes (inflection point) and the rate of the CI decrease with age (slope coefficient) are under control of the same major gene. Non-major gene effects shared by pedigree members (residual familial correlations) were found to be statistically insignificant. Approximately 73% of inter-individual variation in CI was attributable to the effects explicitly included in the model.

Adolescent↗

Recessive inheritance of obesity in familial non-insulin-dependent diabetes mellitus, and lack of linkage to nine candidate genes.

Segregation analysis of body-mass index (BMI) supported recessive inheritance of obesity, in pedigrees ascertained through siblings with non-insulin dependent diabetes mellitus (NIDDM). BMI was estimated as 39 kg/m2 for those subjects homozygous at the inferred locus. Two-locus segregation analysis provided weak support for a second recessive locus, with BMI estimated as 32 kg/m2 for homozygotes. NIDDM prevalence was increased among those subjects presumed to be homozygous at either locus. Using both parametric and nonparametric methods, we found no evidence of linkage of obesity to any of nine candidate genes/regions, including the Prader-Willi chromosomal region (PWS), the human homologue of the mouse agouti gene (ASP), and the genes for leptin (OB), the leptin receptor (OBR/DB), the beta3-adrenergic receptor (ADRB3), lipoprotein lipase (LPL), hepatic lipase (LIPC), glycogen synthase (GYS), and tumor necrosis factor alpha (TNFA).

Adult↗

Family resemblance for fasting blood glucose in a population of Japanese Americans.

The pattern of inheritance of fasting blood glucose was examined in a Japanese cohort of 500 nuclear families living in Hawaii. A principal component of glucose was defined to improve the ranking of diabetics and individuals receiving treatment (medication and/or diet) for hyperglycemia, thereby allowing as well as possible for inability to determine untreated levels in patients. Results from path and segregation analysis show that family resemblance for glucose is low in this population. The additive variation can be explained by a cultural model of inheritance without introducing intergenerational differences, a maternal-paternal effect, or even genetic parameters. Heritability is approximately 0.125. Complex segregation analysis provides no convincing evidence for a major gene, with preliminary support based upon leptokurtic outliers in five families disappearing on further analysis by partial truncation. A claim by other workers of a major recessive gene for hyperglycemia may be due to their failure to allow for treatment, skewness, and multifactorial heritability. In future, the search for major loci acting on liability to hyperglycemia should use multiple determinations of fasting glucose or be addressed to more primary and repeatable variables than fasting blood glucose.

Adult↗

Segregation of a major gene influencing ovulation in progeny of Lacaune meat sheep.

Inheritance of the ovulation rate (OR) in the Lacaune meat breed was studied through records from a small nucleus of 36 hyper-prolific ewes screened on farms on the basis of their natural litter size, and from progeny data of three selected Lacaune sires. These sires were chosen at the AI centre according to their breeding values estimated for the mean and the variability of their daughters' litter size. Non-carrier Lacaune dairy ewes were inseminated to produce 121 F1 daughters and 27 F1 sons. Twelve sons (four from each sire) were used in turn to inseminate non-carrier Lacaune dairy ewes providing 260 BC progeny ewes. F1 and BC progeny were brought from private farms and gathered after weaning on an experimental farm where ovulation rates were recorded in the first and second breeding seasons. With an average of 6.5 records each, the mean OR of hyper-prolific ewes was very high (5.34), and 38.4% of records showed a rate of 6 or more. F1 data showed high repeatability of OR (r = 0.54) within ewe, with significant variability among ewes. High OR (> or = 4) were observed in each family. A segregation analysis provided a significant likelihood ratio and classified the three founders as heterozygous. BC ewes also displayed high repeatability of OR (r = 0.47) and the mean OR varied considerably between families (from 1.24 to 1.78). Seven of the 12 BC families presented high-ovulating ewes (at least one record > or = 4) and segregation analysis yielded a highly significant likelihood ratio as compared to an empirical test distribution. The high variability of the mean ovulation rate shown by a small group of daughters of BC ewes inseminated by putative carrier F1 rams, and the very high ovulation rate observed for some of these ewe lambs, confirmed the segregation of a major gene with two co-dominant alleles borne by an autosome. The difference between homozygous non-carriers and heterozygous ewes was about one ovulation on the observed scale and 2.2 standard deviations on the underlying scale.

Animals↗

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.

Adolescent↗