RFLPs at the baboon insulin-like growth factor 1 (IGF1) and the IGF1 receptor (IGF1R) loci.
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Alleles↗
Biomedical subjects
C M Kammerer
Publications and source records attributed to C M Kammerer.
Effects of age, sex, and heredity on measures of bone mass in baboons (Papio hamadryas).
Bone mass and bone density were estimated in 219 pedigreed baboons (Papio hamadryas) by radiographic morphometry of the left second metacarpal. Compact bone width (total bone width--medullary canal diameter) and bone ratio (compact bone width/total bone width) decreased with increasing age squared in both sexes. The heritability of medullary canal diameter was 0.64 +/- 0.11, of compact bone width was 0.40 +/- 0.15 and of bone ratio was 0.67 +/- 0.13. The results indicate baboons are a useful model for studies of age, sex and genetic effects on bone mass.
Aging↗
Evidence for a major gene affecting postchallenge insulin levels in Mexican-Americans.
Hyperinsulinemia, which is considered a hallmark of insulin resistance, precedes the development of non-insulin-dependent diabetes mellitus (NIDDM). Results of family and twin studies have shown that heredity influences insulin resistance and insulin levels. In Caucasian families ascertained through two or more NIDDM siblings, it has been reported that single genes with large effects, i.e., major genes, influence both fasting and 1-h postchallenge insulin levels. To determine whether a major gene affects 2-h postchallenge insulin levels in Mexican-Americans, we conducted segregation analyses using data collected on 527 pedigreed individuals from 27 families in San Antonio, TX. Probands for the families were randomly ascertained and all first-, second-, and third-degree relatives aged 16 years and older were invited to participate. Subjects received a 2-h oral glucose tolerance test, and diabetes was diagnosed according to World Health Organization criteria. We found that an autosomal dominant major gene best described the inheritance of 2-h insulin levels (ln-transformed) in these 27 families. Of the individuals in the population, 17% were homozygous for the 2-h low-insulin allele (back-transformed mean = 125 pmol/l) and 83% were heterozygous or homozygous for the 2-h high-insulin allele (back-transformed mean = 406 pmol/l). This major gene accounted for 31% of the variance in ln(2-h insulin levels) in this population. Using quantitative trait linkage analyses, we excluded tight linkage between this gene affecting 2-h insulin levels and three candidate loci for insulin levels: the insulin receptor gene, the low-density lipoprotein receptor gene, and the glucokinase gene.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Evidence for linkage of postchallenge insulin levels with intestinal fatty acid-binding protein (FABP2) in Mexican-Americans.
Single genes with large effects may contribute to insulin resistance or influence susceptibility to non-insulin-dependent diabetes mellitus (NIDDM). In the Pima Indians, results from sib-pair analysis have suggested that a gene on chromosome 4q influences both fasting insulin levels and maximal insulin action. We conducted sib-pair and logarithm of odds (LOD)-score linkage analysis to seek evidence for linkage between genes influencing insulin levels and chromosome 4q loci. Analyses were conducted on nondiabetic individuals from 28 different families participating in the San Antonio Family Diabetes Study. All subjects received a 2-h oral glucose tolerance test. Fasting insulin levels were measured in 382 nondiabetic individuals, and 2-h insulin levels were measured in 366 individuals. Initial sib-pair linkage analysis revealed a possible association between 2-h post-glucose challenge insulin levels and the intestinal fatty acid-binding protein (FABP2) locus located in the region of chromosome 4q28-31 (P = 0.006). Subsequent sib-pair linkage analysis of 11 additional chromosome 4q markers supported this hypothesis. We next conducted segregation analyses to estimate allele frequencies and other model parameters for the putative locus influencing 2-h insulin levels. Results of LOD-score linkage analysis indicated possible linkage between the major gene described by the segregation model and FABP2. Using combined segregation and linkage analysis, we obtained a LOD-score of 2.80 at recombination frequency of 0.0 between FABP2 and the putative locus influencing 2-h insulin levels. The maximum likelihood estimate of the allele associated with low insulin levels was 0.21.(ABSTRACT TRUNCATED AT 250 WORDS)
Carrier Proteins↗
RFLPs in the baboon renin locus.
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Alleles↗
NIDDM in Mexican-American families. Heterogeneity by age of onset.
OBJECTIVE: Heredity has long been known as a risk factor for non-insulin-dependent diabetes mellitus (NIDDM), but the mode of inheritance of NIDDM remains unclear. We examined the distribution of diabetes in 29 Mexican-American families ascertained on a diabetic proband. RESEARCH DESIGN AND METHODS: Probands represented a random sample of diabetic Mexican Americans residing in low-income neighborhoods from San Antonio, TX. A total of 375 family members of these diabetic probands were examined, and diabetes was diagnosed according to the World Health Organization plasma glucose criteria. RESULTS: The prevalence of diabetes decreased from 28.2% in first-degree relatives of the probands to 13.3% in second-degree relatives to 11.1% in third-degree relatives. When compared with Mexican Americans with no parental history of diabetes, this represents an excess of diabetes of 2.0-, 1.3-, and 1.1-fold in first-, second-, and third-degree relatives, respectively. Five of the 29 probands (17%) had an age of diabetes onset < 40 years. In the first-degree relatives of these early-onset probands, diabetes prevalence was 47.0% (16 of 34) compared with only 24.1% (34 of 141) in the first-degree relatives of the 24 late-onset probands. After adjustment for age, this excess represented a fivefold increase in the odds of diabetes among relatives of the early-onset probands compared with relatives of the late-onset probands (P < 0.001). Moreover, the 16 affected family members of the early-onset probands had a mean age of diabetes onset of 42.7 years compared with 49.9 years for the 34 affected members of the late-onset probands, although this difference was not statistically significant (P = 0.13). CONCLUSIONS: NIDDM may be genetically heterogeneous in this Mexican-American population, with family members of early-onset diabetes patients being at higher risk for NIDDM than family members of late-onset diabetes patients.
Adolescent↗
Baboon apolipoprotein A-IV. Identification of Lys76-->Glu that distinguishes two common isoforms and detection of length polymorphisms at the carboxyl terminus.
Various protein isoforms have been identified for human apolipoprotein A-IV (apoA-IV). However, investigations of their physiological effects have been limited because of low frequencies for many of the apoA-IV variants. Recent discovery of extensive variation in baboon apoA-IV using isoelectric focusing (IEF) makes this primate species an excellent model for genetic studies of apoA-IV. In this study, the molecular basis for net charge differences between two common apoA-IV isoforms (I and E) was determined by cloning and sequencing of intestinal cDNAs from homozygous baboons. An A-->G substitution was found in the third amphipathic repeat of the E isoform. This substitution causes a Lys-->Glu substitution at amino acid position 76 (Lys76-->Glu), adding two negative charges to the E isoform compared to the I isoform, consistent with their relative mobilities on IEF gels. Restriction isotyping was used to identify the substitution in leukocyte DNA from 15 baboons that had been typed by IEF, thus verifying Lys76-->Glu as the basis for the charge differences between the I and E isoforms. Physiological effects of the Lys76-->Glu substitution on high density lipoprotein-C levels were investigated in 431 baboons carrying the E and I isoforms. These studies revealed that the I isoform was associated with higher levels of high density lipoprotein-C on a high cholesterol, saturated fat diet (p = 0.04). The cDNA sequences showed that the carboxyl terminus of baboon apoA-IV contains a region of hydrophilic repeats (Glu-Gln-X-Gln) that is the largest yet found in any species (nine repeats compared to three to five repeats in human, mouse, and rat). A common length polymorphism was identified that inserts a single amino acid to form a five amino acid repeat. This is the first report of this type of length variation (insertion of a single amino acid rather than insertion of an entire repeat) in this region. In addition, a rare variant was found that inserts an entire four-amino-acid repeat, similar to the human apoA-IV-0 isoform.
Amino Acid Sequence↗
A DNA polymorphism for lecithin:cholesterol acyltransferase (LCAT) is associated with high density lipoprotein cholesterol concentrations in baboons.
We investigated the effects of a polymorphic PvuII site in the gene for lecithin:cholesterol acyltransferase (LCAT) on serum high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I) concentrations in a population of 750 pedigreed baboons. We also tested for genotype by diet interactions using data on HDL-C and apo A-I concentrations on two diets (chow and high-cholesterol, saturated fat). A significant (P < 0.001) association between the LCAT genotypes and HDL-C levels was observed. On both diets, animals homozygous for the less common allele had HDL-C levels that averaged 18-19% lower than animals homozygous for the more common allele. HDL-C levels of the heterozygotes were intermediate. The LCAT RFLP accounted for approximately 5% of the variation in HDL-C levels on the two diets. We observed no strong evidence for an LCAT genotype by diet interaction effect.
Alleles↗
Exploring the HDL likelihood surface.
Using random initial parameter estimates, three segregation analysis models of the inheritance of HDL2 in the Berkeley GAW8 data set were maximized 5000 times each. Initial parameter estimates were assumed to be uniformly distributed on intervals formed by parameter boundaries. The three models were unrestricted, environmental, and Mendelian regressive type A models. Likelihood ratio tests of the global maxima rejected the Mendelian model and accepted the environmental model. However, tests using local maxima accepted the Mendelian model and both rejected and accepted the environmental model. Patterns among the initial parameter estimates of convergent runs were examined to develop empirical rules to increase the frequency of convergence. These rules were tested using data on apoAI in the Berkeley GAW8 data set.
Genetic Predisposition to Disease↗
Linkage between complement components 6 and 7 and glutamic pyruvate transaminase in the marsupial Monodelphis domestica.
The sixth and seventh components of complement were found to be polymorphic and tightly linked in the laboratory opossum (Monodelphis domestica), as they are in eutherian mammals. In addition, strong evidence for linkage of the C6-C7 haplotype to the gene for glutamic pyruvate transaminase (GPT) was obtained for females but not for males. This result, combined with previous observations, established as a generality that recombination is severely reduced in females of this species by comparison with males. It also establishes synteny of C6-C7 and GPT in a marsupial species, as exists in mice. Because these loci are not syntenic in humans, the results imply that this synteny is ancestral to the separation of marsupials and eutherians and that it was broken relatively recently in the mammalian lineage leading to human beings. The newly described C6 and C7 polymorphisms provide additional power for developing a linkage map for M. domestica and for localizing genes that confer susceptibility to diseases for which this species is used as a model.
Alanine Transaminase↗
Correlated expression of atrial myosin heavy chain and regulatory light chain isoforms with pressure overload hypertrophy in the non-human primate.
OBJECTIVE: The aim was to determine the extent to which myosin heavy chain and light chain isoform transitions in atrial myocardium are coordinately regulated under pathological conditions in tissue from normal baboons, hypertensive baboons with myocardial hypertrophy, and baboons in which hypertrophy had regressed. METHODS: Quantitative distributions of myosin heavy chain (MHC) and regulatory myosin light chain (MLC2) isoforms in atrial myocardium from 35 adult baboons were determined by electrophoresis under denaturing conditions and laser densitometry. RESULTS: A significant association was observed between the ratios of MHC and MLC2 isoforms in atrial myocardium (r = 0.73, p < 0.001, n = 69). Expressions of alpha MHC and atrial MLC2 (ALC2) isoforms were correlated in atrial myocardium, as were those of beta MHC and ventricular MLC2 (VLC2) isoforms. In a subset of baboons with experimentally induced renal hypertension (n = 12) both beta MHC and VLC2 isoforms were found at higher levels in left atria than were present in normotensive baboons (p = 0.006, n = 15). Left atria from hypertensive baboons with regressed LVH contained intermediate levels of both beta MHC and VLC2 isoforms. CONCLUSIONS: There is tight coupling between the expression of myosin subunit isoforms under pathological conditions from a primate species closely related to humans. The data suggest that the synthesis of these subunits of myosin may be coordinated at the molecular level.
Animals↗
Linkage between two blood-group markers in rhesus monkeys (Macaca mulatta).
Using marker data on an extensive pedigreed population from the Wisconsin Regional Primate Research Center, we report the first genetic linkage in rhesus monkeys (Macaca mulatta). Five blood-group markers (G, I, J, K, and Q) and one serum protein marker (transferrin) were analyzed. Linkage analyses indicate the existence of loose linkage between G and Q (maximum lod score, Zmax = 4.84 at theta m = 0.314 +/- 0.38, theta f = 0.266 +/- 0.054). The genetic linkage described here constitutes the initial step toward the description of a genetic map in this species.
Animals↗
Selective breeding to develop lines of baboons with high and low blood pressure.
Lines of baboons with high and low blood pressure were developed by selective breeding. Blood pressure was measured in 456 adult feral baboons under ketamine immobilization by direct arterial cannulation. Males with blood pressures two standard deviations and females with blood pressures one standard deviation above and below the cumulative mean were selected as progenitors. High males were mated with high females and low males were mated with low females. We measured blood pressure and plasma renin activity on 100 progeny, 54 males and 46 females, greater than 44 months of age with an abbreviated tether protocol and software program for data collection. Mean systolic and diastolic nighttime pressures for the high line were 126/72 and for the low line were 114/65 mm Hg. Line differences for systolic (12 mm Hg) and for diastolic (7 mm Hg) pressures were significant (p < 0.001). The line difference for plasma renin activity (1.1 [ng/mL]/hr) was not significant. Progeny pressures ranged from 84/49 to 191/126 mm Hg. There was no sex effect on blood pressure or plasma renin activity line differences. Heritability of systolic pressure was 0.46 +/- 0.19 and of diastolic pressure was 0.32 +/- 0.19. These results indicate that, by selective breeding and rigorous measurement of blood pressure, lines of baboons with significant difference in blood pressure can be developed.
Animal Husbandry↗
Distribution of specific apolipoproteins determined by immunoblotting of baboon lipoproteins resolved by polyacrylamide gradient gel electrophoresis.
A method for the quantitative assessment of apolipoprotein distributions among baboon serum lipoproteins is described. The method combines the precise and reproducible separation of lipoproteins by polyacrylamide gradient gel electrophoresis with the specificity of immunoblotting. The method permits the measurement of distributions for any apolipoprotein for which there are antibodies available. Radioactive secondary antibodies are used to expose X-ray film, and distributions are determined by densitometry. Absorbance is linearly related to both antigen and antibody concentrations. The method is reproducible, with the mean coefficient of variation calculated to be 0.118, and has a high repeatability (r2 = 0.97). The immunoblotting method can be employed to measure the fine details of lipoprotein phenotypes as they are influenced by genotype and environment.
Animals↗
Linkage heterogeneity between the C3 and LDLR and the APOA4 and APOA1 loci in baboons.
We detected linkage in baboons between loci for the third component of complement (C3) and the low-density lipoprotein receptor (LDLR), lod score = 5.53, and loci for apolipoprotein A1 (APOA1) and apolipoprotein AIV (APOA4), lod score = 14.59. We also found evidence for linkage heterogeneity among the baboon pedigrees between LDLR and C3 (P = 0.04) and between APOA1 and APOA4 (P = 0.01).
Animals↗
Multivariate genetic analysis of nevus measurements and melanoma.
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Genetic Linkage↗
Severely reduced recombination in females of the South American marsupial Monodelphis domestica.
The gray short-tailed opossum, Monodelphis domestica, is a model species for studying the underlying mechanisms that govern recombination. We have identified a new marker, PI (protease inhibitor), in M. domestica and demonstrate its linkage to AK1 (adenylate kinase 1). The rate of recombination in females of this species is approximately one fifth the rate in males, as might be predicted from the difference in chiasma frequency between the two sexes.
Adenylate Kinase↗
Mixed model segregation analysis of LDL-C concentration with genotype-covariate interaction.
Mixed model complex segregation analyses have in the past ignored the possibility of genotype-covariate interaction. Only in the nonmixed model with polygenic heritability equal to zero have segregation analyses been performed that allowed for genotype specific regression of the phenotype on covariates. We present an extension of Hasstedt's [1982] mixed model likelihood approximation which does allow for genotype-covariate interaction in the mixed model. Following description of this approximation, we validate the likelihood calculation by a Monte Carlo procedure based on the actual pedigree and missing data structure used in a complex segregation analysis of low density plus very low density lipoprotein cholesterol (LDL-C + VLDL-C) in baboons. The observed averages of the bootstrap parameter estimates adequately recover the generating values, which included parameters specifying genotype-covariate interaction. We then applied both a traditional complex segregation analysis and an analysis with genotype-covariate interaction to test for the presence of a major locus affecting LDL-C levels in baboons. The model including genotype-covariate interaction was significantly different from the model without interactions, and strongly supported the hypothesis that there is a segregating Mendelian locus as opposed to a random environmental factor. This major locus accounts for approximately 46% of the variance in LDL-C levels, as compared to 40% explained by a locus with no genotype-covariate interaction.
Animals↗