Biomedical subjects

L Susan Pletscher

Publications and source records attributed to L Susan Pletscher.

12 recordsLinked to original sources

PubMed2006

Quantitative trait loci for body size components in mice.

Do body size components, such as weights of internal organs and long bone lengths, with different functions and different developmental histories also have different genetic architectures and pleiotropic patterns? We examine murine quantitative trait loci (QTL) for necropsy weight, four long bone lengths, and four organ weights in the LG/J x SM/J intercross. Differences between trait categories were found in number of QTL, dominance, and pleiotropic patterns. Ninety-seven QTLs for individual traits were identified: 52 for long bone lengths, 30 for organ weights, and 15 for necropsy weight. Results for long bones are typically more highly significant than for organs. Organ weights were more frequently over- or underdominant than long bone lengths or necropsy weight. The single-trait QTLs map to 35 pleiotropic loci. Long bones are much more frequently affected in groups while organs tend to be affected singly or in pairs. Organs and long bones are found at the same locus in only 11 cases, 8 of which also include necropsy weight. Our results suggest mainly separate genetic modules for organ weights and long bone lengths, with a few loci that affect overall body size. Antagonistic pleiotropy, in which a locus has opposite effects on different characteristics, is uncommon.

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PubMed2006

Genetic characterization of a new set of recombinant inbred lines (LGXSM) formed from the inter-cross of SM/J and LG/J inbred mouse strains.

A new set of LGXSM recombinant inbred (RI) strains is presented. The RI strain panel consists of 18 remaining strains of the original 55 founding strains. Strain characterization is based on 506 polymorphic microsatellites and 4,289 single nucleotide polymorphisms (SNPs) distributed across the genome. Average microsatellite inter-marker distance is 4.80+/-4.84 Mb or 2.91+/-3.21 F(2) cM. SNPs are more densely spaced at 0.57+/-1.27 Mb. Ninety-five percent of all microsatellite inter-marker intervals are separated by less than 15.00 Mb or 8.50 F(2) cM, while 95% of the SNPs are less than 0.95 Mb apart. Strains show expected low levels of nonsyntenic association among loci and complete genomic independence. During inbreeding, the RI strains went through strong natural selection on the agouti locus on Chromosome 2, especially when the epistatically interacting tyrosinase locus on Chromosome 7 carried the wild-type allele. The LG/J and SM/J strains differ in a large number of biomedically important traits, and they and their inter-cross progeny have been used in multiple mapping studies. The LGxSM RI strain panel provides a powerful new resource for mapping the genetic bases of complex traits and should prove to be of great biomedical utility in modeling complex human diseases such as obesity and diabetes.

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PubMed2005

Maternal genotype affects adult offspring lipid, obesity, and diabetes phenotypes in LGXSM recombinant inbred strains.

Maternal effects on offspring phenotypes occur because mothers in many species provide an environment for their developing young. Although these factors are correctly "environmental" with respect to the offspring genome, their variance may have both a genetic and an environmental basis in the maternal generation. Here, reciprocal crosses between C57BL/6J and 10 LGXSM recombinant inbred (RI) strains were performed, and litters were divided at weaning into high-fat and low-fat dietary treatments. Differences between reciprocal litters were used to measure genetic maternal effects on offspring phenotypes. Nearly all traits, including weekly body weights and adult blood serum traits, show effects indicative of genetic variation in maternal effects across RI strains, allowing the quantitative trait loci involved to be mapped. Although much of the literature on maternal effects relates to early life traits, we detect strong and significant maternal effects on traits measured at adulthood (as much as 10% of the trait variance at 17 or more weeks after weaning). We also found an interaction affecting adult phenotype between the effects of maternal care between RI strain mothers and C57BL/6J mothers and a later environmental factor (dietary fat intake) for some age-specific weights.

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PubMed2005

Genetic variation and correlation of dietary response in an advanced intercross mouse line produced from two divergent growth lines.

Levels of human obesity have increased over the past 20 years worldwide, primarily due to changes in diet and activity levels. Although environmental changes are clearly responsible for the increasing prevalence of obesity, individuals may show genetic variation in their response to an obesogenic environment. Here, we measure genetic variation in response to a high-fat diet in a mouse model, an F16 Advanced Intercross Line derived from the cross of SM/J and LG/J inbred mouse strains. The experimental population was separated by sex and fed either a high-fat (42% of energy from fat) or low-fat (15% of energy from fat) diet. A number of phenotypic traits related to obesity and diabetes such as growth rate, glucose tolerance traits, organ weights and fat pad weights were collected and analysed in addition to serum levels of insulin, free fatty acids, cholesterol and triglycerides. Most traits are different between the sexes and between dietary treatments and for a few traits, including adult growth, fat pad weights, insulin and glucose tolerance, the dietary effect is stronger in one sex than the other. We find that fat pad weights, liver weight, serum insulin levels and adult growth rates are all phenotypically and genetically correlated with one another in both dietary treatments. Critically, these traits have relatively low genetic correlations across environments (average r =0.38). Dietary responses are also genetically correlated across these traits. We found substantial genetic variation in dietary response and low cross environment genetic correlations for traits aligned with adiposity. Therefore, genetic effects for these traits are different depending on the environment an animal is exposed to.

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PubMed2005

The evolution of genetic architecture. I. Diversification of genetic backgrounds by genetic drift.

The genetic architecture of a phenotype plays a critical role in determining phenotypic evolution through its effects on patterns of genetic variation. Genetic architecture is often considered to be constant in evolutionary quantitative genetic models. However, genetic architecture may be variable and itself evolve when there are dominance and epistatic interactions among alleles at the same and different loci, respectively. The evolution of genetic architecture by genetic drift is examined here by testing the breeding value of four standard inbred mouse strains mated across a set of 26 related recombinant quasi-inbred (RqI) lines generated from the intercross of the Large (LG/J) and Small (SM/J) inbred mouse strains. Phenotypes of interest include age-specific body weights, growth, and adult body composition. If the genetic architecture of these traits has differentiated by genetic drift during the production of the RqI strains, we should observe interactions between tester strain and RqI strain. The breeding values of the tester strains will change relative to one another depending on which RqI strain they are crossed to. The study included an average of 15.1 offspring per cross, over a total of 100 different crosses. Multivariate and univariate analyses of variance indicate that there is strongly significant interaction for all traits. Interaction is more pronounced in males than in females and accounted for an average of about 40% of the explained variation in males and 30% in females. These results indicate that the genetic architecture of these traits has differentiated by genetic drift in the RqI strains since their isolation from a common founder population. Further analysis indicates that this differentiation results in changes in the order of tester strain effects so that common patterns of selection in these differentiated populations could result in the fixation of different alleles.

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PubMed2005

Fine-mapping gene-by-diet interactions on chromosome 13 in a LG/J x SM/J murine model of obesity.

Obesity is one of the most serious threats to human health today. Although there is general agreement that environmental factors such as diet have largely caused the current obesity pandemic, the environmental changes have not affected all individuals equally. To model gene-by-environment interactions in a mouse model system, our group has generated an F(16) advanced intercross line (AIL) from the SM/J and LG/J inbred strains. Half of our sample was fed a low-fat (15% energy from fat) diet while the other half was fed a high-fat (43% energy from fat) diet. The sample was assayed for a variety of obesity- and diabetes-related phenotypes such as growth rate, response to glucose challenge, organ and fat pad weights, and serum lipids and insulin. An examination in the F(16) sample of eight adiposity quantitative trait loci previously identified in an F(2) intercross of SM/J and LG/J mouse strains reveals locus-by-diet interactions for all previously mapped loci. Adip7, located on proximal chromosome 13, demonstrated the most interactions and therefore was selected for fine mapping with microsatellite markers. Three phenotypic traits, liver weight in male animals, serum insulin in male animals, and reproductive fat pad weight, show locus-by-diet interactions in the 127-kb region between markers D13Mit1 and D13Mit302. The phosphofructokinase (PFK) C (Pfkp) and the pitrilysin metalloprotease 1 (Pitrm1) genes are compelling positional candidate genes in this region that show coding sequence differences between the parental strains in functional domains.

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PubMed2004

Pleiotropic effects on mandibular morphology II: differential epistasis and genetic variation in morphological integration.

The evolution of morphological modularity through the sequestration of pleiotropy to sets of functionally and developmentally related traits requires genetic variation in the relationships between traits. Genetic variation in relationships between traits can result from differential epistasis, where epistatic relationships for pairs of loci are different for different traits. This study maps relationship quantitative trait loci (QTLs), specifically QTLs that affect the relationship between individual mandibular traits and mandible length, across the genome in an F2 intercross of the LG/J and SM/J inbred mouse strains (N = 1045). We discovered 23 relationship QTLs scattered throughout the genome. All mandibular traits were involved in one or more relationship QTL. When multiple traits were affected at a relationship QTL, the traits tended to come from a developmentally restricted region of the mandible, either the muscular processes or the alveolus. About one-third of the relationship QTLs correspond to previously located trait QTLs affecting the same traits. These results comprise examples of genetic variation necessary for an evolutionary response to selection on the range of pleiotropic effects.

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PubMed2004

Genetic evidence for discordance between obesity- and diabetes-related traits in the LGXSM recombinant inbred mouse strains.

Obesity and its comorbidities, particularly type 2 diabetes, have become serious public health problems over the past few decades. Although the current pandemic is largely caused by societal environmental changes in diet, variation in response to these changes have, in part, a genetic basis. Here we address the genetic basis for both obesity- and diabetes-related traits themselves and dietary fat responses for these traits in a set of recombinant inbred mouse strains formed from the cross of LG/J with SM/J (LGXSM lines) fed a standard low-fat (15% calories from fat) or high-fat (42% calories from fat) diet. We found substantial genetic variation for most of the traits studied. Weight at time of death, liver weight, and weight of the reproductive fat pad had especially high heritabilities, whereas heart weight and serum levels of free fatty acids and triglycerides had low heritabilities. Genetic correlations were very high among fat pad weights and serum leptin, indicating shared genetic variation between fat levels and hormonal appetite control. These obesity traits were moderately correlated with adult growth, liver weight, and serum insulin and cholesterol levels. A majority of traits also displayed genetic variation in response to a high-fat diet, especially the weight of the reproductive and renal fat pads as well as the liver. Genetic correlations in dietary response followed a pattern similar to that found for the traits themselves. Several strains manifested discordant responses for obesity, glucose, and insulin, consistent with the presence of genotypes protective for diabetes in the presence of obesity. These recombinant inbred strains represent potentially valuable new models for dissecting the complex physiological relationships among obesity and diabetes.

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PubMed2004

Quantitative trait loci for obesity- and diabetes-related traits and their dietary responses to high-fat feeding in LGXSM recombinant inbred mouse strains.

Genetic variation in response to high-fat diets is important in understanding the recent secular trends that have led to increases in obesity and type 2 diabetes. The examination of quantitative trait loci (QTLs) for both obesity- and diabetes-related traits and their responses to a high-fat diet can be effectively addressed in mouse model systems, including LGXSM recombinant inbred (RI) mouse strains. A wide range of obesity- and diabetes-related traits were measured in animals from 16 RI strains with 8 animals of each sex fed a high- or low-fat diet from each strain. Marker associations were measured at 506 microsatellite markers spread throughout the mouse genome using a nested ANOVA. Locations with significant effects on the traits themselves and/or trait dietary responses were identified after correction for multiple comparisons by limiting the false detection rate. Nonsyntenic associations of marker genotypes were common at QTL locations so that the significant results were limited to loci still significant in multiple QTL models. We discovered 91 QTLs at 39 locations. Many of these locations (n = 31) also showed genetic effects on dietary response, typically because the loci produced significantly larger effects on the high-fat diet. Fat depot weights, leptin levels, and body weight at necropsy tended to map to the same locations and were responsible for a majority of the dietary response QTLs. Basal glucose levels and the response to glucose challenge mapped together in locations distinct from those affecting obesity. These QTL locations form a panel for further research and fine mapping of loci affecting obesity- and diabetes-related traits and their responses to high-fat feeding.

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PubMed2003

Pleiotropic effects on mandibular morphology I. Developmental morphological integration and differential dominance.

Pleiotropy refers to a single genetic locus that affects more than one phenotypic trait. Pleiotropic effects of genetic loci are thought to play an important role in evolution, reflecting functional and developmental relationships among phenotypes. In a previous study, we examined pleiotropic effects displayed by quantitative trait loci (QTLs) on murine mandibular morphology in relation to mandibular structure and function. In replicating most of our previous QTLs and increasing our sample size, this study strengthens and extends our earlier results. As in our previous study, we find that QTL effects tend to be restricted to developmentally or functionally related traits. In addition, we examine patterns of differential dominance for pleiotropic QTL effects. Differential dominance occurs when dominance patterns for a single locus vary among traits. We find that multivariate overdominance is a common and substantial phenomenon, and may potentially provide an explanation for the persistence of heterozygosity in natural populations.

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PubMed2003

Diet, obesity, and hyperglycemia in LG/J and SM/J mice.

OBJECTIVE: To examine the differential response of obesity- and diabetes-related traits to a high- or low-fat diet in LG/J and SM/J mice. We also examined food consumption in these strains. RESEARCH METHODS AND PROCEDURES: Mice were placed on a high- or low-fat diet after weaning. Animals were weighed once per week and subjected to glucose tolerance tests at 20 weeks. At sacrifice, fat pads and internal organs were removed along with serum samples. For food consumption, LG/J and SM/J mice of each sex were assigned to a high-fat or low-fat diet after reaching maturity. Mice were weighed three times per week, and food consumed was determined by subtraction. RESULTS: LG/J animals consume more total food, but SM/J animals consume more food per gram of body weight. LG/J mice grow faster to 10 weeks but slower from 10 to 20 weeks, have higher cholesterol and free fatty acid levels, and have lower basal glucose levels and better response to a glucose challenge than SM/J mice. For most traits, SM/J mice respond more strongly to a high-fat diet than LG/J mice, including body weight and growth, basal glucose levels, organ weights, fat distribution, and circulating triglycerides and cholesterol levels. DISCUSSION: Obesity-related phenotypes, as well as response to increased dietary fat, differ genetically between LG/J and SM/J and can, therefore, be mapped. This study indicates that the cross of SM/J and LG/J mice would be an excellent model system for the study of gene-by-diet interaction in obesity.

Adipose Tissue↗

PubMed2002

Quantitative trait loci for maternal performance for offspring survival in mice.

Maternal performance refers to the effect that the environment provided by mothers has on their offspring's phenotypes, such as offspring survival and growth. Variations in maternal behavior and physiology are responsible for variations in maternal performance, which in turn affects offspring survival. In our study we found females that failed to nurture their offspring and showed abnormal maternal behaviors. The genetic architecture of maternal performance for offspring survival was investigated in 241 females of an F(2) intercross of the SM/J and LG/J inbred mouse strains. Using interval-mapping methods we found two quantitative trait loci (QTL) affecting maternal performance at D2Mit17 + 6 cM and D7Mit21 + 2 cM on chromosomes 2 and 7, respectively. In a two-way genome-wide epistasis scan we found 15 epistatic interactions involving 23 QTL distributed across all chromosomes except 12, 16, and 17. These loci form several small sets of interacting QTL, suggesting a complex set of mechanisms operating to determine maternal performance for offspring survival. Taken all together and correcting for the large number of significant factors, QTL and their interactions explain almost 35% of the phenotypic variation for maternal performance for offspring survival in this cross. This study allowed the identification of many possible candidate genes, as well as the relative size of gene effects and patterns of gene action affecting maternal performance in mice. Detailed behavior observation of mothers from later generations suggests that offspring survival in the first week is related to maternal success in building nests, grooming their pups, providing milk, and/or manifesting aggressive behavior against intruders.

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