Ty T. Vaughn

Mapping quantitative trait loci for murine growth: a closer look at genetic architecture

Over 20 years ago, D. S. Falconer and others launched an important avenue of research into the quantitative of body size growth in mice. This study continues in that tradition by locating quantitative trait loci (QTLs) responsible for murine growth, such as age-specific weights and growth periods, and examining the genetic architecture for body weight. We identified a large number of potential QTLs in an earlier F2 intercross (Intercross I) of the SM/J and LG/J inbred mouse strains. Many of these QTLs are replicated in a second F2 intercross (Intercross II) between the same two strains. These replicated regions provide candidate regions for future fine-mapping studies. We also examined body size and growth QTLs using the combined data set from these two intercrosses, resulting in 96 microsatellite markers being scored for 1045 individuals. An examination of the genetic architecture for age-specific weight and growth periods resulted in locating 20 separate QTLs, which were mainly additive in nature, although dominance was found to affect early growth and body size. QTLs affecting early and late growth were generally distinct, mapping to separate chromosome locations. This QTL pattern indicates largely separate genetic and physiological systems for early and later murine growth, as Falconer suggested. We also found sex-specific QTLs for body size with implications for the evolution of sexual dimorphism.

Genetic architecture of adiposity in the cross of LG/J and SM/J inbred mice

Abstract. The genetic basis of variation in obesity in human populations is thought to be owing to many genes of relatively small effect and their interactions. The LG/J by SM/J intercross of mouse inbred strains provides an excellent model system in which to investigate multigenic obesity. We previously mapped a large number of quantitative trait loci (QTLs) affecting adult body weight in this cross. We map body composition traits, adiposity, and skeletal size, in a replicate F2 intercross of the same two strains containing 510 individuals. Using interval-mapping methods, we located eight QTLs affecting adiposity (Adip1–8). Two of these adiposity loci also affected tail length (Adip4 and Adip6) along with seven additional tail length QTLs (Skl1–7). A further four QTLs (Wt1–4) affect adult weight but not body composition. These QTLs have relatively small effects, typically about 0.2–0.4 standard deviation units, and account for between 3% and 10% of the variance in individual characters. All QTLs participated in epistatic interactions with other QTLs. Most of these interactions were due to additive-by-additive epistasis, which can nullify the apparent effects of single loci in our population. Adip8 interacts with all the other adiposity QTLs and seems to play a central role in the genetic system affecting obesity in this cross. Only two adiposity QTLs, Adip4 and Adip6, also affect tail length, indicating largely separate genetic control of variation in adiposity and skeletal size. Body size and obesity QTLs in the same locations as those discovered here are commonly found in mapping experiments with other mouse strains.

EPISTASIS AND THE EVOLUTION OF ADDITIVE GENETIC VARIANCE IN POPULATIONS THAT PASS THROUGH A BOTTLENECK

Traditional models of genetic drift predict a linear decrease in additive genetic variance for populations passing through a bottleneck. This perceived lack of heritable variance limits the scope of founder‐effect models of speciation. We produced 55 replicate bottleneck populations maintained at two male‐female pairs through four generations of inbreeding (average F = 0.39). These populations were formed from an F2 intercross of the LG/J and SM/J inbred mouse strains. Two contemporaneous control strains maintained with more than 60 mating pairs per generation were formed from this same source population. The average level of within‐strain additive genetic variance for adult body weight was compared between the control and experimental lines. Additive genetic variance for adult body weight within experimental bottleneck strains was significantly higher than expected under an additive genetic model This enhancement of additive genetic variance under inbreeding is likely to be due to epistasis, which retards or reverses the loss of additive genetic variance under inbreeding for adult body weight in this population. Therefore, founder‐effect speciation processes may not be constrained by a loss of heritable variance due to population bottlenecks.

Genetic variation in body weight gain and composition in the intercross of Large (LG/J) and Small (SM/J) inbred strains of mice

Os experimentos de intercruzamento de cepas constituem um valioso meio de mapear genes que afetam caracteres quantitativos complexos. Nos estudamos a variabilidade genetica do intercruzamento das cepas procriadas por endogamia de camundongos Large (LG/J) e Small (SM/J), como um guia para estudos de mapeamento genico. Dez machos SM/J foram cruzados com 10 femeas LG/J, apos o que os animais foram acasalados aleatoriamente para produzir as geracoes intercruzadas F1, F2 e F3. Os 1632 animais da geracao F3 das 200 familias de irmaos completos foram usados para calcular a herdabilidade e as correlacoes geneticas dos caracteres medidos. Um subgrupo de familias foi submetido a adocao cruzada apos o nascimento, para permitir a avaliacao da importância dos efeitos maternos pos-natais. Foram coletados dados semanais de peso corporal da 1a a 10a semanas, assim como dados de necropsia do peso corporal, peso de orgaos, peso do coxim gorduroso reprodutor e comprimento de cauda nas geracoes intercruzadas. Nao houve heterose para pesos especificos para idade ou caracteres de necropsia, exceto pelo fato de que o peso da 1a semana foi o maior na geracao F2, indicando heterose dos efeitos maternos nas maes da geracao F1. Encontramos herdabilidade moderada/alta para a maioria dos pesos especificos para a idade e dos caracteres de necropsia. Os efeitos maternos foram significantes para os pesos especificos para a idade da 1a a 4a semana, mas desapareceram completamente para o peso de 10 semanas. Os efeitos maternos para os caracteres de necropsia foram pequenos e nao estatisticamente significantes. Os pesos especificos para a idade mostraram um padrao de correlacao tipico, com declinio da correlacao a medida que a diferenca em idades aumentava. Entre os caracteres de necropsia, os pesos corporal e do coxim gorduroso reprodutor mostraram alta correlacao genetica. A maioria das outras correlacoes geneticas foram pequenas ou moderadas. O intercruzamento entre cepas procriadas por endogamia de camundongos SM/J e LG/J constituem fonte valiosa para o mapeamento de loci de caracteres quantitativos para o tamanho corporal e sua composicao e morfologia.

Contribution of maternal effect QTL to genetic architecture of early growth in mice

Existing approaches to characterizing quantitative trait loci (QTL) utilize a paradigm explicitly focused on the direct effects of genes, where phenotypic variation among individuals is mapped onto genetic variation of those individuals. For many characters, however, the genotype of the mother via its maternal effect accounts for a considerable portion of the genetically based variation in progeny phenotypes. Thus the focus on direct effect QTL may result in an insufficient or misleading characterization of genetic architecture due to the omission of the potentially important source of genetic variance contributed by maternal effects. We analyze the relative contribution of direct and maternal effect (ME) QTL to early growth in mice using a three-generation intercross of the Small (SM/J) and Large (LG/J) inbred mouse lineages. Using interval mapping and composite interval mapping, direct effect (DE) QTL for early growth (change in body mass during the interval from week 1 to 2) were detected in the F2 generation of the intercross (n = 510), where no maternal genetic effect variance is present (all individuals are progeny of genetically identical F1 mothers). ME QTL were detected by treating the phenotypes of cross-fostered F3 pups as a characteristic of their nurse-dam (n = 168 dams with cross-fostered progeny). Five DE QTL, significant at a chromosome wide level (α = 0.05), were detected, with two significant at a genome wide level. FourME QTL significant at the chromosome wide level were detected, with three significant at the genome wide level. A model containing only DE QTL accounted for 11.8% of phenotypic variance, while a model containing only ME QTL accounted for 31.5% of the among litter variance in growth. There was no evidence for pleiotropy of DE and ME loci since there was no overlap between loci detected in these two analyses. Epistasis between all pairs of loci was analyzed for both DEs and MEs. Ten pairs of loci showed significant epistasis for MEs (α = 0.05 corrected for multiple comparisons) while four pairs showed significant epistasis for DEs on early growth.

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 × 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.

Epistasis affecting litter size in mice

Litter size is an important reproductive trait as it makes a major contribution to fitness. Generally, traits closely related to fitness show low heritability perhaps because of the corrosive effects of directional natural selection on the additive genetic variance. Nonetheless, low heritability does not imply, necessarily, a complete absence of genetic variation because genetic interactions (epistasis and dominance) contribute to variation in traits displaying strong heterosis in crosses, such as litter size. In our study, we investigated the genetic architecture of litter size in 166 females from an F2 intercross of the SM/J and LG/J inbred mouse strains. Litter size had a low heritability (h2 = 12%) and a low repeatability (r = 33%). Using interval‐mapping methods, we located two quantitative trait loci (QTL) affecting litter size at locations D7Mit21 + 0 cM and D12Mit6 + 8 cM, on chromosomes 7 and 12 respectively. These QTL accounted for 12.6% of the variance in litter size. In a two‐way genome‐wide epistasis scan we found eight QTL interacting epistatically involving chromosomes 2, 4, 5, 11, 14, 15 and 18. Taken together, the QTL and their interactions explain nearly 49% (39.5% adjusted multiple r2) of the phenotypic variation for litter size in this cross, an increase of 36% over the direct effects of the QTL. This indicates the importance of epistasis as a component of the genetic architecture of litter size and fitness in our intercross population.

The effect of a population bottleneck on the evolution of genetic variance/covariance structure.

It is well known that standard population genetic theory predicts decreased additive genetic variance (Va) following a population bottleneck and that theoretical models including interallelic and intergenic interactions indicate such loss may be avoided. However, few empirical data from multicellular model systems are available, especially regarding variance/covariance (V/CV) relationships. Here, we compare the V/CV structure of seventeen traits related to body size and composition between control (60 mating pairs/generation) and bottlenecked (2 mating pairs/generation; average F = 0.39) strains of mice. Although results for individual traits vary considerably, multivariate analysis indicates that Va in the bottlenecked populations is greater than expected. Traits with patterns and amounts of epistasis predictive of enhanced Va also show the largest deviations from additive expectations. Finally, the correlation structure of weekly weights is not significantly different between control and experimental lines but correlations between necropsy traits do differ, especially those involving the heart, kidney and tail length.