Direct and maternal genetic effects on body weight maturing patterns in mice

Summary Direct and maternal genetic effects were evaluated for maturing patterns of body weight in mice using a crossfostering design. Crossfostering was performed in one group using dams from populations selected for rapid growth rate (M16 and H₆) and their reciprocal F₁. crosses. A second crossfostering group consisted of dams from the respective control populations (ICR and C₂) and their reciprocal F₁. 's. Population differences were partitioned into direct and maternal effects due to genetic origin, correlated selection responses, heterosis and cytoplasmic or sex-linked effects. Degree of maturity was calculated at birth, 12, 21, 31 and 42 days of age by dividing body weight at each age by 63-day weight. Absolute and relative maturing rates were calculated in adjacent age intervals between birth and 63 days. Genetic origin effects (ICR vs. C₂; M16 vs. H₆) were significant for many maturity traits, with average direct being more important than average maternal genetic effects. In general, correlated responses to selection for maturity traits were larger in the M16 population (M16 vs. ICR) than in the H₆ population (H₆ vs. C₂) and correlated responses in average direct effects were larger than average maternal effects. Positive correlated responses in average direct effects were found for relative maturing rates at all ages and for absolute maturing rates from 31 to 63 days. Apparent correlated responses in degree of maturity were negative for M16 and H₆. However, further analysis suggested that the correlated response for degree of maturity in H₆ may be positive at later ages and negative at earlier ages. Direct and maternal heterosis for degree of maturity was positive in the selected and control crosses. Absolute and relative maturing rates showed positive heterosis initially, followed by negative heterosis. Reciprocal differences due to the cytoplasm or sex-linkage were not important for patterns of maturity.Paper No. 5244 the Journal Series of the North Carolina Agricultural Experiment Station, Ealeigh, Animal Research Institute Contribution No. 683 and Agricultural University at Wageningen Contribution No. 654–490–12On leave from the Animal Research Institute, Agriculture Canada at Ottawa, OntarioOn leave from the Department of Animal Husbandry, Agricultural University at Wagenitgen, the Netherlands     

Environmental maternal influences on body composition in mice selected for body weight

Summary The effect of the postnatal maternal environment, simulated by rearing mice in litters of three, six or nine, on body weight and body composition was investigated in three lines of mice differing widely in growth rate. The lines were selected for high (H₆) and low (L₆) 6-week body weight while the control line was maintained by random selection. Body weight and weights and percentages of ether extract, water, ash and protein at 21, 42, 63 and 84 days were recorded. With few exceptions, there were positive correlated responses to selection in body weight and in weights of body components. At 21 and 42 days the correlated responses were larger in L₆ mice than in H₆ mice. Body weight and weights of body components were larger for mice reared in litters of three than for those reared in litters of nine. Also, mice reared in litters of six were intermediate in body weight and weights of some of the body components between those reared in litters of three and nine. Differences in body weight and weights of body components due to postnatal maternal environment were small by comparison with differences due to genetic line. There were significant line by maternal environment interactions in body weight at 21 days and in ether extract weight at 21 and 63 days. Line and maternal environment differences in percentages of body components did not follow any consistent trend. The results for percentages of body components were further complicated by line x maternal environment interactions. In general, both line and postnatal maternal environmental differences in percentages of body components diminished with age.Paper No. 5670 of the Journal Series of the North Carolina Agricultural Experiment Station, Raleigh, North Carolina 27650. The use of trade names in this publication does not imply endorsement by the North Carolina Agricultural Experiment Station of the products named, nor criticism of similar ones not mentioned     

Sexual dimorphism and direct and maternal genetic effects on body weight in mice

Summary Genetic and phenotypic parameters for three-, six- and eight-week body weight and for weight gain between three and six weeks of age were estimated from data collected over 14 generations in a randombred control population. Genetic parameters were also estimated for sexual dimorphism in body weight and gain. Heritability estimates were substantial for body weight at all ages and for body weight gain. Additive maternal variances were also large. Estimates of the covariance between direct and maternal genetic effects were negative and substantial for three- and six-week weights and gain. Also the covariance between maternal effects on weaning weight and direct genetic effects on six- and eight-week weights were negative. These results indicate a consistent antagonism between maternal and direct genetic effects in this population.The analysis of sexual dimorphism yielded estimates of 0.87±.09 and 0.71±.14 for the correlation between additive direct effects on males and females for six-week weight and body weight gain respectively. Corresponding heritability estimates were 0.07±.09 and 0.11±.09. Heritability estimates for sexual dimorphism in three- and eight-week weights were negative.Journal Paper No. 3687 of the North Carolina State University Agricultural Experiment Station. This investigation was supported in part by NIH Grant No. GM11546.     

Growth and body composition of mice selected for high body weight

To elucidate the influence of high body weight selection on body compositional relationships, the accumulation of lipid, protein, and ash was investigated in two lines of mice selected for high 42-day body weight (H lines) and an unselected foundation population (FP). The two H lines differed in population size and were designated as the high-large (HL) and high-small (HS) lines. Logistic body growth curves revealed that HL mice exhibited an accelerated growth rate and reached a higher mature body weight than FP or HS mice. Over the range of body weights examined, HL mice had more lipid, less protein, and less ash than FP or HS mice of the same sex and body weight. However, HL lipid accumulation (relative to body weight increase) was not accelerated in comparison to that of FP mice. This study suggests that the existing model of selection-mediated compositional changes requires expansion to account for the ability of high-growth selection to direct an acceleration of body growth without a correlated enhancement of the relative rate of fat accumulation.     

QTLs for pre- and postweaning body weight and body composition in selected mice

In an intercross between the high-body-weight-selected mouse line NMRI8 and the inbred line DBA/2, we analyzed genetic effects on growth during the suckling period and after weaning during the juvenile phase of development. QTL mapping results indicated that a switch of gene activation might occur at the age of three weeks when animals are weaned. We found QTLs for body weight with major effects at the age of two and three weeks when animals are fed by their mothers, and QTLs with highest effects after weaning when animals have to live on their own under ad libitum access to food. Specific epistatic effects on body weight at two and three weeks and epistatic interaction influencing growth after weaning support this finding. QTL effects explained the greatest variance during puberty when animals grow fastest and become fertile. In the present study, all except one QTL effect for early body weight had dominance variance components. These might result from direct single-locus-dominant allelic expression, but also from the identified epistatic interaction between different QTLs that we have found for body weight at all ages. Beside body weight, body composition traits (muscle weight, reproductive fat weight, weight of inner organs) were analyzed. Sex-dimorphic QTLs were found for body weight and fat deposition. The identified early-growth QTLs could be the target of epigenetic modifications which might influence body weight at later ages.     

Uterine and postnatal maternal effects in mice selected for differential rate of early development.

A series of mouse lines was produced by long-term restricted index selection for divergent rate of growth during early and late postnatal development. The selection program was based on the following treatments: E(+) and E(-) lines were selected to alter birth to 10-day weight gain while holding late gain for both lines constant and a control line was established via random selection. Using embryo transfer and crossfostering methodology, we partitioned postnatal growth for E(+), E(-), and C lines into progeny genetic, uterine maternal, and nurse maternal components. Selection for differential early growth resulted in correlated response in uterine and nurse maternal effects on body weights, with significant genetic-by-environment interactions. Significant uterine effects were also observed in tail length measurements. Direct uterine effects on body weight were relatively small and resulted in growth rate differences early in development. Nurse effects were large, resulting in modification of progeny growth trajectory especially during early postnatal development. Genetic-by-uterine interactions were large and demonstrate progeny-specific effects of the prenatal uterine environment.     

Disentangling prenatal and postnatal maternal genetic effects reveals persistent prenatal effects on offspring growth in mice

Mothers are often the most important determinant of traits expressed by their offspring. These "maternal effects" (MEs) are especially crucial in early development, but can also persist into adulthood. They have been shown to play a role in a diversity of evolutionary and ecological processes, especially when genetically based. Although the importance of MEs is becoming widely appreciated, we know little about their underlying genetic basis. We address the dearth of genetic data by providing a simple approach, using combined genotype information from parents and offspring, to identify "maternal genetic effects" (MGEs) contributing to natural variation in complex traits. Combined with experimental cross-fostering, our approach also allows for the separation of pre- and postnatal MGEs, providing rare insights into prenatal effects. Applying this approach to an experimental mouse population, we identified 13 ME loci affecting body weight, most of which (12/13) exhibited prenatal effects, and nearly half (6/13) exhibiting postnatal effects. MGEs contributed more to variation in body weight than the direct effects of the offsprings' own genotypes until mice reached adulthood, but continued to represent a major component of variation through adulthood. Prenatal effects always contributed more variation than postnatal effects, especially for those effects that persisted into adulthood. These results suggest that MGEs may be an important component of genetic architecture that is generally overlooked in studies focused on direct mapping from genotype to phenotype. Our approach can be used in both experimental and natural populations, providing a widely practicable means of expanding our understanding of MGEs.     

Changes in the body composition of mice selected for high and low eight week weight

Summary Body composition was studied in three lines of mice, one selected for high (H) and one for low (L) 8 week weight, and one maintained as an unselected control (C). After 25 generations 8 week weights were 41.2g, 30.6 g and 20.5g for the H, C and L lines. Mice were sampled from the lines and analysed for fat, protein, ash and water at generations 14 and 25. Apart from fat in the H line, there was little alteration due to selection in the relationships between individual body components and total body weight. In the H line, the contribution of fat to body weight gain was considerably increased. Although leaner than the C and L mice at low body weights, H line mice rapidly became fatter with increasing body weight. Selection appeared to reduce the body weight at which fat was deposited at its maximum rate in the H line. The H and C lines were equally fat at body weights of 29.0 g and 21.6 g at generations 14 and 25 respectively. Body weights at points of inflection of the growth curves of the H, C and L lines at generation 25 were 18.3 g, 14.3 g and 12.8 g. The implications of these findings for meat species slaughtered at set weights are discussed.     

Rate,composition and efficiency of growth in mice selected for large and small body weight

Summary Mice selected for high (H₆) and low (L₆) 6-week body weight and a randombred control population (C₁) were characterized for rate, composition and efficiency of growth. Individual body weights were obtained from birth to 8 weeks of age on 682 mice representative of the three lines. Individual whole carcass determinations of water, fat, ash and protein (residual) were obtained for 180 mice sampled weekly from 3–8 weeks of age. Efficiency of feed utilization was estimated from individual body weight and feed consumption data obtained on 189 mice from 3–8 weeks of age. Growth curves for body weight and gain in body weight, constructed by line and sex, showed a temporary retardation of maximum growth rate in the L₆ line, which was attributed in part to an extended depression in growth following weaning. The composition of growth yielded no evidence that the more rapid growth rate in the H₆ line resulted from an increase in fat deposition relative to the other carcass components. A decrease in fat percent at 7 weeks of age in the H₆ and C₁ lines was not evident in the L₆ line until 8 weeks of age. Females had a higher percentage carcass fat than did males during the 4–7 weeks growth period, but this difference was essentially reduced to zero by 8 weeks of age. Percentage water was highly correlated negatively with percentage fat. Percentages protein and ash were essentially constant across lines and ages. A positive relation between rate and efficiency of growth was observed between lines. Consistent sex differences, males more efficient than females, were observed prior to 6 weeks of age, but were not evident in the later (6–8 week) data.

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Zusammenfassung Bei Mäusen, die auf hohes (H₆) und geringes (L₆) 6 Wochen-Körpergewicht selektiert waren, und einer unselektierten Kontrollpopulation (C₁) wurde die Zuwachsrate, die Veränderung des Wasser-, Fett-, Protein- und Aschegehaltes während des Wachstums sowie die Wuchsleistung untersucht. Das Körpergewicht von der Geburt bis zum Alter von 6 Wochen wurde an 682 einzelnen Mäusen, die repräsentativ für die drei Linien sind, festgestellt. Die Ermittlung des Wasser-, Fett-, Asche- und (Rest-)Proteingehaltes der Tiere erfolgte wöchentlich für 180 Mäuse im Alter von 3–8 Wochen. Die Futterverwertung (Wuchsleistung) wurde für 189 drei bis acht Wochen alte Mäuse auf Grund von Einzelgewichten und Futterverbrauch geschätzt.Die Wachstumskurven für Körpergewicht und Gewichtszunahme, nach Linien und Geschlecht zusammengestellt, zeigten bei der L₆-Linie eine zeitweilige Verzögerung der maximalen Zuwachsrate, was z. T. einer längeren Wachstumsdepression nach der Entwöhnung zugeschrieben wird. Es ergab sich kein Beweis dafür, daß die schnellere Wachstumsrate bei der H₆-Linie auf eine Erhöhung der Fetteinlagerung im Verhältnis zu den anderen Komponenten zurückzuführen ist. Ein Rückgang des Fettgehalts, der bei den H₆- und C₁-Linien im Alter von 7 Wochen festzustellen war, wurde bei der Linie L₆ erst nach 8 Wochen sichtbar. Weibliche Tiere hatten im Alter von 4–7 Wochen einen höheren Körperfettgehalt als männliche, im Alter von 8 Wochen war dieser Unterschied aber nicht mehr vorhanden. Der Wassergehalt war in hohem Maße negativ mit dem Fettgehalt korreliert. Die Protein- und Ascheanteile waren im wesentlichen für die Linien und untersuchten Wuchsperioden konstant. Zwischen den Linien wurde eine positive Relation hinsichtlich Wuchsrate und Wuchsleistung festgestellt. Deutliche Geschlechtsunterschiede wurden bis zum Alter von 6 Wochen beobachtet, und zwar wuchsen die Männchen schneller als die Weibchen, später (6.–8. Woche) waren keine Unterschiede mehr feststellbar.

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Paper number 2640 of the Journal Series of the North Carolina State University Agricultural Experiment Station, Raleigh, North Carolina. Supported by Public Health Service Grant GM 11546-05. Computation was supported by NIH Grant No. FR-00011. The senior author was supported by NIH Training Grant No. 2-Tl-GM-296.     

Growth and body composition changes in mice selected for high post-weaning weight gain on two levels of feeding

Summary Two lines of mice were selected for high post-weaning weight gain (3 to 6 weeks) adjusted for 3 week weight. One line (F) was grown on freely available food and the other (S) on a feeding scale set at the same level for all mice. Food intake of the S line averaged 80% of the F line. The realised heritabilities after 6 generations of selection were 0.38±0.06 and 0.33±0.07 for the F and S lines, respectively. In generation 7, mice from the F and S lines and from an unselected control line (C) were compared on both free and set levels of feeding from 3 weeks to 9 weeks of age. Measurements taken were growth rate, appetite, food conversion efficiency (weight gain/food intake) and body composition (fat, protein, ash, water). The F and S lines grew more rapidly and efficiently than the C line on both levels of feeding, each line performing best on the level of feeding on which it was selected. The average genetic correlation between growth rates of the same line on the two feeding levels was 0.54±0.10. The F line grew 19% faster and was 9% more efficient than the S line on free feeding but the S line grew 15% faster and was 15% more efficient than the F line on set feeding. Relative to the C line, food intake per day on free feeding was 4% higher in the F line and 6% lower in the S line. There was no difference between the lines in food intake/g body weight. The rate of deposition of all body components increased in both selection lines. In the F, S and C lines respectively, efficiencies of gains in body components (10²x gain/food) were 1.79, 1.31 and 1.06 for fat, 1.53, 1.63 and 1.22 for protein and 5.88, 6.45 and 4.98 for protein + water. Apparently energy lost as heat was reduced in both the F and S lines. The partitioning of energy retained was altered in favour of more fat in the F line and more protein in the S line.     

Decreased postnatal survival and altered body weight regulation in procolipase-deficient mice.

In vitro, pancreatic triglyceride lipase requires colipase to restore activity in the presence of inhibitors, like bile acids. Presumably, colipase performs the same function in vivo, but little data supports that notion. Other studies suggest that colipase or its proform, procolipase, may have additional functions in appetite regulation or in fat digestion during the newborn period when pancreatic triglyceride lipase is not expressed. To identify the physiological role of procolipase, we created a mouse model of procolipase deficiency. The Clps-/- mice appeared normal at birth, but unexpectedly 60% died within the first 2 weeks of life. The survivors had fat malabsorption as newborns and as adults, but only when fed a high fat diet. On a low fat diet, the Clps-/- mice did not have steatorrhea. The Clps-/- pups had impaired weight gain and weighed 30% less than Clps+/+ or Clps+/- littermates. After weaning, the Clps-/- mice had normal rate of weight gain, but they maintained a reduced body weight compared with normal littermates even on a low fat diet. Despite the reduced body weight, the Clps-/- mice had a normal body temperature. To maintain their weight gain in the presence of steatorrhea, the Clps-/- mice had hyperphagia on a high fat diet. Clps-/- mice had normal intake on a low fat diet. We conclude that, in addition to its critical role in fat digestion, procolipase has essential functions in postnatal development and in regulating body weight set point.     

The genetic relationship between the Hbb locus and body size in a population of mice divergently selected for six-week body weight.

Both pleiotropy and linkage were examined as possible explanations for the fixation of the Hbb3 allele in the six Large lines of a population of mice divergently selected for six-week body weight (six replicates in each direction and six controls). A survey of over 1200 individuals in the lines still segregating at the Hbb locus excluded pleiotropy as a possible explanation. The results showed a nonsignificant effect of haemoglobin genotype on body weight. The linkage relationship of the Hbb locus was examined using a backcross mating system. The Hbb3 c+ region (chromosome 7) of a Large line was backcrossed into its corresponding Small line (Hbb4 c). The resultant difference in body weight between the two segregants (Hbb8 c+ [Hbb4 c; Hbb4 c/Hbb4 c) was measured. The results suggested linkage as the most plausible explanation for the fixation of the Hbb4 allele in the six Large lines.     

Heterosis among lines of mice selected for body weight

Summary After treatment of one strain of A. bitorquis and 12 strains of A. bisporus in modified monokaryotization solution, three types of mycelia were received: one is the original di- or heterokaryon, the other two were proven to be neohaplonts in A. bitorquis and two strains of A. bisporus. In neohaplonts of good fruiting strains, homokaryotic fruiting was observed.     

Heterosis among lines of mice selected for body weight

Summary To examine the effect of selection on levels of heterosis, crosses were made between three groups of six lines of mice, one group unselected (controls) and the other two selected for high (large lines) and low (small lines) 6-week body weight, respectively. The coefficient of inbreeding of each line was about 0.60. Each line was crossed reciprocally to one line from each of the parental groups, as well as producing purebred progeny. Heterosis for 3-week weight, 6-week weight and 3–6 week gain averaged 0.0%, 2.4% and 4.2%, respectively, and was higher for males than for females. Heterosis was more extensive in crosses involving large or control lines than in crosses with small lines. There was no detectable heterosis in several measures of developmental rate, such as age at vaginal opening. Food conversion efficiency and carcass composition were measured on a sample of the animals. Food consumption, gonadal fat pad weight, and hindquarters weight, each expressed as a proportion of body weight, exhibited –4.0%, 5.6%, and 2.3% heterosis, respectively.     

Role of growth hormone in the genetic change of mice divergently selected for body weight and fatness

To elucidate the involvement of growth hormone (GH) in the genetic change produced by long-term selection in growth and fatness, a 'GH knock-out study' on over 900 mice was undertaken. Lines used had been selected for more than 50 generations for high (PH) and low (PL) body weight (initially protein mass) at 70 d(ays) and for high (F) and low fat content (L) at 98 d, producing a 3-fold difference in body weight and a 5-fold difference in fat content. GH deficiency was achieved by repeated backcrossing into each line a recessive mutant gene (lit) which has a defective GH releasing factor receptor. In the absence of GH, the P lines still differ in body weight (21 d to 98 d): e.g. at 98 d homozygous lit/lit: PH = 24.2 g, PL = 10.0 g; wild-type (wt): PH = 57.4 g, PL = 18.7 g. The effect of the GH deficiency on body weight (untransformed) was very much larger in the PH than in the PL line, but the interaction was much smaller, although still significant, on the log scale. This indicates that changes in the GH system contribute only a small part of the selection response in growth. GH deficiency increased fat percentage in all lines (including P), especially in males (99 d, males lit/lit: F = 26.4%, L = 6.9%; wt: F = 22.0%, L = 4.8%; females: 20.2%, 5.2%, 20.7%, 3.0%) with significant genotype x line and genotype x sex interactions. The interactions between the effects of the lit gene and the genetic background were, however, relatively small compared with these main effects and again indicate that other systems contributed most of the selection response.     

The influence of phenotypic and genetic effects on maternal provisioning and offspring weight gain in mice

Close interactions between mother and offspring are said to result in a coevolution of parental and offspring genotypes such that offspring are adapted in their solicitation behaviour to obtain maternal provisioning that maximizes their fitness. Few empirical studies have been conducted in this field and it remains unclear whether maternal provisioning and offspring weight gain are influenced by the same set of maternal and offspring phenotypic and genotypic factors. Using a cross-foster, split-litter design in mice, we found that overall maternal provisioning and offspring weight gain are significantly correlated but are affected by a different set of parameters, except for the effect of maternal bodyweight. While the level of maternal provisioning was influenced by both offspring and foster mother genotype, offspring weight gain was only affected by the number of males in the mixed litter. We suggest that this disparity may hint at the inefficiency of offspring solicitation behaviour or effects of sibling competition.