Experiment
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.
The authors identified several significant ME loci affecting body weight. The focal population was composed of the F2 and F3 generations from an intercross between the Large (LG/J) and Small (SM/J) inbred mouse strains. To generate the intercross population, 10 SM/J males were mated to 10 LG/J females, producing 52 F1 individuals. These animals were randomly mated to produce 510 F2 animals, a subset of which represents the parents in the study. These F2 animals were randomly mated to produce 1632 F3 individuals in 200 full-sibling families, although offspring from only 195 of these families (N = 1552) were phenotyped and genotyped. Half litters were reciprocally crossfostered at random between pairs of females that gave birth on the same day. In this study the focus was limited to those mice that were crossfostered: 611 F3 individuals from 168 families.
Animals were weighed weekly from 1 to 10 weeks of age. To understand the influence of maternal effects on preweaning growth, the authors included growth traits calculated as the difference in weight from week 1 to 3 (preweaning growth), as well as the separate phases of growth from week 1 to 2 and week 2 to 3.
A variance partitioning analysis using comparisons of cross-fostered and nonfostered pups (Kramer et al. 1998) in the F3 generation of the intercross showed that postnatal maternal effects are a major determinant of body weight for the first 4 weeks of life (accounting for 2130% of the variance in preweaning weights). Nurse effects peak at week 2, where they account for ~35% of the variance, and rapidly decline to <5% by week 6. In contrast, the dam variance starts high (~32% at week 1), slowly increases to a peak of ~45% at week 6, and then declines slightly to asymptote at just over 40% of the variance.
All F2 and F3 individuals were genotyped at 353 autosomal loci, using the Illumina Golden-Gate assay, with an average map distance between markers in the F2 generation of 4 cM. The genotype data from parents and offspring were used to reconstruct chromosomal haplotypes. Haplotype reconstruction was done using the integer linear programming (ILP) algorithm in the program PedPhase. Haplotype reconstruction yielded a set of unordered haplotypes for the F2 animals and a set of ordered haplotypes (i.e., ordered by parent-of-origin of alleles, such that the reciprocal heterozygotes can be distinguished) for the F3 animals. The use of ordered genotypes allows for the inclusion of genomic imprinting effects in the analysis of genetic architecture. All coordinates relative to NCBI 37 (mm9). For each trait, a mixed model was fitted at each marker location using maximum likelihood as implemented in the Mixed Procedure in SAS (SAS version 9.1; SAS Institute).
Genetic linkage analysis identified 19 loci significantly correlated with maternal effect growth rate phenotypes:
Egrme4 (early growth rate, maternal effect 4) maps to Chr 16: 25.4 - 44.4 Mb with a peak LOD score at 31.9 Mb. Egrme4 exerts a positive dominant effect on early growth rate.
Egrme5 (early growth rate, maternal effect 5) maps to Chr 2: 82.2 - 118.0 Mb with a peak LOD score at 112.1 Mb. Egrme5 exerts a positive additive effect on early growth rate.
Mgrme1 (mid growth rate, maternal effect 1) maps to Chr 6: 140.5 - 147.3 Mb with a peak LOD score at 147.3 Mb. Mgrme1 exerts a positive additive effect on mid growth rate.
Lgrme1 (late growth rate, maternal effect 1) maps to Chr 1: 3.2 - 37.8 Mb with a peak LOD score at 11.0 Mb. Lgrme1 exerts a positive additive effect on late growth rate.
Lgrme2 (late growth rate, maternal effect 2) maps to Chr 6: 140.5 - 147.3 Mb with a peak LOD score at 147.3 Mb. Lgrme2 exerts positive additive and imprinting effects on late growth rate.
Lgrme3 (late growth rate, maternal effect 3) maps to Chr 11: 84.8 - 96.6 Mb with a peak LOD score at 90.6 Mb. Lgrme3 exerts a positive additive effect on late growth rate.
Wogrme1 (week one growth rate, maternal effect 1) maps to Chr 7: 117.6 - 134.5 Mb with a peak LOD score at 122.7 Mb. Wogrme1 exerts a positive dominant effect on week one growth rate.
Wfogrme1 (week four growth rate, maternal effect 1) maps to Chr 6: 140.5 - 147.3 Mb with a peak LOD score at 147.3 Mb. Wfogrme1 exerts a positive additive effect on week four growth rate.
Wfigrme1 (week five growth rate, maternal effect 1) maps to Chr 6: 140.5 - 147.3 Mb with a peak LOD score at 147.3 Mb. Wfigrme1 exerts a positive additive effect on week five growth rate.
Wsigrme1 (week six growth rate, maternal effect 1) maps to Chr 1: 3.2 - 37.8 Mb with a peak LOD score at 11.0 Mb. Wsigrme1 exerts a positive additive effect on late growth rate.
Wsigrme2 (week six growth rate, maternal effect 2) maps to Chr 6: 140.5 - 147.3 Mb with a peak LOD score at 147.3 Mb. Wsigrme2 exerts a positive additive effect on week six growth rate.
Wsigrme3 (week six growth rate, maternal effect 3) maps to Chr 11: 84.8 - 96.6 Mb with a peak LOD score at 90.6 Mb. Wsigrme3 exerts a positive additive effect on week six growth rate.
Wsegrme1 (week seven growth rate, maternal effect 1) maps to Chr 1: 3.2 - 37.8 Mb with a peak LOD score at 11.0 Mb. Wsegrme1 exerts a positive additive effect on late growth rate.
Wsegrme2 (week seven growth rate, maternal effect 2) maps to Chr 6: 140.5 - 147.3 Mb with a peak LOD score at 147.3 Mb. Wsegrme2 exerts positive additive and imprinting effects on week seven growth rate.
Wegrme1 (week eight growth rate, maternal effect 1) maps to Chr 1: 3.2 - 37.8 Mb with a peak LOD score at 11.0 Mb. Wegrme1 exerts a positive additive effect on late growth rate.
Wegrme2 (week eight growth rate, maternal effect 2) maps to Chr 6: 140.5 - 147.3 Mb with a peak LOD score at 147.3 Mb. Wegrme2 exerts positive additive and imprinting effects on week eight growth rate.
Wngrme1 (week nine growth rate, maternal effect 1) maps to Chr 1: 3.2 - 37.8 Mb with a peak LOD score at 11.0 Mb. Wngrme1 exerts a positive additive effect on late growth rate.
Wngrme2 (week nine growth rate, maternal effect 2) maps to Chr 6: 140.5 - 147.3 Mb with a peak LOD score at 147.3 Mb. Wngrme2 exerts a positive additive effect on week nine growth rate.
Wtgrme1 (week ten growth rate, maternal effect 1) maps to Chr 1: 3.2 - 37.8 Mb with a peak LOD score at 11.0 Mb. Wtgrme1 exerts a positive additive effect on late growth rate.
Several additional suggestive and chromosomally significant QTL are described in Tables 1, 2, and 3 of the manuscript.
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