Mapping Data

Experiment

• Experiment
  TEXT-QTL
• Chromosome
  3
• Reference
  J:313290 Starcher AE, et al., A systems approach using Diversity Outbred mice distinguishes the cardiovascular effects and genetics of circulating GDF11 from those of its homolog, myostatin. G3 (Bethesda). 2021 Sep 2;
• ID
  MGI:7286092

Genes

Gene	Assay Type
Gdfsc1	visible phenotype
Smc1	visible phenotype

Notes

• Reference
  The Diversity Outbred heterogeneous stock (J:DO) is a developing mouse population derived from progenitor lines of the Collaborative Cross (CC). The CC is a panel of recombinant inbred (RI) mouse strains that combines the genomes of eight genetically diverse founder strains - A/J, C57BL/6J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ - to capture nearly 90% of the known variation present in laboratory mice (Churchill et al. 2004). Animals from 160 incipient CC lines at early stages of inbreeding were used to establish the DO population, which is maintained by a randomized outbreeding strategy that avoids brother-sister matings. The DO and CC populations thus capture the same set of natural allelic variants derived from a common set of eight founder strains, with DO mice being outbred and the CC population being inbred.
  
  CTC (2004), Churchill, G. A., et al. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nat Genet. 36, 1133-7.
• Experiment
  The heart adapts to excessive loading stresses by eccentric or concentric hypertrophy. Growth differentiation factor 11 (GDF11) is a member of the TGF-b protein family that has been implicated in the development of cardiac hypertrophy. While some studies have suggested that systemic GDF11 protects against cardiomyocyte enlargement and left ventricular wall thickening, there remains uncertainty about the true impact of GDF11 and whether its purported effects are actually attributable to its homolog myostatin. This study was conducted to resolve the statistical and genetic relationships among GDF11, myostatin, and cardiac hypertrophy in a mouse model of human genetics, the Diversity Outbred (DO) stock.
  
  DO mice (n = 225) were purchased from The Jackson Laboratory (J:DO, JAX stock #009376). Genotyping was performed via the Giga Mouse Universal Genotyping Array (GigaMuga) (Morgan et al. 2015), on the Illumina Infinium platform. Genotypes and phenotypic data were imported into the R/qtl2 software for genetic mapping (Broman et al. 2019). Genotype probabilities were calculated based on the single nucleotide polymorphism (SNP) genotypes using a hidden Markov Model (Broman and Sen 2009). Mapping analysis was performed to determine the associations between genotype and phenotype and accounted for kinship using the "leave one chromosome out" method (Yang et al. 2014; Broman et al. 2019). Sex was included as a covariate in the genome scans. Statistical significance thresholds were established through permutation tests (Churchill and Doerge 1994).
  
  In the DO population, serum GDF11 concentrations positively correlated with cardiomyocyte cross-sectional area, while circulating myostatin levels were negatively correlated with body weight, heart weight, and left ventricular wall thickness and mass.
  
  Genetic analyses revealed that serum GDF11 concentrations are modestly heritable (0.23), and genetic mapping identified one suggestive peak for serum GDF11 concentrations (genome coordinates relative to GRCm38/mm10):
  
  Gdfsc1 (GDF11 serum concentration 1) maps to Chr 3: 3.039589 - 9.983782 Mb in close proximity to the gene Hey1, a transcriptional repressor. Bioinformatic analyses located putative binding sites for the HEY1 protein upstream of the Gdf11 gene in the mouse and human genomes.
  
  In contrast, serum myostatin concentrations were more heritable (0.57) than GDF11 concentrations, and genetic mapping of serum myostatin levels discovered a single significant locus:
  
  Smc1 (serum myostatin concentration 1) maps to Chr 3: 52.26269 - 52.71985 Mb. The peak is located in close proximity to protein-coding gene Forkhead Box O1 (FoxO1; MGI:1890077). C57BL/6J contributes the high allele at Smc1 (inferred from Figure 4).
  
  No significant peaks were found for phenotypes related to heart size or histology in normal adulthood.