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Burly1 is a mouse QTL for lean body mass that maps to a 0.8-Mb region of chromosome 2

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Abstract

To fine map a mouse QTL for lean body mass (Burly1), we used information from intercross, backcross, consomic, and congenic mice derived from the C57BL/6ByJ (host) and 129P3/J (donor) strains. The results from these mapping populations were concordant and showed that Burly1 is located between 151.9 and 152.7 Mb (rs33197365 to rs3700604) on mouse chromosome 2. The congenic region harboring Burly1 contains 26 protein-coding genes, 11 noncoding RNA elements (e.g., lncRNA), and 4 pseudogenes, with 1949 predicted functional variants. Of the protein-coding genes, 7 have missense variants, including genes that may contribute to lean body weight, such as Angpt41, Slc52c3, and Rem1. Lean body mass was increased by the B6-derived variant relative to the 129-derived allele. Burly1 influenced lean body weight at all ages but not food intake or locomotor activity. However, congenic mice with the B6 allele produced more heat per kilogram of lean body weight than did controls, pointing to a genotype effect on lean mass metabolism. These results show the value of integrating information from several mapping populations to refine the map location of body composition QTLs and to identify a short list of candidate genes.

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Acknowledgements

We gratefully acknowledge the assistance with animal breeding of Rebecca James, Liang-Dar (Daniel) Hwang, Zakiyyah Smith, Matt Kirkey, Amy Colihan, and Laurie Pippett. We also acknowledge Richard Copeland and the consistent high-quality assistance of the animal care staff at the Monell Chemical Senses Center, and thank them for their service. Michael G. Tordoff and Gary K. Beauchamp commented on a draft of the manuscript. We thank two anonymous reviewers for their time spent providing constructive comments on this manuscript.

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  1. Monell Chemical Senses Center, 3500 Market St, Philadelphia, PA, 19104, USA

    Cailu Lin, Brad D. Fesi, Michael Marquis, Natalia P. Bosak, Anna Lysenko, Mohammed Amin Koshnevisan, Fujiko F. Duke, Maria L. Theodorides, Theodore M. Nelson, Amanda H. McDaniel, Mauricio Avigdor, Charles J. Arayata, Lauren Shaw, Alexander A. Bachmanov & Danielle R. Reed

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  1. Cailu Lin
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335_2018_9746_MOESM1_ESM.tif

Supplementary Fig. S1 Correlations among three measures, body weight and lean body mass by DEXA and MR, in male mice of each mapping population. (a) Comparison of MR and DEXA results. (b) Comparison of body weight and lean body mass by MR (red data points) or DEXA (green data points). Despite the small sample size of two populations (B6-Chr2129 and C57BL/6ByJ), the three measures are highly correlated (r-values=0.62–0.95, p<0.00001). “B6.129-Burly1” refers to all congenic mice from Table 1. (TIF 105 KB)

Supplementary Table S1 (DOC 29 KB)

335_2018_9746_MOESM3_ESM.tif

Supplementary Fig. S2: Monthly lean body mass in male mice from two populations: mice with B6 background (a; n=319) and mice with 129 background (b; n=13). Monthly lean body mass increased significantly (*p<0.05) from 90 to 180 days for both strains. There is no significant difference (p=0.84) in lean body mass between 150 and 180 days for the 129 strain. (TIF 60 KB)

Supplementary Table S2 (XLSX 11 KB)

335_2018_9746_MOESM5_ESM.tif

Supplementary Fig. S3: The Burly1 locus region was isolated by comparing the 18 informative congenic strains. (a) Average lean body weight compared using a general linear model with body weight as a covariate, among all congenic mice grouped by genotype at each marker. The x-axis shows marker positions in Mb on chromosome 2 (mChr2); y-axis, –log10-transformed p-values. (b) We determined which congenic strains retained the Burly1 locus (i.e., were ’positive’) by comparing within each strain (shown at left) the average lean body weights of littermates with and without the donor fragment. Black bar indicates the donor region retained the Burly1 locus; gray bar, donor region did not retain the locus; blue bar, region contributed by the host strain. For the three strains labeled with the red $, there was no reliable genotype effect on lean body mass. Burly1-positive strains share a common region (red lines; 0.8 Mb from rs33197365 at 151.9 Mb to rs3700604 at 152.7 Mb) that Burly1-negative strains do not share. (c) Comparison of allele effect across strains. The allele effect direction matches that from the consomic mice, with the B6 allele increasing the trait. (TIF 351 KB)

Supplementary Table S3 (XLSX 12 KB)

335_2018_9746_MOESM7_ESM.tif

Supplementary Fig. S4: The Burly1 is a lean-body-mass-specific locus that has no effect on body fat mass in all congenic strains. (a) Average body fat weight compared using a general linear model with body weight as a covariate, among all congenic mice within each congenic strain grouped by genotype at each marker. The x-axis shows marker positions in Mb on chromosome 2 (mChr2); y-axis, –log10-transformed p-values. The blue bar shows the confidence interval of the fat locus, defined by a drop of 2 units of –log p-value. (b) The 0.8 Mb Burly1 region defined in the congenic strains, which is out of the fat locus region (blue bar in a). (c) A significant genotype effect on body fat mass was found only in strains C1 and C2 (red asterisks in b) that retain the two largest 129-derived donor fragments, and no genotype effect was found for the other 16 strains. Thus, the location of the fat locus differs from the Burly1 region. *p<0.05; post hoc tests. (TIF 336 KB)

Supplementary Table S4 (XLSX 11 KB)

335_2018_9746_MOESM9_ESM.tiff

Supplementary Fig. S5: Statistical comparison of Pearson correlation coefficients for body weight and each organ weight in congenic mice grouped by the Burly1 genotype (H=129/B6: N=169; A=B6/B6: N=198). (TIFF 1020 KB)

Supplementary Table S5 (XLSX 16 KB)

335_2018_9746_MOESM11_ESM.tif

Supplementary Fig. S6: No Burly1 genotype response to oral glucose tolerance tests in mice and their littermate controls from congenic strain C2.5. Data are mean ± SEM of genotype, and the significance of the genotype effect was evaluated by post hoc tests using p=0.05 as a significance level. (TIF 51 KB)

Supplementary Table S6 (XLSX 10 KB)

335_2018_9746_MOESM13_ESM.tif

Supplementary Fig. S7: Statistical category of variants within the Burly1 region based on their predicted variant effect. (TIF 115 KB)

Supplementary Table S7 (XLSX 24 KB)

Supplementary Table S8 (XLSX 11 KB)

Supplementary Table S9 (XLSX 54 KB)

Supplementary Table S10 (XLSX 17 KB)

Supplementary Table S11 (DOCX 15 KB)

Supplementary Table S12 (XLSX 11 KB)

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Lin, C., Fesi, B.D., Marquis, M. et al. Burly1 is a mouse QTL for lean body mass that maps to a 0.8-Mb region of chromosome 2. Mamm Genome 29, 325–343 (2018). https://doi.org/10.1007/s00335-018-9746-7

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