Date Published: May 1, 2013
Publisher: American Physiological Society
Author(s): Ian C. Dunn, Simone L. Meddle, Peter W. Wilson, Chloe A. Wardle, Andy S. Law, Valerie R. Bishop, Camilla Hindar, Graeme W. Robertson, Dave W. Burt, Stephanie J. H. Ellison, David M. Morrice, Paul M. Hocking.
Animal domestication has resulted in changes in growth and size. It has been suggested that this may have involved selection for differences in appetite. Divergent growth between chickens selected for egg laying or meat production is one such example. The neurons expressing AGRP and POMC in the basal hypothalamus are important components of appetite regulation, as are the satiety feedback pathways that carry information from the intestine, including CCK and its receptor CCKAR (CCK1 receptor). Using 16 generations of a cross between a fast and a relatively slow growing strain of chicken has identified a region on chromosome 4 downstream of the CCKAR gene, which is responsible for up to a 19% difference in body weight at 12 wk of age. Animals possessing the high-growth haplotype at the locus have lower expression of mRNA and immunoreactive CCKAR in the brain, intestine, and exocrine organs, which is correlated with increased levels of orexigenic AGRP in the hypothalamus. Animals with the high-growth haplotype are resistant to the anorectic effect of exogenously administered CCK, suggesting that their satiety set point has been altered. Comparison with traditional breeds shows that the high-growth haplotype has been present in the founders of modern meat-type strains and may have been selected early in domestication. This is the first dissection of the physiological consequences of a genetic locus for a quantitative trait that alters appetite and gives us an insight into the domestication of animals. This will allow elucidation of how differences in appetite occur in birds and also mammals.
Dense genotyping of chromosome 4 identified SNPs with strong association with body weight and growth in the F8 AIL generation (Fig. 1). The SNPs with the most significant P values were close to the CCKAR, also known as the CCK1 receptor, in the IUPHAR nomenclature or CCKAR in the Chicken Gene Nomenclature Consortium nomenclature (http://www.agnc.msstate.edu/). The highest scoring marker, ch4snp-131-132-4046-S-2, is at position 77,192,329, which is 1.56 Mbp downstream of the CCKAR locus (Table 2 and Fig. 2).
We have for the first time demonstrated that a change in a component of a satiety signaling system underlies the largest QTL for growth in chickens (32, 65), the first QTL for growth in which the underlying gene function has been understood in chickens. In mammals, the role of IGF-II in pig growth (72) and the double muscling caused by myostatin in breeds of cattle (26) are the only examples where function has been elucidated. The CCK system has been investigated as a cause of increased appetite of rapid growing strains of chicken (60) with limited success but, it has now been proven that expression of the seven-transmembrane domain CCKAR G protein receptor is responsible for part of the difference in growth between strains. This QTL has been observed repeatedly (34, 47, 64, 71), and the coincidence of the CCKAR gene at the locus has been noted (54), and a gene 5 Mbp upstream, TBC1D1, was proposed as a candidate from a selective sweep study (57). However, the physiological basis of the locus has never been elucidated. The most significant marker in both the F8 and F16 AIL generations was ch4snp-131-132-4046-S-2, 1.56 Mbp downstream of the CCKAR locus. In an earlier study, the QTL explained 3.6% of the total variance (65) in the F2, and in this study the best marker explained just under 5% of the variance in the F8 and F16. This is somewhat less than the 15–30% explained by the IGF-II locus in pigs but is in line with many QTLs (72). Comparison of the F8 and F16 populations did not further define the location. There are genes in the vicinity of this SNP, notably KCNIP4, SLIT2, and LCORL, that have been associated with human stature, but none are obvious candidates for altering growth and food intake. Of the genes in the loci that we did measure, we saw no difference in expression with genotype. In a whole genome study of egg weight, a trait correlated with body weight, the most significant SNP in 1-Mbp windows was at position 78,775,527, with a SNP of lesser effect at 78,724,797 (75). This may be the same locus underlying the difference in expression of CCKAR, and it confirms that the likely locus is at least 1.5 Mbp and perhaps 3 Mbp downstream of the CCKAR gene itself.
All authors were supported by the Biotechnology and Biological Sciences Research Council and the Roslin Institute through Institute Strategic Grant funding. C. A. Wardle and C. Hindar were supported by a Wellcome Trust vacation studentship to I. C. Dunn and S. L. Meddle, respectively. S. J. L. Ellison was supported by a vacation studentship from Pfizer to S. L. Meddle.
No conflicts of interest, financial or otherwise, are declared by the authors.
I.C.D. and P.M.H. contributed to the conception and design of the research; I.C.D., P.M.H., P.W., C.A.W., V.B., C.H., G.W.R., D.W.B., S.J.E., and D.M.M. performed the experiments; I.C.D., P.M.H., S.M., P.W., C.A.W., A.L., V.B., C.H., G.W.R., D.W.B., S.J.E., and D.M.M. analyzed the data; I.C.D., P.M.H., S.M., P.W., C.A.W., A.L., S.J.E., and D.M.M. interpreted the results of the experiments; I.C.D., S.M., and V.B. prepared the figures; I.C.D. drafted the manuscript; I.C.D., P.M.H., S.M., P.W., C.A.W., V.B., and D.W.B. edited and revised the manuscript; I.C.D., P.M.H., S.M., P.W., C.A.W., A.L., V.B., C.H., G.W.R., D.W.B., S.J.E., and D.M.M. approved the final version of the manuscript.