Progress 10/01/08 to 09/30/13
Outputs
Target Audience: The target audience of this research are individual dairy producers and private companies providing or using genotyping services, such as Merial Ltd, Pfizer (Zoetis), Neogene, Alta Genetics, Select Sires, and the scientific community in the fields of animal genomics and lactation biology. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? This research has provided training to graduate students, post-doctoral students and international visiting graduate students. How have the results been disseminated to communities of interest? Results have been disseminated through publication in scientific journals and by oral presentations at national and international meetings. What do you plan to do during the next reporting period to accomplish the goals? We plan to utilize the RNA sequencing in the continuation of our studies examining gene regulation in relation to the content of milk components affecting human health, nutrition and processing properties of milk. The overall purpose of this research is to develop efficient approaches to select cows with improved lactation and milk compostion.
Impacts
What was accomplished under these goals?
1) The outcomes of this project provide the dairy industry the knowledge to select animals to produce milk with the desired or improved milk composition for traits like, milk protein variants to improve cheese yield, fat composition and oligosaccharide content. 2) Our result demonstrate how RNA-Sequencing methodology, metabolic pathway analysis and association studies can be combined as a powerful approach to study complex traits in cattle related to milk and lactation. 3) The development of appropriate non-invasive sampling methods of milk secretory cells have extended our work in cattle comparing the transcriptome of milk, to study the biology of lactation in other mammalian species, like primates.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2013
Citation:
C�novas, A., G. Rinc�n, A. Islas-Trejo, R. Jimenez-Flores, A. Laubscher and J. F. Medrano 2013. RNA-Sequencing to study gene expression and SNP variation associated with citrate content in cow's milk. Journal of Dairy Science 96:2637-2648.
- Type:
Journal Articles
Status:
Published
Year Published:
2013
Citation:
DeAtley, K.L., M.L. Colgrave, M.G. Thomas, M.R.S. Fortes, J.F. Medrano, G. Rincon, A. Islas-Trejo, R.L. Ashley, G.A. Silver, A. Reverter, A. Canovas, and W.M. Snelling 2013. Analysis of six neuropeptides detected in hypothalamus and pituitary gland of pre- and post- pubertal Brangus heifers. Proceedings, Western Section, American Society of Animal Science Vol. 64.
- Type:
Journal Articles
Status:
Published
Year Published:
2013
Citation:
Chitwood, J., G. Rincon, G.G. Kaiser, J.F. Medrano and P.J. Ross 2013. SNP analysis and genomic annotation of individual bovine embryos using RNA-Sequencing. BMC Genomics 14:350.
- Type:
Journal Articles
Status:
Published
Year Published:
2013
Citation:
Ulloa, P., A. Pena, C. lizama, C. Araneda, P. Iturra, R, Neira, J.F. Medrano 2013. Growth response and expression of muscle growth-related candidate genes in adult zebrafish (Danio rerio) fed plant and fishmeal protein-based diets. Zebrafish 10:99-109.
- Type:
Journal Articles
Status:
Published
Year Published:
2013
Citation:
Lemay, D.G., R.C. Hovey, S.R. Hartono, K. Hinde, J.T. Smilowitz, F. Ventimiglia, K.A. Schmidt, J.W. Lee, A. Islas-Trejo, P.I. Silva, I. Korf, J.F. Medrano, P.A. Barry, J.B. German 2013. Sequencing the transcriptome of milk production: milk trumps mammary tissue. BMC Genomics. 14:872.
- Type:
Journal Articles
Status:
Published
Year Published:
2013
Citation:
Oberbauer, A.M., J.M. Belanger, G. Rincon, A. C�novas, A. Islas-Trejo, R. Gularte-M�rida, M.G. Thomas, J.F Medrano 2013. Bovine and murine tissue expression of insulin like growth factor-I. Gene. 2013 Dec 12. pii: S0378-1119(13)01615-6. doi: 10.1016/j.gene.2013.11.089.
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Progress 01/01/12 to 12/31/12
Outputs
OUTPUTS: Objective 1: Create shared genomic tools and reagents and sequence information to enhance the understanding and discovery of genetic mechanisms affecting traits of interest. We have utilized RNA sequencing of milk somatic cells, metabolic pathway analysis and association studies as a road map to identify genetic variation in functional target genes determining complex trait phenotypes. A productive application of this approach has been the study gene expression and SNP variation associated with citrate content in cow's milk in relation to the technological properties of milk. The technological properties of milk have significant importance for the dairy industry. Citrate, a normal constituent of milk, forms one of the main buffer systems that regulate the equilibrium between Ca2+ and H+ ions. Higher than normal citrate content is associated with poor-coagulation properties of milk. In order to identify the genes responsible for the variation of citrate content in milk in dairy cattle the metabolic steps involved in citrate and fatty acid synthesis pathways in ruminant mammary tissue using RNA-Sequencing were studied. Genetic markers that could influence milk citrate content in Holstein cows were used in a marker-trait association study to establish the relationship between 74 SNP in 20 candidate genes and citrate content in 250 Holstein cows. This analysis revealed six SNP in key metabolic pathway genes (IDH1, PDHB, PKM2 and SLC25A1) significantly associated with increased milk citrate content. The amount of the phenotypic variation explained by the six SNP ranged from 10.1% to 13.7%. Also, genotype-combination analysis revealed the highest phenotypic variation was explained combining IDH1_23211, PDHB_5562 and SLC25A1_4446 genotypes. This specific genotype combination explained 21.3% of the phenotypic variation (p=0.00007). The largest citrate associated effect was in the 3' UTR region of the SLC25A1 gene which is responsible for the transport of citrate across the mitochondrial inner membrane. PARTICIPANTS: Alma Islas, SRAIII, laboratory support, UCDavis; Gonzalo Rincon, Project Scientist, UCDavis; Angela Canovas, Post-Doc, UCDavis. TARGET AUDIENCES: Target audiences of this project are the scientific community, individual producers and private companies providing genotyping and breeding services, such as, Pfizer (Zoetis), Neogene, AI bull studs, Dairy producers. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Our result demonstrate how RNA-Sequencing methodology, metabolic pathway analysis and marker-trait association studies can be combined as a powerful approach to study complex traits in cattle, and to fine map genes responsible of complex traits phenotypes. Results from this study open the door to utilize a molecular marker approach to improve important manufacturing properties of milk.
Publications
- Warden, C.H., R. Gularte-Merida, J.S. Fisler, S. Hansen, N. Shibata, A. Le, J.F. Medrano and J.S. Stern 2012. Leptin receptor interacts with rat chromosome 1 to regulate renal disease traits. Physiological Genomics 2012 Sep 11. [Epub ahead of print]
- Wickramasinghe, S., G. Rincon, A. Islas-Trejo, J.F. Medrano 2012. Transcriptional profiling of bovine milk using RNA sequencing. BMC Genomics 13:45
- Barboza M, J Pinzon, S Wickramasinghe, JW Froehlich, I Moeller, JT Smilowitz, LR Ruhaak, J Huang, B Lonnerdal, JB German, JF Medrano, BC Weimer, CB Lebrilla 2012. Glycosylation of Human Milk Lactoferrin exhibits dynamic changes during early lactation enhancing its role in pathogenic bacteria-host interactions. Mol Cell Proteomics 11(6):M111.015248, Epub 2012 Jun 19.
- Casellas, J., R. J. Gularte, C.R. Farber, L. Varona, M. Mehrabian, E.E. Schadt, A. J. Lusis, A.D. Attie, B.S. Yandell and J.F. Medrano 2012. Genome Scans for Transmission Ratio Distortion Regions in Mice. Genetics 191(1):247-59.
- Luna-Nevarez, P., G. Rincon, J.F. Medrano, D.G. Riley, C. C. Chase Jr., S. W. Coleman, K. L. DeAtley, A. Islas-Trejo, G. A. Silver and M. G. Thomas 2012. Identificacion de un polimorfismo del gen PAPP-A2 asociado a la fertilidad en vaquillas de la Raza Romosinuano criadas bajo un ambiente subtropical. Revista Mexicana de Ciencias Pecuarias 3(2):185-200.
- Baeza, M.C., P.M. Corva, L.A. Soria, E. Pavan, G. Rincon and J. F. Medrano 2012. Genetic variants in a lipid regulatory pathway as potential tools for improving the nutritional quality of grass-fed beef. Animal Genetics 2012 Jun 13. doi: 10.1111/j.1365-2052.2012.02386.x. [Epub ahead of print]
- Fortes, M. R. S , W. M. Snelling, A. Reverter, Shivashankar H. Nagaraj, S. Lehnert, R. J. Hawken, K. L. DeAtley, S. O. Peters, G. A. Silver, G. Rincon, J. F. Medrano, A. Islas-Trejo, M. G. Thomas 2012. Gene network analyses of first service conception in Brangus heifers: use of genome and trait associations, hypothalamic-transcriptome information, and transcription factors. J Anim Sci. 90(9):2894-906.
- Clifford, A.J., K. Chen, L. McWade, G. Rincon, S-H. Kim, D.M. Holstege, J.E. Owens, B.Liu, H-G. Muller, J.F. Medrano, J.G. Fadel, A. J. Moshfegh, D. J. Baer, J. A. Novotny 2012. Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC, CRBP2, CETP, and SCARB1 are significant predictors of plasma homocysteine normalized to red blood cell folate concentrations in healthy adults. Journal of Nutrition 142(9):1764-71.
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Progress 01/01/11 to 12/31/11
Outputs
OUTPUTS: Objective 1: Create shared genomic tools and reagents and sequence information to enhance the understanding and discovery of genetic mechanisms affecting traits of interest. 1) Transcriptome analysis of somatic cells in milk in Holstein cows: Milk samples were collected from Holstein cows at 15, 90 and 250 days of lactation, and RNA was extracted from the pelleted milk cells. Gene expression analysis was conducted by Illumina RNA sequencing. Genes encoding caseins, whey proteins and enzymes in lactose synthesis pathway showed higher expression in early lactation. The majority of genes in the fat metabolism pathway had high expression in transition and peak lactation milk. Most of the genes encoding for endogenous proteases and enzymes in ubiquitin-proteasome pathway showed higher expression along the course of lactation. The results revealed that 69% of NCBI Btau 4.0 annotated genes are expressed in bovine milk somatic cells. Most of the genes were ubiquitously expressed in all three stages of lactation. However a fraction of the milk transcriptome has genes devoted to specific functions unique to the lactation stage. This is the first study to describe the comprehensive bovine milk transcriptome in Holstein cows. 2) Performance of Illumina and Affymetrix Bovine High Density Genotyping Platforms in Holsteins and Jerseys: The performance of the Illumina High-Density Bovine BeadChip Array (777,962 SNP) and the Affymetrix Axiom Genome-Wide BOS 1 Array (648,874 SNP) was evaluated using DNA samples derived from 10 Holstein and 6 Jersey cattle. Data were edited to remove SNP having a call rate less than 90%, and those in linkage disequilibrium (r2 ≥ 0.9). All samples were successfully genotyped (≥98% SNP genotyped) with both platforms. Based on genomic position, 107,896 SNP were shared between the two platforms. Both Affymetrix BOS 1 and Illumina BovineHD genotyping platforms are well designed and provide high quality genotypes and similar coverage of informative SNP. Despite fewer total SNP on BOS 1, 19% more SNP remained after LD pruning, resulting in a smaller gap size (5.2kb vs 6.9kb) relative to BovineHD. Genome-wide CNV analyses were performed using intensity files from both platforms. The BovineHD platform provided an advantage on the CNV data compared to the BOS 1 because of the larger number of SNP, higher intensity signals and lower background effects. PARTICIPANTS: Alma Islas, SRAIII, laboratory support, UCDavis Gonzalo Rincon, Project Scientist, UCDavis Saumya Wickramasinghe, PhD graduate student, UCDavis TARGET AUDIENCES: Target audiences of this project are the scientific community, individual producers and private companies providing genotyping and breeding services, such as, Pfizer, Merial Ltd., AI bull studs like Select sires. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Our results of RNA sequencing on milk somatic cells demonstrate that milk somatic cells are representative of the mammary gland transcriptome and can be used as an alternative tissue to study gene expression of milk-related traits. Milk somatic cells were shown to adapt to different molecular functions according to the biological need of the animal, providing a valuable insight into the biology of lactation in the cow, as well as useful avenues for future research on the bovine lactome. The analysis of the Affymetrix and Illumina high density genotyping platforms demonstrated that the combined use of both platforms significantly improved coverage over either platform alone and reduced the gap size between SNP, providing a valuable tool for fine mapping QTL and multibreed animal evaluation. .
Publications
- Wickramasinghe, S., G. Rincon and J. F. Medrano 2011. Variants in the pregnancy associated plasma protein-A2 gene on BTA16 are associated with daughter calving ease and productive life in Holstein cattle. Journal of Diary Science 94:1552-1558.
- Momozawa,Y., V. Deffontaine, E. Louis, J.F. Medrano 2011. Characterization of bacteria in biopsies of colon and stools by high throughput sequencing of the V2 region of bacterial 16s rRNA gene in human. PLoS One 6(2):e16952.
- DeAtley, K.L., G. Rincon, C.R. Farber, J.F. Medrano, P. Luna-Nevarez, R.M. Enns, D.M. VanLeeuwen, G. A. Silver, and M. G. Thomas. 2010. Genetic analyses involving microsatellite ETH10 genotypes on bovine chromosome 5 and performance trait measures in Angus and Brahman-influenced cattle. J. Anim. Sci. 89(7):2031-41.
- Wickramasinghe,S., S. Hua, G. Rincon, A. Islas-Trejo, J.B. German, C.B. Lebrilla, J.F. Medrano 2011. Transcriptome profiling of bovine milk oligosaccharide metabolism genes using RNA-Sequencing. PLoSOne 6(4):e18895
- Rincon, G., K. Tengvall, J.M. Belanger, L. Lagoutte, J.F. Medrano, C. Andre, A. Thomas, C. Taylor Lawley, M.S.T. Hansen, K. Lindblad-Toh, A.M. Oberbauer, 2011. Comparison of buccal and blood-derived canine DNA for array-based genome-wide association studies. BMC Research Notes 4(1):226.
- Wickramasinghe, S., and J.F. Medrano 2011. Primer On Genes Encoding Enzymes In Sialic Acid Metabolism In Mammals. Biochimie 93(10):1641-6.
- Rincon, G. A.D. Islas-Trejo, A.R. Castillo, D.E. Bauman, B.J. German, J.F. Medrano 2011. Polymorphisms in genes in the SCD/SREBP1 signaling pathway are associated with milk fatty acid composition in Holstein cattle. J. Dairy Research 25:1-10.
- Rincon, G., K. Weber, A.L. Van Eenennaam, B. Golden, J.F. Medrano 2011. Performance of bovine high density genotyping platforms in Holsteins and Jerseys. J. Dairy Science 94(12):6116-21.
- Helwig, M., S.-N. Leeb, J.R. Hwang, A. Ozawaa, J.F. Medrano and I. Lindberg 2011. Dynamic modulation of PC2-mediated precursor processing by 7B2. J Biol Chem. 286(49):42504-13.
- Baeza, M. C., P.M. Corva, L.A. Soria, G. Rincon, J.F. Medrano, E. Pavan, E. Villarreal, A. Schor, L. Melucci, C. Mezzadra, M.C. Miquel 2011. Genetic markers of body composition and carcass quality in grazing Brangus steers. Genetics and Molecular Research 10 (4): 3146-3156.
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Progress 01/01/10 to 12/31/10
Outputs
OUTPUTS: Objective 1: Create shared genomic tools and reagents and sequence information to enhance the understanding and discovery of genetic mechanisms affecting traits of interest. 1) Comparison of the milk somatic cells and mammary gland transcriptome: Next-generation RNA sequencing was used to examine expression patterns in bovine mammary gland tissue and in milk somatic cells. A total of 11,672 genes were expressed in both tissues, 4% of the genes were expressed only in mammary tissue and 11.5% were expressed only in the milk somatic cell transcriptome. The results show that milk somatic cells are representative of the mammary gland transcriptome and can be used as an alternative tissue to study gene expression of milk traits. 2) Transcriptome of transition and late lactation Holstein cows: RNA expression was also examined in cows at day 15 (transition) and day 250 (late) lactation. Genes encoding milk proteins had the most abundant transcripts in transition milk and genes involved in immune regulation and cell defense had the most abundant transcripts in late lactation. About 8,000 genes had ubiquitous expression in somatic cells and most of these genes were localized to intracellular organelles and intrinsic membranes. 4,359 genes had significant change in expression between the two stages and these genes were localized in extracellular matrix or vesicles. Our results revealed that 48-51% of annotated genes are expressed in the bovine milk transcriptome and provide a valuable insight into the bovine lactome. This is the first study to compare the bovine milk transcriptome at two stages of lactation using RNA-Seq. 3) SNP discovery in the bovine milk transcriptome: Seven milk somatic cell samples from Holstein cows at different stages of lactation were analyzed by RNAseq. SNP detection analysis revealed 100,734 SNP in Holstein samples and a large number of those corresponded to differences between the Holstein breed and the Hereford reference assembly. The number of polymorphic SNP within Holstein cows was 33,045. The accuracy of RNA-Seq SNP discovery was tested by comparing SNP detected in a set of 42 candidate genes expressed in milk that had been resequenced earlier using Sanger sequencing technology. Our results confirm that analyzing the transcriptome using RNA-Seq technology is an efficient and cost effective method to identify SNP in transcribed regions. The study provided guidelines to maximize the accuracy of SNP discovery and the prevention of false-positive SNP detection, and provided more than 33,000 SNP located in coding regions of genes expressed during lactation. PARTICIPANTS: Alma Islas, SRAIII, laboratory support, UCDavis Gonzalo Rincon, Project Scientist, UCDavis Saumya Wickramasinghe, PhD graduate student, UCDavis Angela Canovas, visiting PhD student from IRTA, Spain Joaquim Casellas, visiting scholar from IRTA, Spain Thomas Nakanishi, UCDavis senior undergraduate laboratory intern TARGET AUDIENCES: Target audiences of this project are individual producers and private companies providing genotyping and breeding services, such as, Pfizer, Merial Ltd., AI bull studs like Select sires. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Our results demonstrate that milk somatic cells are representative of the mammary gland transcriptome and can be used as an alternative tissue to study gene expression of milk-related traits. A system was developed to examine gene regulatory components affecting differences in milk composition between cows at different stages of lactation. We also demonstrated that RNAseq provides an efficient and cost effective method for SNP discovery, and to examine structural differences in regulatory regions. We plan to utilize the described sequencing approach on milk cells to determine gene regulatory targets and SNP variation in relation to the oligosaccharide metabolism of milk as a means of developing selection strategies to improve the content of bovine milk oligosaccharides as a source of prebiotics for infant formulas. We also plan to define structural variation between dairy breeds in genes expressed in milk somatic cells during lactation.
Publications
- Rijnkels,M., C. Freeman-Zadrowski, J. Hernandez, V. Potluri, A. Lin, G. Rincon, A.D. Islas, L. Wang, W. Li, J.F. Medrano 2010. Insight in development and functional differentiation of the mammary gland; a chromatin perspective. 9th World Congress of Genetics Applied to Livestock Production (WCGALP), Leipzig-Germany, No. 0976.
- Medrano, J.F. and G. Rincon 2010. Genes involucrados en la determinacion de la composicion y rendimiento de la leche. In: Genetica de Animales Domesticos, Editores G. Giovambattista and P. Peral-Garcia, Editorial Inter-Medica S.A., Argentina.
- Canovas, A, G. Rincon, A.D. Islas, S. Wickramasinghe, and J. F. Medrano 2010. SNP Discovery in the bovine milk transcriptome using RNA-Seq technology. Mammalian Genome 21:592-598.
- Luna-Nevarez, P., G. Rincon, J. F. Medrano, D. G. Riley, C. C. Chase, Jr., S. W. Coleman, D. M. VanLeeuwen, K. L. DeAtley, A. Islas-Trejo, G. A. Silver, and M. G. Thomas 2010. Single nucleotide polymorphisms in the growth hormone - insulin like growth factor axis in straightbred and crossbred Angus, Brahman, and Romosinuano heifers: population genetic analyses and association of genotypes with reproductive phenotypes. J. Anim. Sci. (Dec 23, 2010; Epub ahead of print)
- Medrano, J.F., A. Ahmadi and J. Casellas 2010. Dairy Cattle Breeding Simulation Program (DCBSP v.4.9), a simulation program to teach animal breeding principles and practices. Journal of Dairy Science 93:2816-2826. Casellas, J., C.R. Farber, R.A. Verdugo and J.F.Medrano 2010. Segregation analysis of a sex ratio distortion locus in congenic mice. J Heredity 101:351-359 (Epub Dec 2009)
- Verdugo, R.A., C.R. Farber, C.H. Warden and J.F. Medrano 2010. Serious limitations of the QTL/Microarray approach for QTL gene discovery. BMC Biology 8:96 (Epub Jul 2010)
- Medrano, J.F., G. Rincon and A.D. Islas 2010. Comparative analysis of bovine milk and mammary gland transcriptome using RNA-Seq. 9th World Congress of Genetics Applied to Livestock Production (WCGALP), Leipzig-Germany, No. 0852
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Progress 01/01/09 to 12/31/09
Outputs
OUTPUTS: Objective 1: Create shared genomic tools and reagents and sequence information to enhance the understanding and discovery of genetic mechanisms affecting traits of interest. 1-SNP discovery in candidate genes for economically important traits in cattle: The objective of this investigation is to discover SNP in candidate genes, to identify markers influencing economically important traits (efficiency of growth, carcass traits, milk yield and composition) in cattle. The strategy consists of selecting genes based on functional hypotheses and comparative maps of bovine QTL. SNP are identified by resequencing coding and regulatory regions of genes in a diverse DNA resource panel of unrelated beef and dairy animals and Tag SNP are chosen for genotyping. We have used this approach to identify SNP associated with milk fat composition, milk and protein in yield in BTA4 (JDS 2009), milk oligosaccharide content (sialyal and fucosyl transferases), BTA6 regulators of the casein gene cluster, growth traits in beef cattle (GHR promoter, JAS 2008), carcass traits in beef cattle (Stat6, Anim Genet 2009) and growth and milk traits (BTA5 GH/IGF1 pathway genes). These sets of markers were combined to develop a new genotyping platform that has been validated for association studies in large beef cattle populations in Argentina (Brangus) and Uruguay (Hereford). Among the above targets, a panel of 15 tag SNP in the STAT6 gene were genotyped in 1500 beef cattle samples. Three SNP were found to be significantly associated with: back fat, calculated yield grade, cutability, hot carcass weight, dry matter intake, days on feed, back fat rate and average daily gain. These results have been validated two other beef cattle populations (Brangus and Hereford), providing support to the value of these markers for marker-assisted selection and management in beef cattle. During 2009, 40 genes related to the GH/IGF signaling pathway were resequenced in 52 samples from Bos taurus (beef and dairy) and Bos indicus origin; of 878 newly discovered SNP, 250 tag SNP were selected for genotyping to perform marker-trait association studies. 2-RNASeq and microarray analysis to examine mammary transcriptome in relation to oligosaccharide composition of milk: The objective of this project is to annotate the bovine milk glycome and to study the expression of key glycosylation genes in Holstein, Jersey and Brown Swiss cows at different stages of lactation. Milk samples were collected from Holstein, Jersey and Brown Swiss cows in their first or second lactation at 1, 15, 90 and 250 days of lactation. RNASeq and microarray analysis were used to examine differential patterns of expression of glycosylation genes. An average of 17 million sequence reads per sample was aligned to the NCBI bovine genome assembly which includes 27,368 annotated genes. Our results will define the patterns of regulation of oligosaccharide content in bovine milk and will define the means to genetically enrich bovine milk with beneficial oligosaccharides. PARTICIPANTS: Alma Islas, SRAIII, laboratory support, UCDavis Gonzalo Rincon, post-doctoral trainee, UCDavis Saumya Wickramasinghe, graduate student, UCDavis Stewart Bauck (collaborator, sponsor and contact) Merial Ltd., has sponsored research a UCDavis. TARGET AUDIENCES: Target audiences of this project are individual producers and private companies providing genotyping and breeding services, such as Merial Ltd., AI bull studs like Alta Genetics and Select sires. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
SNP identification in candidate genes affecting specific metabolic pathways associated with milk composition phenotypes is an important step towards developing genetic markers to improve product quality. Our approach has targeted genes in specific metabolic pathway to identify genetic markers associated with economically important traits in cattle.
Publications
- Casellas, J., C.R. Farber, R.J. Gularte, K.A. Haus, C.H. Warden and J.F. Medrano 2009. Evidence of maternal QTL affecting growth and obesity in adult mice. Mammalian Genome 20:269-280.
- Farber C.R., A.J.Alten, E.A.Farber,V. De Vera, R. Gularte, A. Islas-Trejo, P. Wen, S. Horvath, M. Lucero, A.J. Lusis, J.F. Medrano 2009. Genetic dissection of a major mouse obesity QTL (Carfhg2): Integration of gene expression and causality modeling. Physiol Genomics 37(3):294-302.
- Lemay, D.G., D.J. Lynn, W.F. Martin, M.C. Neville, T. M. Casey, G. Rincon, E. V. Kriventseva, W. C. Barris, A. S. Hinrichs, A, J Molenaar, K. S. Pollard, N. J. Maqbool, E, M, Zdobnov, R. L. Tellman, J. F. Medrano, J. B. German, M. Rijnkels 2009. The bovine lactation genome: insights into the evolution of mammalian milk. Genome Biology 10:R43
- Lipkin E., K. Straus, R.T.Stein, A. Bagnato, F. Schiavini, L. Fontanesi, V. Russo, I. Medjugorac, M. Dolezal, J.F. Medrano, A. Friedmann and M. Soller 2009. Evaluation of different measures of linkage disequilibrium, and effect of sample size and population structure on linkage disequilibrium between microsatellite markers in dairy and dual purpose cattle. Genetics 181:691-699.
- Rincon, G., A. Islas-Trejo, J. Casellas, E. Lipkin, M. Soller and J. F. Medrano 2009. Fine Mapping and Association Analysis of a Quantitative Trait Locus for Milk Protein Percentage on BTA4. J. Dairy Sci. 92:758-64.
- Rincon, G., E. A. Farber, C. R. Farber, J. D. Nkrumah and J.F. Medrano 2009. Polymorphisms in the STAT6 gene and their association with carcass traits in feedlot cattle. Animal Genetics 40 ( 6): 878-882
- The Bovine Genome Sequencing and Analysis Consortium, C.G. Elsik, R.L. Tellman, K.C. Worley 2009. The genome sequence of Taurine cattle: A window to ruminant biology and evolution. Science 324:522-527.
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Progress 01/01/08 to 12/31/08
Outputs
OUTPUTS: Objective 1: Enhance and integrate genetic and physical maps of agriculturally important animals for cross species comparisons and sequence annotation. We have applied an approach to discover single nucleotide polymorphisms (SNPs) in candidate genes, to identify markers influencing economically important traits (efficiency of growth, carcass traits, milk yield and composition) in cattle. Our strategy consists of selecting genes based on functional hypotheses and literature information formulated from knowledge of metabolic pathways, from mouse QTL and QTG discoveries integrated with comparative maps of bovine QTL to identify SNP. Functional SNP are identified by resequencing coding and regulatory regions of genes in a diverse DNA resource panel of different beef and dairy breeds from unrelated animals. From the genotype of the sequenced animals, linkage disequilibrium blocks are defined for each gene to choose a minimal information subset of Tag SNP for genotyping. We have used this approach effectively to resequence genes and identify SNP associated with milk fat composition (SREBP1 pathway), milk and protein in yield in BTA4 (JDS 92:758-64, 2009), growth traits in beef cattle (GHR promoter, JAS 86:3315-3323, 2008), carcass traits beef cattle (Stat6) and growth and milk traits (BTA5 GH/IGF1 pathway genes). We have examined the association of the Stat6 gene in relation to carcass and feedlot traits in beef cattle. From earlier work we demonstrated that microsatellite ETH10 is located within the 5' UTR of the bovine STAT6 gene (Farber and Medrano 2003, Animal Genetics 34, 11-18). ETH10 has been strongly associated with marbling in Wagyu cattle (Barendse, Australia). Stat6 is the principal transcription factor involved in interlukin-4 (IL-4) and IL-13 signaling. STAT6 has also been shown to be activated by the full length form and not the truncated form of the leptin receptor in cell culture, implicating it as a potential mediator of the anti-obesity effects of leptin. We resequence 47 animals in 16kb of the full length STAT6 gene and discovered a total of 39 SNP. From the 39 SNP, a panel of 15 tag SNP were genotyped in 1500 beef cattle samples with phenotypes to perform the marker-trait association analysis for 14 different beef traits. We found 3 SNP that were highly significantly associated with: back fat, calculated yield grade, cuttability, hot carcass weight, dry matter intake, days on feed, back fat rate and average daily gain. These three SNP were present in all Bos taurus beef breeds. Our results provide evidence that polymorphisms in the STAT6 associated with feedlot and carcass traits are useful quantitative trait nucleotides for applications in marker-assisted selection and management in beef cattle. PARTICIPANTS: Alma Islas, SRAIII, laboratory support, UCDavis Gonzalo Rincon, post-doctoral trainee, UCDavis Dr. Milton Thomas (collaborator) University of New Mexico, Las Cruces, NM; spent a USDA sponsored sabbatical at UCDavis. Stewart Bauck (collaborator, sponsor and contact) Merial Ltd., has sponsored research a UCDavis. Dr. Bruce Golden (contact) Chair dept of Dairy Sci, Cal-Poly, San Luis Obispo TARGET AUDIENCES: Target audiences of this project are individual producers and private companies providing genotyping and breeding services, such as Merial Ltd., AI bull studs like Alta Genetics and Select sires. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
SNP identification in candidate genes affecting specific metabolic pathways associated milk composition phenotypes is an important step towards developing association studies to identify genetic markers to improve product quality. Our approach has targeted genes in specific metabolic pathway to identify genetic markers associated with economically important traits in cattle.
Publications
- Farber, C.R., J. Chitwood, S.N Lee, R. Verdugo, A. Islas-Trejo, G. Rincon, I. Lindberg and J.F. Medrano 2008. Overexpression of secretory granule neuroendocrine protein 1 (Sgne1) increases enzymatic activity of PCSK2 and is inversely correlated with body weight in congenic mice. BMC Genetics 9:34.
- Casellas, J. and J.F. Medrano 2008. Lack of Socs2 expression reduces lifespan in high-growth mice. AGE Journal 30:245-249. Casellas, J. and J.F. Medrano 2008. Within-generation mutation variance for litter size in inbred mice. Genetics 179:2147-2155.
- Garrett, A.J., G. Rincon, J.F. Medrano, M.A. Elzo, G.A. Silver and M.G. Thomas 2008. Promoter region of the bovine growth hormone receptor gene: single nucleotide polymorphism discovery in cattle and association with performance in Brangus bulls. Journal of Animal Science 86:3315-3323.
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Progress 01/01/07 to 12/31/07
Outputs
OUTPUTS: Develop high-resolution comparative genome maps aligned across species that link agricultural animal maps to those of the human and mouse genomes. We have utilized mouse congenic strains as a tool to fine map and isolate segregating QTL and to define the function of the underlying genes. We have characterized a unique mouse model (high growth, HG) that is due to a deletion of the Socs2 gene. HG mutation produces a 30-50% increase in post-weaning growth rate and feed conversion efficiency, and the phenotype is influenced by genetic interactions with genes in Chr. 2, 9, 11 and 17. QTL mapping for mouse chromosome 17 was performed in a population of 1,545 F2 mice from the HQ17hg/hg (80Mb CAST/EiJ congenic on a C57BL/6J background) x C57BL/6J intercross. A two-stage genotyping approach was used, genotyping first 11 microsatellites and then a sample of recombinant animals with a panel of 42 SNPs. Composite interval mapping was able to refine the position of the previously
reported Adip18 or Obq4 QTL to a 1.84 Mb (0.58 cM) interval harboring three known candidate genes, that were also differentially expressed between the congenic and background strains. One of the genes is involved in the reward signaling of the brain affecting food preference, suggesting that the higher fat deposition in this strain is a consequence of increased food intake stimulated by reward stimuli at feeding. Objective 2: Increase marker density of existing linkage maps used in QTL mapping and integrate them with physical maps of animal chromosomes. We have ongoing projects for SNP discovery in cattle candidate genes important for traits related to growth and milk fat composition. We have examined genes in cattle Chr 5 related to GH/Igf1 signaling pathway, genes related to the SREBP1 pathway that regulate the activity of fatty enzyme desaturases, and genes identified from our mouse fine mapping studies. Promoter, coding and non-coding regions of genes are being sequenced to
identify SNPs in a diverse DNA resource consisting of 8 individual from 6 breeds of cattle, followed by association studies in resource bull and cow populations with phenotypes.
PARTICIPANTS: Alma Islas, SRAIII, laboratory support, UCDavis Charles Farber, graduate student, Ph.D. genetics, UCDavis 2005 Ricardo Verdugo, graduate student, Ph.D. genetics, UCDavis 2007 Lisa Goldberg, graduate student, M.S. Biology, UCDavis 2007 Gonzalo Rincon, post-doctoral trainee, UCDavis Dr. Milton Thomas (collaborator) University of New Mexico, Las Cruces, NM; spent a USDA sponsored sabbatical at UCDavis. Stewart Bauck (collaborator, sponsor and contact) Merial Ltd., has sponsored research a UCDavis. Gary DeGraaf (contact) dairy producer in Visalia, CA. visited to learn and understand our work applying molecular markers to dairy cattle. Dr. Bruce Golden (contact) Chair dept of Dairy Sci, Cal-Poly, San Luis Obispo
TARGET AUDIENCES: Target audiences of this project are individual producers and private companies providing genotyping and breeding services, such as Merial Ltd., AI bull studs like Alta Genetics and Select sires, and dairy producers like Gary DeGraaf Provide information on target audiences for efforts designed to cause a change in knowledge, actions, or conditions.
PROJECT MODIFICATIONS: none
Impacts
The goal of livestock genomic projects is to identify genes underlying economically important traits. Currently, almost all of the genes affecting quantitative traits are anonymous; we know them only as quantitative trait loci (QTL). In situations where a mouse model can be identified for a given trait, the gene discovery phase for a potential QTL can be significantly facilitated and the power of the experimental model can be utilized to establish the functional role of the genes.
Publications
- Farber C. and Medrano J.F. (2007) Subcongenic partitioning of multiple growth and obesity quantitative trait loci (QTL) closely linked in repulsion on mouse chromosome 2. Mammalian Genome 18:635-645.
- Farber, C.R., J. Chitwood, S.N Lee, R. Verdugo, A. Islas-Trejo, G. Rincon, I. Lindberg and J.F. Medrano 2007. Overexpression of secretory granule neuroendocrine protein 1 (Sgne1) increases enzymatic activity of PCSK2 and is negatively correlated with body weight and obesity in congenic mouse models. BMC genetic (under review)
- Lisa Goldberg 2007. Fine Mapping Growth and Obesity Quantitative Trait Loci (QTL) using Subcongenic Strains of Mouse Chromosome 2, Masters-Animal Biology, UCDavis. 08/2007.
- Ricardo A. Verdugo 2007. Genetic Dissection of Growth and Obesity Traits in a Mouse Congenic Strains using Transcript Profiling and High Density Mapping, Ph.D.-Genetics, UCDavis. 12/2007.
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Progress 01/01/06 to 12/31/06
Outputs
Objective 1: Develop high-resolution comparative genome maps aligned across species that link agricultural animal maps to those of the human and mouse genomes. We are utilizing mouse models to fine map and identify QTL associated with growth and body composition. Our mouse models utilizing the high growth (hg) mutation in the mouse is particularly useful to identify modifier loci that interact with the growth hormone signaling pathway. QTL on mouse Chrs. 2, 9, 11 and 17 that interact with hg and harbor genes influencing growth rate, carcass protein, carcass ash, femur length and carcass fat are being analyzed with congenic and subcongenic strains. Utilizing congenic and subcongenic strains targeted to each chromosome we have captured and fine map QTL. In combination with expression profiling with microarrays and real-time quantitative PCR (qPCR) we have defined candidate genes that are being functionally studied. Comparative maps to bovine corresponding to the QTL
regions have been developed and utilized to define targets for SNP discovery and association studies. Objective 2: Increase marker density of existing linkage maps used in QTL mapping and integrate them with physical maps of animal chromosomes. We have ongoing projects for SNP discovery in cattle candidate genes important for traits related to meat and milk fat composition. Promoter, coding and non-coding regions of genes are being sequenced to identify SNPs in a diverse DNA resource consisting of 8 individual from 6 breeds of cattle. Genes identified from the mouse fine mapping project are directly included in this analysis.
Impacts
The goal of livestock genomic projects is to identify genes underlying economically important traits. Currently, almost all of the genes affecting quantitative traits are anonymous; we know them only as quantitative trait loci (QTL). In situations where a mouse model can be identified for a given trait, the gene discovery phase for a potential QTL can be significantly facilitated and the power of the experimental model can be utilized to establish the functional role for the gene/s, potentially for any mammalian species.
Publications
- Farber, C. R., P.M. Corva and J.F. Medrano 2006. Genome-wide isolation of growth and obesity QTL using mouse speed congenic strains. BMC Genomics 7(1):102
- Gularte, R.J. 2006. Fine Mapping distal mouse chromosome 2 for growth and obesity traits using overlapping subcongenic strains. M.S. thesis in Animal Biology, UC Davis.
- Rincon, G. , A.E. Young, D.L. Bannasch, J.F. Medrano 2007. Characterization of variation in the canine suppressor of cytokine signaling-2 (SOCS2) gene. Genetics and Molecular Research (In Press)
- Farber, C.R. and J.F. Medrano 2007. Fine mapping reveals sex bias in QTL affecting growth, skeletal size and obesity-related traits on mouse chromosomes 2 and 11. Genetics (In press
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Progress 01/01/05 to 12/31/05
Outputs
Objective 1: Develop high-resolution comparative genome maps aligned across species that link agricultural animal maps to those of the human and mouse genomes. We are utilizing mouse models to fine map and identify QTL associated with growth and body composition. Our mouse models utilizing the high growth (hg) mutation in the mouse is particularly useful to identify modifier loci that interact with the growth hormone signaling pathway. QTL on mouse Chrs. 2, 9, 11 and 17 that interact with hg and harbor genes influencing growth rate, carcass protein, carcass ash, femur length and carcass fat are being analyzed with congenic and subcongenic strains. Utilizing expression profiling with microarrays and real-time quantitative PCR (qPCR) in brain RNA from a mouse chromosome 2 congenic intercross we identified 5 expression QTgenes (eQTL). One of these genes is involved in proprotein processing in the pathway controlling food intake. This gene is localized in the middle
portion of bovine chromosome 13, that contains QTL for retail product yield, rib fat weight, rib muscle weight and yearling weight. Objective 2: Increase marker density of existing linkage maps used in QTL mapping and integrate them with physical maps of animal chromosomes. We have ongoing projects for SNP discovery in cattle candidate genes important for traits related to meat and milk fat composition. Promoter, coding and non-coding regions of genes are being sequenced to identify SNPs in a diverse DNA resource consisting of 6 individual from 8 breeds of cattle. Genes identified from the mouse fine mapping project will be directly included in this analysis.
Impacts
The goal of livestock genomic projects is to identify genes underlying economically important traits. Currently, almost all of the genes affecting quantitative traits are anonymous; we know them only as quantitative trait loci (QTL). In situations where a mouse model can be identified for a given trait, the gene discovery phase for a potential QTL can be significantly facilitated and the power of the experimental model can be utilized to establish the functional role for the gene/s, potentially for any mammalian species.
Publications
- Farber, C. R., P.M. Corva and J.F. Medrano 2005. Confirmation of genetic interactions between growth and obesity QTL on mouse chromosome 2 and high growth (hg) using congenic strains on two genetic backgrounds. BMC Genomics (submitted).
- Wu, R., C. Ma, W. Hou, P. Corva and J.F Medrano 2005. Functional Mapping of Quantitative Trait Loci That Interact With the hg Mutation to Regulate Growth Trajectories in Mice. Genetics 17:239-249.
- Verdugo, R. A. and J.F. Medrano 2005. Comparison of Gene Coverage of Mouse Oligonucleotide Microarray Platforms. BMC Genomics (submitted)
- Farber, C. R., P.M. Corva and J.F. Medrano 2005. Characterization of QTL from six genomic regions affecting growth and obesity in high growth (hg) mice using modified speed congenic strains. BMC Genomics (submitted).
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Progress 01/01/04 to 12/31/04
Outputs
Objective 1: Develop high-resolution comparative genome maps aligned across species that link agricultural animal maps to those of the human and mouse genomes. The hg deletion is a partially recessive mutation that results in a 30-50% increase in mature body size in mice which is due to absence of the suppressor of cytokine signaling-2 (Socs-2) gene, a negative regulator of cytokine signaling. We have identified quantitative trait loci (QTL) which modify the effect of the high growth (hg). QTL on Chrs. 2, 9, 11 and 17 were found to interact with hg and influence growth rate from 2-9 weeks, carcass protein, carcass ash, femur length and carcass fat. To fine map and identify the genetic basis of each QTL we have developed congenic and subcongenic strains of each QTL region. These strains are being analyzed using expression profiling and bioinformatics strategies aimed to detect epistasis between modifier QTL and hg. Objective 2: Increase marker density of existing
linkage maps used in QTL mapping and integrate them with physical maps of animal chromosomes. An in silico approach was developed to identify homologies existing between mapped horse microsatellite flanking sequences and GenBank nucleotide sequences. A total of 129 horse microsatellite flanking sequences had significant matches to human genomic sequence, genes or expressed sequence tags. These microsatellites were mapped in human, providing useful links between the equine and human comparative maps.
Impacts
The goal of livestock genomic projects is to identify genes underlying economically important traits. Currently, almost all of the genes affecting quantitative traits are anonymous; we know them only as quantitative trait loci (QTL). In situations where a mouse model can be identified for a given trait, the gene discovery phase for a potential QTL can be significantly facilitated and the power of the experimental model can be utilized to establish the functional role for the gene/s, potentially for any mammalian species. We expect that our integrative approaches to identify QTL will not only lead to the identification of the genes modifying the effect of hg, but also serve as a model to accelerate the discovery rate of modifier loci in other species.
Publications
- Warden, C.H., S. Stone, S. Chiu, A.L. Diament, D. Shattuck, R.Riley, P.Corva, J.Easlick, J.S. Fisler and J.F. Medrano 2004. Identification of a congenic mouse line with obesity and body length phenotypes. Mammalian Genome 15:460-71.
- Corva, P.M., N.C. Mucci, K. Evans and J.F. Medrano 2004. Diet effects on reproduction in high growth (hg/hg) female mice that are deficient in the Socs-2 gene. Reproduction, Nutrition, Development 44:303-312.
- The Complex Trait Consortium 2004. The Collaborative Cross, a community resource for the genetic analysis of complex traits. Nature Genetics 36:1133 - 1137.
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Progress 01/01/03 to 12/31/03
Outputs
Objective 1: Develop high-resolution comparative genome maps aligned across species that link agricultural animal maps to those of the human and mouse genomes. The hg deletion is a partially recessive mutation that results in a 30-50% increase in mature body size in mice and is due to absence of the suppressor of cytokine signaling-2 (Socs-2) gene, a negative regulator of cytokine signaling. We have identified quantitative trait loci (QTL) which modify the effect of the high growth (hg). QTL on Chrs. 2, 9, 11 and 17 were found to interact with hg and influence growth rate from 2-9 weeks, carcass protein, carcass ash, femur length and carcass fat. To fine map and identify the genetic basis of each QTL we have developed an integrative approaches, combing genetic and bioinformatics strategies. The bioinformatics approach is aimed at exploiting the knowledge of epistasis between the modifier QTL and hg and the comparative genome maps of human and mouse. We have
constructed GH signaling pathway maps, enabling rapid identification of candidate genes which map to QTL regions and possibly interact with Socs-2. Our current pathways contain 146 genes and serve as the foundation for candidate gene identification. Objective 2: Increase marker density of existing linkage maps used in QTL mapping and integrate them with physical maps of animal chromosomes. An in silico approach was developed to identify homologies existing between mapped livestock and horse microsatellite flanking sequences and GenBank nucleotide sequences. A total of 67 bovine, 44 porcine, 21 chicken and 129 horse microsatellite flanking sequences had significant matches to human genomic sequence, genes or expressed sequence tags. These microsatellites were mapped in human providing useful links between the comparative maps of humans and livestock.
Impacts
The understanding of the genetic process controlling animal growth in a model organism will allow the isolation and study of homologous genes in domestic animals that could be used to select faster growing and more efficient animals. The in silico mapping approach increased the number of genes and EST sequences anchored to livestock and horse genome maps, as well as the human comparative maps.
Publications
- Farber, C.R. and J.F. Medrano, 2003. Identifying the genetic basis of high growth (hg) modifier quantitative trait loci (QTL): Integration of genetic and bioinformatics-supported approaches. Complex trait Consortium, Oxford, UK July 1-3, 2003.
- Farber, C.R. and J.F. Medrano 2004. Identification of putative homology between horse microsatellite flanking sequences and cross-species ESTs, mRNAs and genomic sequences. Animal Genetics (In press)
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Progress 01/01/02 to 12/31/02
Outputs
Objective 1: Develop high-resolution comparative genome maps aligned across species that link agricultural animal maps to those of the human and mouse genomes. The High Growth (HG) mouse mutation is a 460 Kb deletion of chromosome 10 which causes a 30-50% increase in growth in the homozygous animal. We have identified three genes within the deletion, suppressor of cytokine signaling-2 (Socs-2), caspase and RIP adaptor with death domain (Raidd/Cradd), and Plexin C1 (Vespr). The two deletion breakpoints lie in within the second introns of both Socs-2 and Plexin C1, resulting in the formation of a novel expressed fusion transcript between Socs-2 and Plexin C1 in HG mice. We have mapped and sequened Socs-2 in cattle and pig and have identified polymorphisms in these species to examine association of Socs-2 and growth related traits. Objective 2: Increase marker density of existing linkage maps used in QTL mapping and integrate them with physical maps of animal
chromosomes. An in silico approach was developed to identify homologies existing between mapped livestock microsatellite flanking sequences and GenBank nucleotide sequences. A total of 67 bovine, 44 porcine and 21 chicken microsatellite flanking sequences had significant matches to human genomic sequence, genes or expressed sequence tags. These microsatellites were mapped in human providing useful links between the comparative maps of humans and livestock.
Impacts
The understanding of the genetic process controlling animal growth in a model organism will allow the isolation and study of homologous genes in domestic animals that could be used to select faster growing and more efficient animals. The development of our in silico mapping approach significantly increased the number of genes and EST sequences anchored to the bovine, porcine and chicken genome maps, as well as the number of links between various human-livestock comparative maps.
Publications
- Wong, M.J., Islas-Trejo, A.D., Horvat, S. and Medrano, J.F. 2002. Structural characterization of the mouse High Growth deletion and discovery of a novel fusion transcript between suppressor of cytokine signaling-2 (Socs-2) and viral encoded semaphoring receptor (Plexin C1). Gene 299:153-163.
- Farber, C.R. and Medrano, J.F. 2002. In silico anchoring of ESTs, genes and genomic sequence to bovine, porcine and chicken genome maps using SSLP markers. Animal Genetics (in press).
- Farber, C.R., Smith, T.P.L. and Medrano, J.F. 2002. Comparative radiation hybrid mapping of the mouse high growth (hg) region in cattle and pigs. Plant, Animal & Microbe Genomes X Conference January 12-16, 2002. San Diego, CA (Abstract).
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Progress 01/01/01 to 12/31/01
Outputs
Develop high-resolution comparative genome maps aligned across species that link agricultural animal maps to those of the human and mouse genomes. The high growth (hg) gene in mouse was identified as suppressor of citokine signaling-2. This gene is deleted in hg mice producing a deregulation of essential hormones in the growth process. We have mapped the gene to cattle and pig chromosome 5 and are identifying polymorphisms in these animals that could be used to examine association of this gene and growth related traits. Sequencing is in progress to study the complete 500 kb deleted region in hg mice and to define the deletion breakpoints. Objective 2: Increase marker density of existing linkage maps used in QTL mapping and integrate them with physical maps of animal chromosomes. A genome-wide scan was completed to identify Quantitative Trait Loci (QTL) associated with growth in a population segregating hg. Significant loci were detected on chromosomes 2, 5, 8, 9, 11
and 17 affecting growth rate, carcass lean mass (protein and ash) and fat mass, and bone length. Interaction between hg and other QTL were detected as changes in gene action. We have initiated the creation of congenic lines to identify isolate the correspond QTL.
Impacts
The understanding of the genetic process controlling animal growth in a model organism will allow the isolation and study of homologous genes in domestic animals that could be used to select faster growing and more efficient animals. Knowledge about interactions between loci, especially when major genes are involved, is essential to understand the complex genetic regulation of growth rate and body size in mammals.
Publications
- Horvat, S. and J.F. Medrano. 2001. Lack of Socs2 expression causes the high growth phenotype in mice. Genomics 72:209-212.
- Corva, P.M., S. Horvat and J.F. Medrano 2001. Quantitative trait loci affecting growth in high growth (hg) mice. Mammalian Genome 12:284-290.
- Corva, P.M. and J.F. Medrano. 2001. Quantitative Trait Loci (QTL) mapping for growth in the mouse: A review. Genetic Selection and Evolution 33:105-132.
- Maddox, J.F., K.P. Davies, A.M. Crawford, D.J. Hulme, D. Vaiman, E.P. Cribiu, B.A. Freking, K.J. Beh, N.E. Cockett, N. Kang, C.D. Riffkin, R. Drinkwater, S.S. Moore , K.G. Dodds, J.M. Lumsden, T.C. van Stijn, S.H. Phua, D.L. Adelson, H.R. Burkin, J.E Broom, J. Buitkamp, L. Cambridge, W.T. Cushwa, E. Gerard, S.M. Galloway, B. Harrison, R.J. Hawken, S. Hiendleder, H.M. Henry, J.F. Medrano, K.A. Paterson, L. Schibler, R.T. Stone, B. van Hest B. 2001. An enhanced linkage map of the sheep genome comprising more than 1000 loci. Genome Res. 11:1275-1289.
- Bunger, L, A. Laidlaw, G. Bulfield, E.J. Eisen, J.F. Medrano, G.E. Bradford, F. Pirchner, U. Renne, W. Schlote, W.G. Hill. 2001 Inbred lines of mice derived from long-term on growth selected lines: unique resources for mapping growth genes. Mamm. Genome 12:678-686.
- DeNise, S. and J.F. Medrano 2001. Genetic Technologies in Cow-Calf Operations. In: Factors Affecting Calf Crop: Biotechnology of Reproduction. Editors: M.J. Fields, R.S. Sand and J.V. Yelich, CRC Press, Florida.
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Progress 01/01/00 to 12/31/00
Outputs
1) Mapping and identification of the high growth gene (hg), a gene that increases weight gain and mature body size in mice: The high growth (hg) gene containing segment has been genetically and physically mapped to a 500 kb deletion in mouse chromosome 10. Work has concentrated in analyzing BAC clones spanning the deletion to identify all potential transcripts by shotgun sequencing and identification of transcripts in the BAC sub-clones using a cDNA screening-hybridization approach. Transgenic mice have been produced with one of the BACs to aid in the identification of the causative gene by rescuing the phenotype. 2) A genome-wide scan was performed to identify Quantitative Trait Loci (QTL) associated with growth in a population segregating hg. All segregating hghg mice (262 mice) from an F2 cross of lines C57BL/6J-hg/hg with line CAST/EiJ were screened with 79 microsatellites. Significant loci were detected on chromosomes 2, 5, 8, 9, 11 and 17 affecting growth rate,
carcass lean mass (protein and ash) and fat mass, and bone length. Interaction between hg and other QTL were detected as changes in gene action.
Impacts
Body growth and the efficiency of growth are important economic components of the livestock industry. The understanding of the genetic process controlling animal growth in a model organism will allow the isolation and study of homologous genes in domestic animals that could be used to select faster growing and more efficient animals. Knowledge about interactions between loci, especially when major genes are involved, is essential to understand the complex genetic regulation of growth rate and body size in mammals.
Publications
- P.M. Corva and J.F. Medrano. 2000. Diet effects on weight gain and body composition in high growth (hg/hg) mice. Physiological Genomics 3:17-23.
- Smith J, I.R. Paton, S. Horvat, J.F. Medrano, D.W. Burt. 2000. Mapping the RAIDD gene of chicken (Gallus gallus): identification of a region homologous to the mouse high-growth region. Mamm Genome 11:706-709.
- Cargill, S.L., G.B. Anderson, T.R. Famula and J.F. Medrano. 2000. Effectc of the high growth (hg) locus on reproductive functions in High Growth (HG) females mice. Growth Dev Aging 64:21-31.
- P.M. Corva. 2000. Identification of modifiers of high growth (HG), a mutation that increases body size in the mouse. Ph.D. dissertation, U.C. Davis
- Corva, P.M., S. Horvat and J.F. Medrano. 2000. Genome-wide scan for the detection of weight and body composition qtl interacting with the mouse high growth locus. (Abst.) Plant and Animal Genome Conference (PAG-VIII), San Diego, CA, January 9-12, 2000.
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Progress 01/01/99 to 12/31/99
Outputs
1) Identification of QTL in the mouse genome interacting with the high growth gene, hg, a gene that increases weight gain and mature body size in mice: The objective of this study is to identify QTL affecting animal growth and body composition. All segregating hghg mice (274 mice) from an F2 cross of lines C57BL/6J-hg/hg with line CAST/EiJ were screened with 80 microsatellites to scan the genome. Data analysis identified significant growth QTL in various chromosomes. These chromosomal regions are currently under study to identify potential candidate genes. 2) Mapping of hg: The high growth (hg) gene containing segment has been genetically and physically mapped to a 500 kb deletion in mouse chromosome 10. Within this region, the Raidd/Cradd gene was identified as a potential candidate for hg, but transgenic studies have not yet confirmed this gene to be hg. Raidd/Cradd is a protein that serves as an adaptor molecule for death proteases in the apoptotic-signaling
pathway. We have concentrated our work in analyzing the BAC clones spanning the deletion to identify other potential genes. Exon trapping, shotgun sequencing, and cDNA hybridization of BAC sublibraries have been used to search for expressed sequences. Several novel transcripts are currently being evaluated. The molecular cloning of hg will permit the functional characterization of this gene and enable the isolation and study of homologous genes in domestic animals and man.
Impacts
Body growth and the efficiency of growth are important economic components of the livestock industry The understanding of the genetic process controlling animal growth in a model organism will allow the isolation and study of homologous genes in domestic animals that could be used to select faster growing and more efficient animals.
Publications
- Horvat, S., J. McWhir, B.A. Freking and J.F. Medrano. 1999. Isolation and evaluation of candidate genes for the high growth (hg) mutation in mice. 13th International Mouse Genome Conference. October 31- November 3, 1999 Philadelphia, PA. (Abst.)
- Corva, P. M. and J.F. Medrano. 2000. Diet effects on weight gain and body composition in high growth (hg/hg) mice. (Submitted to Physiological Genomics)
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Progress 01/01/98 to 12/31/98
Outputs
1) Identification of QTL in the mouse genome interacting with the high growth gene, hg, a gene that increases weight gain and mature body size in mice: The objective of this study is to identify loci interactions that affect animal growth. All segregating hghg mice (260 mice) from an F2 cross of lines C57BL/6J-hg/hg with line CAST/EiJ have been screened with 65 microsatellites to scan the genome. Data is being analyzed to identify interactions between marker pairs. 2) Body composition parameters have been studied in an experiment that includes the effects of energy (fat) and protein levels in the diet on growth of high growth and control mice. Mature (12 wks of age) high growth mice are 56% larger than normal mice but consume only 40% more food, indicating a higher food conversion efficiency. Organ weights are proportional to body size, and body fat in high growth is only 18% higher than control mice. Therefore, high growth mice are relatively leaner than controls. 3)
Mapping of hg: The fine genetic mapping of hg revealed that a deletion is responsible for high growth effect. Analysis of clones within the deleted region led to the identification of the murine Raidd/Cradd gene as a potential candidate for hg. Raidd/Cradd is a protein that serves as an adaptor molecule for death proteases in the apoptotic-signaling pathway. It may be possible that the increase in cell number observed in high-growth is the result of alterations in the apoptosis pathway.
Impacts
(N/A)
Publications
- Horvat, S., and Medrano, J.F. 1998. A 550-kb YAC and BAC contig encompassing the high growth deletion in mouse chromosome 10 and identification of the murine Riadd/Cradd gene in the candidate
- Poli, M., and Medrano, J.F. 1998. Linkage analysis of the pigmented (black) skin spotting (ps) gene in cattle. Plant and Animal Genome VI, San Diego, CA, Jan. 18-22, 1988.
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Progress 01/01/97 to 12/01/97
Outputs
1) Identification of QTLs in the mouse genome interacting with the high growth gene, a gene that increases weight gain and mature body size in mice: An F2 cross of congenic line C57-hg/hg (Mus musculus domesticus) with line CAST/EiJ (Mus musculus castaneur) is being screened with microsatellites to scan the genome. Initially all the segregating hghg mice (approx. 300 mice) will be screened to identify loci having significant effects on growth and body composition. Data will be analyzed to identify interactions between marker pairs. Genotyping the rest of the population in these regions will move the analysis to a second level confirming the position of growth QTLs, detecting regions of the genome that may be interacting with hg and refining the interval map of significant QTLs. 2) To define body composition parameters, we have conducted an experiment to analyze the effects of energy (fat) and protein levels on growth and body composition of high growth and control
mice. High growth mice are 50% larger than normal mice, they consume more food and have a higher food conversion efficiency. Body composition was related to the protein energy ratio of the diets, with no interactions between genotypes. 3) Mapping of hg: The fine genetic mapping of hg revealed that a deletion is responsible for the high growth effect. A marker within the deletion was used as an entry point for physical mapping and cloning of the hg-containing segment. Work is underway to identify the gene responsible for the high growt.
Impacts
(N/A)
Publications
- SUMMERS, P. and MEDRANO, J.F. 1997. Delayed myogenesis associated with muscle fiber hyperplasia in high growth mice. J. Exper. Biol. &
- GUTIERREZ-ADAN, A., CUSHWA, W., ANDERSON, G.B. and MEDRANO, J.F. 1997. Use of an ovine specific Y-chromosome RAPD marker for PCR sexing of ovine embryos. Anim. Gen. 28:135-138.
- HORVAT, S. and MEDRANO, J.F. 1997. Positional cloning of the mouse high growth (hg) gene: Physical and transcript mapping within the candidate region. Proc. 1st Congress of the Genetics Soc. of
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Progress 01/01/96 to 12/30/96
Outputs
1) Genetic mapping of RAPD markers to the sheep genome: 53 randomly amplified polymorphic DNA (RAPD) markers were mapped to the sheep genome and one of these RAPDs was physically localize to the Y chromosome by in-situ hybridization. Two ovine-specific DNA marker were identify, one to study cell distribution in sheep-goat interspecific chimeras, and one utilized for embryo sexing. The results indicate RAPDs can be a useful and economical marker system in domestic animal genome mapping. 2) Mapping of high growth (hg), a gene that increases weight gain and mature body size in mice: The fine genetic mapping of hg revealed that a deletion is responsible for the high growth effect. A marker within the deletion was used as an entry point for physical mapping and cloning of the hg-containing segment utilizing Yeast Artificial Chromosome (YAC) and Bacterial Artificial Chromosome (BAC) clones. Using exon trapping we have identified a 304 bp candidate exon fragment in the hg
region and the isolation of the entire cDNA corresponding to the exon fragment is now underway. The molecular cloning of hg will permit the functional characterization of this gene and enable the isolation and study of homologous genes in domestic animals and man.
Impacts
(N/A)
Publications
- Cushwa, W. and J.F. Medrano. 1996. Applications of the random amplified polymorophic DNA (RAPD) assay for genetic analysis of livestock species. Animal Biotech 7:11-31
- Cushwa, W., K.G. Dodds, A.M. Crawford and J.F. Medrano. 1996. Identification and genetic mapping of a random amplified polymorphic DNA (RAPD) markers to the sheep genome. Mamm Genome 7:580-585
- Horvat, S. and J.F. Medrano. 1996. Fine genetic mapping of hte region surrounding the ghig growth (gh) locus in mouse chromosome 10: targeting random amplfied polymorphic DNA (RAPD) markers. Mamma Genome 7:312-314
- Horvat, S. and J.F. Medrano. 1996. The high growth (hg) locus maps to a deletion in mouse chromosome 10. Genomics 36: 546-549
- Reiser, K., P. Summers, J.F. Medrano, R. Rucker, J. Last, and R. McDonald. 1996.The effects of elevated circulating IGF-1 on the extracellular matrix in high growth C57BL/6Jmice. Amer. J. Phys 40:R696-R703.
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Progress 01/01/95 to 12/30/95
Outputs
1) Genetic mapping of RAPD markers to the sheep genome: RAPD markers were mappedin the Ag Research International Mapping Flock (IMF). IMF parental DNA samples were screened with 131 RAPD primers and all visibly-segregating polymorphisms present in 3 or more pedigrees were screened in the progeny. 53 RAPD polymorphisms, resulting from 44 different primers, were assigned a locus name (University of California Davis Ovine 1 - 53). 45 of the 53 markers were successfully mapped in the Ag Research sheep genetic linkage map using CRIP-MAP software. 3 types of evidence were utilized to support the assumption of homology of RAPD markers scored in different families: pedigree evaluation, segregation analysis, and Southern blot analysis. Results demonstrate the RAPD assay as a powerful approach for identifying polymorphisms that can be used as markers for constructing a sheep genetic linkage map. 2. Fine genetic mapping of high growth (hg) in mouse chromosome 10, a locus that
increases weight gain and mature body size. To facilitate fine mapping of hg, a dense map of markers in the hg region was developed. 7 new random amplified polymorphic DNA markers (RAPD) were targeted to the hg region using bulk segregant analysis and fine-mapped along with all available microsattellite markers. The fine map of hg should enable studies of the homologous region in domestic animal species and may lead to identification of important quantitative trait growth genes providing a possible tool for genetic improvement.
Impacts
(N/A)
Publications
- COCKETT, N.E., BUNCH, T.D., MEDRANO, J.F., SNOWDER, G.D., KEELE, J. AND BEATTIE, C. 1994. Current status of the ovine genome map. J. Anim. Sci.72(1):6/J. Dairy Sci. 77(1):6.
- HORVAT, S. and MEDRANO, J.F. 1995. Interval Mapping of the high growth (hg), a Major Locus That Increases Weight Gain in Mice. Genetics 139:1737-1748.
- HORVAT, S. 1995. Genetic and physical mapping of high growth (hg), a major locus that increases body size in mice. Ph.D Thesis
- CUSHWA, W. 1995. Genetic and physical mapping in sheep using random amplified polymorphic DNA (RAPD) markers. Ph.D Thesis
- COCKETT, N.E. and MEDRANO, J.F. 1996. Use of the sheep genome map. Beltsville Symposium XX: Biotechnology's role in the genetic improvement of farm animals. (in-press)
- CUSHWA, W. and MEDRANO, J.F. 1996. Applications of the random amplified polymorphic DNA (RAPD) assay for genetic analysis of livestock species. Animal Biotechnology (in press).
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