Progress 03/15/06 to 03/14/10
Outputs
OUTPUTS: Our long-term goal is to identify & elucidate mechanisms by which cattle genes enhance animal resistance to infectious agents & improve animal health. One of the proven genomic targets for association with animal health & disease is the major histocompatibility complex (MHC). the specific hypothesis to be tested in this project is that genes in the bovine MHC are organized & transmitted as a few haplotype blocks that can be reliably identified by a subset of definitive DNA markers. We exploited a large number of simple sequence tandem repeats (STRs) discovered within the BoLA sequence to examine the haplotype structure underlying the MHC of cattle & exploit haplotype structure to identify predictive single nucleotide polymorphisms (tagSNPs) suitable for high through put genotyping for disease association studies. The objective of this project was to reconstruct BoLA haplotype structure based on inheritance of integrated SNP and microsatellite markers to search for polymorphisms associated with animal health phenotypes. Variation identified in silico from the bovine genome sequencing project and by PCR based genotyping methods was used to develop a dense set of DNA markers for the bovine MHC (BoLA). Inheritance patterns were determined by analysis of cattle in multi-generation pedigrees and used to build a haplotype structure for BoLA. A total of 71 markers were designed from the bovine genome sequence to genotype a high resolution radiation hybrid panel and derive a dense genetic map of the bovine MHC. This map was used to inform assembly of the bovine MHC sequence and to position 27 SNPs from the bovine SNP project and to identify 37 simple tandem repeats (SSRs) and 17 BovA2 repeats as additional genetic markers. The collective markers were used to examine linkage disequilibrium (LD) among the combined marker set and define the haplotype structure of the bovine MHC. The general conclusion of this study is that recombination within BoLA is sufficiently high to degrade any LD that may have existed among the markers used. This conclusion is similar to the results of the HAPMAP study of LD in four specific chromosomal regions. Our estimate is that additional markers spaced no more than 10Kb apart will be required to detect significant LD in the cattle MHC and to identify highly informative and efficient tagSNPs for MHC/disease associations. PARTICIPANTS: Dr. Loren Skow served as PI and project director. He was responsible for supervising the genotyping activities, directing technical staff and students, and mentoring graduate and post-doctoral students. He also coordinated communications among project personnel. Dr. Charles Huber provided biostatistcal support for the project, especially in analysis of LD and construction of haplotypes. Dr. Morgan Scott provided DNA samples and valuable input in to design of experiments. Mrs Marian Cothran and Renuka Chowdhary were employed at different times as research technicians on this project. Their responsibilities include general laboratory duties, record keeping and ordering. Ms. Krista Fritz was employed as a graduate student on this project and used data from the project to develop and defend her Ph.D. thesis in 2009. Dr. Candice Brinkmeyer-Langford participated in the analysis of radiation hybrid mapping and haplotype structure as a part of her post-doctoral training. TARGET AUDIENCES: Nothing significant to report during this reporting period. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
The results of this research demonstrated that additional molecular markers will be required to appropriately search for genetic components of disease resistance, understand the processes involved in host: pathogen interactions and improve our ability to identify cattle at risk for infectious diseases. The impact of this research will be improved animal health and productivity and a more accurate understanding of the role of genetics in determining health or disease in cattle and other species of animals.
Publications
- The Bovine Genome Sequencing and Analysis Consortium, The Genome Sequence of Taurine Cattle: A window to ruminant biology and evolution. 2009. Science. 324(5926):522-528.
- Brinkmeyer-Langford CL, Childers CP, Fritz K, Gustafson-Seabury A, Cothran M, Raudsepp T, Womack JE, Skow LC. A high resolution RH map of the bovine major histocompatibility complex. 2009. BMC Genomics 10:182-192.
- Sena L, Schneider M P C, Brenig BB, Honeycutt RL, Honeycutt DA, Womack JE and Skow LC. Polymorphism and gene organization of Bubalus bubalis MHC-DQB show homology to BoLA DQB region. Animal Genetics (2010). In press.
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Progress 03/15/08 to 03/14/09
Outputs
OUTPUTS: The long-term goal of this projectis to exploit the resources provided by the bovine genome sequencing project to improve animal health and reduce or eliminate disease. The specific goals of this project target the bovine MHC as a source of variation in immune response and disease resistance and a valuable target for manipulation for improved animal health. Specifically we have constructed haplotypes of the bovine MHC and integrated additional markers into those haplotypes to produce a panel of SNPs sufficient to identify all known cattle MHC haplotypes. We are presently fabricating a SNP chip for high through-put haplotyping and expect to implement this technology to seek associations of bovine MHC with susceptibility to mastitis and response to vaccine (BVD) PARTICIPANTS: Not relevant to this project. TARGET AUDIENCES: Not relevant to this project. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
These results of this research have resulted in a new genotyping tool to provide efficient, economical heotyping of the bovine MHC. This tool will bavailable without restrictions to scientits seeking to better understand the role of genomics in animal health and diosease.
Publications
- The Bovine Genome Sequencing and Analysis Consortium. 2009.The Genome Sequence of Taurine Cattle: A Window to Ruminant Biology and Evolution. Science 324(5926):522-528,2009.
- The Bovine HapMap Consortium. 2009. Genome-Wide Survey of SNP Variatio Uncovers the Genetic Structure of Cattle Breeds. Science 324(5926):528,2009
- Brinkmeyer-Langford, CL, Childers C. Fritz K. Gustafson- Seabury A. Cothran M.Raudsepp, T. Womack, JE and Skow, LC. 2009. A High Resolution RH Map of the Bovine Major Histocompatibility Complex. BMC Genomics 2009, 10:182-189.
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Progress 03/15/07 to 03/14/08
Outputs
The long term goal of this project is to identify genetic factors that determine host susceptibility to infectious diseases. Genes in the bovine major histocompatibility complex (MHC) encode proteins that play critical roles in the initial stages of an immune response to pathogenic organisms. Therefore the MHC is a prime candidate region for seeking associations between genes and susceptibility to infectious diseases. In the initial year of this project we used markers designed from the bovine genome sequence to genotype a high resolution radiation hybrid panel and derive a dense genetic map of the bovine MHC. This map was used to inform assembly of the bovine MHC sequence and to position 27 SNPs from the bovine SNP project and to identify 37 simple tandem repeats (SSRs) and 17 BovA2 repeats as additional genetic markers. Additional SNPs were identified by in silico analysis of the bovine sequence aligned against other bovine sequences deposited in Genbank. We have
sequenced the STR and BovA2 amplicons and identified flanking SNPs closely positioned to the STR and BovA2 markers as marker specific haplotypes called SNPSTRs. We are currently determining linkage disequilibrium (LD) among the combined marker set to define the haplotype structure of the bovine MHC and to identify highly informative and efficient tagSNPs for localizing the genetic material responsible for MHC/disease associations. The tagSNPs will be used to interrogate animals from cattle populations showing variation in disease susceptibility (brucellosis, Johne's disease, mastitis) or vaccine response.
Impacts
The results of this research will help us understand the processes involved in host: pathogen interactions and improve our ability to identify cattle at risk for infectious diseases. The impact of this research will be improved animal health and productivity and a more accurate understanding of the role of genetics in determining health or disease in cattle and other species of animals.
Publications
- No publications reported this period
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Progress 03/15/06 to 03/15/07
Outputs
Genes in the bovine major histocompatibility complex (MHC) encode proteins that play critical roles in the initial stages of an immune response to pathogenic organisms. Therefore the MHC is a prime candidate region for seeking associations between genes and susceptibility to infectious diseases. In the initial year of this project we used markers designed from the bovine genome sequence typed across a high resolution radiation hybrid panel to derive a dense genetic map of the bovine MHC. This map was used to inform assembly of the bovine MHC sequence. The sequence assembly was used then used to position 27 SNPs from the bovine SNP project and identify simple tandem repeats (SSRs) as potential sources of additional genetic markers. Additional SNPs were identified by in silico analysis of the bovine sequence aligned against other bovine sequences deposited in Genbank. We have initiated sequencing of the STR amplicons to identify additional SNPs closely positioned to
STRs as haplotypes called SNPSTRs.. In the current year we will determine linkage disequilibrium among these markers and define the haplotype structure of the bovine MHC as a prelude to development of highly informative and efficient tagSNPs for localizing the genetic material responsible for MHC/disease associations.
Impacts
The results of this research will help us understand the processes involved in host: pathogen interactions, improve our ability to identify cattle at risk for infectious diseases and inform the immunobiology of other species of animals. The impact of this research will be improved animal health and productivity and a more accurate understanding of the role of genetics in determining health or disease.
Publications
- No publications reported this period
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