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Validating Genetic Markers Dick Quaas, Cornell University Mark Thallman, USMARC Alison Van Eenennaam, UC Davis Cooperative Extension Specialist Animal Biotechnology and Genomics [email protected] Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education OVERVIEW Background Issues with validation NBCEC validation process Location of data/webpage Summary of results to date Where are we going ? Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Commercial companies are now offering DNA markers for use in Marker-Assisted Selection (MAS) for given traits Marker-assisted selection is the process of using the results of DNA testing to assist in the selection of individuals to become parents in the next generation. Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education What is a Genetic Marker ? A DNA sequence variation that has been associated with a given trait in one or more populations Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Current applications: Marker-assisted selection Testing for genetic defects e.g. BLAD Testing for single gene traits e.g. coat color Marker-assisted selection for multigenic or quantitative traits e.g. tenderness Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Traits that are most likely to benefit from MAS (descending order) Simply inherited genetic defects, carcass quality and palatability attributes, fertility and reproductive efficiency, maintenance requirements carcass quantity and yield, milk production and maternal ability, and growth performance. Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Quantitative traits with markers currently commercialized or under development Meat Tenderness Quality Grade (Marbling) Beef Cattle Feed Efficiency Meat Yield Disease Resistance Dairy Form Milk and Milk Component Yield Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Validation Prior to moving genetic markers from discovery populations to commercialization, it is important to validate their purported effects on the trait of interest in different breeds and environments, and assess them for correlated responses in associated traits Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Scarcity of independent validation populations...... One of the biggest challenges in validation is the scarcity of independent cattle populations with sufficient phenotypic data to assess the association between various traits and newly discovered genetic markers, and this makes it difficult and expensive to do large-scale field evaluations. Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education ...is going to become a bigger problem. As more markers associated with a variety of traits enter the marketplace, it will become increasingly difficult to find independent populations with suitable phenotypes for validation studies. There is a need for the development of large, wellorganized, thoroughly-phenotyped populations for marker validation studies. Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Tests currently on the US market for qualitative beef traits Name Trait Desired Genotype • GeneSTAR® Quality Grade **** • GeneSTAR® Tenderness ****** • Igenity Tender GENE Van Eenennaam 10/26/2006 Tenderness “5” Animal Biotechnology and Genomics Education http://www.nbcec.org/nbcec/ Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education NBCEC validation process The genotyping company requests validation of their claims and is responsible for genotyping DNA samples. Ideally analyses included both Bos taurus and Bos indicus reference populations, although such populations with the appropriate phenotypes and all allele frequencies were not readily available. Phenotypic data and DNA were mostly collected as part of the Carcass Merit Project. The NBCEC then performs an analysis to determine whether there is an association between the results of the genetic test and the phenotype for the claimed trait. Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education GeneSTAR Quality Grade GeneSTAR Quality Grade TG5 + M2 – CMP Charolais sires (Angus dams) only – (CMP Herefords 99:1 M2 allele freq.) Results – Small, nonsignificant effect on marbling – Significant effect on % Choice or better Conclusion – Modestly effective, primarily due to TG5, Stars aren’t equal; TG5 >>>M2 Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Selection for Marbling Progeny from Angus bulls with high (>.4) and low (< -0.16) EPDs for marbling were compared. 74% of high offspring graded choice versus 47% of low EPD offspring. Vieselmeyer, B. A., R. J. Rasby, B. L. Gwartney, C. R. Calkins, R. A. Stock, and J. A. Gosey. 1996. Use of expected progeny differences for marbling in beef: I. Production traits. J Anim Sci. 74:1009-1013. Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Tenderness Marker Summary GeneSTAR Tenderness IGENITY Tendergene Bovigen & Merial each market a 3 SNP marker panel for tenderness – 2 identical calpain SNP: CAPN1 316 & 4751 from MARC – 1 calpastatin SNP Bovigen: CAST-T1 (Genetic Solutions) Merial: UoG-CAST (U. of Guelph) – Validation was carried out on over 1,000 Bos taurus and Bos indicus cattle. Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Frequencies of favorable alleles Calpastatin SNP (UoG-CAST or T1) Taurus: 60-90% favorable alleles Brahmans: ~40-60% favorable Calpain 316 Taurus: ~20 % favorable (C) Brahmans: ~2% favorable Calpain 4751 Taurus: ~50 % favorable (C) Brahmans: ~5-10% favorable Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education The two 3-SNP tenderness panels are effective About 2.25 lbs difference between “best” & ”worst” genotypes Should expect .75-1.5 lb. by making herd homozygous depending on breed From the perspective of genetic improvement, the beef industry may have the opportunity to make improvement in tenderness by increasing the frequency of the CAPN1 316/4751 C-C haplotype Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Selection for Tenderness $ Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Ancillary Analyses 4 leptin SNP UASM1, UASM2, exon2fb, A252T GHR – Traits analyzed: Carcass wt, REA, Fat thick., YG, Marbling score – Results: Leptin SNP not associated with traits; (A252T not polymorphic) GHR associated with REA & YG but favorable allele rare Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education This is a young industry.... Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education “1954 version of what 'home computers' might look like in 50 years time (i.e. 2004)” Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Wrong Expert Predictions “There is no reason anyone would want a computer in their home.” Ken Olson, president of Digital Equipment Corp. 1977 “I think there's a world market for about five computers” Thomas J. Watson, chairman of the board of IBM. 1943 Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education “what escaped their vision was that science might come up with new and different ways of commercializing and using new technologies.” Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Where are we going ? As more markers associated with a variety of traits enter the marketplace, it will become increasingly difficult to find independent populations with suitable phenotypes for validation studies. Validation studies can also serve to generate information (size of allelic substitutions in a range of production environments, allele frequencies in different populations and breeds, and effects of genotypes on non-target traits) that is essential for the process of incorporating DNA tests into the national cattle evaluation – “GE EPD”. Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education Questions ? Van Eenennaam 10/26/2006 Animal Biotechnology and Genomics Education