Validating Genetic Markers

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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
• alvaneenennaam_at_ucdavis.edu

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OVERVIEW

• Background
• Issues with validation
• NBCEC validation process
• Location of data/webpage
• Summary of results to date
• Where are we going ?

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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.
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What is a Genetic Marker ?
A DNA sequence variation that has been associated
with a given trait in one or more populations
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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

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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.

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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

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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

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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.

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...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, well-organized,
  thoroughly-phenotyped populations for marker
  validation studies.

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Tests currently on the US market for qualitative
beef traits
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http//www.nbcec.org/nbcec/
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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.

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GeneSTAR Quality Grade

• GeneSTAR Quality Grade TG5 M2
• CMP Charolais sires (Angus dams) only
• (CMP Herefords 991 M2 allele freq.)
• Results
• Small, nonsignificant effect on marbling
• Significant effect on Choice or better
• Conclusion
• Modestly effective, primarily due to TG5, Stars
  arent equal TG5 gtgtgtM2

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Selection for Marbling

• Progeny from Angus bulls with high (gt.4) and low
  (lt -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. 741009-1013.
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Tenderness Marker SummaryGeneSTAR 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.

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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

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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

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Selection for Tenderness

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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

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This is a young industry....
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1954 version of what 'home computers' might look
like in 50 years time (i.e. 2004)
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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
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what escaped their vision was that science might
come up with new and different ways of
commercializing and using new technologies.
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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.

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Questions ?