Transcript Dr. Alison Van Eenennaam

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 ?
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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
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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
Van Eenennaam 10/26/2006
Animal Biotechnology and Genomics Education
Current applications:
Marker-assisted selection
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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
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Traits that are most likely to
benefit from MAS (descending order)
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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
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Quantitative traits with markers
currently commercialized or under
development
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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
Van Eenennaam 10/26/2006
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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, 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/
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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.
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
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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.
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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)
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– Validation was carried out on over 1,000 Bos
taurus and Bos indicus cattle.
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Frequencies of favorable alleles
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Calpastatin SNP (UoG-CAST or T1)
Taurus: 60-90% favorable alleles
 Brahmans: ~40-60% favorable
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Calpain 316
Taurus: ~20 % favorable (C)
 Brahmans: ~2% favorable
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Calpain 4751
Taurus: ~50 % favorable (C)
 Brahmans: ~5-10% favorable
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Van Eenennaam 10/26/2006
Animal Biotechnology and Genomics Education
The two 3-SNP tenderness
panels are effective
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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
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4 leptin SNP
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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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Van Eenennaam 10/26/2006
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This is a young industry....
Van Eenennaam 10/26/2006
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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.”
Van Eenennaam 10/26/2006
Animal Biotechnology and Genomics Education
Where are we going ?
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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