Multiple-Trait Selection in a Single-Gene World

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Multiple-Trait Selection in a Single-Gene World

• David Notter
• Department of Animal and Poultry Sciences
• Virginia Tech

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Genetic Markers and NCE

• Genetic Markers have the potential to improve the
  effectiveness of NCE
• However, for most traits, genetic markers will
  not account for enough of the genetic variation
  to allow them to be used as the only selection
  criterion
• Instead, methods must be developed to combine
  information on genetic markers with performance
  data

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Types of Marker-Assisted Selection

• Gene-Assisted Selection (GAS)
• A DNA sequence variant exists within the gene
• May be the actual causal mutation or just
  associated with it
• Linkage-Disequilibrium MAS (LD-MAS)
• Marker is not a part of the gene, but is very
  tightly linked with the favorable form of the QTL
• Linkage-Equilibrium MAS (LE-MAS)
• Marker is loosely linked to the QTL. The
  association can differ among families (sires)

Garrick and Johnson, 2003
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A MAS Marker
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A GAS Marker
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Judging the Importance of a Marker

• The Size of Marker Effect
• How different are the different marker genotypes?
• Degree of Dominance of the Marker
• Are heterozygotes intermediate or do they
  resemble one of the homozygotes?
• The Marker Frequency
• Is the marker common or rare within a breed?
• The Proportion of the Genetic Variance in the
  Trait Accounted for by the Marker
• How much variation (opportunity for improvement)
  exists independent of the marker?

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The Marker Effect
For the GeneStar marbling (thyroglobulin) marker,
the difference in marbling score between
homozygotes is 3.5 to 11 (Hetzel, 2003). In
Angus cattle (AAA, 2004), with a mean marbling
score of about 6.0, this would give 2a 0.48, or
about one half of a marbling score.
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Degree of Dominance of the Marker
Genotype Effect MM a
Mm a ? Dominant marker Mm 0 ?
Co-dominant marker Mm -a ? Recessive
marker mm -a

The GeneStar marbling marker is
approximately codominant in its effect on marbling
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Genestar Genetic Marker
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Genetic Variance Accounted for by a Codominant
Marker
s2A-M 2p(1-p)a2 h2M 2p(1-p)a2 / s2P

• h2M is the marker heritability
• a is the marker effect
• p is the frequency of the marker
• s2P is the phenotypic variance

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Frequency of the Marker
p h2 h2M
0.50 0.50 0.125




h2M .25 h2 at p .50
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Frequency of the Marker
p h2 h2M
0.50 0.50 0.125
0.75 0.48 0.100



h2M .25 h2 at p .50
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Frequency of the Marker
p h2 h2M
0.50 0.50 0.125
0.75 0.48 0.100
0.90 0.46 0.050


For GeneStar Marbling with p 0.50, h2M 0.04,
which accounts for 11 of the additive variance
in marbling score. Thus 89 is associated
with other, currently unidentified, genes.
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Frequency of the GeneStar Marbling Marker in
Various Breeds
Breed Frequency
B. Angus 0.30
R. Angus 0.45
Simmental 0.29
Wagyu 0.65


From Hetzel, 2003--Approximate
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Overview of Issues Involved in Marker Assisted
Selection

• The size of the effect what is the difference
  (2a) between individuals homozygous for
  alternative marker alleles?
• Must be estimated and validated
• The importance of the effect what is the
  economic effect of a change in marker genotype?
• The mechanism of gene action is the marker
  dominant, recessive, or
  co-dominant?

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Overview of Issues Involved in Marker Assisted
Selection

• The importance of other genes compare the marker
  heritability (h2M) to the overall h2 to determine
  the need for continued data recording and gene
  discovery.
• The frequency of the favorable marker
• Frequencies near 0.5 support the most rapid and
  immediate improvement
• High frequencies imply limited impact
• Low frequency markers result in a lag period, and
  have lots of potential, but raise concern about
  loss of genetic diversity and impact on other
  traits

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Integrating Marker Information into National
Genetic Evaluations

• Genes and markers will continue to be discovered
• Many will not be of general utility, but some
  will be useful
• Comprehensive genotyping of many animals may be
  possible but is not yet a reality
• Partial genotyping of subsamples of animals is
  more realistic for the immediate future.

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How Might Breed Associations Respond?

• We are effectively being told that there is
  something outside NCE that makes an animals
  better or worse than his EPDs might indicate
• Yet for proven sires, the EPD is a more
  definitive predictor of progeny performance and
  genetic worth
• Markers are valuable mainly for young (unproven)
  animals, for traits not included in the EPDs, or
  for traits that take a long time to evaluate
  accurately

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How Might Breed Associations Respond?

• Explicitly identify the genes and markers of
  interest to the breed
• Develop a DNA collection strategy
• Develop a genotyping strategy
• Develop validation strategies
• Incorporate marker information into NCE

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How Might Breed Associations Respond? Explicitly
identify the genes and markers of interest to the
breed

• Identify the known genes and LD markers of
  interest to the breed
• Might also identify a set of informative
  microsatellite markers for use in gene discovery
• This will be an evolving array, but provides
  guidance for the genes and markers that will be
  supported in NCE

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How Might Breed Associations Respond? Develop a
DNA collection strategy

• Evaluate simple techniques for DNA acquisition
  and physical storage fluoroacetate papers, hair,
  etc.
• Dont extract DNA until you need it.
• Capacity for repeated extractions.
• Identify high-priority animals, but dont
  necessarily rule out storage of (for example)
  blood on all registered or performance-recorded
  animals

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Blood samples on Perforated FTATM Cards
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How Might Breed Associations Respond? Develop a
genotyping strategy

• Breed associations need to ensure access to
  genotypes on their animals and become
  repositories for those genotypes
• Multiplex genotyping capacity is needed to
  allow efficient genotyping of individual animals
  for many genes/markers
• Develop a genotyping plan for high-use (legacy)
  sires, and perhaps samples of their calves (i.e.,
  to screen for segregating markers)

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How Might Breed Associations Respond? Develop
validation strategies

• New markers must be validated to determine if
  initial results are repeatable
• New markers must be validated in different breeds
• Markers must be validated for both the primary
  trait and for correlated traits
• Genotyping strategies can be designed to support
  validation strategies

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How Might Breed Associations Respond?
Incorporate marker information into NCE

• We know very little about how this will happen!
• We do know that marker information will continue
  to evolvewe will always be behind!
• Must be able to continuously incorporate new
  markers into NCE
• Marker information will enhance, but certainly
  not replace, performance data and EPDs

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How Might Breed Associations Respond? Take
Control of the Use of Genetic Markers in NCE

• Knowledge and resources to allow breeders and
  their organizations to impact marker detection
  and development
• Rapid evaluation of frequencies of new genetic
  variants and markers
• Rapid and efficient validation of newly proposed
  markers

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How Might Breed Associations Respond? Issues in
the Incorporation of Marker Information into NCE

• Are marker effects fixed or random?
• What is the genetic base for a marker effect?
• What are the effects of a marker on other traits?
  How do we estimate these accurately?
• How do we validate marker effects in different
  environments and management systems?
• How do we check if a marker stops working?
• How to handle animals that are not genotyped or
  genotyped for only a few markers?

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Using Markers in NCE Are the marker effects
fixed or random?

• If fixed, then we make a constant adjustment to
  the EPD based on marker genotype
• If random, then even if we know the genotype
  exactly, we still hedge our bets to allow for
  recombination, interactions of the marker with
  the environment or the background genotype, or
  other unknown variations in the gene
• But HOW do we hedge? Estimate sire x marker or
  marker x environment interaction variances?

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A GAS Marker can, at least hypothetically, be
considered a fixed effect (but somehow it seems
too simple!)
Genotype EPD MM a Mm d Mm - a
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Other, unknown sequence variants could be present
in some animals and invalidate the effects of
the known marker. We need to prepare ourselves
for things like this!
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LE-MAS Markers effectively must be
considered random effects to allow for
recombination
LE-MAS Markers must be reconfirmed in such sires,
which appears likely to limit their appeal

???
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Using Markers in NCEWhat is the genetic base for
a marker effect?

• Depends on, and changes with, the frequency of
  the marker
• As marker approaches fixation, the favorable form
  becomes less and less useful.

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Using Markers in NCEWhat are the effects of a
marker on other traits? How do we estimate these
accurately?

• Major validation issue
• We will immediately credit an animal for the
  known, favorable marker effect, but only slowly
  identify that animal as possibly inferior for
  correlated effects
• Linkage with performance records is mandatory, as
  is adequate genotyping of offspring of both sexes

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Using Markers in NCEWhat about animals that are
not genotyped or are genotyped for only a few
markers?

• Many animals will likely not be genotyped
• We will therefore need to infer the possible
  genotypes of such animals using the genotypes of
  their relatives
• Thallman has developed one methodology to
  accomplish thisthere may be others

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Conclusions

• The search for markers will continue
• The bovine gene map will accelerate the search
  for and the rate of discovery of genetic markers
• BIF is facing a developmental effort to use these
  DNA technologies that may rival the
  implementation of BLUP EPDs
• The BIF Guidelines are going to get thicker
  again!