Marker Assisted and Genomic Selection

"linked" markers are measured in..

% recombination or centimorgans

what is linkage disequilibrium?

nonrandom distribution of alleles into the gametes

what is a linked marker?

nucleotide difference being measured is not responsible for the phenotype, but is predictive of the phenotype may be due to single or many genes

what is a causative marker?

nucleotide difference being measured is responsible for the phenotype

the closer they are..

the more often they sort together

distribution of the trait across the genome

the number of genes affecting the trait is important -traits affected by lots of genes with small effects are difficult to identify -only traits with higher heritabilities will be detected if only genes of small effects are responsible for a trait

r^2 is...

the proportion of genetic variation caused by the alleles at the causative mutation that is explained by markers

why is SNP's being used to describe genetic relationships a challenge? what is a solution?

These associations won't hold up across the population or across generations Solution may be to genotype by sequencing of sires when costs become low enough

SNP's can be used to describe..

genetic relationships -May attribute effects due to relationships within the reference population as being associated with a trait

what is linkage?

greater association in inheritance of 2 or more genes than is to be expected from independent assortment

Including individuals from all target breeds in the reference population..

improves the accuracy of GEBV

how does genomic selection allow accurate breeding values for young animals?

it potentially leads to doubling of the rate of genetic gain through selection and breeding from bulls at 2 years of age rather than 5 years (by reducing generation interval) -save 92% of bull breeding companies costs -even larger gains could be made by genotyping potential dams of young bulls and selecting them on GEBV

what is linkage mapping based on?

linkage disequilibrium

why use thousands of markers?

quantitative traits (health and production traits) often are the result of many genes will modest effects rather than a single gene with a large effect marker assisted selection with a few markers resulted in modest gains in quantitative traits cost of genotyping was high

Linkage Disequilibrium can be measured by..

r^2

what is genomic selection?

refers to decisions that are based on genomic breeding values (GEBV) and uses thousands of markers to determine values in unproven animals

U.S study

reported reliabilities of GEBV for 3576 US and Canadian Holstein bulls

sequenced genome demonstrated..

that GEBV predicted from markers alone were accurate -in simulations, accuracies of .85 were achieved with markers alone

accuracy of GEBV increases greatly as..

the average r^2 between adjacent markers increases

linkage disequilibrium can be used in marker assisted selection as a predictor of..

the causative mutation

once haplotypes are identified, one SNP can be represent..

the entire DNA region of the haplotype without having to look at all of the other SNP's in the haplotype -provides same info as using all SNP's

If they are 50 cM or greater..

they will sort independently

Marker Assisted Selection provides opportunity to enhance response to selection, particularly in..

traits with low heritability phenotypes that are difficult to measure (behavior), expensive to obtain (disease resistance), or are late onset (carcass)

What was the initial genomic selection study in australia?

used 798 Holstein-Fresian bulls with 50k SNP panel BLUP Accuracies of GEBV were considerably greater than the sire EBV currently used for progeny testing

when genes are in linkage disequilibrium, do they

yes

4 reasons to use genomic selection

1. genomic selection allows prediction of very accurate breeding values for young animals 2. opportunity to increase selection intensity 3. more appropriate balance in the direction of genetic gain 4. potential to limit breeding

Using linkage mapping based on Mendel's Law of Independent Assortment, genes A or a, B or b, or C or c would have what percent chance of being present in the offspring?

50%

If there are 10 centimorgans between 2 genes what percentage of the time will they sort together?

90%

What is a solution to this problem?

By using multiple breeds in the reference population this can be avoided because the SNP must be very close (in high LD) to be associated with the trait

Summary of Studies

Common finding was that for most dairy traits, it appeared that there were many genes of small effect for most traits Some genes had moderate to large effects -DGAT1 had large effect on fat percentage GEBV calculated with pedigree information was more reliable than pedigree information alone

what are DNA markers?

DNA region that is variant between animals allele may be associated or predictive of the phenotype the variation in the DNA may be detected in different ways (SNP)

However it doesn't account for the possibility that..

Genes have different effects in different breeds and populations Mutations affecting production traits are not necessarily polymorphic in different breeds

Accuracy of genomic selection is dependent on..

Level of linkage disequilibrium b/w the markers and causative mutation Number of animals with phenotypes and genotypes in the reference population Heritability of the trait Distribution of effects of the trait across the genome

Genomic Selection Conclusions

Potential to deliver the largest increase in the rate of genetic gain for the dairy industry in the past 20 years Genomic selection is already underway in the US and other countries Increase in reliabilities of GEBV over EBV for bull calves with no daughter records ranges from 2 to 20% Challenges with genomic selection that have yet to be adequately addressed Research is continuing ...

How is GEBV calculated?

Reference population is genotyped and phenotyped Effects of individual SNP's are calculated Effects of the SNP's or haplotypes are summed across the whole genome to predict GEBV

Netherlands Study

Reference population of 1583 bulls genotyped with 57,600 SNP's Increase in reliability of GEBV over parent average EBV at the time of birth was 33% (fat percentage), 19% (kilograms of protein), 15% (feet and legs), 13% (udder depth, SCS) and 9% fertility.

New Zealand study

Reference population of 4500 bulls progeny tested by the Livestock Improvement Corporation Used 44,146 SNP's Reliabilities of GEBV for young bulls with no daughter information ranged from 50-67% for milk production, live BW, fertility, scrotal circumference, longevity compared w/ 34% for parental average BV

because linkage disequilibrium decays over generations(through recombination at meiosis)..

SNP effects must be periodically reestimated

SNP

Single Nucleotide Polymorphism when one nucleotide is substituted for another

what is a haplotype?

a region of DNA that is inherited as a unit

why are genes linked?

because they reside on the same chromosome with relatively short distance from one another

size of haplotype varies between..

breeds of animals species gender chromosomes within chromosomes

How does genomic selection provide opportunity to increase selection intensity?

can screen greater number of bull calves or dams with markers to increase selection intensity

Types of markers

causative linked

accuracy of marker assisted selection depends on..

causative mutation closeness of marker (if not causative mutation) number of genes involved in trait if gene has major effect on trait if genes interact to cause trait environmental effects mode of inheritance

what is required to increase accuracy further?

denser markers

sequenced genome led to..

discovery of millions of SNP's dramatic drop in cost of genotyping

effects of individual SNP's

effects of loci that contribute to genetic variation are captured can estimate the effects of haplotypes as well