ASCI 304 Midterm #2

Bovine genetics in 1990s

DNA genetic markers, linkage mapping, marker assisted selection (MAS)

Bovine genetics in 2001

Genome-wide selection has been proposed, linkage disequilibrium

QTL mapping defn

Process of finding genomic regions (markers, genetic variants, genes) associated with variation in phenotype

3 categories of QTL mapping

1) Linkage analyses (LE) (designed crosses)

2) Candidate gene approach

3) Genome-wide association analysis (GWAS)

What is linkage analyses?

- Based on designed crosses

- Small number of markers

- Within family linkage disequilibrium (marker not working in other populations)

- Require large number of progeny

What is the candidate gene approach assumption?

- Gene involved in the physiology of the trait COULD harbor a mutation causing variation in that trait

What is candidate gene approach?

The mutations (direct markers or LD markers) within this gene will be tested for association with the phenotypes

Why do we perform candidate approach studies?

- Limited fund for genotyping or sequencing

- Fine mapping?

What is fine mapping?

Process in genetics that refines the location of casual variants within a region identified by a Genome-Wide Association Study - it aims to pinpoint the specific genetic variants most likely responsible for a trait or disease

Candidate gene approach defn

Discovery of polymorphisms/genetic variants in candidate genes and their regulatory regions - CRITERIA FOR SELECTING SNPs

Is the SNP in perfect LD with the QTL allele? (candidate gene approach criteria for selecting SNPs)

SNP could be in perfect LD with the causative mutation itself in the population

If the SNP is in a coding region of a gene... (candidate gene approach criteria for selecting SNPs)

Does the SNP have an obvious effect on function, and can function be illustrated? Change the AA translated by the gene (missense mutation) and affects enzymatic/protein activity

If the SNP is in a noncoding region of a gene... (candidate gene approach criteria for selecting SNPs)

Does the SNP have a role in alternate splicing?

If the SNP is in a promoter... (candidate gene approach criteria for selecting SNPs)

Does the SNP alter the expression of the gene?

If the SNP is in a regulatory region... (candidate gene approach criteria for selecting SNPs)

Does this SNP alter the transcription of the gene?

STEP 1 - How to perform association analyses using candidate gene approach?

1) Identify the genes and discovery of genetic variants

STEP 2 - How to perform association analyses using candidate gene approach?

2) Identify a target population that is segregating for the trait of interest

STEP 3 - How to perform association analyses using candidate gene approach?

3) Biological sample collection (from hair/blood/ear notch)

STEP 4 - How to perform association analyses using candidate gene approach?

4) DNA extraction

STEP 5 - How to perform association analyses using candidate gene approach?

5) Genotyping or sequencing: Genotype the population sample with some markers to cover the gene

STEP 6 - How to perform association analyses using candidate gene approach?

6) Quality control for genotypes and phenotypes

Step 6 - Explanation

1. SNPs with a call-rate lower than 90%

2. Animal with call-rate lower than 90%

3. SNPs with a heterozygosity that deviates by more than 15% from the expected value

4. SNPs are not in Hardy-Weinberg Equilibrium

5. SNPs that were assumed to be misplaced

6. Minor allele frequency threshold >0.01

7. Duplication in genotyping (identical analysis)

STEP 7 - How to perform association analyses using candidate gene approach?

7) Association analysis

Step 7 - What is the association analysis assumption?

The polymorphism (SNP) in the gene underlies the variation in the phenotypes of the trait. But it might be just in close linkage disequilibrium with the QTL

- For each marker, test for an association between the marker genotypes and the phenotypes for trait of interest (average daily gain, feed efficiency)

STEP 8 - How to perform association analyses using candidate gene approach?

8) Validation population

Step 8 - What is validation pouplation?

- Replication in an independent sample

- Cross-validation

What is cross-validation?

Testing the predictability of these discovered SNPs/genetic variants

- Divide the data to shuffled groups and within each group you have reference and validation pop

What are the possible linear models for association analysis?

- Genotype model

- Allele substitution effect model (regression on number of alleles)

- Haplotype model

Today, US dairy cattle produce ____ times more milk today than in 1945 and ___ as much as 1970, per cow

FOUR; TWICE

Genomics as a precision tool (3 steps)

1) Merge data from several sources (economics, performance, health, genetic predictions)

2) Create key metrics to demonstrate the impact farm economic viability, environmental sustainability, and animal welfare

3) Scientific, technical materials to support impact of animal health genetics on environmental sustainability

Describe genomic selection in dairy cattle.

- Traditional selection relies on observable traits and pedigree information

- Use of DNA markers to predict the genetic value of animals increases accuracy, hence faster genetic change

What does genomic selection matter in dairy cattle?

- Improves accuracy of breeding decisions

- Enhances traits like milk production, health, and fertility

- Reduces costs and increases efficiency in dairy farming

How does genomic evaluation happen?

- Traits are polygenic - influenced by many genes with small effects

- SNPs are used to track these genes

- Genomic selection uses SNP data to estimate breeding values (GEBVs)

What is the traditional genetic prediction model?

Model: BLUP (Best linear unbiased prediction)

Purpose: Predicts breeding values using pedigree and phenotypic data

Data used: Phenotypes (milk yield), pedigree relationships

Model structure: y = Xb + Zu + e

What is the genomic prediction model?

Model: GBLUP (Genomic best linear unbiased prediction)

Purpose: Predicts breeding values using genomic data (SNP markers)

Data used: Genotypes (SNPs), phenotypes

Model structure: y = Xb + Zu + e

EBV relationship

Estimated breeding value / 2 = PTA (predicted transmitting ability

GEBV relationship

Genomic estimated breeding value / 2 = GPTA (Genomic predicted transmitting ability)

10 Steps to genomic results

1) Customer collects samples

2) Customer submits order

3) Customer ships samples

4) Order is processed and any changes are communicated to the customer

5) Pedigree nomination is placed at the Council on Dairy Cattle Breeding (CDCB)

6) Sample run and genotypes sent to CDC for evaluation

7) CDCB reports preliminary GPTA results and provides parentage correction opportunities

8) Customer reviews suggested parentage

9) Dairies on approved AUTO ACCEPT list are accepted

10) Final monthly GPTAs reported to customer

What is the genetic architecture of milk yield?

- Polygenic traits = milk yield is shaped by many genes with small effects

- Regulatory elements = enhances, miRNAs, and IncRNAs modulate gene expression

- Key genes: DGAT1, GLYCAM1 and others directly influence milk production

- Outcome: Components collectively influence milk yield, which can be predicted using GEBVs

What are the 6 financial drivers of profitability?

1) Milk yield (energy corrected)

2) Heifer survival

3) Fertility

4) Mortality

5) Somatic cell scores

6) Net herd replacement costs

Impact of adverse health events is significant in ____ and ____.

cows; calves

Ex) Displaced abomasum - culling risk of 26.9

Ketosis = 32.5%

Lameness = 16%

Calf mortality, calf respiratory, calf scours

What is directional selection?

Type of natural or artificial selection that favors individuals at one extreme of a trait distribution.

Over time, this causes a population shift.

What is a population shift?

Average value of the trait moves in the direction of the favored extreme

If farmers consistently select cows with higher milk yield, over generations...

- Avg milk yield increases

- Genetic architecture of population shifts toward alleles that support higher production

What is CLARIFIDE?

Balance of production, fertility, longevitiy, type, and health traits to deliver maximum profit (CDCB evaluation, wellness traits, calf wellness, cow fertility, genetic conditions)

Explain a common scenario as CLARIFIDE.

- Test all dairy heifers

- Rank using DWP$

- Sell bottom 10-20% within cohort (typically birth month or breeding group); beef semen, ETC recipients

- Use sexed dairy semen and beef semen to minimize the number of dairy bull calves born

- Every 4-6 months, monitor and re-evaluate the farm's strategy and adjust as necessary

How can we maintain genetic variation?

Genetic variation persists, especially when the selection is not absolute or when new mutations and migrations introduce additional variation

Describe the genetics and sustainability dataset

Increases production for the economic viability of the farm without adverse environmental impacts or animal welfare consequences

What are inferior and superior genetics?

Defined based on DWP$ index best and worst quartiles

What is intensity metrics?

Metrics as expressed as resources/waste per million lbs.

In a 1000-cow herd that requires 22% fewer replacement heifers to maintain size...

135 fewer heifer replacements, 760 tons less feed, 15.7 tons less than CH4

What are the current and future trends in genetics?

- Integration of precision tools (on farm software, activity monitoring, genomics to leverage such tools, analytics tools)

- New traits under development (DMI, residual dry matter intake)

- New selection index (methane intensity)

- Data-driven decisions (heifer inventory management, optimize fertility protocols)

- Optimize resource use (less labor, enhancement of profitability)

- Improve animal welfare (less human interventions, reduction of disease incidence)

What are the key messages of dairy cattle genomics?

- Coupling genomics to other precision tools has the potential to significantly increase the profitability of dairy farms

- Genomics + feed efficiency will accelerate the reduction of waste and minimize the environmental footprint of dairy farms

- Career paths in dairy industry: Animal husbandry skills, analytical proficiency