Gene mapping, gene-set analysis and genomic

prediction of pregnancy loss in dairy cattle

Anil Sigdel
PhD student, Quantitative Genetics and Genomics
Animal & Dairy Sciences Graduate Seminar
April 09, 2021
sigdel@wisc.edu
Presentation Outline
Genetic dissection and prediction of pregnancy loss

 Genetic analysis of pregnancy loss

 genetic parameters for pregnancy loss using alternative models

 Gene mapping and gene-set analysis

 genes, pathways, and mechanisms associated with pregnancy loss

 Genomic prediction
 genome-enabled prediction of pregnancy loss
Why is pregnancy loss an important economic trait?

 
 pregnancy loss is a major factor affecting production, reproduction and economic efficiency
 dairy cows: fertilization 70-75%  calving rate 30-35%
 pregnancy loss is expensive:
calving interval, milk production, veterinary costs, and culling rate

 pregnancy losses during the embryonic period (1st 42-days): 25-40%

 pregnancy losses during the fetal period: 2-12%
What’s the economic cost of pregnancy loss?

1. value of a new pregnancy: USD 222

2. cost of a pregnancy loss: USD 323

cost of pregnancy loss

increases with gestation length

(Cabrera, 2016)
Does genetics affect pregnancy loss?

trait model # records h2 (%) references

Insemination
interval (49-100 Linear 77,193 10.04% Gershoni et al., (2020)
days)

Early abortion Linear 43,743 2.00% Carthy et al., (2015)

Early abortion Threshold 3,775 17% Bamber et al., (2009)

Fetal loss: a unique dataset

Data Nulliparous Primiparous Multiparous

No. records 23,910 20,495 13,793

Pregnancy loss, % 8.3 13.5 13.7

Animals in pedigree 33,149 29,209 20,883

Genotyped Animals 11,847 8,864 4,522

Genotyped sires 1,097 1,012 822

Genotyped dams 10,750 7,852 3,700

What models to use ?
fetal loss recorded as binary, count and ordinal trait

Linear Model Probit Model Poisson Model

(linear trait) (binary trait) (count trait)
   𝒍= 𝜼+𝝐 𝒍𝒐𝒈
  ( 𝝀 )=𝜼+ 𝝐
Statistical Model

 
=
  function of the expected value of pregnancy loss

vector of fixed effects including:

o year-season of breeding (39 levels)
o types of breeding (2 levels; insemination or embryo transfer)
o days in milk (DIM) at the day of breeding (3 levels; only for lactating cows)
o occurrence of uterine diseases (binary trait, only for lactating cows)

 = vector of cow random additive genetic effects

= vector of random effects for service sire

 
=N
Heritability of fetal mortality

binary trait count trait ordinal trait

Is fetal loss a novel fertility trait?

Genetic correlations of fetal loss versus other fertility traits

Binary trait Count trait Ordinal trait

Gene mapping: why do we use ssGWAS?

′ ′
  𝑿 𝑿 𝑿 𝒁 ′

[ 𝒁′ 𝑿 𝒁 ′ 𝒁 + 𝝀 𝑨− 𝟏 ][ ] [ ]
^
𝒃
𝒖
^
= 𝑿
𝒁′ 𝒚
𝒚

−𝟏 −𝟏
combine all available information:
phenotypes, pedigree, genotypes
 
𝐀 →𝐇
  𝟎 𝟎
𝑯
−𝟏
=𝑨
−𝟏
+
[ 𝟎 𝑮−𝟏 − 𝑨 −
𝟐𝟐
𝟏
]
candidate genomic regions:
% of genetic variance
 
Genomic Scans

Genes implicated in placental

development, fetal growth, immune
modulation, pregnancy maintenance
and calcium signaling

genotype by parity interaction

Gene-set analysis

 goal: test the association of gene-sets (group of functionally related genes)

 opportunity to identify pathways/mechanisms underlying complex phenotypes

1st assign SNPs to Genes 3rd association analysis

SNPs Genes Gene-Sets

2nd assign Genes to Gene-Sets

gene-set: group of genes that share some properties
(Gene Ontology, KEGG Pathways, InterPro, Reactome, Medical Subject Headings)
Calcium signaling

Steroid metabolism

Fetal development

Gene-set
Immunity analysis

Cellular proliferation

Membrane
permeability

Cell-cell attachment
Gene signaling pathways

Wnt, Hedgehog, Notch, MAPK, Hippo, mTOR and TGFβ pathways

Genomic Prediction

 goal: predict the outcome of a breeding event (pregnant vs abortion)

 model predictive ability evaluated using ten-fold cross validation with ten replicates
TST

TST

TST

training set testing set

prediction metrics: TST

 sensitivity (the proportion of aborted cows that were correctly classified)

 specificity (the proportion of pregnant cows that were correctly classified)
 area under the curve (ROC)
Genomic Prediction: primiparous

Observed values Observed values

Predicted values

Total

Predicted values
Total

60852 1760 62612 60845 1273 62118

58 8300 8358 65 8787 8852
Total
Total 60910
60910 10060
10060 70970
70970 Total 60910 10060 70970
Total 60910 10060 70970
linear model, linear-kernel; Sn(0.783) probit model, linear-kernel; Sn(0.828)

Observed values Observed values

Predicted values
Total
Predicted values

Total

60852 1760 62612 60846 1270 62116

58 8300 8358 64 8790 8854
Total
Total 60910
60910 10060
10060 70970
70970 Total
Total 60910
60910 10060
10060 70970
70970
linear model, gaussian-kernel; Sn(0.783) probit model, gaussian-kernel; Sn(0.829)
Take home messages

 pregnancy loss (fetal period) is a heritable trait

 pregnancy loss (fetal period) is weakly correlated with other fertility traits

 genes/gene-sets implicated in pregnancy maintenance, placental and fetal development

 some pathways are relevant throughout different stages of gestation

 genomic prediction of fetal loss is feasible

 probit models using Gaussian kernels showed the best performance

 future research: genomic prediction considering also sire’s genome (genomic mating)
Acknowledgments

Lab members
Dr. Francisco Peñagaricano
Thanks for your attention ! Lihe Liu
Hendyel Pacheco
Ligia Cavani
Larissa Novo

North Florida Holsteins