heat tolerance, real-life genomics and gxe issues
TRANSCRIPT
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Heat tolerance, real-life genomics and GxE issues
Ignacy MisztalUniversity of Georgia
ILRI – LiveGene Seminar, Addis Ababa, 3 February 2016
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Research in Misztal’s lab at UGA
• 8-15 people (Postdocs + grad students+ visitors)
• Focus on practical results
• Only provider of genetic (genomic) evaluation software in US– Holsteins Assoc– Angus Assoc +_– Major pig companies – Cobb (broiler chicken)
• High scientific output: 10 papers/year over 10 years
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Current Projects
• Genomic selection (single step methodology)
• Genetics of:– heat stress– mortality– competition (social interaction)
• Issues in genetic evaluation in dairy, beef, pigs and chicken (also sheep and fish)
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Genetics of Heat Tolerance in Holsteins
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Selection and environment
Almost all dairy bulls selected in mild or cold environments
Assume genetic relationship between mild and hot performance antagonistic
Is selection indirectly against heat tolerance?
Can one select for heat tolerance?
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How to proceed with genetic studies in heat tolerance?
What data to record on heat tolerance? Recording of rectal temperatures or respiration rate
expensive
What models to use?
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Production and heat indexPr
oduc
tion
Heat index
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AssumptionsPr
oduc
tion
f(heat index)
cow 2
cow 3
cow 1
Breeding value: BV = a + f(THI)*v
a – regular breeding value v – heat-tolerance breeding valuef(THI) – function of temperature humidity index
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Studies
Ravagnolo et al., 2000ab and 2002ab
Milk test days from Georgia or FL
NR45-90 from FL
THI from weather stations
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Effect of THI on daily milk production
48
49
50
51
52
53
54
55
56
57
58
59
55 57 59 61 63 65 67 69 71 73 75 77 79 81 83 85
slope= -0.46
lb
THI
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0.52
0.54
0.56
0.58
0.6
0.62
0.64
0.66
0.68
0.7
0.72
50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84
THI
NR
45Effect of THI on Non-return rate at 45 days
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Genetic component for heat stress present Genetic correlations between regular and heat
stress effects -0.40
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National genetic evaluation of Holsteins for heat tolerance
Can one identify heat-tolerant sires in Holsteins?What are they?
Bohmanova et al. (2005 and 2006)
National US data
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Differences between most 100 and least 100 heat tolerant sires
Milk -1100kgFat% +0.2%Prot% +0.1%
Dairy Form -1.4Udder +0.7
Longevity +0.90Fertility +1.6
Total Index +36
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Comments Currently selection against heat tolerance in fluid markets
Heat tolerant cows may also be stress tolerant in general Welfare perspective (comfort, mortality, susceptibility to diseases)
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Does heat stress vary by parity?
Ignacio AGUILAR*1,2, Ignacy MISZTAL1 and Shogo TSURUTA1
1 Animal and Dairy Science Department, University of Georgia2 Instituto Nacional de Investigación Agropecuaria, Las Brujas, Uruguay
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Genetic trends of daily milk yield for 3 parities – regular effect
First Second Third
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Genetic trends for heat stress effect at 5.5o C over the threshold
First Second Third
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ssGBLUP for Heat Stress in Holsteins (Aguilar, 2011)
• Multiple-Trait Test-Day model, heat stress as random regression
• ~ 90 millions records, ~ 9 millions pedigrees• ~ 3,800 genotyped bulls
• Computing time• Complete evaluation ~ 16 hRegular effect -first parity Heat stress effect – first parity
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Heat stress in Days Open (Oseni et al, 2003)
Seasonal trends for DO in Georgia
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Days open in Thai crosses
Boonkum et al., 2011
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Conception rate in Iranian Holsteins
Jan
FebMarc
hApr
May Jun Ju
lAug Sep Oct
Nov Dec35
40
45
50
55
Mokhtar et al, 2013
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Heat stress-summary
• Can evaluate Holsteins for heat stress– Negative correlations with production
• Largest effect in later parities– Poor survival in hot climates
• AI companies not much interested in heat tolerance – small market
• Hot areas - revolution with sexed semen
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Genetics of growth in pigs under different heat loads (Zumbach et al., 2007)
• Pigs in NC or TX exposed to heat stress
• Heat stress affect growth • How to model heat stress for
growth?
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pigs with wings - 27
Heat stress and reproductive capacity of sows in Spain (Bloemhof et al.)
Two lines: Adapted (I) and Performance (D)
10.510.710.911.111.311.511.711.912.112.312.5
1 2 3 4 5 6 7 8 9 10 11 12
Month of insemination
Tota
l num
ber p
igle
ts b
orn
ID
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Focus on research in animal breeding
• Quantitative genetics and BLUP (up to 1990)
• QTL and marker assisted selection (up to 2007)
• Genomic selection (now)
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SNP chips and genetic evaluation
• Meuwissen et al. paper
• Early claims of prediction for life with 1000 genotypes
• Initial Experiences– Encouraging results if > 2k genotypes and 50k chips– No long-range prediction under selection
• Multistep methods to use phenotypes of ungenotyped animals
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Multistep genomic evaluation in dairy (VanRaden, 2008)
BLUPDD or deregressed proofs
BayesX or GBLUP &
Index hard to calculate
Index &
y
GEBV
DGV*w1
PA *w2
PI *w3
Deregression good if only if high accuracy animals
Complex
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National Swine Improvement Federation Symposium, Dec. 2008 (31) Paul VanRaden2008
Value of Genotyping More Bulls
Bulls R2 for Net Merit
Predictor Predicted PA Genomic Gain
1151 251 8 12 4
2130 261 8 17 9
2609 510 8 21 13
3576 1759 11 28 17
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Typical result of assuming different SNP distributions
Verbyla et al, 2009
59586060595959
Similar results with genomic relationships and SNP effects
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Single-step evaluation (Misztal et al., 2009)
Merge pedigree relationship matrix (A) and genomic relationships (G) into a joint matrix (H) and use in BLUP
H=A+”modifications due to genomic information”
Single-step GBLUP = ssGBLUP
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Inverse of matrix that combines pedigree and genomic relationships
-1 -1-1 -1
22
0 0H = A +
0 G - AAguilar et al., 2010
Christensen and Lund, 2010Boemcke et al., 2010
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Single-Step / Unified Method
• Simple and fast• Any model• Usually more accurate than other methods • Now industry standard
• Lots of research at UGA– Extensive quality control– Approximation of accuracies– Origin of convergence problems (except in broilers)– GWAS– …
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• Large research interest in GWAS• Limitations of classical and Bayesian methods
Can ssGBLUP be used for GWAS?
ssGBLUP for GWAS
05/01/2023 PAG 2012 Meeting
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Correlations between QTLs and clusters of SNP effects - simulation
1 2 4 8 16 3245
50
55
60
65
70
75
80
85
SNP cluster size
BayesBSingle SNPssGWAS/1
Wang et al., 2012
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Comparison of Three Methods (broilers)
ssGBLUPIterations on SNP (it3)
Classical GWAS
BayesB
0.8%
2.5%
23%
Wang et al., 2012
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Plots and accuracies in Zhang et al. (2010)
simulation
BayesBAcc 0.83
Weighted RRGBLUPAcc 0.75
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GWAS findings• Better estimates of QTL effects with a cluster of adjacent SNP – why
and what size?
• BayesB gives inflating readings but misses a lot– Multiple SNP solutions for same GEBV? Singularity problem?– Only informal reporting. Why?
• Little or no improvement in accuracy of GEBV with large number of genotypes– Are many large SNP readings artifacts?– Impacts on papers in high-impact journals
05/01/2023 PAG 2012 Meeting
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Result with GWA
• Best correlations with QTL with cluster of SNP• Manhattan plots: Few or no common peaks between
breeds or lines• Peaks smaller with larger number of genotypes• Weird behavior of BayesB
– “con-artist method”
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Size problem
• Number of genotyped animals– About 1 million Holsteins – Close to 200,000 Angus
• Big computations – what to do
• APY methodology – based on large haplotype sizes in farm populations
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APY with Holsteins (Fragomeni et al., 2015)
G needed G-1
APY inverse
Regular inverse
Correlations of GEBV with regular inverse
23k bullsas proven
17k cows as proven
> 0.99
> 0.99
20k random animals as proven
> 0.99
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Costs with 570k genotyped animals(Masuda et al., 2016)
• 10 M US Holsteins for type• Computing time for APY inverse 2h
– Would be one month with direct inverse
• Genomic single-step sGBLUP evaluation ~ 2 times more expensive than BLUP
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Why APY works?
• Limited dimensionality of genomic information– Limited number of independent SNP clusters– Limited number of independent chromosomal segments (Me)
• Dimensionality ≈10000 for cattle, 4000 for swine, ≈3000 for broilers (Pocrnic et al., 2016)
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Impact of reduced dimensionality• Lmited resolution of GWAS ≈1/(2Ne) Morgans
– About 0.5 to 5 Mbases farm animals– About 2-5 Kbases in humans (Li et al., 2012)
• Seems impossible to find causative SNP with GWAS in farm animals (e.g., Veerkamp et al., 2015)
• Can use APY with sequence data if causative SNP identified and qualified by other means– (Brøndum et al., 2014)– Do causative SNP with large effect exist?
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Genetic selection in chicken
• 60+ generations of selection (Eitan and Soller, 2002 & 2012)• Great progress for production traits• Problems with reproduction and disease resistance• Problems solved by management (environmental changes), • not genetics
• No reduction of genetic variance• Important genes become fixed and selection follows with new genes
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Selection as optimization• Some traits improve, some traits deteriorate
• Hard to detect deterioration if low heritability and small data sets
• Need improved management to compensate
• Why efficiency differs by commercial species? • Pigs and chicken - environment strongly controlled • Dairy - environment controlled• Beef – environment little controlled
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Can large QTL exist despite selection?
• Genetics and genomics of mortality in US Holsteins
• (Tokuhisa et al, 2014; Tsuruta et al., 2014)
• 6M records, SNP50k genotypes of 35k bulls
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Milk – first parity
Mortality – first parity
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African connections at UGAGraduate students
Saudi Oseni – Dept head in NigeriaEmannuel Lutaaya –UgandaNamibia
Dr. Boly – Burkina FasoILRI (Dempfle, McClintock, Gibson)South Africa – universities
UNDP-FAO
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RenumberingRENUMF90
BLUP in memoryBLUPF90
Variance component estimationREMLF90 AIREMLF90GIBBS2F90 THRGIBBS2F90
BLUP – iteration on dataBLUP90IODFCBLUP90IOD
Approximate accuraciesACCF90
Sample analysisPOSTGIBBSF90
Computing of extra matricesPreGSF90
GEBV to SNP conversionsGWASPostGSF90Predictions via SNP
PredGSF90
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Summary• Long time from first idea to practical results
• Commercial twists
• Genomic selection now mature• Lots of exaggeration and misinformation• Need large data sets across species
• Selection as optimization - winners known but what are the losers
• UGA has tools and focuses on deliverables
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Acknowledgements
Yutaka Masuda APY +YAMS
Shogo Tsuruta ALL
Daniela Laurenco Studies+papers+social
Breno FragomeniAPY+pigs
Ignacio AguilarProgramming+advice
Andres LegarraSound theories + papers
Ivan Pocrnic
APY
• Grants from Holsteins Assoc., Angus Assoc., Cobb-Vantress, Zoetis, Smithfield, PIC,…
• AFRI grant 2015-67015-22936 from USDA NIFA• Collaborators
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Different interest of different players• Universities and research institutes
• Grants• Papers• Awards
• Genomic companies• Selling services• Selling itself
• Breeding companies• Long term profit• Keeping job
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1. PROP12. ESRRG3. PPARG
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Modeling issues in genomic selection
• Many quantitative issues– Nucleus - commercial performance– Mortality– Heat stress– New problems (e.g., survival of low-weight piglets)
• Need to have:– Good selection index– Good model– Troubleshooting skills