Genomic selection and systems biology – lessons from dairy cattle breeding

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Presentation made to the staff of Keygene, NV, in Wageningen, The Netherlands.

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Genomic selection and systems biology – lessons from dairy cattle breeding

  1. 1. J. B. Cole Animal Improvement Programs Laboratory Agricultural Research Service, USDA Beltsville, MD 20705-2350, USA john.cole@ars.usda.gov Genomic  selec+on  and   systems  biology  –  lessons   from  dairy  ca5le  breeding  
  2. 2. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (2)   Cole   Dairy Cattle   9 million cows in US   Attempt to have a calf born every year   Replaced after 2 or 3 years of milking   Bred using artificial insemination   Popular bulls have 10,000+ progeny   Cows can have many progeny though superovulation and embryo transfer
  3. 3. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (3)   Cole   Embryo transferred to recipient" Parents selected" Dam inseminated" Bull born" Semen collected (1 y)" Daughters born (9 m later) " Daughters have calves (2 y later)" Bull receives progeny test" (5 y)" Genomic Test" Lifecycle of bull
  4. 4. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (4)   Cole   Phenotypes recorded   Monthly recording   Milk, fat, and protein yields   Somatic cell count (udder health)   Visual appraisal for type traits   Breed associations record pedigree   Calving difficulty and stillbirth
  5. 5. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (5)   Cole   Available data Type of Data Number of Records Cows with lactation data 28,394,976 Lactations 68,373,863 Individual test days 508,574,532 Dystocia records 20,770,758 Animals in pedigree file 58,893,009 Genotyped bulls 105,654 Genotyped cows 276,173
  6. 6. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (6)   Cole   0 50000 100000 150000 200000 250000 300000 1004 1008 1012 1104 1108 1112 1204 1208 1212 1304 Bulls Cows Cole" Many animals have been genotyped Evaluation Date (YYMM)" Genotypes" 381,827 genotyped animals" Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (6)  
  7. 7. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (7)   Cole   How does genetic selection work?   ΔG = genetic gain each year   reliability = how certain we are about our estimate of an animal’s genetic merit (genomics can é)   selection intensity = how “picky” we are when making mating decisions (management can é)   genetic variance = variation in the population due to genetics (we can’t really change this)   generation interval = time between generations (genomics can ê)
  8. 8. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (8)   Cole  8" Calculation of genomic evaluations   Deregressed PTA derived from traditional evaluations of predictor animals   Allele substitution effects estimated for 45,188 SNP   Polygenic effect estimated for genetic variation not captured by SNP   Selection index combination of genomic and traditional not included in genomic
  9. 9. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (9)   Cole   Many chips are available HD" 50KV2 " LD " GGP HD!   BovineSNP50   Version 1 54,001 SNP   Version 2 54,609 SNP   45,188 used in evaluations   High-density (HD)   777,962 SNP   Only 50K SNP used,   Low-density (LD)   6,909 SNP   Geneseek Genomic Profiler & GGP-HD
  10. 10. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (10)   Cole   What is a SNP genotype worth? For the protein yield (h2=0.30), the SNP genotype provides information equivalent to an additional 34 daughters" Pedigree is equivalent to information on about 7 daughters "
  11. 11. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (11)   Cole   And for daughter pregnancy rate (h2=0.04), SNP = 131 daughters" What is a SNP genotype worth?"
  12. 12. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (12)   Cole   High density SNP chip   Currently only 50K subset of SNP used   Some increase in accuracy from better tracking of QTL possible   Realized gains have been small   Potential for across-breed evaluations   Requires few new HD genotypes once adequate base for imputation developed
  13. 13. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (13)   Cole   Low density SNP chip   6909 SNP mostly from SNP50 chip   Evenly spaced across 30 chromosomes   Addresses performance issues with 3K while providing low-cost genotyping   Provides over 98% accuracy imputing 50K genotypes
  14. 14. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (14)   Cole   Parentage validation and discovery   Parent-progeny conflicts detected   Animal checked against all other genotypes   Reported to breeds and requesters   Correct sire usually detected   Maternal grandsire checking   SNP at a time checking   Haplotype checking more accurate   Breeds moving to accept SNP in place of microsatellites
  15. 15. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (15)   Cole   Imputation   Based on splitting the genotype into individual chromosomes   Missing SNP assigned by tracking inheritance from ancestors and descendants   Imputed dams increase predictor population   3K, LD, & 50K genotypes merged by imputing SNP not on LD or 3K
  16. 16. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (16)   Cole   Genotypes and haplotypes   Genotypes indicate how many copies of each allele were inherited   Haplotypes indicate which alleles are on which chromosome   Observed genotypes partitioned into the two unknown haplotypes   Pedigree haplotyping uses relatives   Population haplotyping finds matching allele patterns
  17. 17. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (17)   Cole   Haplotyping program – findhap.f90   Begin with population haplotyping   Divide chromosomes into segments, ~250 to 75 SNP / segment   List haplotypes by genotype match   Similar to fastPhase, IMPUTE   End with pedigree haplotyping   Detect crossover, fix noninheritance   Impute nongenotyped ancestors
  18. 18. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (18)   Cole   O-Style Haplotypes Chromosome 15
  19. 19. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (19)   Cole   We’re working on new tools
  20. 20. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (20)   Cole   Recessive defect discovery   Check for homozygous haplotypes   7 to 90 expected but none observed   5 of top 11 are potentially lethal   936 to 52,449 carrier sire-by-carrier MGS fertility records   3.1% to 3.7% lower conception rates   Some slightly higher stillbirth rates   Confirmed Brachyspina same way
  21. 21. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (21)   Cole   Impact on producers   Young-bull evaluations with accuracy of early 1st­crop evaluations   AI organizations marketing genomically evaluated 2-year-olds   Rate of genetic improvement may increase by up to 50%   Studs reducing progeny-test programs
  22. 22. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (22)   Cole   Why genomics works in dairy   Extensive historical data available   Well-developed genetic evaluation program   Widespread use of AI sires   Progeny test programs   High-valued animals, worth the cost of genotyping   Long generation interval which can be reduced substantially by genomics
  23. 23. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (23)   Cole   Where do we go from here?   We found a few QTL   Most traits show infinitessimal inheritance   Dominance effects also are small   What about epistasis?   Systems biology – gene/protein/ transcription factor networks
  24. 24. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (24)   Cole  24" We confirmed known QTL Cole, J.B. et al. 2009. Distribution and location of genetic effects for dairy traits. ICAR Tech Ser. 13:355–360."
  25. 25. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (25)   Cole   Gene set enrichment analysis-SNP Gene pathways (G)" GWAS results" Score increase is proportional to SNP test statistic" Nominal p-value corrected for multiple testing" Pathways with moderate effects" Holden et al., 2008 (Bioinformatics 89:1669-1683. doi:10.2527/jas.2010-3681)" SNP ranked by significance (L)" SNP in pathway genes (S)" Score increases for each Li in S" Permutation test and FDR" Includes all SNP, S, that are included in L" The more SNP in S that appear near the top of L, the higher the Enrichment Score"
  26. 26. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (26)   Cole   Association weight matrix   Find gene coexpression networks (Fortes et al., 2010)   Select SNP by significance, correlation, dist’n, etc. −  Favor intragenic SNP significant across traits   Construct weight matrix −  Rows are SNP, columns are traits cols −  Cells are normalized z-score of the additive effect of ith SNP on jth trait   Significant correlations are identified using PCIT (Reverter and Chan, 2008) and visualized −  Cells randomly permuted as control
  27. 27. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (27)   Cole   Can we identify regulatory networks? Fortes et al., 2011 (J. Animal Sci. 89:1669-1683. doi:10.2527/jas.2010-3681)" Candidate genes and pathways that affect age at puberty common to both breeds"
  28. 28. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (28)   Cole   Network analysis Fortes et al., 2011 (J. Animal Sci. 89:1669-1683. doi:10.2527/jas.2010-3681)" Gene network – the red center identifies highly connected nodes." Subnetwork of interacting transcription factors from the puberty network." Subnetwork of interacting transcription factors from a collection of mouse and human data. (Validation step.)"
  29. 29. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (29)   Cole   Enriched pathways Fortes et al., 2011 (J. Animal Sci. 89:1669-1683. doi:10.2527/jas.2010-3681)"
  30. 30. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (30)   Cole   Transcription factor network Fortes et al., 2011 (J. Animal Sci. 89:1669-1683. doi:10.2527/jas.2010-3681)" Yellow genes were submitted to database. Other nodes were mined from FunCoup. Red: protein- protein interaction Blue: mRNA coexpression"
  31. 31. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (31)   Cole   How do we rank allele effects?   GSEA and AWM require that we order SNP on some criterion   p-values (actual or nominal)   q-values (false discovery rate)   Not all models provide p-values   Allele substitution effects (not so good)   Scaled substitution effects (better)   It’s not clear (to me) which is best
  32. 32. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (32)   Cole   Aren’t P-values easy?   Single SNP, fixed-effects model   Inflation of error variances   Spurious associations   e.g., Plink   Multiple SNP, mixed-effects model   Accounts for population structure   e.g., TASSEL, GoldenHelix SVS
  33. 33. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (33)   Cole   A recent example from dairy   Extreme birth weights are associated with increased risk of stillbirth and calving difficulty   Birth weights are not measured on most dairy farms in the US   With German colleagues, we developed a predictor based on traits we do measure
  34. 34. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (34)   Cole   GWAS for birth weight PTA h" Cole et al.(2013), unpublished data"
  35. 35. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (35)   Cole   KEGG pathways for birth weight What does regulation of the actin cytoskeleton have to do with birth weight in cattle? That is, do these results make sense?" Maybe…these pathways may be involved in establishment & maintenance of pregnancy, as well as coordination of growth and development. " Cole et al.(2013), unpublished data"
  36. 36. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (36)   Cole   A new project   The Brown Swiss, Holstein, and Jersey breeds experience dystocia at different rates   We are applying the AWM method of Fortes et al. to these data   The goal is to identify gene networks…   Common to all breeds   Different by breed
  37. 37. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (37)   Cole   We have divergent populations Cole et al., 2005 (J. Dairy Sci. 88(4):1529–1539)"
  38. 38. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (38)   Cole   Challenges   Annotation   This is a mess in the cow   The reference assembly may not be representative of all taurine cows   Validation   Doing functional genomics with large mammals is expensive – who pays?   When have we proven something?
  39. 39. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (39)   Cole   Conclusions   We’re not going to find big QTL for most traits   We may identify gene networks affecting complex phenotypes   We’re learning how much we don’t know about functional genomics in the cow   Validation remains a problem
  40. 40. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (40)   Cole   Partners   Illumina   Marylinn Munson   Cindy Lawley   Christian Haudenschild   BARC   Curt Van Tassell   Lakshmi Matukumalli   Tad Sonstegard   Missouri   Jerry Taylor   Bob Schnabel   Stephanie McKay   Alberta   Steve Moore   USMARC – Clay Center   Tim Smith   Mark Allan iBMAC Consortium" Funding Agencies"   USDA/NRI/CSREES   2006-35616-16697   2006-35205-16888   2006-35205-16701   USDA/ARS   1265-31000-081D   1265-31000-090D   5438-31000-073D   Merial   Stewart Bauck   NAAB   Godon Doak   ABS Global   Accelerated Genetics   Alta Genetics   CRI/Genex   Select Sires   Semex Alliance   Taurus Service
  41. 41. Keygene  N.V.,  Wageningen,  The  Netherlands,  28  May  2013  (41)   Cole   Questions? http://gigaom.com/2012/05/31/t-mobile-pits-its-math-against-verizons-the-loser-common-sense/shutterstock_76826245/"

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