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Marker-assisted Selection : Opportunities in sheep and goat

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  1. Marker-assisted Selection : Opportunities in sheep and goat D. Boichard INRA, Animal Genetic Department, Jouy en Josas, France D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  2. Introduction • Many QTL experiments carried out in the last 10 years • Variable designs : outbred populations / crossbreeding ; experimental facility or field data (GDD) ; general purpose design / design targeted to one trait or one gene • Increasing number of results : QTL or identified genes • Most frequently advocated goal : To integrate these results in MAS D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  3. Introduction (2) • A dilemna : • QTL : • Predictable task to detect QTL (time, budget) • Early and Possible but Difficult Use in MAS • Identified Genes • Less predictable task, although easier than in the past, due to newly available tools (BAC libraries, RH maps, human, mice and other genome sequences) • Relative Ease of use in MAS D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  4. General properties of MAS • Definition : MAS = any selection procedure incorporating DNA (markers or genes) information • When optimized, MAS always enhances selection technical efficiency • by increasing selection intensity • or by increasing prediction accuracy • or by decreasing generation interval D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  5. General properties of MAS (2) • But use of molecular information only is rarely optimal : • QTL and genes explain only a fraction of the genetic variability • Several traits are usually selected • Optimal MAS should include both molecular and phenotypic informations D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  6. General properties of MAS (3) • MAS is particularly efficient when • Classical selection is NOT efficient, I.E., when • phenotypes are not observed (sex-limited traits, invasive measures such as disease challenge or meat quality traits) or observed late in life (survival)) • phenotypes are little informative (low heritability, recessive or low penetrance determinism) • phenotypes are expensive to record • In constrast, MAS could be of limited interest for heritable traits with early and cheap recording D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  7. General properties of MAS (4) • MAS is also particularly efficient when • The number of QTL or genes is limited • They explain a large fraction of the genetic variability • Genotyping cost is low • Genes are identified D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  8. Present use of MAS • But today, MAS use seems to be limited • to major genes or transgenes in plants • to few major genes and defects in animals • Because of • its high cost • a lack of confidence of the breeders • a limited number of genes fully characterized • time required to adapt the selection structures D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  9. The 3 steps for gene identification (1) • QTL primo-localisation • Large confidence interval of location • Linkage disequilibrium is restricted to a limited number of generations • In outbred populations, LD is limited to families • => it is not possible to select for given marker alleles D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  10. The 3 steps for gene identification (2) • QTL fine-mapping • Small confidence interval of location (1 cM) • Linkage disequilibrium at the population level over many generations • => It is possible to select for given marker alleles or haplotypes associated to desired QTL alleles • Gene identification • => Selection on favourable gene alleles D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  11. The 3 corresponding MAS procedures The gene is identified as well as the causal mutations : MAS3 The most favourable but still a rare situation Easy to use : selection applies on genotypes (possibly in combination with phenotypes) Recommended approach : selection of the total BV, i.e. the sum of the effect of the major gene and the polygenic effect (BLUP with major gene) Cost limited to a simple test of the candidates and, possibly, to intellectual property fees D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  12. The 3 MAS procedures A QTL is located in a large marker bracket : MAS1 The most frequent and difficult to use situation Marker alleles do not provide information on the QTL alleles Marker information is used to trace QTL over generations… … and to estimate probabilities of identity by descent (PID) between two chromosomal segments D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  13. M1 Q M2 Q or PID=P(QQ1)=1-rMQ PID=rMQ PID=(1-rM)(1-rN)/(1-rMN) PID=rM rN/(1-rMN) M1 Q N1 N1 N2 PID=(1-rM) rN/rMN PID=rM (1-rN) /rMN The 3 MAS procedures M1 Q1 M2 Q2 D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  14. The 3 MAS procedures A QTL is located in a large marker bracket : MAS1 For quantitative traits, the PID are used to build the relationship matrix at the QTL, and this information is included in a marker-assisted BLUP (Fernando & Grossman and extensions) gi = ui + Sqtl ( vs +vm ) High cost : several markers by QTL (marker bracket, non- informativity) many non-candidates should be genotyped Limited efficiency loss of information at the markers level, recombination loss of information at the QTL level D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  15. The 3 MAS procedures A QTL is accurately mapped : MAS2 Intermediate situation LD is present at the population level LD could be used by selecting on some marker alleles For quantitative traits, LD could be used in a MA-BLUP as in MAS1, but assuming related founder QTLs, with PID being a function of marker information Much more efficient than MAS1, primarily because of the lack of recombinants and because the better across-families information Several markers to genotype - No IP fee D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  16. The MAS1 French experience in dairy cattle • Large GDD design carried out in 1996-99 (Boichard et al, GSE, 2003) 14 families, 1548 sons, 169 markers • 12 QTL selected for MAS, each explaining 10-20% of the genetic variance D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  17. Choice of markers 43 markers (2-4 microsatellites per region) The accurate QTL location is unknown => large intervals of 5 to 30 cM Assumption of linkage equilibrium between markers and QTL at the population level => Marker information is used to estimate PID between QTL of relatives Relatives with phenotypic information should be genotyped D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  18. AIBulls candidates 1stcropdaughters Males (<1year) Youngbull Dams (<1,5y) « historicals » Choice of genotyped animals (8,000/year) D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  19. Cost • The major part of the cost (95%) is related to genotyping work • Entirely charged to 8 French breeding companies • Each company is charged for its candidates … • … but also for the historicals • 1.5€ / genotype, 70€/animal • MAS cost per bull entering progeny test: 500€ • MAS cost per elite bull : 5000€ to 10,000€ (up to 150 genotyped animals / bull) • Cost easily affordable in dairy cattle, easily balanced by a small reduction in number of sampling bulls (-3%) • …whereas it allows a reduction >15% D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  20. MAS in small ruminants • Such a large cost is not affordable in small ruminants • MAS in small ruminants is limited to MAS3 or maybe MAS2 • We clearly need to go up to the characterization of the QTL or, at least, their fine mapping D. Boichard, IWMGQSG, December 8-11 2004, Toulouse

  21. MAS in small ruminants • Even with MAS3, genotyping cost is rather high compared to the value of the animals • It should be reserved in priority to breeding animals with a large genetic contribution : AI males, their dams, possibly natural mating bulls Thank you for your attention !!! D. Boichard, IWMGQSG, December 8-11 2004, Toulouse