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					The Role of Epistasis in the
Control of Complex Traits
  Örjan Carlborg and Chris Haley
         Roslin Institute



                                   July 2003
                  Epistasis
• Epistasis = interactions between alleles at
  different loci
• Relatively neglected in quantitative genetics
• More attention in qualitative genetics where
  several types of epistasis has been found for
  e.g. coat colour phenotypes



                                        July 2003
Examples of classic epistasis
                                                  Hybrid dysgenesis
                                                       Dominant epistasis
                                             1

                                           0.5




                               Phenotype
                                             0

                                           -0.5

                                             -1
                                                  AA                                       BB Locus 2
                                                             Aa                Bb
                               Locus 1                               aa   bb



           Complementary epistasis                                                                    Duplicate epistasis
                                                   1                                        1

                                                   0.8                                     0.8


                                                                               Phenotype
                                                         Phenotype




                                                   0.6                                     0.6

                                                   0.4                                     0.4

                                                   0.2                                     0.2

                                                   0                                         0
                                                                                                                              BB Locus 2
           AA                                BB                                                  AA                      Bb
                                                                                                        Aa
 Locus 1        Aa                Bb              Locus 2                        Locus 1                       aa   bb
                     aa   bb


                                                                                                                                July 2003
           Epistasis and QTL
• Most QTL mapping studies focus on
  detection of marginal effects assuming
  absence of epistasis
• Assumption of no epistasis based on low
  estimates of epistatic variances from
  quantitative genetic studies
• Some studies have searched for epistasis
  between QTL with significant marginal
  effects
                                       July 2003
       Why consider epistasis?
• Similar cellular mechanisms affect
  quantitative and qualitative traits
• Increased power to detect QTL which
  mediate their effects through interactions
• Epistasis could bias estimates of additive and
  dominance effects
• Epistasis could help in the interpretations of
  QTL mapping results
                                        July 2003
  Methodology to detect epistasis
• Need procedure to detect QTL with marginal
  effects as well as entirely epistatic QTL
• One option (Carlborg and Andersson, 2002):




                                     July 2003
  Increased power to detect QTL
• Possible to detect novel QTL pairs with very
  small or no marginal effects at all possible for
  the individual QTL
• Increased support for QTL with close to
  significant marginal effects




                                         July 2003
       New epistatic QTL detected
• Some QTL can not be detected by their marginal
  effects
• E.g. QTL pair affecting hatch weight in chicken




                                        July 2003
     New epistatic QTL detected
• Simultaneous mapping of epistatic QTL
  increases significance for some QTL with
  minor marginal effects
                                            Growth rate in JF x WL chicken F2
               50
                                                            Genome wide F-profile
                                                                                                                                                                                       22
               45
                                                            5% genome wide marginal significance
                                                                                                                                                                                       20
                                                            Chromosome number




                                                                                                                                                                                            Cromosome number
               40
                                                                                                                                                                                       18

               35
                                                            5% genome wide interacting QTL
                                                                                                                                                                                       16
     F-value




               30                                                                                                                                                                      14

                                                                                                                                                                                       12
               25
                                                                                                                                                                                       10
               20
                                                                                                                                                                                       8
               15
                                                                                                                                                                                       6
               10
                                                                                                                                                                                       4
                5                                                                                                                                                                      2

                0                                                                                                                                                                      0
                    1
                        106
                              211
                                    316
                                          421
                                                526
                                                      631
                                                            736
                                                                  841
                                                                        946
                                                                              1051
                                                                                     1156
                                                                                            1261
                                                                                                   1366
                                                                                                          1471
                                                                                                                 1576
                                                                                                                        1681
                                                                                                                               1786
                                                                                                                                      1891
                                                                                                                                             1996
                                                                                                                                                    2101
                                                                                                                                                           2206
                                                                                                                                                                  2311
                                                                                                                                                                         2416
                                                                                                                                                                                2521
                                                                        Genomic location (cM)

                                                                                                                                                                                                               July 2003
  Bias in estimation of QTL effects
• Estimates of marginal genetic effects are the
  average effect of the alleles at a locus across all
  alleles at all other genomic loci
• By identifying interactions between loci one
  can obtain additional information about e.g.
  – In which genetic background a QTL has its most
    influential effects
  – How further studies should be designed to
    maximise the chance to replicate a QTL

                                           July 2003
Bias in estimation of QTL effects
                            Dominant epistasis
                   320
                   300
       Phenotype
                   280
                   260
                   240
                   220
                    200
                          BB                          aa    Locus 1
                                  Bb             Aa
               Locus 2                 bb   AA


              Effect       Marginal         Genetic background
                                         LL          JL        JJ
                   a1          -3.2     -31.5        7.0      4.7
                   d1           0.0      8.5        -3.5      -1.5
                   a2          -7.0     -22.6       -9.5     13.6
                   d2          -7.3     -24.2      -10.8     16.7



                                                                      July 2003
   Additional variance explained
• The estimates of the relative amount of
  variance attributable to epistasis depend on
  the genetic model used in the study
• The simplest and most commonly used model
  is that of Mather and Jinks
• Alternatives include the Cockerham model



                                      July 2003
     Additional variance explained
• Epistasis explains a considerable portion of
  the genetic variance (Mather-Jinks model)
Species   Type      Traits      No traits    % Epistatic variance         Reference
                                            Mean Max          Min
Chicken    F2      Growth          5        46%     79%        0%    Carlborg et al. 2003a
Chicken    F2      Growth          3        26%     31%       19%    Carlborg et al. 2003b
Mouse     RBC     Diabetes         4        27%     33%       19%      Kim et al. 2001
Mouse      F2     Behaviour        5        49%     81%       16%   Shimomura et al. 2001
Mouse     RBC    Hypertension      1        16%     16%       16%    Sugyiama et al. 2001




                                                                          July 2003
 Genetic mechanisms of epistasis
• By understanding more about the nature of
  QTL interactions, one can:
  – Be more precise when selecting candidate genes
  – Better select the strategy for replicating a QTL
  – Get higher efficiency in marker assisted selection
    (MAS)
• Need to explore Genotype-Phenotype
  patterns for epistatic QTL

                                            July 2003
   Genetic mechanisms of epistasis
• Chicken F2 intercross between growth and
  layer selection lines:
  – 21 epistatic QTL pairs detected
  – 17 pairs could be associated with one of 4 types of
    epistasis




                                             July 2003
   Genetic mechanisms of epistasis
• Chicken F2 intercross – 4 common types of epistasis:
                       A)                          Growth 6 to 9 weeks of age                                 B)                                               Bodyweight 6 weeks of age




                       1200,0
                                                                                                                                250,0

                       1000,0
                                                                                                                                200,0
                        800,0
           Deviation




                                                                                                                    Deviation
                                                                                                                                150,0
                        600,0


                        400,0                                                                                                   100,0


                         200,0                                                            LL                                        50,0
                                                                                                                                                                                                     LL
                                                                                     BL
                             0,0                                                           Chr 5, 127 cM                                                                                        BL
                                                                                BB                                                           0,0                                                      Chr 6, 34 cM
                                          BB
                                                         BL                                                                                               BB                               BB
                                                                     LL                                                                                              BL

             C)
                                              Chr 3, 63 cM                                                                                                                      LL


                                                                                                                            D)
                                                                                                                                                          Chr 1, 383 cM
                                                        Growth 3 to 6 weeks of age

                                                                                                                                                                    Bodyweight 6 weeks of age




                                      200,0                                                                                                   160,0
                                      180,0
                                                                                                                                              140,0
                                      160,0
                                      140,0                                                                                                   120,0
                          Deviation




                                      120,0                                                                                                   100,0
                                                                                                                                 Deviation




                                      100,0
                                                                                                                                                   80,0
                                       80,0
                                       60,0                                                                                                        60,0

                                        40,0                                                                                                       40,0
                                                                                                    BB
                                        20,0                                                                                                                                                                   BB
                                                                                               BL                                                  20,0
                                         0,0                                                         Chr 27, 0 cM                                                                                         BL
                                                                                          LL                                                        0,0                                                         Chr 18, 13 cM
                                                   BB
                                                               BL                                                                                              BB                                    LL
                                                                           LL                                                                                             BL
                                                  Chr 1, 145 cM                                                                                                                       LL
                                                                                                                                                               Chr 1, 150 cM



                                                                                                                                                                                                                            July 2003
               Conclusions
• Epistasis is abundant
• Epistasis increases power in QTL mapping
  – Novel QTL detected and more variance explained
• Epistasis might be needed to replicate QTL
  findings and clone QTL
• Can not understand control of complex traits
  without considering epistasis


                                         July 2003
           Acknowledgements
• Roslin Institute
  – Dave Burt, Paul Hocking, DJ deKoning
• Swedish University of Agricultural Sciences
  – Leif Andersson, Per Jensen, Susanne Kerje, Karin
    Schutz
• The Knut and Alice Wallenberg foundation
• NGSSC
• BBSRC

                                           July 2003

				
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