3 . Questions of Context Irapuato, 20th October 2011

1. 3. Questions of Context Irapuato, 20th October 2011

2. Lecture 3: Questions of context 1. Revision of basic terminology 2. Dominance – interactions among alleles 3. Epistasis – interactions among genes 4. Heterosis – interactions among genomes Ruairidh Sawers, Oct 2011

3. Revision of basic terminology 1 Dominant allele: Form expressed even when heterozygous with a second recessive allele Dominant phenotype: The phenotype of the genotype containing the dominant allele; the parental phenotype expressed in the heterozygote Incomplete dominance: Expression of a phenotype in the heterozygote that is intermediate to the parental phenotypes Codominance: Expression of both parental phenotypes in the heterozygote Epistasis: Phenotypic expression at one locus dependent on the genotype at a second locus Ruairidh Sawers, Oct 2011

4. Revision of basic terminology 2 Heterosis: Superior performance in F1 hybrids relative to their parents Mid-parent heterosis: F1 performance exceeding the mean of the two-parents Better parent heterosis: F1 performance exceeding the higher performing parent Overdominance: The genotypic value of the heterozygote exceeds that of either homozygote Pseudo-overdominance: Dominant acting alleles linked in repulsion creating an apparent overdominant effect Ruairidh Sawers, Oct 2011

5. Interaction Ruairidh Sawers, Oct 2011

6. (Non) Additivity A B A + B aa Aa AA Ruairidh Sawers, Oct 2011

7. Dominance: non-additivity of genotypic values “…hybrids, as a rule, are not exactly intermediate between the parental species. With some of the more striking character … the intermediate, indeed, is nearly always to be seen; in other cases, however, one of the two parental characters is so preponderant that it is difficult, or quite impossible, to detect the other in the hybrid.” Mendel, 1865 “…hybrids, as a rule, are not exactly intermediate between the parental species. With some of the more striking character … the intermediate, indeed, is nearly always to be seen; in other cases, however, one of the two parental characters is so preponderant that it is difficult, or quite impossible, to detect the other in the hybrid.” Mendel, 1865 i.e. typically there is neither complete dominance, nor complete additivity of the parental phenotypes in the F1 Ruairidh Sawers, Oct 2011

8. Dominance: non-additivity of genotypic values A1A2 Genotype A1A1 A2A2 Genotypic value a 0 (1+k)a 2a k = 0, A1and A2completely additive k = 1, A2 completely dominant Ruairidh Sawers, Oct 2011

9. Dominance: non-additivity of genotypic values Genotype A1A2 A1A2 A2A2 Genotypic value a 0 (1+k)a 2a k = 0, A1and A2completely additive k = 1, A2completely dominant k = -1, A1completely dominant Ruairidh Sawers, Oct 2011

10. Dominance: non-additivity of genotypic values Genotype A1A1 A1A2 A2A2 Genotypic value a 0 (1+k)a 2a k = 0, A1and A2completely additive k = 1, A2completely dominant k = -1, A1completely dominant 0< k <1, A2 incompletely dominant (-1< k <0, A1incompletely dominant ) Ruairidh Sawers, Oct 2011

11. Dominance: non-additivity of genotypic values Genotype A1A1 A1A2 A2A2 Genotypic value a 0 (1+k)a 2a k = 0, A1and A2completely additive k = 1, A2completely dominant k = -1, A1completely dominant 0< k <1, A2 incompletely dominant (-1< k <0, A1 incompletely dominant ) k>1, overdominance (k<1, underdominance) => heterosis (?) Ruairidh Sawers, Oct 2011

12. Fisher’s Decomposition of the Genotypic Value (1918) Ruairidh Sawers, Oct 2011

13. The basis of dominance: Kacser-Burns kinetic model “WT” situation near the plateau of a hyperbolic reaction norm: Large effect mutations (i.e. on yield) typically reduce activity Recessive reduced-activity mutations a consequence of the hyperbolic Small effect mutations tend to linearity; i.e. no dominance Ruairidh Sawers, Oct 2011

14. Incomplete dominance at the maize Oil yellow1 locus Ruairidh Sawers, Oct 2011

15. Dominant negative effect at maize Oy1 Ruairidh Sawers, Oct 2011

16. Multiple alleles In natural populations, many alleles may be present at any locus Fisher’s regression model easily accommodates multiple alleles A gradation of phenotypic values > allelic series Classic examples include ABO blood-groups and coat colour in rabbits Test for allelism using expectation based on Mendelian ratios Ruairidh Sawers, Oct 2011

17. Allelic diversity at Pink scutelum1 (Bai et al., Genetics 2007) WT ps1-m18(Ac) ps1-m7(Ac) Ruairidh Sawers, Oct 2011

18. Epistasis Where k ≠ 0, the phenotypic consequence of substitution of a given allele at a given locus depends on the nature of the second allele at the locus The effect an allele has, however, is also determined by the action of other genes; characters are not determined by only one locus In lab experiments, a researcher may try and use material that only differs in the locus of interest In practice, interactions BETWEEN loci will impact the phenotype Epistasis Ruairidh Sawers, Oct 2011

19. Petal pigments in foxglove (Digitalis) M Precursors Anthocyanin Throat spots W Rest of petal D + Ruairidh Sawers, Oct 2011

20. Petal pigments in foxglove (Digitalis) Ruairidh Sawers, Oct 2011

21. Example: Dominant epistasis in a Foxglove dihybrid cross The three loci M, D and W are not genetically linked (RF=50%) In the following cross material is “fixed” for the large M allele i.e. all plants are M/M and the locus can be ignored Consider two pure bred lines DDwwand ddWW The lines are crossed to give an F1, and subsequently self-pollinated to give an F2 Ruairidh Sawers, Oct 2011

22. Example: Dominant epistasis in a Foxglove dihybrid cross – F1 x x DdWw DD ww ddWW Ruairidh Sawers, Oct 2011

23. Example: Dominant epistasis in a Foxglove dihybrid cross – F2 DdWw Filial 1 (F1) x 12 : 3 : 1 F2 Ratio (phenotypic) All plants carrying a W allele are white with spots IRRESPECTIVE of which allele(s) they carry at the D locus W is EPISTATIC to D (Dominant epistasis) Ruairidh Sawers, Oct 2011

24. Epistasis as interaction of genotypic values BB, Bb bb aa Aa AA Ruairidh Sawers, Oct 2011

25. “the longer of the two parental stems is usually exceeded by the hybrid…Thus, for instance, stems of 1 ft. and 6 ft. in length yielded without exception hybrids which varied in length between 6 ft. and 7½ ft.” Gregor Mendel, 1865

26. Heterosis Heterosis: Superior performance in F1 hybrids relative to their parents Mid-parent heterosis: F1 performance exceeding the mean of the two-parents Better parent heterosis: F1 performance exceeding the higher performing parent Springer and Stuper, Gen Res 2008 Better parent heterosis has great importance agronomically Ruairidh Sawers, Oct 2011

27. Heterosis The magnitude of heterosis varies among species Heterosis is the result of variation at multiple genomic loci The level of heterosis varies among traits and is not correlated among different hybrids of the same species Most agronomic heterotic traits are highly polygenic Heterosis for different traits is determined at non-redundant loci Heterosis typically increases with genetic distance between parents – but only up to a point! Furthermore, the relationship is not strong enough to be used as an accurate predictive tool In an agronomic context, generation of lines greatly biases the nature of allelic variation present; heterosis is not a general property of allelic combinations Ruairidh Sawers, Oct 2011

28. Heterotic traits in maize Ruairidh Sawers, Oct 2011

29. Models for heterosis Dominance model: Recessive, deleterious alleles fixed in each inbred parent are complemented by dominant beneficial alleles present in the other parent Overdominance model: The heterozygous state per seis superior to either homozygous state Current thinking favours action of the dominance model at most loci Ruairidh Sawers, Oct 2011

30. Pseudo-overdominance Dominant acting alleles linked in repulsion creating an apparent overdominant effect A b a B M1 M2 X a B A b M1 M2 A b M1 a B M2 Ruairidh Sawers, Oct 2011

31. Mechanistic explanations of heterosis Dominance model Complementation Overdominancemodel Epistatic effects Advantages of mid-parent expression Altered Protein-protein interactions Novel epigenetic states Altered siRNA-based gene regulation Ruairidh Sawers, Oct 2011

32. Heterosis v Inbreeding Depression Heterosis: Superior performance in F1 hybrids relative to their parents Inbreeding depression: Reduced mean performance in a population resulting from increasing homozygosity (note: allele frequencies not changed) ID is an inevitable consequence of dominance; or if k=0, there will be no ID F1 heterosis is the result of extreme gametic phase disequilibrium Heterosis can arise entirely by epstasis Ruairidh Sawers, Oct 2011

33. “In the present state of our knowledge it is impossible to predict … what will be the relative vigor of … hybrid offspring. That is an important relation which future investigators must unlock for us… Getting the seed-corn that shall produce the record crop …[may require] going back each year to the original combination, instead of selecting from among the hybrid offspring the stock for continued breeding” George Schull, 1908

34. Summary

35. Revision of basic terminology 1 Dominant allele: Form expressed even when heterozygous with a second recessive allele Dominance phenotype: The phenotype of the genotype containing the dominant allele; the parental phenotype expressed in the heterozygote Incomplete dominance: Expression of a phenotype in the heterozygote that is intermediate to the parental phenotypes, and closer to one parent than the other Codominance: Expression of both parental phenotypes in the heterozygote Epistasis: Phenotypic expression at one locus dependent on the genotype at a second locus Ruairidh Sawers, Oct 2011

36. Revision of basic terminology 2 Heterosis: Superior performance in F1 hybrids relative to their parents Mid-parent heterosis: F1 performance exceeding the mean of the two-parents Better parent heterosis: F1 performance exceeding the higher performing parent Overdominance: The genotypic value of the heterozygote exceeds that of either homozygote Pseudo-overdominance: Dominant acting alleles linked in repulsion creating an apparent overdominant effect Ruairidh Sawers, Oct 2011

37. Allele Interactions Genetic interactions can give rise to non-Mendelian patterns of inheritance The phenotypic consequence of substitution of a given allele at a given locus may depend on the nature of the second allele at the locus The phenotypic consequence of substitution of a given allele at a given locus may depend on the nature of the alleles at other loci (epistasis) At a population level, the mean phenotype is not just the average of allele effects but depends on the context the alleles are in; i.e. the level of heterozygosity or homozygositiy in the population Ruairidh Sawers, Oct 2011

38. “If certain … size factors [QTL] can be found linked with factors for qualitative [Mendelian] characters it should be possible to study independently the size factors within each linkage group.” Karl Sax, 1923