Allele interactions: Terms used to specify interactions between alleles of the same gene: Dominant/recessive incompletely dominant codominant

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1 Biol 321 Feb 3, 2010 Allele interactions: Terms used to specify interactions between alleles of the same gene: Dominant/recessive incompletely dominant codominant Gene interactions: the collaborative efforts of two or more genes in specifying the phenotype for a specific trait. Terms used to specify interactions between alleles of different genes: no interaction independent, additive contribution to phenotype (unmodified Mendelian ratio: AaBb X AaBb 9:3:3:1) complementary gene action (modified Mendelian ratio AaBb X AaBb 9:7) epistatic (epistasis) (modified Mendelian ratio AaBb X AaBb 9:4:3 for recessive epistasis) modifier (influences but doesn t mask trait) suppressor (suppression) a type of modifier 1

2 The color and patterning of pigmentation in cats, dogs, mice and other mammals results from the interaction of several different genes 2

3 and many other genes Crosses on BOARD 3

4 F2 segregation data Which genes were het in the F1? 4

5 Epistasis: a form of gene interaction in which one gene interferes with the expression of another C-B- black pigment C-bb brown pigment Cc (ccb- or ccbb) albino c allele is epistatic to B gene Epistasis: a form of gene interaction in which one gene interferes with the expression of another (non-allelic) gene so that the phentype is governed by the former gene and not by the latter gene an allele of one gene hides or masks the effects of an allele of another gene the cc allele in the homozygous state masks the expression of the other genes involved in pigment biosynthesis What is the molecular explanation for this phenomenology? 5

6 A gene (agouti) B gene C gene D gene (dilute) S gene spotted or splotch Coat Color in Mammals Alleles A- yellow band on hair shaft aa yellow band absent ligand for Mc1R (see below) inhibits synthesis of black/brown a = loss of function B- black pigment bb brown pigment modifier tyrosinase-related Protein 1 (TYRP1) dilutes black to brown & no effect on red (molecular function unclear) b = loss of function C- pigment present cc pigment absent loss-of-function mutation epistatic to all other genes codes for tyrosinase (see below) c = loss of function D- full expression of pigment dd diluted pigment modifier MLPH: MELANOPHILIN Affects melanosome distribution in the cell: dilutes black to grey and red to fawn d = loss of function S- spots s + s + no spots affect melanocyte migration S = dominant mutant allele Function pigment distribution on hair shaft pigment type presence or absence of pigment pigment intensity presence or absence of spots 6

7 Agouti downregulates tyrosinase which acts at more than one point in the pathway. The synthesis of black/brown pigments is affected more than yellow pigments for reasons that aren t entirely clear (and there were contradictory explanations in different references ) pheomelanin = red or yellow eumelanin = black 7

8 Mammalian Coat Color: Adding other genes (next page) Melanocortin 1 receptor (MC1R aka extensin) (variant alleles of this gene cause red hair in humans) MC1R interacts with: melanocyte stimulating hormone (not shown on next page) causes eumelanin to be synthesized exclusively agouti signalling peptide inhibits Mc1r and causes synthesis of yellow melanins β defensin = K locus: K B dominant to k y 30 NOVEMBER 2007 VOL 318 SCIENCE Genetic analysis of mammalian color variation has provided fundamental insight into human biology and disease. In most vertebrates, two key genes, Agouti and Melanocortin 1 receptor (Mc1r), encode a ligandreceptor system that controls pigment type-switching, but in domestic dogs, a third gene is implicated, the K locus, whose genetic characteristics predict a previously unrecognized component of the melanocortin pathway. We identify the K locus as b-defensin 103 (CBD103) and show that its protein product binds with high affinity to the Mc1r and has a simple and strong effect on pigment type-switching in domestic dogs and transgenic mice. These results expand the functional role of b-defensins, a protein family previously implicated in innate immunity, and identify an additional class of ligands for signaling through melanocortin receptors. 8

9 What type of gene interactions are described in the legend to this figure? 30 NOVEMBER 2007 VOL 318 SCIENCE 9

10 The coat color examples considered above focus on easily visualized phenotypes such as pigmentation It is important to keep in mind, though, that the same principles apply to all traits whether they relate to morphology or physiology or developmental processes. 10

11 ABO blood group genetics: A and B alleles are codominant A and B are completely dominant to O O means not A and not B (this is important) 11

12 H gene ABO gene REMEMBER: O means not A and not B (this is important) 12

13 In a 1945 trial, a woman accused Charlie Chaplin of fathering her child. The ABO blood types were as follows: woman Chaplin child Phene Genotype A O B Revised genotype When the California jury declared that Chaplin was the father of the child, the Boston Herald commented: "California has in effect decided that black is white, two and two are five, and up is down." Do you agree with the jury or with the press? Can you use the principle of epistasis to rescue the reputation of the jury system? 13

14 Infidelity or Epistasis? The Bombay Phenotype: BEFORE FRIDAY Fill in genotype table Answer question on the next page Bombay genotype = hh genotype frequency in Bombay = 1x10-4 genotype frequency in northern Europe = 1x

15 The complicated relationship between genes and phenotypes Coat Variation in the Domestic Dog Is Governed by Variants in Three Genes 2 OCTOBER 2009 VOL 326 SCIENCE Coat color and type are essential characteristics of domestic dog breeds. Although the genetic basis of coat color has been well characterized, relatively little is known about the genes influencing coat growth pattern, length, and curl. We performed genome-wide association studies of more than 1000 dogs from 80 domestic breeds to identify genes associated with canine fur phenotypes. Taking advantage of both inter- and intrabreed variability, we identified distinct mutations in three genes, RSPO2, FGF5, and KRT71 (encoding R-spondin 2, fibroblast growth factor 5, and keratin-71, respectively), that together account for most coat phenotypes in purebred dogs in the United States. Thus, an array of varied and seemingly complex phenotypes can be reduced to the combinatorial effects of only a few genes. What type of gene interaction is seen here? NOTE: - represents ancestral allele (found in wolves) + = variant allele 7 out of 8 combos are shown here Which is missing? 15