Textbook assignment: Chapter 4, pages 88 - 95 (pages 95-100 are now part of Lecture 9).
Important terms to learn:
Introduction: This lecture and the first half of the next lecture sample a number of examples of the effects of interaction between alleles at two or more genetic loci in determining the final phenotype of an individual. This lecture focuses on the ways in which alleles at one genetic locus can influence phenotypic expression of alleles at other loci and on the unusual F2 phenotypic ratios that are produced by such interactions. In the next lecture, we will examine continuous phenotypic variation and the ways in which alleles at more than one locus interact in an additive manner to influence a quantitative phenotype, such as the size of an individual or the degree of pigmentation expressed.
Combinations of gene pairs: In some cases, independent assortment of alleles at two different loci that have different patterns of dominance, partial dominance or codominance can lead to unusual phenotypic ratios. The example cited in the textbook involves the mating of two individuals who are both blood type AB and also heterozygous for albinism +/a. The AB blood types will segregate in a 1:2:1 ratio and the albinism will segregate in a 3:1 ratio. Since these are independently assorting events, the product rule will yield six different phenotypes in the following ratios.
Discontinuous variation: Before entering into a discussion of gene interactions, the textbook makes a distinction between discontinuous variation where phenotypic traits differ from one another in discrete steps such that each phenotype can be clearly distinguished from the others and continuous variation, where there is no easily distinguished borderline between phenotypes, such as size or intensity of pigmentation. We will begin with discontinuous variation.
Epistasis: The term epistasis is derived from a Greek word that means stoppage. Epistasis is most correctly used to describe situations where alleles at one genetic locus can directly alters phenotypic expression of alleles at another locus. However, the term is also frequently used in a more generic sense to describe other types of modification of expression of one gene by another. In cases where direct masking of expression occurs, the locus whose expression is masked is described as hypostatic, and the locus whose alleles cause the masking is described as epistatic.
Epistasis in Bombay phenotype: We have already observed an example of epistasis in failure of expression of type A and type B blood groups by individuals with the Bombay phenotype who are homozygous for rcessive mutation h that blocks addition of a fucose molecule to the H substance precursor and thus prevents expression of type A or type B by individuals who carry the IA or IB alleles. In matings of individuals who are blood type AB and heterozygous Hh, 1/4 will be homozygous hh and thus have type O blood irrespective of the Ia and IB genes that they carry. Among the 3/4 of the progeny that are HH or Hh, there will be a 1:2:1 distribution of blood types A:AB:A. This will yield a final phenotypic distribution of 3/16 type A, 6/16 type AB, 3/16 type B, and 4/16 type O. Note that the individuals who test as type O are actually h/h individuals who appear phenotypically to be type O because they make no H substance for the addition of acetylgalactosamine or galactose. Their genotypes at the ABO locus are actually 1:2:1 AA:AB:BB.
Altered phenotypic ratios: The patttern of epistasis obtained when the Bombay phenotype interacts with codominant A and B blood type alleles to generate a 6:4:3:3 F2 phenotypic ratio is only one of many cases in which unusual F2 ratios can be obtained. Figure 4.7 on page 91 of our textbook illustrates 5 different modified F2 ratios that can be obtained in dihybrid crosses with various types of epistatic interaction that involve only fully dominant and fully recessive behavior of the alleles that are involved. The situation can become even more complex if intermediate phenotypes due to codominance or partial dominance are allowed, as illustrated by case 8 in Figure 4.8 of the textbook. However, only a few of these situations are fully explored in the text. We will largely follow its lead, but you should be aware that a large number of additional possibilities exist.
Phenotype-based description of genotype: To keep our discussions of gene interactions as simple as possible, we will be using a simplified designation to represent all genotypes that yield a dominant phenotype. For genes where there is full dominance, any genotype that contains at least one copy of the dominant ellele will be designated by the symbol for the dominant allele followed by a dash in in the second position. Thus, A- describes any genotype that produces a dominant A phenotype (either AA or Aa). Similarly, the designation A-B- indicates any genetic combination that yields both dominant A and dominant B phenotypes (AABB, AABb, AaBB, or AaBb).
Gene nomenclature in textbook examples: In an attempt to simplify comparisons of various gene interactions, the authors of our textbook have arbitrarily designated the genetic loci that they work with in each pattern of interaction as A and B. This may be a source of confusion from time to time because the actual genes that they are discussing also have standard designations that differ from A and B. You will find this to be particularly confusing when we discuss coat color in mice, because the actual genes that we will be talking about have letter designations that partially overlap the arbitrary A and B designations that the textbook authors use. .
Coat color in mice: Multiple genes are involved as described below: As you work with these genes, please keep in mind that the arbitrary A and B designations used by the textbook authors are not the same as the real life designations. In the discussion that follows, I have used the actual mouse genetics designations with some cross-references to the arbitrary textbook names. In particular, the locus I will be referring to as C/c (coat color)is generically called B/b in the textbook. The locus designated B/b by mouse geneticists causes a black pigment to become brown in the homozygous recessive state. These genetic loci and their alleles are explained more fully below.
The agouti (A/a) locus causes cyclic switching between black and yellow hair pigment in the dominant (A-) phenotype. This is what gives wild mice their mousy gray color. The recessive aa phenotype is solid black because the yellow is not switched on at all. Dominant yellow (Ay) occurs when yellow stays on. This genetic locus has been designated "A" by the authors, which is not in itself confusing.
The brown (B/b) locus Is named for the recessive phenotype, which causes the hair pigment to be brown instead of black. A functional wild type allele (B- genotype) is required to synthesize black pigment. Combined with aa, the bb genotype yields a solid brown (rather than black) mouse. Combined with A-, it yields a cinnamon (rather than agouti) mouse. THIS IS NOT THE LOCUS DESIGNATED "B" IN THE TEXTBOOK. Our current textbook chooses to ignore the brown locus entirely and focus only on agouti (A/a) and coat pigment (C/c) genes (with the latter generically called B/b).
The coat color (C/c) locus must be in the dominant form (C-) to obtain any coat color at all. The recessive phenotype (cc) is albino, with no coat color at all. THIS IS THE LOCUS THAT THE TEXTBOOK ARBITRARILY REFERS TO AS "B".
Epistatic effect of cc genotype: The cc recessive (albino) phenotype exhibits complete epistasis over any combination of A and B genes. Thus mice with a cc genotype are always white irrespective of the other coat color genes they carry. The textbook examines the F2 from a cross of a mouse from a true-breeding agouti strain (AACC) and a true breeding white strain that is also homozygous for the recessive lack of the agouti allele (aacc). The phenotypic ratio of the progeny is 9 agouti:3 black:4 albino. Because of the epistatic effect of the cc phenotype, the 3/16 of the progeny that are A-cc and the 1/16 of the progeny that are aacc are all albino, with phenotypic effects of the various genotypes at the A/a locus totally masked. progeny) are albino and in this case causes the ratio of pigmented (agouti plus black) to albino to be 3:1.
Trihybrid cross of agouti, brown and coat color genes: The overall interplay of these three genes causes a complex pattern of inheritance of coat color that can be analyzed readily through use of the product rule, and diagramed through use of the branching line approach. Remember that cc is totally epistatic over any other effects, and that in animals that have a C- genotype, the A and B genes interact to yield agouti (A-B- phenotype), black (aaB- phenotype), cinnamon (A-bb phenotype), and brown (aabb phenotype). The expected phenotypic combinations from AaBbCc x AaBbCc would be as follows:
Additional loci: Even this is not the whole story. There are also at least three more genes involved in the coloration of mice (and many other mammals): Dilute (D/d) causes diluted intensity of pigment in the recessive; Pink (P/p) causes unpigmented eyes that look pink in the recessive; Spotted (S/s) causes spotted pigmentation in the recessive. For these six genes together, the frequency of the all dominant phenotype in the F2 by the branched line method would be (3/4)6 = 729/4096 and the frequency of the all recessive phenotype would be (1/4)6 = 1/4096.
Nothing below this line will be on the September 16, 1998 examination.
Dominant inhibitory loci: The second generic example presented in the textbook involves dominant inhibitory loci, which mask expression of whatever genes are present at a second locus. This effect is similar to the albino coat color gene in mice, except that it is dominant, rather than recessive, and thus expressed in 3/4 of the F2 progeny. An example is fruit color in squash, where dominant white is epistatic over a second locus that makes the fruit yellow in the dominant form and green in the recessive form. This results in an F2 ratio of 12/16 white, with the remaining colored fruit in a typical 3:1 ratio of 3/16 yellow and 1/16 green. (See case 2, figure 4.8, in the textbook).
Complementary gene action: Blocking of any one step in a sequential enzymatic process can prevent a final result. Anthocyanin pigment synthesis in sweet peas is an example where blocking either of two steps prevents pigment formation. Only the double dominant phenotype has both enzymes functional and can make pigment. The F2 progeny ratio is 9 pigmented (A-B-) to 7 unpigmented (A-bb, aaB-, or aabb). This is ilustrated in the textbook, (Case 3, Figure 4.8). Similar results can also be obtained obtained if the products of two independently coded enzymes must interact to yield the final product. Please note that some purists do not consider complementary gene action to be an example of epistasis because it involves two steps in the same pathway rather than modification of the effects of one gene by another. However, three different texts for this course have included it under epistasis.
Duplicate gene action: If either of two genes can achieve the same result, both halves of the redundant process must be blocked to prevent phenotypic expression. Only the double recessive will exhibit the mutant phenotype (15:1 phenotypic ratio in F2). Additional ways to achieve unusual phenotypic ratios are included in Figure 4.8, and a few are discussed in greater detail.
Fruit shape in summer squash: An unusual combination is seen in the shape of the fruit of summer squash, where two separate loci have additive effects on fruit shape. Elongated fruit are homozygous recessive at two separate loci (aabb) that influence shape. At the other extreme, fruit that have at least one dominant allele at each of the two loci (A-B-) are flattened to a disc shape (Figure 4.10). Fruit that are recessive at one of the loci but have at least one dominant allele at the other exhibit an intermediate spherical shape, with no obvious phenotypic difference based on which of the loci carries the dominant allele or alleles (A-bb or aaB-). This results in an F2 phenotypic ratio of 9/16 disc-shaped, 6/16 spherical, and 1/16 elongated. This may be a simplistic case of the additive effects of alleles at separate loci discussed for continuous variability later in the chapter, although there is some difference in that each locus appears to exhibit a definite dominance/recessiveness relationship.
Brown, scarlet, and white eyes: An even stranger case occurs in Drosophila eye color mutations. We have already discussed the white-eyed locus, which has multiple alleles that can have rather diverse effects on eye color. Please keep in mind that the effects discusse below here are caused by interaction of two completely different loci, even though one of the consequences of their interaction can be white eyes that are phenotypically the same as those caused by the w/w phenotype.
Two pigments needed for wild-type eye color: The deep red color of the eyes of wild type Drosophila is caused by the presence of two different types of pigment. The mutant strain brown (bw/bw) fails to make a scarlet pigment, and has brown eyes because only brown pigment is made. It is confusing, but very important to remember that brown eyed flies fail to make scarlet pigment. Similarly, the mutant strain scarlet (st/st) has scarlet eyes because they fail to make brown pigment. Thus, the locus called brown codes for an enzyme involved in the synthesis of scarlet pigment, and the locus called scarlet codes for an enzyme involved in the synthesis of brown pigment. Note that naming genetic loci for the effects of recessive (loss of function) mutations can become very confusing, as illustrated by this case.
Loss of both pigments results in white eyes: In the double mutant strain (bw/bw, st/st), neither pigment is made and the eyes are white. Thus, as illustrated in Figure 4.11, the F2 of a cross of a true-breeding brown-eyed fly and a true-breeding scarlet-eyed fly will yield 9/16 wild type, 3/16 brown-eyed, 3/16 scarlet-eyed, and 1/16 white-eyed. As we shall see in a future lecture, a loss of function mutation in a single sex-linked genetic locus, designated w for white eyes, can have the same phenotypic effect as the simultaneous presence of homozygous b/b and st/st mutations.
Continuous variation and polygenic inheritance: All material on these topics (textbook pages 95-100) has been moved to lecture 9, where it has beem integrated into a more advanced discussion that includes material from Chapter 7.