Complex gene interactions in coat color -...

Genetica perScienzeNaturalia.a. 08-09 prof S. Presciuttini

GENE INTERACTION

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Gene interaction and modified dihybrid ratios The genes of an individual do not operate isolated from one another, but obviously The genes of an individual do not operate isolated from one another, but obviously

are functioning in a common cellular environment. Thus, it is expected interactions are functioning in a common cellular environment. Thus, it is expected interactions between genes would occur.between genes would occur.

Genetic analysis can identify the genes that interact in the determination of a Genetic analysis can identify the genes that interact in the determination of a particular biological property. The key diagnostic is that two interacting genes particular biological property. The key diagnostic is that two interacting genes produce produce modified dihybrid ratios.modified dihybrid ratios.

There are various types of interactions, and they lead to a range of different There are various types of interactions, and they lead to a range of different modifications. An important distinction is between genes interacting in different modifications. An important distinction is between genes interacting in different biological pathways and those interacting in the same pathway.biological pathways and those interacting in the same pathway.

Generally, interacting genes in two different pathways produce an FGenerally, interacting genes in two different pathways produce an F22 with four with four phenotypes corresponding to the four possible genotypic classes. However, when phenotypes corresponding to the four possible genotypic classes. However, when the mutations are in one biological pathway, different ratios are seen. Usually there the mutations are in one biological pathway, different ratios are seen. Usually there are only two or three phenotypes resulting from various combinations of the are only two or three phenotypes resulting from various combinations of the genotypic classes. genotypic classes.


An early experiment with chicken combIn an In an experimentexperiment performed in 1907, performed in 1907, Bateson and Punnett analyzed the Bateson and Punnett analyzed the comb comb shapeshape of chicken of chicken..

Crossing a pure breed with the “rose” comb with a pure breed with the “pea” Crossing a pure breed with the “rose” comb with a pure breed with the “pea” comb,comb,

they obtained an F1 with a new phenotype, termed “walnut”:they obtained an F1 with a new phenotype, termed “walnut”:

At first sight, the situation could be that of a simple case of intermediate At first sight, the situation could be that of a simple case of intermediate dominance. However, a surprise was found by crossing the F1: another dominance. However, a surprise was found by crossing the F1: another new new phenotype not seen in the parents appeared in the F2phenotype not seen in the parents appeared in the F2, and the segregation ratios , and the segregation ratios were typical of a dihybrid cross:were typical of a dihybrid cross:

9 rose : 3 pea : 3 walnut : 1 single9 rose : 3 pea : 3 walnut : 1 single


Genotypes in the comb phenotype The modes of gene interaction and the genotypes were determined by The modes of gene interaction and the genotypes were determined by

performing the appropriate testcrosses.performing the appropriate testcrosses. It was shown that the genotypes of the initial parents were:It was shown that the genotypes of the initial parents were:

Rose = RRRose = RR//pppp and and Pea = rrPea = rr//PPPP Therefore, genotypically the Therefore, genotypically the F2 was composed as followsF2 was composed as follows: :

Phenotypes Genotypes FrequencyWalnut R-P- 9/16Rose R-pp 3/16Pea rrP- 3/16Single rrpp 1/16

ThThus, two different loci interact in determining what may be described us, two different loci interact in determining what may be described as a variation at a single phenotypeas a variation at a single phenotype


The 9:3:4 modified ratio

The The ww and and mm genes are not linked. If homozygous white and magenta genes are not linked. If homozygous white and magenta plants are crossed, the Fplants are crossed, the F11 and F and F22 are as follows: are as follows:

If one or more intermediates in a biochemical pathway is colored, then a different F2 ratio is produced. In this example, taken from the plant blue-eyed Mary (Collinsia parviflora), the pathway is as follows:

Complemention results in a wild-type F1, though a 9:3:4 ratio in the F2 is produced. This kind of interaction is called Complemention results in a wild-type F1, though a 9:3:4 ratio in the F2 is produced. This kind of interaction is called epistasisepistasis,, which literally means “standing on”; this is a case of which literally means “standing on”; this is a case of recessive epistasisrecessive epistasis. .

http://www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=iga.glossdiv.6078


Coat-color inheritance in Labrador retrievers

Two alleles Two alleles BB and and bb of a pigment of a pigment gene determine (a) black and (b) gene determine (a) black and (b) brown, respectively. At a separate brown, respectively. At a separate gene, gene, EE allows color deposition in allows color deposition in the coat, and the coat, and ee//ee prevents prevents deposition, resulting in (c) the gold deposition, resulting in (c) the gold phenotype. This is a case of phenotype. This is a case of recessive epistasis. Thus the three recessive epistasis. Thus the three homozygous genotypes are (a) homozygous genotypes are (a) BB//BB ; ; EE//EE, (b) , (b) bb//bb ; ; EE//EE, and (c) , and (c) BB//BB ; ; ee//ee or or bb//bb ; ; ee//ee. The progeny of . The progeny of a dihybrid cross would produce a a dihybrid cross would produce a 9:3:4 ratio of black:brown:golden. 9:3:4 ratio of black:brown:golden.


A molecular mechanism for recessive epistasis.Two representative genes encode Two representative genes encode enzymes catalyzing successive steps in enzymes catalyzing successive steps in the synthesis of a blue petal pigment. The the synthesis of a blue petal pigment. The substrates for these enzymes are colorless substrates for these enzymes are colorless and pink, respectively, so null alleles of and pink, respectively, so null alleles of the genes will result in colorless (white) the genes will result in colorless (white) or pink petals. The epistasis is revealed in or pink petals. The epistasis is revealed in the double mutant because it shows the the double mutant because it shows the phenotype of the earlier of the two blocks phenotype of the earlier of the two blocks in the pathway (that is, white). Hence the in the pathway (that is, white). Hence the mutation in the earlier gene precludes mutation in the earlier gene precludes expression of any alleles of a gene acting expression of any alleles of a gene acting at the later step. at the later step.


The 9:7 modified ratio We now return to the example of petal color in harebells. Two We now return to the example of petal color in harebells. Two

different white-petaled homozygous lines were crossed and the Fdifferent white-petaled homozygous lines were crossed and the F11 was was blue flowered, showing complementation. What will be the Fblue flowered, showing complementation. What will be the F22 resulting from crossing the Fresulting from crossing the F11 plants? plants?

The results show that homozygosity for the recessive mutant allele of either gene or The results show that homozygosity for the recessive mutant allele of either gene or both genes causes a plant to have white petals. To have the blue phenotype, a plant both genes causes a plant to have white petals. To have the blue phenotype, a plant must have at least one dominant allele of both genes. must have at least one dominant allele of both genes.

The F2 shows both blue and The F2 shows both blue and white plants in a ratio of 9:7. white plants in a ratio of 9:7. How can these results be How can these results be explained? The 9:7 ratio is explained? The 9:7 ratio is clearly a modification of the clearly a modification of the dihybrid 9:3:3:1 ratio with the dihybrid 9:3:3:1 ratio with the 3:3:1 combined to make 7. 3:3:1 combined to make 7.


Complex gene interactions in coat color

The analysis of coat color in mammals is a beautiful example of how The analysis of coat color in mammals is a beautiful example of how different genes cooperate in the determination of overall coat different genes cooperate in the determination of overall coat appearance. The mouse is a good mammal for genetic studies because appearance. The mouse is a good mammal for genetic studies because it is small and thus easy to maintain in the laboratory, and because its it is small and thus easy to maintain in the laboratory, and because its reproductive cycle is short.reproductive cycle is short.

It is the best-studied mammal with regard to the genetic determination It is the best-studied mammal with regard to the genetic determination of coat color. The genetic determination of coat color in other of coat color. The genetic determination of coat color in other mammals closely parallels that of mice, and for this reason the mouse mammals closely parallels that of mice, and for this reason the mouse acts as a model system. We shall look at examples from other acts as a model system. We shall look at examples from other mammals as our discussion proceeds. At least five major genes mammals as our discussion proceeds. At least five major genes interact to determine the coat color of mice: the genes are A,interact to determine the coat color of mice: the genes are A, B, C, D, B, C, D, and Sand S


The A gene This gene determines the distribution of pigment in the hair. The wild-This gene determines the distribution of pigment in the hair. The wild-

type allele type allele AA produces a phenotype called produces a phenotype called agouti.agouti. Agouti is an overall Agouti is an overall grayish color with a brindled, or "salt-and-pepper," appearance. It is a grayish color with a brindled, or "salt-and-pepper," appearance. It is a common color of mammals in nature. The effect is caused by a band common color of mammals in nature. The effect is caused by a band of yellow on the otherwise dark hair shaft. of yellow on the otherwise dark hair shaft.

In the nonagouti phenotype (determined by In the nonagouti phenotype (determined by the allele the allele aa), the yellow band is absent, so ), the yellow band is absent, so there is solid dark pigment throughout. The there is solid dark pigment throughout. The lethal allele lethal allele AAYY, discussed in an earlier , discussed in an earlier section, is another allele of this gene; it section, is another allele of this gene; it makes the entire shaft yellow. Still another makes the entire shaft yellow. Still another allele allele aatt results in a "black-and-tan" effect, results in a "black-and-tan" effect, a yellow belly with dark pigmentation a yellow belly with dark pigmentation elsewhere.elsewhere.


The B gene This gene determines the color of pigment. There are two major This gene determines the color of pigment. There are two major

alleles, alleles, BB coding for black pigment and coding for black pigment and bb for brown. The allele for brown. The allele BB gives the normal agouti color in combination with gives the normal agouti color in combination with AA but gives solid but gives solid black with black with a/aa/a. The genotype . The genotype AA//-- ; ; b/bb/b gives a streaked brown color gives a streaked brown color called called cinnamon,cinnamon, and and a/aa/a ; ; b/bb/b gives solid brown. gives solid brown.

In horses, the breeding of domestic lines seems to have eliminated the In horses, the breeding of domestic lines seems to have eliminated the AA allele that determines the agouti phenotype, although certain wild allele that determines the agouti phenotype, although certain wild relatives of the horse do have this allele. The color we have called relatives of the horse do have this allele. The color we have called brownbrown in mice is called in mice is called chestnutchestnut in horses, and this phenotype also is in horses, and this phenotype also is recessive to black. recessive to black.


The C gene The wild-type allele The wild-type allele CC permits color expression, and the allele permits color expression, and the allele cc prevents color prevents color

expression. The expression. The c/cc/c constitution is epistatic to the other color genes. The constitution is epistatic to the other color genes. The c/cc/c animals animals are of course albinos. Albinos are common in many mammalian species and have are of course albinos. Albinos are common in many mammalian species and have also been reported among birds, snakes, and fish.also been reported among birds, snakes, and fish.

In most cases, the gene codes for the melanin-producing enzyme tyrosinase. In In most cases, the gene codes for the melanin-producing enzyme tyrosinase. In rabbits an allele of this gene, the rabbits an allele of this gene, the chch (Himalayan) allele, determines that pigment will (Himalayan) allele, determines that pigment will be deposited only at the body extremities. In mice the same allele also produces the be deposited only at the body extremities. In mice the same allele also produces the phenotype called phenotype called HimalayanHimalayan, and in cats the same allele produces the phenotype , and in cats the same allele produces the phenotype called called SiameseSiamese..

The allele The allele chch can be considered a version of the can be considered a version of the cc allele with heat-sensitive allele with heat-sensitive expression. It is only at the colder body extremities that expression. It is only at the colder body extremities that chch is functional and can is functional and can make pigment. In warm parts of the body it is expressed just like the albino allele make pigment. In warm parts of the body it is expressed just like the albino allele cc. . This allele shows clearly how the expression of an allele depends on the This allele shows clearly how the expression of an allele depends on the environment.environment.


The D gene The D gene controls the intensity of pigment specified by the other coat color genes. The D gene controls the intensity of pigment specified by the other coat color genes.

The genotypes The genotypes D/DD/D and and D/dD/d permit full expression of color in mice, but permit full expression of color in mice, but d/dd/d "dilutes" the color, making it look milky. The effect is due to an uneven distribution "dilutes" the color, making it look milky. The effect is due to an uneven distribution of pigment in the hair shaft. Dilute agouti, dilute cinnamon, dilute brown, and dilute of pigment in the hair shaft. Dilute agouti, dilute cinnamon, dilute brown, and dilute black coats all are possible. A gene with such an effect is called a black coats all are possible. A gene with such an effect is called a modifier genemodifier gene..

In horses, the D allele shows In horses, the D allele shows incomplete dominance. incomplete dominance. The The ffigureigure shows how dilution shows how dilution affects the appearance of affects the appearance of chestnut and bay horses. Cases chestnut and bay horses. Cases of dilution in the coats of house of dilution in the coats of house cats also are commonly seen.cats also are commonly seen.


The S gene The S gene controls the distribution of coat pigment throughout the The S gene controls the distribution of coat pigment throughout the

body. In effect, it controls the presence or absence of spots. The body. In effect, it controls the presence or absence of spots. The genotype S/ results in no spots, and s/s produces a spotting pattern genotype S/ results in no spots, and s/s produces a spotting pattern called piebald in both mice and horses. This pattern can be called piebald in both mice and horses. This pattern can be superimposed on any of the coat colors considered so far, with the superimposed on any of the coat colors considered so far, with the exception of albino.exception of albino.


Summary of coat color genetics in mice The normal coat appearance in wild The normal coat appearance in wild

mice is produced by a complex set mice is produced by a complex set of interacting genes determining of interacting genes determining pigment type, pigment distribution pigment type, pigment distribution in the individual hairs, pigment in the individual hairs, pigment distribution on the animal's body, distribution on the animal's body, and the presence or absence of and the presence or absence of pigment. Such interactions are pigment. Such interactions are deduced from crosses in which two deduced from crosses in which two or more of the interacting genes are or more of the interacting genes are heterozygous for alleles that modify heterozygous for alleles that modify the normal coat color and pattern. the normal coat color and pattern. Interacting genes such as those in Interacting genes such as those in mice determine most characters in mice determine most characters in any organism.any organism. Some of the pigment patterns in Some of the pigment patterns in

micemice


Modifier genes Modifier gene action can be based on many different molecular mechanisms. One Modifier gene action can be based on many different molecular mechanisms. One

case involves regulatory genes that bind to the upstream region of the gene near the case involves regulatory genes that bind to the upstream region of the gene near the promoter and affect the level of transcription. Positive regulators increase ("up-promoter and affect the level of transcription. Positive regulators increase ("up-regulate") transcription rates, and negative regulators decrease ("down-regulate") regulate") transcription rates, and negative regulators decrease ("down-regulate") transcription rates.transcription rates.

As an example, consider the regulation of a gene As an example, consider the regulation of a gene G. GG. G is the normal allele coding is the normal allele coding for active protein, whereas for active protein, whereas gg is a null allele (caused by a base-pair substitution) that is a null allele (caused by a base-pair substitution) that codes for inactive protein. At an unlinked locus, codes for inactive protein. At an unlinked locus, RR codes for a regulatory protein codes for a regulatory protein that causes high levels of transcription at the that causes high levels of transcription at the GG locus, whereas locus, whereas rr yields protein that yields protein that allows only a basal level. If a dihybrid allows only a basal level. If a dihybrid G/gG/g ; ; R/rR/r is selfed, a 9:3:4 ratio of protein is selfed, a 9:3:4 ratio of protein activity is produced, as follows:activity is produced, as follows:


Penetrance and Expressivity PenetrancePenetrance is defined as the percentage of individuals with a given genotype who is defined as the percentage of individuals with a given genotype who

exhibit the phenotype associated with that genotype. For example, an organism may exhibit the phenotype associated with that genotype. For example, an organism may have a particular genotype but may not express the corresponding phenotype have a particular genotype but may not express the corresponding phenotype because of modifiers, epistatic genes, or suppressors in the rest of the genome or because of modifiers, epistatic genes, or suppressors in the rest of the genome or because of a modifying effect of the environment. Alternatively, absence of a gene because of a modifying effect of the environment. Alternatively, absence of a gene function may intrinsically have very subtle effects that are difficult to measure in a function may intrinsically have very subtle effects that are difficult to measure in a laboratory situation.laboratory situation.

Another term for describing the range of phenotypic Another term for describing the range of phenotypic expression is calledexpression is called expressivityexpressivity.. Expressivity Expressivity measures the extent to which a given genotype is measures the extent to which a given genotype is expressed at the phenotypic level. Different degrees expressed at the phenotypic level. Different degrees of expression in different individuals may be due to of expression in different individuals may be due to variation of the allelic constitution of the rest of the variation of the allelic constitution of the rest of the genome or to environmental factors.genome or to environmental factors. This figure This figure illustrates the distinction between penetrance and illustrates the distinction between penetrance and expressivity. expressivity.

Complex gene interactions in coat color -...

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