genetica per scienze naturali a.a. 03-04 prof s. presciuttini from genes to phenotypes at one level,...

Genetica per Scienze Naturalia.a. 03-04 prof S. Presciuttini

From Genes to Phenotypes At one level, geneticists tend to think of genes in isolation. In At one level, geneticists tend to think of genes in isolation. In

reality, genes don't act in isolation. The proteins and RNAs they reality, genes don't act in isolation. The proteins and RNAs they encode contribute to specific cellular pathways that also receive encode contribute to specific cellular pathways that also receive input from the products of many other genes. Furthermore, input from the products of many other genes. Furthermore, expression of a single gene is dependent on many factors, including expression of a single gene is dependent on many factors, including the specific genetic backgrounds of the the specific genetic backgrounds of the organismorganism and a range of and a range of environmental conditionsenvironmental conditions, , temperature, nutritional conditions, temperature, nutritional conditions, population density, and so on. population density, and so on.

Gene actionGene action is a term that covers a very complex set of events, and is a term that covers a very complex set of events, and there is probably no case where we understand all the events that there is probably no case where we understand all the events that transpire from the level of expression of a single gene to the level of transpire from the level of expression of a single gene to the level of an organism's phenotype. an organism's phenotype.

Two importantTwo important generalizations about the complexity of gene action generalizations about the complexity of gene action:: 1. There is a one-to-many relationship of genes to phenotypes.1. There is a one-to-many relationship of genes to phenotypes. 2. There is a one-to-many relationship of phenotypes to genes.2. There is a one-to-many relationship of phenotypes to genes.


One-to-many relationship of genes to phenotypes This relationship is called This relationship is called pleiotropypleiotropy. Pleiotropy is inferred from the observation . Pleiotropy is inferred from the observation

that mutations selected for their effect on one specific character are often found to that mutations selected for their effect on one specific character are often found to affect other characters of the organism. This might mean that there are related affect other characters of the organism. This might mean that there are related physiological pathways contributing to a similar phenotype in several tissues.physiological pathways contributing to a similar phenotype in several tissues.

For example, the white eye-color mutation in For example, the white eye-color mutation in DrosophilaDrosophila results in lack of pigmentation results in lack of pigmentation not only in compound eyes but also in ocelli (simple eyes), sheaths of tissue surrounding not only in compound eyes but also in ocelli (simple eyes), sheaths of tissue surrounding the male gonad, and the Malpighian tubules (the fly's kidneys). In all these tissues, the male gonad, and the Malpighian tubules (the fly's kidneys). In all these tissues, pigment formation requires the uptake of pigment precursors by the cells. The white pigment formation requires the uptake of pigment precursors by the cells. The white allele causes a defect in this uptake, thereby blocking pigment formation in all these allele causes a defect in this uptake, thereby blocking pigment formation in all these tissues.tissues.

Often, pleiotropy involves multiple events that are not obviously physiologically Often, pleiotropy involves multiple events that are not obviously physiologically related.related.

For example, the dominant For example, the dominant DrosophilaDrosophila mutation mutation DichaeteDichaete causes the wings to be held causes the wings to be held out laterally but also removes certain hairs on the back of the fly; furthermore, the out laterally but also removes certain hairs on the back of the fly; furthermore, the mutation is inviable when homozygous. mutation is inviable when homozygous. This example shows a real limitation in the This example shows a real limitation in the way dominant and recessive mutations are named.way dominant and recessive mutations are named. The reality is that a single The reality is that a single mutation can be both dominant and recessive, depending on which aspect of its mutation can be both dominant and recessive, depending on which aspect of its pleiotropic phenotype is under consideration. In general, genetic terminology is not up to pleiotropic phenotype is under consideration. In general, genetic terminology is not up to the task of representing this level of pleiotropy and complexity in one symbol, and there the task of representing this level of pleiotropy and complexity in one symbol, and there is a certain arbitrary or historical aspect as to how we name alleles.is a certain arbitrary or historical aspect as to how we name alleles.


One-to-many relationship of phenotypes to genes This This conceptconcept is based on the observation that many different genes is based on the observation that many different genes

can affect a single phenotype. This is easy to understand in terms of a can affect a single phenotype. This is easy to understand in terms of a character such as eye color, in which there are complex metabolic character such as eye color, in which there are complex metabolic pathways with numerous enzymatic steps, each encoded by one or pathways with numerous enzymatic steps, each encoded by one or more gene products. more gene products. Genetic heterogeneityGenetic heterogeneity is the term used to refer is the term used to refer to a given condition that may be caused by different genes.to a given condition that may be caused by different genes.

One goal of genetic analysis is to identify all the genes that affect a One goal of genetic analysis is to identify all the genes that affect a specific phenotype and to understand their genetic, cellular, specific phenotype and to understand their genetic, cellular, developmental, and molecular roles. To do this, we need ways of developmental, and molecular roles. To do this, we need ways of sorting mutations and genes.sorting mutations and genes. WWe e first first will will considerconsider how we can use genetic analysis to determine if two how we can use genetic analysis to determine if two

mutants are caused by mutational hits in the same gene (that is,mutants are caused by mutational hits in the same gene (that is, they are alleles they are alleles) ) or in different genes.or in different genes.

Later, we will consider how genetic analysis can be used to make inferences Later, we will consider how genetic analysis can be used to make inferences about gene interactions in developmental and biochemical pathways.about gene interactions in developmental and biochemical pathways.


The complementation test The allelism test that finds widest application is the complementation The allelism test that finds widest application is the complementation

test, which is illustrated in the following example.test, which is illustrated in the following example. Consider a species of Consider a species of flowerflower in which the wild-type color is blue. in which the wild-type color is blue. WWe have e have

induced three white-petaled mutants and induced three white-petaled mutants and have obtained have obtained pure-breeding strainspure-breeding strains ((all homozygousall homozygous)). We can call the mutant strains $, £, and ¥, using currency . We can call the mutant strains $, £, and ¥, using currency symbols to avoid prejudicing our thinking concerning dominance.symbols to avoid prejudicing our thinking concerning dominance. In each case In each case the results show that the mutant condition is determined by the recessive allele the results show that the mutant condition is determined by the recessive allele of a single gene. However, are they three alleles of one gene, or of two or three of a single gene. However, are they three alleles of one gene, or of two or three genes? The question can be answered by asking if the mutants genes? The question can be answered by asking if the mutants complementcomplement each other.each other.

Complementation is the production of a wild-type phenotype Complementation is the production of a wild-type phenotype when two recessive mutant alleles are united in the same cell.when two recessive mutant alleles are united in the same cell.


Performing the complementation test In a diploid organism the complementation test is performed by intercrossing In a diploid organism the complementation test is performed by intercrossing

homozygous recessive mutants two at a time and observing whether or not the homozygous recessive mutants two at a time and observing whether or not the progeny have wild-type phenotype. If recessive mutations represent alleles of the progeny have wild-type phenotype. If recessive mutations represent alleles of the same gene, then obviously they will not complement because they both represent same gene, then obviously they will not complement because they both represent lost gene function. Such alleles can be thought of generally as lost gene function. Such alleles can be thought of generally as aa’’ and and a"a", using , using primes to distinguish between two different mutant alleles of a gene whose wild-primes to distinguish between two different mutant alleles of a gene whose wild-type allele is type allele is aa++. These alleles could have different mutant sites but would be . These alleles could have different mutant sites but would be functionally identical. The heterozygote functionally identical. The heterozygote aa’’/a"/a" would be would be

However, two recessive mutations in different genes would have wild-type function However, two recessive mutations in different genes would have wild-type function provided by the respective wild-type alleles. Here we can name the genes provided by the respective wild-type alleles. Here we can name the genes a1a1 and and a2a2, after their mutant alleles. Heterozygotes would be , after their mutant alleles. Heterozygotes would be a1/+a1/+ ; ; +/a2+/a2 (unlinked genes) (unlinked genes) or or a1+/+a2a1+/+a2 (linked genes), and we can diagram them as follows: (linked genes), and we can diagram them as follows:


Mutants that complement We nowWe now return to the return to the flowerflower example and intercross the mutant example and intercross the mutant strains strains

to test for complementation. Assume the results of intercrossing to test for complementation. Assume the results of intercrossing mutants $, £, and ¥ are as follows:mutants $, £, and ¥ are as follows:

From this set of results we would conclude that mutants $ and £ must From this set of results we would conclude that mutants $ and £ must be caused by alleles of one gene (say be caused by alleles of one gene (say w1w1) because they do not ) because they do not complement; but ¥ must be caused by a mutant allele of another gene complement; but ¥ must be caused by a mutant allele of another gene ((w2w2).).

The molecular explanation of such results is often in terms of The molecular explanation of such results is often in terms of biochemical pathways in the cell. How does complementation work at biochemical pathways in the cell. How does complementation work at the molecular level? Although it is conventional to say that it is the molecular level? Although it is conventional to say that it is mutants that complement, in fact the active agents in mutants that complement, in fact the active agents in complementation are the proteins produced by the wild-type alleles.complementation are the proteins produced by the wild-type alleles.


The biochemical explanation The normal blue color of the flower is caused by a blue pigment called anthocyanin. The normal blue color of the flower is caused by a blue pigment called anthocyanin.

Pigments are chemicals that absorb certain parts of the visible spectrum; in the case of the Pigments are chemicals that absorb certain parts of the visible spectrum; in the case of the harebell the anthocyanin absorbs all wavelengths except blue, which is reflected into the eye harebell the anthocyanin absorbs all wavelengths except blue, which is reflected into the eye of the observer. However, this anthocyanin is made from chemical precursors that are not of the observer. However, this anthocyanin is made from chemical precursors that are not pigments; that is, they do not absorb light of any specific wavelength and simply reflect back pigments; that is, they do not absorb light of any specific wavelength and simply reflect back the white light of the sun to the observer, giving a white appearance. The blue pigment is the the white light of the sun to the observer, giving a white appearance. The blue pigment is the end product of a series of biochemical conversions of nonpigments. Each step is catalyzed by end product of a series of biochemical conversions of nonpigments. Each step is catalyzed by a specific enzyme coded by a specific gene. We can accommodate the results with a pathway a specific enzyme coded by a specific gene. We can accommodate the results with a pathway as follows:as follows:

A mutation in either of the genes in homozygous condition will lead to the accumulation of a A mutation in either of the genes in homozygous condition will lead to the accumulation of a precursor, which will simply make the plant white. Now, the mutant designations can be precursor, which will simply make the plant white. Now, the mutant designations can be written as follows:written as follows:


ComplementationThree phenotypically identical white Three phenotypically identical white mutants, $, £, and ¥, are intercrossed mutants, $, £, and ¥, are intercrossed to form heterozygotes whose to form heterozygotes whose phenotypes reveal whether or not the phenotypes reveal whether or not the mutations complement each other. mutations complement each other. (Only two of the three possible (Only two of the three possible crosses are shown here.) If two crosses are shown here.) If two mutations are in different genes (such mutations are in different genes (such as £ and ¥), then complementation as £ and ¥), then complementation results in the completion of the results in the completion of the biochemical pathway (the end biochemical pathway (the end product is a blue pigment in this product is a blue pigment in this example). If mutations are in the example). If mutations are in the same gene (such as $ and £), no same gene (such as $ and £), no complementation occurs because the complementation occurs because the biochemical pathway is blocked at biochemical pathway is blocked at the step controlled by that gene, and the step controlled by that gene, and the intermediates in the pathway are the intermediates in the pathway are colorless (white).colorless (white).


Interactions Between the Alleles of One GeneIncomplete DominanceIncomplete Dominance Four-o'clocksFour-o'clocks are plants native to tropical America. Their name comes from the fact are plants native to tropical America. Their name comes from the fact

that their flowers open in the late afternoon. When a wild-type four-o'clock plant that their flowers open in the late afternoon. When a wild-type four-o'clock plant with red petals is crossed with a pure line with white petals, the Fwith red petals is crossed with a pure line with white petals, the F11 has pink petals. If has pink petals. If

an Fan F22 is produced by selfing the F is produced by selfing the F11, the result is, the result is

Because of the 1:2:1 ratio in the FBecause of the 1:2:1 ratio in the F22, we can deduce an inheritance pattern based on , we can deduce an inheritance pattern based on

two alleles of a single gene. However, the heterozygotes (the Ftwo alleles of a single gene. However, the heterozygotes (the F11 and half the F and half the F22) are ) are

intermediate in phenotype, suggesting an incomplete type of dominance. Inventing intermediate in phenotype, suggesting an incomplete type of dominance. Inventing allele symbols, we can list the genotypes of the four-o'clocks in this experiment as allele symbols, we can list the genotypes of the four-o'clocks in this experiment as cc++//cc++ (red), (red), c/cc/c (white), and (white), and cc++//cc (pink). (pink).


Incomplete dominance Incomplete dominance describes the general situation in which the phenotype of a Incomplete dominance describes the general situation in which the phenotype of a

heterozygote is intermediate between the two homozygotes on some quantitative heterozygote is intermediate between the two homozygotes on some quantitative scale of measurement.scale of measurement.

This fThis figure gives terms for all the theoretical positions on the scale, but in practice it igure gives terms for all the theoretical positions on the scale, but in practice it is difficult to determine exactly where on such a scale the heterozygote is located. is difficult to determine exactly where on such a scale the heterozygote is located. At the molecular level, incomplete dominance is generally caused by a quantitative At the molecular level, incomplete dominance is generally caused by a quantitative effect of the number of "doses" of a wild-type allele; two doses produce most effect of the number of "doses" of a wild-type allele; two doses produce most functional transcript and therefore most functional protein product; one dose functional transcript and therefore most functional protein product; one dose produces less transcript and product, whereas zero doses have no functional produces less transcript and product, whereas zero doses have no functional transcript or product. In cases of full dominance, in the wild-type/mutant transcript or product. In cases of full dominance, in the wild-type/mutant heterozygote either half of the normal amount of transcript and product is adequate heterozygote either half of the normal amount of transcript and product is adequate for normal cell function (the gene is haplo-sufficient), or the wild-type allele is "up-for normal cell function (the gene is haplo-sufficient), or the wild-type allele is "up-regulated" to bring the concentration of transcript up to normal levels.regulated" to bring the concentration of transcript up to normal levels.


Codominance The human ABO blood groups are determined by three alleles of one gene that The human ABO blood groups are determined by three alleles of one gene that

show several types of interaction to produce the four blood types of the ABO show several types of interaction to produce the four blood types of the ABO system. The allelic series includes three major alleles, system. The allelic series includes three major alleles, ii, , IIAA, and , and IIBB, but of course any , but of course any person can have only two of the three alleles (or two copies of one of them). There person can have only two of the three alleles (or two copies of one of them). There are six different genotypes, the three homozygotes and three different types of are six different genotypes, the three homozygotes and three different types of heterozygotes:heterozygotes:

In this allelic series, the alleles In this allelic series, the alleles IIAA and and IIBB each determine a unique antigen, which is each determine a unique antigen, which is deposited on the surface of the red blood cells. These are two forms of a single deposited on the surface of the red blood cells. These are two forms of a single protein. However, the allele protein. However, the allele ii results in no antigenic protein of this type. In the results in no antigenic protein of this type. In the genotypes genotypes IIAA/i/i and and IIBB/i/i, the alleles , the alleles IIAA and and IIBB are fully dominant to are fully dominant to ii. However, in the . However, in the genotype genotype IIAA/I/IBB each of the alleles produces its own antigen, so they are said to be each of the alleles produces its own antigen, so they are said to be codominant.codominant.


Relativity of dominance relationships The human disease sickle-cell anemia gives interesting insight into dominance. The The human disease sickle-cell anemia gives interesting insight into dominance. The

gene concerned affects the molecule hemoglobin, which transports oxygen and is gene concerned affects the molecule hemoglobin, which transports oxygen and is the major constituent of red blood cells. The three genotypes have different the major constituent of red blood cells. The three genotypes have different phenotypes, as follows:phenotypes, as follows:

In regard to the presence or absence of anemia, the HbA allele is obviously In regard to the presence or absence of anemia, the HbA allele is obviously dominant. In regard to blood cell shape, however, there is incomplete dominance. dominant. In regard to blood cell shape, however, there is incomplete dominance. Finally, in regard to hemoglobin itself there is codominanceFinally, in regard to hemoglobin itself there is codominance, as the two hemoglobin , as the two hemoglobin molecules molecules HbA and HbS HbA and HbS can be visualized simultaneously by means of can be visualized simultaneously by means of electrophoresiselectrophoresis

Sickle-cell anemia illustrates that the terms dominance, incomplete dominance, and codominance are somewhat arbitrary. The type of dominance inferred depends on the phenotypic level at which the observations are being made, organismal, cellular, or molecular. Indeed the same caution can be applied to many of the categories that scientists use to classify structures and processes; these categories are devised by humans for convenience of analysis


An anomalous segregation ratio Normal wild-type mice have coats with a rather dark overall pigmentation. A Normal wild-type mice have coats with a rather dark overall pigmentation. A

mutation called mutation called yellowyellow (a lighter coat color) illustrates an interesting allelic (a lighter coat color) illustrates an interesting allelic interaction. If a interaction. If a yellowyellow mouse is mated to a homozygous wild-type mouse, a 1:1 mouse is mated to a homozygous wild-type mouse, a 1:1 ratio of yellow to wild-type mice is always observed in the progeny. This ratio of yellow to wild-type mice is always observed in the progeny. This observation suggests (1) that a single gene with two alleles determines these observation suggests (1) that a single gene with two alleles determines these phenotypic alternatives, (2) that the phenotypic alternatives, (2) that the yellowyellow mouse was heterozygous for these mouse was heterozygous for these alleles, and (3) that the allele for alleles, and (3) that the allele for yellowyellow is dominant to an allele for normal color. is dominant to an allele for normal color.

However, if two However, if two yellowyellow mice are crossed with each other, the result is always as mice are crossed with each other, the result is always as follows:follows:

Note two interesting features in these results. First, the 2:1 phenotypic ratio is a Note two interesting features in these results. First, the 2:1 phenotypic ratio is a departure from the expectations for a monohybrid self-cross. Second, because no departure from the expectations for a monohybrid self-cross. Second, because no cross of cross of yellowyellow × × yellowyellow ever produced all ever produced all yellowyellow progeny, as there would be if progeny, as there would be if either parent were a homozygote, it appears that it is impossible to obtain either parent were a homozygote, it appears that it is impossible to obtain homozygous homozygous yellowyellow mice mice


Letal alleles The explanation for such results is that all The explanation for such results is that all yellowyellow mice are heterozygous for one mice are heterozygous for one

special allele. A cross between two heterozygotes would be expected to yield a special allele. A cross between two heterozygotes would be expected to yield a monohybrid genotypic ratio of 1:2:1. However, if all the mice in one of the monohybrid genotypic ratio of 1:2:1. However, if all the mice in one of the homozygous classes died before birth, the live births would then show a 2:1 ratio of homozygous classes died before birth, the live births would then show a 2:1 ratio of heterozygotes to the surviving homozygotes. The allele heterozygotes to the surviving homozygotes. The allele AAYY for for yellowyellow is dominant to is dominant to the wild-type allele the wild-type allele AA with respect to its effect on color, but with respect to its effect on color, but AAYY acts as a recessive acts as a recessive lethallethal allele with respect to a character we would call allele with respect to a character we would call viability.viability. Thus, a mouse with Thus, a mouse with the homozygous genotype the homozygous genotype AAYY//AAYY dies before birth and is not observed among the dies before birth and is not observed among the progeny. All surviving progeny. All surviving yellowyellow mice must be heterozygous mice must be heterozygous AAYY//AA, so a cross between , so a cross between yellowyellow mice will always yield the following results: mice will always yield the following results:

The expected monohybrid ratio of 1:2:1 would be The expected monohybrid ratio of 1:2:1 would be found among the zygotes, but it is altered to a 2:1 ratio found among the zygotes, but it is altered to a 2:1 ratio in the progeny born because zygotes with a lethal in the progeny born because zygotes with a lethal AAYY/A/AYY genotype do not survive to be counted. This hypothesis genotype do not survive to be counted. This hypothesis is supported by the removal of uteri from pregnant is supported by the removal of uteri from pregnant females of the females of the yellowyellow × × yellowyellow cross; one-fourth of the cross; one-fourth of the embryos are found to be dead. embryos are found to be dead.


What goes wrong in lethal mutations? In many cases it is possible to trace the cascade of events that leads to death. A In many cases it is possible to trace the cascade of events that leads to death. A

common situation is that the allele causes a deficiency in some essential chemical common situation is that the allele causes a deficiency in some essential chemical reaction. The human diseases PKU and cystic fibrosis are good examples of this reaction. The human diseases PKU and cystic fibrosis are good examples of this kind of deficiency. In other cases there is a structural defect. Sickle-cell anemiakind of deficiency. In other cases there is a structural defect. Sickle-cell anemia is is another example.another example.

Whether an allele is lethal or not often depends on the environment in which the Whether an allele is lethal or not often depends on the environment in which the organism develops. Whereas certain alleles would be lethal in virtually any organism develops. Whereas certain alleles would be lethal in virtually any environment, others are viable in one environment but lethal in another. Human environment, others are viable in one environment but lethal in another. Human hereditary diseases provide examples. Cystic fibrosis is a disease that would be hereditary diseases provide examples. Cystic fibrosis is a disease that would be lethal without treatment, and individuals with PKU would not survive in a natural lethal without treatment, and individuals with PKU would not survive in a natural setting in which the special diet would be impossible. As another example, many of setting in which the special diet would be impossible. As another example, many of the alleles favored and selected by animal and plant breeders would almost certainly the alleles favored and selected by animal and plant breeders would almost certainly be eliminated in nature as a result of competition with the members of the natural be eliminated in nature as a result of competition with the members of the natural population. Modern grain varieties provide good examples; only careful nurturing population. Modern grain varieties provide good examples; only careful nurturing by the farmer has maintained such alleles for our benefit.by the farmer has maintained such alleles for our benefit.


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

In most cases, the gene codes for the melanin-producing enzyme In most cases, the gene codes for the melanin-producing enzyme tyrosinase. In rabbits an allele of this gene, the tyrosinase. In rabbits an allele of this gene, the chch (Himalayan) allele, (Himalayan) allele, determines that pigment will be deposited only at the body determines that pigment will be deposited only at the body extremities. In mice the same allele also produces the phenotype extremities. In mice the same allele also produces the phenotype called 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- allele with heat-sensitive expression. It is only at the colder body extremities that sensitive expression. It is only at the colder body extremities that chch is is functional and can make pigment. In warm parts of the body it is functional and can make pigment. In warm parts of the body it is expressed just like the albino allele expressed just like the albino allele cc. This allele shows clearly how . This allele shows clearly how the expression of an allele depends on the environment.the expression of an allele depends on the 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 The SS gene controls the presence or absence of spots by controlling the migration of gene controls the presence or absence of spots by controlling the migration of

clumps of melanocytes (pigment-producing cells) across the surface of the clumps of melanocytes (pigment-producing cells) across the surface of the developing embryo. The genotype developing embryo. The genotype SS//-- results in no spots, and results in no spots, and s/ss/s produces a produces a spotting pattern called spotting pattern called piebaldpiebald in both mice and horses. This pattern can be in both mice and horses. This pattern can be superimposed on any of the coat colors discussed earlier, with the exception of superimposed on any of the coat colors discussed earlier, with the exception of albino, of course. Piebald mutations are also known in humans.albino, of course. Piebald mutations are also known in humans.

We see that the normal coat appearance in wild We see that the normal coat appearance in wild mice is produced by a complex set of mice is produced by a complex set of interacting genes determining pigment type, interacting genes determining pigment type, pigment distribution in the individual hairs, pigment distribution in the individual hairs, pigment distribution on the animal's body, and pigment distribution on the animal's body, and the presence or absence of pigment. Such the presence or absence of pigment. Such interactions are deduced from modified ratios in interactions are deduced from modified ratios in dihybrid crosses. dihybrid crosses. The figure The figure illustrates some of illustrates some of the pigment patterns in mice. the pigment patterns in mice. Interacting genes Interacting genes such as these determine most characters in such as these determine most characters in any organismany organism..


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.

genetica per scienze naturali a.a. 03-04 prof s. presciuttini from genes to phenotypes at one level,...

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