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Polymorphism and Gene Interactions

The existence of more than one form of a particular phenotypic trait in a population is known as polymorphism. Polymorphism can derive from

  • monogenic trait - a single phenotypic trait whose expression is controlled by the action of a single gene locus.
  • polygenic trait - a single phenotypic trait whose expression is controlled/affected by the action of more than one gene locus.


    Monogenic Trait Variability: Multiple Alleles at a Single Gene Locus

    Many genes have more than two alleles, and not all the alleles have equal dominance/recessiveness. While this is not, strictly speaking, a case of gene interactions, it can account for a range of phenotypes that can resemble the results of gene interactions. (At the molecular level, there are very likely multiple genes contributing to these phenotypes.

    Different combinations of multiple alleles at a single locus can produce a range of phenotypes.

    For example, white variegation (V) "chevron" pattern in Clover (Trifolium sp.).

    Coat color in many mammals is affected by the activity of the agouti gene (A). In rabbits and rodents, mutant forms of the agouti gene result in different colors.

    The agouti gene is not directly responsible for producing these patterns. It is very likely a master switch gene that regulates the activity of multiple genes, and is involved in multiple metabolic functions. Some of them surprising.

    Discovering the function of master switch genes can help us understand metabolic disorders that can then be investigated for genetic treatment.

    Codominance vs. Incomplete Dominance

    The alleles of a single gene can interact in ways that result in phenotypic ratios in offspring that are not predicted by Mendel's Laws. Two such phenomena, not to be confused with one another are

  • incomplete dominance
  • codominance

    Examples of Incomplete Dominance

    Flower Petal Color in Japanese Four o' Clocks
    in the Japanese Four o' Clock, Mirabilis jalapa.

    There are two alleles of a gene for flower petal red pigmentation.

    The wild type R1 allele codes for an enzyme vital for the conversion of the precursor in the flower into the xanthophyll pigment.

    The mutant R2 allele produces an enzyme incapable of catalyzing the reaction.

    This recalls the importance of Inborn Errors of Metabolism:

    Tay Sachs Disease


    Examples of Codominance

    Human ABo blood groups

    Humans with type AB blood have two different immunoglobins (IA and IB) inserted into the blood cell membrane. Types A or B have either one or the other, and type o has neither.

    Note: The A & B alleles operate by modifying a wild type mucopolysaccharide terminal sugars.

    Note that Sickle Cell Anemia is another case of codominance; Two different types of hemoglobin are produced in the heterozygote, though the wild type ("normal") hemoglobin provides normal functionality.



    Polygenic Traits: Forms of Interaction

    When multiple genes affect a single trait, their effects can be additive, or one gene can interfere with the expression of another gene at a different locus. In this section, we'll explore some of the various ways different gene loci can interact to affect phenotype.

    Pleiotropy

    When a single gene affects the expression of more than one phenotypic character, the phenomenon is known as pleiotropy (from the Greek pleio meaning "more" and "trop, meaning "change").
  • Sickle Cell Anemia
    The mutation which changes the 6th amino acid from the terminal end of the Beta-protein chain is changed from glutamate to valine, making the chain hydrophobic rather than hydrophilic. Because the mutant hemoglobin precipitates readily in slightly acid conditions (as when the sufferer undergoes physical exertion, dissolving CO2 in the blood), and the malformed rbc's clog the capillaries, causing multiple characteristic phenotypic expressions:

    as well as...

    Recall the silver lining: Heterozygote Advantage in areas where malaria is endemic.

  • Homozygous wild type people have a high incidence of malaria, which can be fatal.
  • Homozygous recessive sickle cell individuals usually have shortened lifespan due to the genetic disorder, but they are not susceptible to malaria.
  • Heterozygotes suffer few or no problematic symptoms of sickle cell anemia, nor are they susceptible to malaria.


    Epistasis/Hypostasis

  • An epistatic gene locus is one that affects the expression of alleles at another, separate gene locus. The gene locus whose expression is affected by the epistatic locus is said to be hypostatic. Multiple genes, each with more than one allele, can interact to produce unexpected phenotypes due to epistatic interactions.

    Pleiotropy can be a result of various epistatic/hypostatic gene interactions, but there are many others, such as...

    Comb Shape in Chickens
    Two loci, each with two alleles, interact to produce four possible phenotypes:

  • Rose gene: R or r
  • Pea gene: P or p

  • Sometimes only a particular allele of an epistatic gene will mask the full expression of alleles at a hypostatic locus.
  • If the allele of the epistatic gene happens to be recessive, the resulting interaction is known as recessive epistasis.
  • A simple example would be albinism.


    Epistasis/Hypostasis alter Metabolic Pathways

    Obviously, the genes themselves do not carve chicken combs out of tissue. Rather, the interacting genes can change a biochemical or develomental sequence. Such gene actions are not always simultaneous, as not all genes "turn on" at the same time during embryo development.

    For example, coat and skin color in Labrador Retrievers can be explained by the non-simultaneous action of two gene loci, B and E.

  • The B locus controls the color of melanin pigment: B is black; b is brown
  • The E locus prevents melanin from being fully deposited in the hair shaft: E is full pigment; e is diluted pigment
  • The E locus is epistatic to the B locus: It prevents the complete deposition of the (already-made) melanin pigment in the hair shaft, though it does not affect deposition in the skin.
  • Thus, the epistatic locus operates "developmentally downstream" (i.e., after the B locus is already expressed) from its hypostatic gene.
  • Possible genotypes/phenotypes: The golden coat is an example of recessive epistasis: the recessive allele of a gene (i.e., the e allele that prevents pigment deposition) exerts epistasis over another locus (the B locus, controlling pigment color), resulting in the pale-colored hair shafts.


    Gene Interactions Produce Polymorphism

    There are countless polygenic traits, from the mundane to the unusual.

    In any population (i.e., group of organisms of the same species that interbreed and live in the same place at the same time), the gene interactions that produce a range of phenotypes for a particular trait can sometimes be traced to the interaction of only a few gene loci.

    Fruit color in Bell Peppers

    At least three loci interact to produce a variety of fruit colors in these plants.

    Different combinations of alleles at the three loci produce multiple phenotypes:

    Skin color in Corn snakes (Elaphe guttata)

    Vertebrates can manufacture two different forms of melanin, brown/black eumelanin and reddish brown phaeomelanin.

    Mammal Coat Color

    At least five genes interact to determine the coat color of mice, and similar genes govern coat color and pattern in other mammals. These vary across species, but their source is common ancestry.

  • The Agouti (A) locus - Determines the distribution of melanin in the hair shaft.

  • The B locus - Pigment coloration. B = black; b = brown
  • The C locus - Expression of pigmentation C = normal color; c = albino; ch = "Himalayan" (color sensitive)
  • The D locus - Controls amount of pigment in the hair shaft. D = wild type; d = dilute (The recessive allele is a modifier gene that affects the expression of the other genes. It is epistatic over those other genes.)
  • The S locus - controls presence or absence of white patches (piebalding) A closer look: Coat Color in Horses
    Coat color in horses is a complex affair, and some mutations are specific to certain breeds of horses. Murindu!

    For those interested in current research in mammal coat genetics, check out the Barsh Lab at Stanford University.


    Discovering the Nature and Mechanisms of Gene Interactions

    Mendel had no tools for discovering how genes interacted. Later researchers devised ingenious experimental methods for generating mutants and observing the effects in the mutants' phenotypes, and how mutant traits were passed to subsequent generations.

    Genetic Dissection via Analysis of Mutants

    Complementation: Inferring Gene Interaction


    In natural populations, the two alleles carried by most individuals result in wild type phenotype. Mutations may occur spontaneously, but rarely the same way in any two individuals.

    This means that if a mutation occurs in a particular member of the species, and it passes on that mutation to its offspring, then inbreeding between those two related individuals is far more likely to result in homozygosity of recessive, mutant alleles than outbreeding with unrelated individuals would.

  • To study the contribution of various genes to a particular trait or biological process in an organism, one must locate (and sometimes induce) mutations at the various loci involved in that trait's expression.
  • For example, if one wished to determine the contribution of various genes to some mode of locomotion in a worm (undoubtedly a trait/process affected by many genes), you need to find mutant worms who have abnormal locomotion.
  • If you have worms with abnormal locomotion, you'd like to find which of these mutant strains have changes at loci different from one another, each of which may affect locomotion in a different way.
  • This means that to develop your strains of interest, you must breed them together to see whether the alleles they pass on will complement the alleles of other mutant strains--or have no affect on the locomotion problems you already see.
  • One way to do this (if your study organism happens to be easy to breed, at least) is via a complementation test.

    Petal color in Harebells


    Inborn Errors of Metabolism: When Genes Go Bad

    The field of Biochemical Genetics is devoted to the study of genetic control of biochemical pathways.

    Many human disorders are known to be inborn and due to flaws in the enzymes that convert one cellular substance into another. For example, an error in any number of enzymes in the phenylalanine pathway can result in a several different types of disorders

  • Phenylketonuria (PKU)

    The amino acid (abbreviated "aa") phenylalanine is a precursor to tyrosine, an aa that serves as a precursor to many different celllular products.

    But there's a happy sidelight to this discovery...

  • In utero, the mutant fetus gets enzyme A from mom. Toxic buildup of waste does not happen until after birth.
  • In the 1950's, it was discovered that PKU kids put on a diet low in phe did not develop phenylketonuria.
  • By about age 6, the sensitive period has passed, and normal diet can resume without damage to the CNS.
  • Today, about 90% of infants are tested for PKU at birth.

    New problem!

  • If a homozygous recessive PKU woman becomes pregnant, the high levels of phe breakdown products in her blood can cross the placenta and damage the CNS of her unborn child, even if the child is heterozygous and would not be a PKU sufferer.
  • To prevent "maternal PKU", mom must resume her low phe diet during pregnancy. It's not 100% successful, but it's better than nothing.
  • The mutant allele is most common in descendants of northern Europeans.
    Mutations in many enzymes in the tyrosine pathway can cause other inborn errors of metabolism.

  • a defect in any one of several enzymes in the series that changes tyrosine to thyroxine results in a form of cretinism.

  • Alkaptonuria ("black urine disease") results from a defect in the enzymatic pathway from tyrosine to harmless waste products (carbon dioxide and water). Hydroxyphenylpyrivate breaks down into homogentisic acid, and without the enzymes to break it down, it is excreted in the urine. Interestingly, homogentisic acid turns black upon exposure to oxygen.

  • A defect anywhere in the enzymatic pathway from tyrosine to melanin (about 17 steps) can lead to albinism.


  • Cystic fibrosis is caused by a faulty protein that in wild type form controls chloride ion transfer across cell membranes in secretory cells.


    Many metabolic pathways involve the products of several genes that work together to facilitate a given process. Enzyme function depends largely on the amino acids of which it is composed, and their precise order. This, in turn, is controlled by the nucleotide sequence of the DNA encoding that particular protein.
    There are

    Since the enzymes determine much of the rest of the organism (including some of the construction of structural proteins and other cellular products), a mistake in the DNA coding for an enzyme can have dire consequences reflected in the physical and/or metabolic makeup of the organism.

    Archibald Garrod first wrote in 1909 that a number of human diseases were probably caused by "Inborn Errors of Metabolism": some fault in a metabolic pathway due to (almost always) deleterious mutation of a normal enzyme.


    Recall:

  • wild type allele of a gene is the one that is most often found in a natural population of a particular species.
  • mutant allele of a gene is the one that is changed (mutated) from the wild type, and is found less frequently in a natural population.


    The first scientists to study this phenomenon in detail were George Beadle and Edward Tatum, who initially worked on an ascomycete fungus, Neurospora, and later on Drosophila. By selecting mutants known to have faulty enzymes in a given metabolic pathway (auxotrophs), Beadle and Tatum were able to compare them to metabolically normal organisms (prototrophs) to discover the enzymes mediating entire metabolic pathways.

    They did this by using known auxotrophic Neurospora . As you will recall,

  • A prototroph is an organism that can survive and grow normally on "minimal medium"--agar supplied with only the most basic ingredients for survival (inorganic salts, a carbon source and water).
  • An auxotroph is a strain of that organism (bacteria or fungi, in most cases) unable to survive on minimal medium without the addition of some nutrient that it cannot make for itself (unlike a prototroph).


  • A leaky mutation reduces but does not destroy phenotypic expression of wild type.
  • A null mutation results in a completely non-functional version of the wild type enzyme.
  • A silent mutation is a change in base sequence that does not alter wild type enzyme function.
  • An information transfer mutation changes the way the mRNA transcript is read. Such a mutation may do any number of things, including...

    Lethal Alleles

    Certain alleles, when present in homozygous recessive condition, cause inviability/death of the homozygous individual. By definition, the gene that has mutated is said to be an essential gene, since its "demise" causes death of the organism that doesn't get its product.
    EXAMPLES:

    Suppressor Genes

    This is an allele that reverses the effects of a recessive mutation at another locus, causing the organism to revert to wild type phenotype.

    But how? There are several ways...

  • nonsense suppressors - Sometimes a mutation will occur that causes premature termination of protein translation (i.e., it inserts a STOP (nonsense) codon in the middle of a protein transcript). However, a tRNA anticodon mutation that allows a tRNA to attach to a stop codon will allow continuation of the protein manufacture. The nonsense mutation is suppressed.

  • congruent protein mutations - If one protein suffers from a mutation that changes its shape (and hence its activity with another protein), this can be overcome if the protein "mate" also undergoes a mutation which makes the two of them work together again.

  • modifier mutations are mutations in a gene that affects the degree of expression of a trait controlled by another locus. (An example is the "dove" or "cinnamon" coat colors of the gerbils we studied earlier, with "dove" being a modified black, and "cinnamon" being a modified agouti coat.) Which brings us to...



    Penetrance and Expressivity


    Environment plays an important role in gene expression.
    In the genes we have studied so far, a mutation is expressed:

    This is not always the case.

    Penetrance

    Genetic Interactions and Pathology: Sickle Cell Anemia

    Variable expressivity can often be explained by gene interactions.


    Expressivity


    Phenotype and Current Conditions

    Human eye color is controlled both by several gene loci and the surrounding lighting. Several loci contribute to the amount of melanin deposited in the stroma of the iris. Eye color genetics is complex, but fun

    Blue isn't a pigment. It's a result of structural refraction.

    Here's some news for all you blue-eyed folks out there.


    Internal Environment Can Affect Gene Expression

    Age-dependent Expression As an organism passes through its life cycle, the expression of its genes changes. This means that some genes are not expressed until later in life. Examples:


    Sex-Dependent Gene Expression

    Example: Feathering morphology in chickens:
    h+ - hen-feathering in male or female (short, erect tail, short body plumage)
    h - cock-feathering in male, if homozygous (long tail, long body plumage)

  • h+h+ - hen feathering in either female or male
  • h+h - hen feathering in female; cock feathering in male
  • hh - hen feathering in female; cock feathering in male

    Females express hen feathering, no matter what their genotype.


    Other examples of sex-limited traits:

  • horns in some mammals
  • lactation in female mammals
  • ovaries in females; testes in males
  • various secondary sex characteristics


    Phenocopies

    In some instances, an environmental factor can mimic the effect of a mutation, if the factor is present during a critical point in development.
    EXAMPLES:
    The impact of a gene at the phenotypic level depends not only on its dominance/recessiveness, but also on the modifying effects of other parts of the genome and on the internal and external environment's impact on expression.

    This brings us to the not-all-that-age-old question: Which is more important in the formation of the organism, Nature (genotype) or Nurture (environment)?

    The answer may turn out to be....it depends.

    The genotype may set the limits for a particular organism's phenotypic potential. The environment works on the plasticity of expression to produce different phenotypes from similar genotypes. This is evident even in identical twins.
    Norm of Reaction: The degree to which phenotype varies with environmental influence.
    We will return to this in more detail, in the Quantitative Genetics portion of the course.


    Maternal Effect

    There's more to maternal inheritance than mitochondria and chloroplasts.

    Direction of Shell Coiling in Lymnaea, a freshwater snail.

    The type of inheritance we're about to cover is known as maternal effect--not maternal inheritance.

    In these snails, there are two directions the shell can coil (when you look at it with the opening facing you:

    (Side note: These snails are hermaphroditic, each having both male and female sex organs. So any given snail can play the part of male or female and donate either eggs or sperm to the next generation. The scientist can thus decide which snails to allow to be the mother or the father. We also have the luxury of allowing them to self-fertilize.)

    If you cross...

    If you cross...

    Turns out that the phenotype of the offspring depends on the genotype of the mother snail. This is known as maternal effect.

    The coiling direction of a particular individual's shell is governed by its mother's genotype.

    Why does this happen?

  • spiral cleavage direction is due to the tilt of the mitotic spindle (right or left) with respect to the direction of the animal/vegetal axis.

  • the tilt direction is governed by the mother's cytoplasm, which is, in turn, controlled by her nuclear DNA.

    the ovum contains maternal cytoplasm. Hence, the direction of the baby snail's shell coiling is determined, not by its own genes, but by the mitotic spindle of it's mother's cytoplasmic legacy.

    Here are all the possibilities:

  • No matter which direction her own shell coils, a DD or Dd mother snail will always produce right-tilting ova. All her babies will be dextral.

  • No matter which direction her own shell coils, a dd mother snail will always produce left-tilting ova. All her babies will be sinistral.


    Maternal effect is also seen in larval development of Ephestia kuehniella, the Flour Moth:

  • kynurenin is a precursor to a particular type of melanin.
  • dominant allele (a+) codes for pigment; recessive allele (a) codes for no pigment. (Mutant individuals cannot produce kynurenin, but if they are provided with it, they can convert it into melanin.)

  • if you cross:

  • if you cross:

    Why?

  • A pigmented mom (even if she's heterozygous) will deposit a limited amount of kynurenin in the cytoplasm in the egg.

  • Even a larva with aa genotype can convert this kynurenin to melanin.
  • As the larva develops, each instar produces less melanin, and by the time it's an adult, it has run out of kynurenin. At this point, it becomes unpigmented.