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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

    Mutation: The Source of Genetic Variation

    To understand how alleles and genes interact, we will first recall how mutation generates genetic variation.

    Mutations and Alleles

    Different alleles of a gene arise by means of mutation: a change in the sequence of DNA.

    In any given population, for any given gene

    • the most frequent allele is termed the wild type allele.
    • Wild type is identified with a "+" symbol.

    • Any allele different from wild type is said to be mutant.
    • Mutant alleles can be identified with a "-"symbol.
    Each allele of a gene in a diploid individual may encode
    • a functional, wild type product
    • a non-functional, mutant product
    • a functional, mutant product

    Under normal circumstances, a diploid individual gets one "dose" of product--functional or not--from each of its two alleles.

    Some possible mutations and their effects:

    Loss-of-Function and Gain-of-Function Mutations

    <--In the illustration at the top left, the functional effect of a mutation can be visualized at the level of
    • mRNA
    • final (enzyme) product

    A loss-of-function mutation eliminates or reduces the function of a wild type gene product:

    • null loss-of-function eliminates gene product function
    • leaky loss-of-function reduces gene product function

    A gain-of-function mutation increases or changes the activity or function of a gene product

    A mutation also can be silent or synonymous

    A silent/synonymous mutation changes a DNA triplet code without changing its encoded amino acid. (Recall the genetic code.)

    • A silent mutation can change a triplet code anywhere in the genome.
    • A synonymous mutation changes a triplet code specifically in a coding sequence (exon).
    • Although the terms "silent" and "synonymous" are sometimes used interchangeably, synonymous mutations are actually a subset of silent mutations:

    A mutation also can be neutral.

    A neutral mutation has no effect on the Darwinian fitness of the individual expressing it.

    • A neutral mutation
      • may or may not have a significant phenotypic effect.
      • is not the same as a silent/synonymous mutation.

    The Molecular Basis of Dominance/Recessiveness

    There are two basic models to describe how an allele can be dominant at the molecular level.


    A gene is said to be haplosufficient if only one working copy is necessary/sufficient for normal expression of the gene's function.

    A gene is said to be haploinsufficient if one working copy is NOT sufficient for normal expression of the gene's function.

    Dominant Negative Mutations

    In some cases, a mutant form of a gene's normal product is not only non-functional, but also will chemically interact with the normal gene product (or its targets) so as to interfere with normal function.

    Such a mutant allele is said to be dominant negative or antimorphic.

    (click on pick for source)

    Several disorders in humans have been traced to dominant negative alleles, including

    Polymorphism and Monogenic Traits: Multiple Alleles at a Single Locus

    Any mutant form of a gene--whether or not it produces a phenotypic effect--is an allele of that gene.
    The various forms of a single gene are known as the multiple alleles, or an allelic series of the gene.

    Some polymorphism in a population can be due to different combinations of multiple alleles at a single locus.
    Example: variegation pattern in Trifolium.

    Example: Coat color controlled by the Agouti locus.

    The agouti locus controls the amount and distribution of eumelanin and phaeomelanin in mammal skin and hair.
    The gene has several alleles that result in different colors in various species of mammals.
    Illustrated here are domestic rabbits (Oryctolagus cuniculus, Order Lagomorpha) expressing different alleles of the agouti locus.

    left to right: agouti, black (melanistic), black and tan, chinchilla, Himalayan

    Like many other multiple alleles, the alleles at the agouti locus exhibit a dominance "hierarchy". For example:

    agouti (AC) > chinchilla (silver) Ach > Himalayan (Ah) > albino (a)

    The nature of these polymorphisms depends on the interactions of the allele products at the molecular level.

    Polymorphism and Monogenic Traits: Incomplete Dominance and Codominance

    Alleles of a single gene can interact to produce phenotypic ratios not predicted by Mendel's Laws.
    Two such phenomena, not to be confused with one another are

    Incomplete Dominance: Flower Pigmentation

    The Japanese Four o' Clock, Mirabilis jalapa has two alleles (R1 and R2) of a gene involved in production of red betacyanin pigments.
    • R1: red pigment produced
    • R2: no pigment produced

    • R1R1: red flowers
    • R2R2: white flowers
    • R1R2: pink (dilute red) flowers
    The wild type R1 allele codes for an enzyme vital for the conversion of the precursor in the flower into the redcpigment.

    The mutant R2 enzyme exhibits loss-of-function: it cannot catalyze the reaction.

    Incomplete Dominance: Tay Sachs Disease

    Hexosaminidase-A is responsible for breaking down lipids.
    A loss-of-function mutation results in an allele encoding non-functional version of hexosaminidase-A.

    In the absence of hex-A, toxic sphingolipids accumulate in the developing brain and peripheral nervous system of the fetus/young child.

    Onset of symptoms begins around six months of age, and include

    • loss of motor coordination
    • blindness
    • deafness
    • difficulty chewing/swallowing
    • eventually, fatal degeneration of the central and peripheral nervous systems
    • TT: normal
    • Tt: half the amount of enzyme produced, but sufficient for normal development
    • tt: no functional enzyme; expression of Tay Sachs disease.
    • Both alleles are expressed (an enzyme is produced by each), but only one is functional.

    The mutant allele is rare, but more common in people of Ashkenazi Jewish descent than other populations.

    Codominance: Human ABO Blood Groups

    In humans, the enzyme histo-blood group ABO system transferase modifies the oligosaccharides on cell surface glycoproteins in many different cell types and tissues.

    Different forms of the enzyme can modify the H antigen (unmodified in type O blood) by adding different types of sugars to its There are three alleles, A, B, and O.

    • The A allele
      • produces A transferase
      • A transferase catalyzes addition of N-acetylgalactosamine to the H antigen terminal sugars

    • The B allele
      • produces B transferase
      • B transferase catalyzes addition of galactose to the H antigen terminal sugars

    • The O allele
      • produces a non-functional enzyme
      • H antigen terminal sugars remain unmodified
      All alleles are expressed in a heterozygous individual, resulting in the four blood types.

    Codominance: Sickle Cell Anemia

    A single point mutation changes the sixth amino acid on hemoglobin's beta chain from glutamate (polar) to valine (non-polar).
    The mutant form, when unoxygenated, tends to bind to other unoxygenated hemoglobin molecules, forming fibers.

    These fibers cause the red blood cell to "sickle". Sickled red blood cells

    • become lodged in capillaries, causing tissue damage
    • are destroyed by the spleen, causing anemia

    • SS genotype
      • normal red blood cells
      • susceptible to malaria parasite Plasmodium spp.

    • Ss genotype
      • enough normal blood cells for functionality
      • mild expression of sickle cell disease
      • NOT susceptible to malaria parasite Plasmodium spp.

    • ss genotype
      • abnormal blood cells
      • full expression of potentially fatal sickle cell disease
      • NOT susceptible to malaria parasite Plasmodium spp.

      Both alleles are expressed in the heterozygote.

    Lethal Alleles

    Some recessive alleles of a gene, when present in homozygous condition, cause inviability of the individual bearing them.
    This effect defines the gene as an essential gene: A non-functional essential gene product results in an inviable organism.

    Here are some examples

    Lethal: Dwarfing Allele in Rabbits

  • DD = normal size
  • Dd = dwarf size (with small ears, head, etc.)
  • dd = lethal "peanut"

    The mutant allele has suffered a loss-of-function mutation that interferes with the normal production of growth hormone.

    The mutation appears to have a global effect on the normal secretory activity of the pituitary gland, which makes it lethal in homozygous condition.

  • Lethal: Yellow Agouti Allele in Mice

    The agouti locus controls the amount and distribution of eumelanin and phaeomelanin in mammal skin and hair.

    The product of the agouti gene is a peptide (131 amino acids long) named the agouti signaling protein (ASIP).

    The agouti signalling peptide has multiple metabolic functions that are still not fully understood.
    Some agouti gene modifications have provided surprising insights into epigentic effects on metabolism.

    It is known that ASIP interferes with the activity of melanocortin receptors.
    The mammalian melanocortin system functions to regulate food intake.

    Yellow fur mutation (or epigenetic modification) of the agouti gene in mice

    • AYAY= agouti fur, normal morphology
    • AYAy = yellow fur, obesity, diabetes
    • AyAy = lethal

    In wild type mice, the agouti gene is highly methylated and shut off.
    In yellow mice, one copy is functional, and its product is constantly expressed.

    The human agouti gene homolog (85% similar to the mouse gene) appears to be more widely expressed in various tissues than in rodent model organisms.

    Lethal: Manx Allele in Cats

    A dominant mutation of the wild type t locus in cats can result in abnormal development of the vertebrae of the sacrum and coccyx (tail).
  • tt = wild type; normal morphology
  • Tt = manx (no tail, abnormal spinal anatomy)
  • TT = lethal deformities of spinal column

  • Other Mutations of Essential Genes

  • Duchenne Muscular Dystrophy (X-linked recessive)
  • Tay Sachs disease
  • Cystic fibrosis
  • Lethal White Overo Syndrome in horses

    Note that many of the mutant alleles we have discussed cause changes in multiple different traits.
    Pleiotropy is the generation of more than one phenotypic effect (which are not always clearly related to one another) caused by a single gene.

    Inborn Errors of Metabolism

    Genes contain the instructions for building and maintaining living organisms.
    They do so by controlling cellular biochemistry in the form of metabolic pathways.

    Biochemical Genetics is the study of genetic control of biochemical pathways.

    Many metabolic pathways involve the products of several genes that work together to facilitate a given process.

    Genes determine amino acid sequence, and amino acid sequence determines protein function. Because enzymes are the biological machines that build an organism's components, an error in the gene coding for an enzyme can have significant consequences.

    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 deleterious mutation of a wild type enzyme.

    George Beadle and Edward Tatum used Neurospora and Drosophila to study inborn errors of metabolism.

    Human Inborn Errors of Metabolism

    Many human disorders are known to be inborn and due to flaws in the enzymes that convert one cellular substance into another.

    An error in a particular enzyme in the phenylalanine pathway can result in a specific disorder.

    Phenylketonuria (PKU)

    The amino acid phenylalanine (phe) is a precursor to tyrosine (tyr), an amino acid precursor in many metabolic pathways.

    Preventing PKU

  • In utero, a fetus homozygous for the mutant PKU allele receives functional p.h. via the placenta.

  • Thus, toxic buildup of phenylpyruvate does not occur until after birth.

  • In the 1950's, it was discovered that if infants with PKU genotype were given on a diet low in phe, they did not develop PKU.

  • 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.

    Maternal PKU

  • If a homozygous recessive PKU woman becomes pregnant, the high levels of phenuylpyruvate in her blood can cross the placenta and damage the CNS of her unborn child, even if the child is homozygous wild type or heterozygous.

  • To prevent maternal PKU, mother must resume her low phe diet during pregnancy.

  • Results are mixed.

  • The mutant allele is most common in descendants of northern Europeans.

    Other Tyrosine Pathway Defects

    Other mutations in the tyrosine pathway can cause different 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).

    You already have seen how a defect anywhere in the enzymatic pathway from tyrosine to eumelanin or phaeomelanin can lead to lack of normal pigmentation or even albinism.

    Cystic fibrosis is caused by a mutant form of a protein that normally controls chloride ion transfer across cell membranes in secretory cells.

  • The mutation shown results in deletion of phenylalanine from a chloride-permeable channel membrane protein.
  • Deletion of the phe disrupts normal chloride channel function.
  • The resulting imbalance of chloride and sodium ions results in abnormally dehydrated mucus.
  • This causes potentially life-threatening problems, from sterility to respiratory failure.

    Using Mutants to Dissect Metabolic Pathways

    Inferring Gene Interactions with Complementation Analysis

    In natural populations, the two alleles carried by most individuals result in wild type phenotype.

    Mutations of the same gene rarely occur exactly the same way in two unrelated individuals.

    Complementation analysis can reveal whether the a single phenotype in several different individuals is the product of the same genetic mutation.

    Petal color in Harebells