The existence of more than one form of a particular phenotypic trait in a population
is known as polymorphism. Polymorphism can derive from
multiple alleles at a single locus
interactions among multiple loci
interactions among multiple loci, each with multiple alleles
environmental influence on gene expression
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
final (enzyme) product
A loss-of-function mutation eliminates or reduces the function of a wild type gene
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
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.
The functional allele of a haplosufficient gene is dominant.
The non-functional allele of a haplosufficient gene is recessive.
A homozygote cannot be distinguished from a heterozygote on the basis of gene product function.
A gene is said to be haploinsufficient if one working copy is NOT sufficient for normal expression of the gene's function.
The non-functional allele of a haploinsufficient gene is effectively dominant.
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
osteogenesis imperfecta ("brittle bone disease")
Normal collagen is trimeric, formed of three intertwined monomers.
In heterozygotes, 50% of the collagen monomers malfunction, wrapping around the other two monomers
The collagen complex is physically distorted, preventing normal incorporation into bone.
The result is poorly formed bones that break easily, a potentially life-threatening condition.
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:
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
Two alleles both produce proteins, but one is
non-functional. This results in heterozygotes producing only half
the amount of protein produced by a homozygous dominant individual.
Two alleles of the same gene are expressed, and
both products are functional, though different.
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
eventually, fatal degeneration of the central and peripheral nervous systems
Tt: half the amount of enzyme produced, but sufficient
for normal development
tt: no functional enzyme; expression of Tay Sachs
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
normal red blood cells
susceptible to malaria parasite Plasmodium spp.
enough normal blood cells for functionality
mild expression of sickle cell disease
NOT susceptible to malaria parasite Plasmodium spp.
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.
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
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.
Active proteins (e.g. enzymes, microtubule proteins, membrane pump
proteins, antibodies) perform chemical functions
Structural proteins (e.g., silk, keratin, collagen) make up the physical structure of the organism
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.
Beadle and Edward Tatum used Neurospora and Drosophila to study inborn errors of metabolism.
They selected mutants with known faulty enzymes in a particular metabolic pathway.
They compared them to metabolically wild type individuals.
In stepwise fashion, they determined which enzymes were non-functional in particular disorders.
This allowed them to discover which enzymes mediated an entire metabolic pathway.
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
An error in a particular enzyme in the phenylalanine
pathway can result in a specific disorder.
The amino acid phenylalanine (phe) is a precursor to tyrosine (tyr), an amino acid precursor in many metabolic pathways.
Wild type: phe is converted to tyr by the enzyme phenylalanine hydroxylase (p.h.)
Mutant allele: encodes a non-functional form of p.h.
Humans with mutant p.h. cannot convert phe to tyr.
The phe deteriorates into a toxic, lipophilic waste
product, phenylpyruvate, that deposits in nervous tissue and damages the developing central nervous system.
severe mental retardation due to phenylketonuria.
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.
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
Results are mixed.
The mutant allele is most common in descendants of northern
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
Hydroxyphenylpyruvate deteriorates into homogentisic acid.
Lacking enzymes to break down homogentisic acid, homozygous mutants pass it in the urine.
Homogentisic acid turns black upon exposure to oxygen.
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.
resulting imbalance of chloride and sodium ions results in abnormally dehydrated