SHEK 2105/ SIK2006: GENETIK ASAS MANUSIA

Extension of Mendelism
Yusrizam Sharifuddin
yusrizam@um.edu.my

Institut Sains Biologi, Universiti Malaya

Institute of Biological Sciences, University of Malaya 1
 Allelic Variation and Gene Function

Why can you possess traits neither of your parents have?

The relationship of genotype to phenotype is rarely as simple as the
dominant and recessive patterns described by Mendel.
(He was lucky!)

Mendel’s experiments showed that ‘factors’ (genes) can exist in alternate forms, with simple
functional dichotomy between alleles → 1:0 ; 1 allele did something, the other did none. This
is an oversimplification (but it was the first step for us to understand genetic inheritance)

Genes can exist in more than two allelic states and each allele can have a different effect on
the phenotype

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 Allelic Variation and Gene Function

• Mendel observed that a heterozygote offspring can show the same phenotype as the
parent homozygote, so he concluded that there were some traits that dominated over other
inherited traits.

•However, the relationship of genotype to phenotype is rarely as simple as the dominant

and recessive patterns described by Mendel.
As the field of genetics progressed, geneticists began to notice a variety of relationships
between alleles that code for the same trait. These allelic interactions were not exclusively
recessive or dominant but they greatly enriched our understanding of how genotype leads
to phenotype.

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 Allelic Variation and Gene Function

Partial or Incomplete Dominance

• Dominance affects the phenotype derived from an organism's genes but it does not affect
the way these genes are inherited.
• Complete dominance occurs when the heterozygote phenotype is indistinguishable from
that of the homozygous parent.
• However, sometimes the heterozygote displays a phenotype that is an intermediate
between the phenotypes of both homozygote parents (one of which is homozygous
dominant, and the other of which is homozygous recessive) → This intermediate phenotype
is a demonstration of partial or incomplete dominance.

• When partial dominance occurs, a range of

phenotypes is usually observed among the offspring

• Although the offspring may show a variety of

phenotypes, each one will lie along a continuum
bracketed by the homozygous parental phenotypes

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 Allelic Variation and Gene Function

Partial or Incomplete Dominance

• When homozygous red flowers (A1A1) are

crossed with homozygous white (A2A2), a
variety of pink-shaded phenotypes result.

• Note, however, that partial dominance is not

the same as blending inheritance.

• After all, when two F1 pink flowers are

crossed, both red and white flowers are found
among the progeny.

• In other words, nothing is different about the

way these alleles are inherited; the only
difference is in the way the alleles determine
phenotype when they are combined.

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 Allelic Variation and Gene Function

Codominance
• Compared to partial dominance, codominance occurs when the phenotypes of both
parents are simultaneously manifested in the same offspring

• Indeed, "codominance" is the specific term for a system in which an allele from each
homozygote parent combines in the offspring and the offspring simultaneously
demonstrates both phenotypes

• An example of codominance occurs in the human ABO blood group system. Many blood
proteins contribute to blood type and the ABO protein system in particular defines which
types of blood you can receive in a transfusion. In a hospital setting, attention to the blood
proteins present in an individual's blood cells can make the difference between improving
health and causing severe illness

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 Allelic Variation and Gene Function

Codominance

• Note that the A and B alleles code for proteins that exist on the surface of red blood cells; in
contrast, the third allele, O, codes for no protein

• Thus, if one parent is homozygous for type A blood and the other is homozygous for type B,
the offspring will have a new phenotype, type AB. In people with type AB blood, both A and B
proteins are expressed on the surface of red blood cells equally. Therefore, this AB phenotype
is not an intermediate of the two parental phenotypes, but rather is an entirely new
phenotype that results from codominance of the A and B alleles.

• Of course, in this system, AB is not the only heterozygote; people may also be AO or BO. All
of these heterozygote genotypes demonstrate the coexistence of two phenotypes within the
same individual. Y. Sharifuddin 7
 Allelic Variation and Gene Function

Codominance

• Codominance implies that there is an independence of allele function

• Codominant alleles are represented by superscripts on the symbol for the gene

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 Allelic Variation and Gene Function

Codominance

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 Allelic Variation and Gene Function

Overdominance
• In some instances, offspring can demonstrate a phenotype that is outside the range
defined by both parents.
• In particular, the phenomenon known as overdominance occurs when a heterozygote has
a more extreme phenotype than that of either of its parents. Indeed, in a few examples, a
trait that shows overdominance sometimes confers a survival advantage in the heterozygote
(Parsons & Bodmer, 1961).

• A well-known example of overdominance occurs in the alleles that code for sickle-cell
anemia.

• Sickle-cell anemia is a debilitating disease of the red blood cells, wherein a single amino
acid deletion causes a change in the conformation of a person's hemoglobin such that the
person's red blood cells are elongated and somewhat curved, taking on a sickle shape.
• This change in shape makes the sickle red blood cells less efficient at transporting
oxygen through the bloodstream.

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 Allelic Variation and Gene Function

Overdominance
• The altered form of hemoglobin that causes sickle-cell anemia is inherited as a codominant
trait. Specifically, heterozygous (Ss) individuals express both normal and sickle hemoglobin,
so they have a mixture of normal and sickle red blood cells. In most situations, individuals
who are heterozygous for sickle-cell anemia are phenotypically normal. Under these
circumstances, sickle-cell disease is a recessive trait.

• Individuals who are homozygous for the sickle-cell allele (ss), however, may have sickling
crises that require hospitalization. In severe cases, this condition can be lethal.

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 Allelic Variation and Gene Function

Overdominance
• Producing altered hemoglobin can be beneficial for inhabitants of countries afflicted with
malaria (Plasmodium falciparum), an extremely deadly parasitic disease. Sickle blood cells
"collapse" around the parasites and filter them out of the blood. Thus, people who carry
the sickle-cell allele are more likely to recover from malarial infection. In terms of
combating malaria, the Ss genotype has an advantage over both the SS genotype, because
it results in malarial resistance, and the ss genotype, because it does not cause sickling
crises. This complex example of overdominance may be the sole reason that the allele
persists in the human population today (Keeton & Gould, 1986).

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 Allelic Variation and Gene Function

Multiple Alleles
• Allelic dominance always depends on the relative influence of each allele for a specific
phenotype under certain environmental conditions.
• For example, in the pea plant (Pisum sativum), the timing of flowering follows a
monohybrid (single-gene) inheritance pattern in certain genetic backgrounds.
• Another example is human blood type

In many cases, there are more than two possible alleles for a single gene. This is multiple
alleles.
• This means that there will be more than the 3 possible genotypes that are possible when
there are only 2 alleles.
• Keep in mind that even though there are 3 or more alleles, there can only be 2 present at
one time in any one individual.
• The genotype-phenotype relationship becomes more complicated when there are more
then 3 genotypes.
• Various dominance patterns are possible.

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 Allelic Variation and Gene Function

Multiple Alleles

• All three alleles are found at appreciable frequencies in human populations

→ the I gene is said to be polymorphic

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 Allelic Variation and Gene Function
Dominance is interaction of alleles for the same gene (at the same locus)

Complete dominance

• One allele completely masks the expression of the other.

• AA and Aa produce the same phenotype.
• So there are three genotypes, but only two phenotypes.
• Although characteristic of most of Mendel's pea traits, later studies showed complete
dominance is often not true. (Actually even Mendel found that complete dominance was
not always the rule for some traits.)

Incomplete dominance

• Sometimes the heterozygous genotype produces a phenotype that is intermediate

between that of the two homozygous genotypes.
• AA and Aa produce different phenotypes.
• It is actually better here not to use the usual A and a as alleles codes. Using something
like A1 and A2 is more logical because neither allele dominates over the other.
• So each genotype has a unique phenotype.

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 Allelic Variation and Gene Function

Codominance

• Similar to incomplete dominance, but the phenotype of the heterozygous individual is not
intermediate between the phenotypes of the homozygous; it a combination of both
phenotypes
• As for incomplete dominance, each of the three genotypes produces its own unique
phenotype.
• Example: human blood types (to be discussed below)
• Segregation is still valid

IMPORTANT: Variation in dominance does not change Mendel's law of segregation. Alleles
still come in pairs and segregate during gamete production. The difference is only in how
the alleles are expressed when two different ones occur together.

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 Allelic Variation and Gene Function

Multiple alleles

• In many cases, there are more than two possible alleles for a single gene. This is multiple
alleles
• This means that there will be more than the 3 possible genotypes that are possible when
there are only 2 alleles
• Keep in mind that even though there are 3 or more alleles, there can only be 2 present at
one time in any one individual
• The genotype-phenotype relationship becomes more complicated when there are more
then 3 genotypes
• Various dominance patterns are possible

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 Allelic Variation and Gene Function

Multiple Alleles
Allelic series

• Functional relationships among the members of a series of multiple alleles can be studied
by making heterozygous combinations through crosses between homozygotes
• Example: the four alleles of the c gene on coat colour

chc, cchc, c+c, cchcch, c+ch , c+cch

c+> cch > ch > c

Phenotypes of different combinations of c alleles in rabbits. The alleles form a series, with
the wild-type allele, c+ (wild type) dominant over all the other alleles and the null allele,
c (albino), recessive to all the other alleles one hypomorphic allele, cch (chinchilla) is partially
dominant over the other ch (Himalayan) allele

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 Allelic Variation and Gene Function

Multiple Alleles
Allelic series

• Example: the four alleles of the c gene on coat colour

chc, cchc, c+c, cchcch, c+ch , c+cch

c+> cch > ch > c

A plausible explanation: - the c gene controls a step in the formation of the black pigment in
the fur.
• Wild type allele (c+) : -fully functional (coloured hair production throughout the body)
• Chinchilla (cch ) and himalayan (ch ) alleles: -partially functional (some coloured hairs only)
• Albino allele (c ): -not functional at all

So,
Amorphic alleles: -non-functional or null; almost always recessive
Hypomorphic alleles: -partially functional; recessive to alleles that are more functional

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 Allelic Variation and Gene Function

Why genetic variation ?

• A mutant allele is created when an existing allele changes to a new genetic state through
mutation. Mutated (changed) allele → mutated (changed) physical composition of the gene →
sometimes generates an allele with detectable phenotypic effect

•But, it is not always possible to assign a new mutation to a gene on the basis of its
phenotypic manifestation

• A simple test can be used to determine the allelic identity of a new mutation, on the
condition that the new mutation is recessive.
• How? – Perform crosses to combine the new recessive mutation with recessive mutations
of known genes. Results:

1. If the hybrid progeny show a mutant phenotype: → the new mutation and the
tester mutation are alleles of the same gene

2. If the hybrid progeny show a wild phenotype: → the new mutation and the
tester mutation are not alleles of the same gene

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 Allelic Variation and Gene Function

Why genetic variation ?

1. If the hybrid progeny show a mutant phenotype: → the new mutation and the
tester mutation are alleles of the same gene

2. If the hybrid progeny show a wild phenotype: → the new mutation and the
tester mutation are not alleles of the same gene

• This test is based on the principle that mutations of the same gene impair the same
genetic function and when combined, the organism will be abnormal for this particular
function → show a mutant phenotype even if the two mutations had an independent origin
• Genes are identified by mutations that change the phenotype in some noticeable way
• High variation among the effects of individual mutations → each organism carries various
different kinds of genes (genetic composition) and each of the gene can mutate in different
ways. Mutations are the important for evolution
• Visible mutations: - morphological/physiological changes; most are recessives, few dominant
• Sterile mutations: -limit reproduction; completely prevent reproduction or just slight
impairment; can be recessive or dominant
• Lethal mutations: interrupt necessary vital functions → death of organism

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 Allelic Variation and Gene Function

Lethal mutations
• Some alleles are lethal in certain genotypes
• When offspring don't survive to be counted, ratios are different than predicted by simple
Mendelian rules. For example, coat colours in mice
There is a dominant allele (Y) which produces
yellow color
• Normally genotypes YY and Yy would produce
the yellow phenotype
• But the YY genotype is lethal, so YY mice do not
survive
• This changes the usual 3:1 dominance ratio in a
Yy x Yy mating because one box of the 4-box
Punnett square never gets counted. Modified
Mendelian ratio when homozygous dominant
ratio is lethal
N.B. As far as the color trait goes, Y is dominant.
But with respect to lethality, this allele is
recessive. The lethal phenotype only occurs in
mice that are homozygous YY. Heterozygous Yy
mice survive normally.
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 Genes Function to Produce Polypeptides

The extensive variation revealed by mutations indicates that organisms contain many different
genes and that these genes can exist in multiple allelic states.
But does not inform us how genes actually affect the phenotype
Beadle & Tatum→ each gene is responsible for the synthesis of a particular polypeptide

• When a gene is mutated, polypeptide product is either changed or not made, leading to
physiological and/or morphological changes.
• Mutations that eliminate or change a polypeptide are generally associated with phenotypic
effect – whether dominant or recessive depends on the nature of the mutation
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 Genes Function to Produce Polypeptides

• Dominant mutations have phenotypic effects in heterozygotes as well as in homozygotes,

whereas recessive mutations have these effects only in homozygotes.

• Recessive mutations → loss-of-function alleles – as the gene involve produces

underfunctional, non-functional or no polypeptide at all. So, little or no clear effect in
heterozygotes.
• Some recessive mutations result in a partial loss of a gene function. For example, the
himalayan allele for coat colour in mammals – pigmented hair on their extremities but not the
rest of their bodies because the polypeptide produced by this allele is functional –
temperature sensitiveness

• Some dominant mutations may also cause loss of a gene function by affecting the amount of
polypeptide(s), especially if the phenotype is sensitive to the amount of that particular gene
product.
How does the dominant mutation
affect gene product in heterozygous
condition with a wild type allele ?

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 Genes Function to Produce Polypeptides

Dominant negative mutations: -dominant mutations which actually interfere with the
function of the wild-type allele by producing polypeptides that limit, antagonise or inhibit
the activity of normal proteins
• Although it would be expected that most mutations would lead to a loss-of-function, it is
possible that a new function could result from the mutation.
• In these cases, the mutation creates a new allele that is associated with a new function or
enhance the wild-type . Any heterozygote containing the new allele along with the original
wild type allele will express the new allele.
• The enhanced function may be generated because the mutation specifies a new
polypeptide or it forces the wild-type polypeptide to be synthesised where or when it
should not be
• Genetically, this will define the mutation as a dominant → gain-of-function mutation
• Example: Antennapedia (Antp) mutation in Drosophila

Antp mutation causes the legs to

develop in place of the antennae
on the head of the fly

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 Gene Action: From Genotype to Phenotype

Phenotypes depend on both the genotype and the environment

Can you suggest the reason(s) why the

rabbit that was reared at lower
temperatures have black hair at its
extremities

• A gene must function in the context of both a biological and a physical environment
• The expression of genes in an organism can be influenced by the environment, including
the external world in which the organism is located or develops, as well as the organism's
internal world, which includes such factors as its hormones and metabolism.
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 Gene Action: From Genotype to Phenotype

Phenotypes depend on both the genotype and the environment

• One major internal environmental influence that affects gene expression is gender, as is
the case with sex-influenced and sex-limited traits. Examples include pattern baldness in
males, possibly due to testosterone. In homozygous females, there is such tendency but
generally involving thinning of the hair
• Similarly, chemicals, temperature, and light are among the external environmental factors
that can determine which genes are turned on and off, thereby influencing the way an
organism develops and functions.
Phenylketonuria (PKU):
• a recessive disorder of amino acid metabolism
• mutation in the gene for the hepatic enzyme phenylalanine hydroxylase (PAH) causing it
to be non-functional
• infants homozygous for this mutant allele accumulate toxic substances in their brains due
to the inability to covert phenylalanine to tyrosine –affect normal brain development,
hence lead to mental ability impairment
• infants with PKU who receive normal diet ingest sufficient phenylalanine and display worst
manifesations of the disease

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 Gene Action: From Genotype to Phenotype

• Dominance relationships between alleles for a given trait can impact phenotypic ratios, but
interactions between different genes can also impact phenotype. Such traits that result from
the interaction among multiple genes and their environment are called complex traits.

• So, given a specific trait, how can we tell whether it is complex? One way to recognize a
complex trait is through inconsistent inheritance patterns in successive generations. For
example, a dominant trait might skip an entire generation yet be expressed in the
subsequent generation. How is this possible? The answer to this question lies in the
concepts of penetrance and expressivity.

Penetrance
• For some traits, a particular genotype does not always produce the expected phenotype.
This is called incomplete (or reduced) penetrance
• Incomplete penetrance applies when a gene is expressed in less than 100% of the
individuals that carry the genotype
• Consider a recessive trait should be expressed in all individuals that have genotype aa. But
suppose that only 85% of those with genotype aa have the recessive phenotype. In this case
the penetrance would be 0.85

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 Gene Action: From Genotype to Phenotype

Penetrance
• A specific example of incomplete penetrance is the human bone disease osteogenesis
imperfecta (OI).

•The majority of people with this disease have a dominant mutation in one of the two genes
that produce type 1 collagen, COL1A1 or COL1A2. Collagen is a tissue that strengthens bones
and muscles and multiple body tissues. People with OI have weak bones, bluish color in the
whites of their eyes, and a variety of afflictions that cause weakness in their joints and teeth.

• However, this disease doesn't affect everyone who has COLIA1 and COLIA2 mutations in
the same way. In fact, some people can carry the mutation but have no symptoms. Thus,
families can unknowingly transmit the mutation from one generation to the next through
someone who carries the mutation but does not express the OI phenotype.

• Incomplete penetrance examples such as OI demonstrate that even monogenic diseases do

not have predictable expression patterns in a population.
Is there a way to explain this
unpredictability ?

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 Gene Action: From Genotype to Phenotype

Expressivity
• Sometimes a gene is not expressed to the same degree in all individuals that have the trait
• Individuals with the same genotype can also show different degrees of the same
phenotype. Expressivity is the degree to which trait expression differs among individuals
• Unlike penetrance, expressivity describes individual variability, not statistical variability
among a population of genotypes. For example, in some genetic diseases, everyone who has
the genotype for the disease may not have the same severity of symptoms
• An example: polydactyly, with the first to report on this phenomenon was C. H. Danforth,
who studied the inheritance of polydactyly among 55 generations of cats.

• He observed that the polydactyly phenotype showed "good penetrance, but variable
expression" because the gene always causes extra toes on the paw, but the number of extra
toes varies widely from cat to cat (Danforth, 1947).

• Through his breeding studies, Danforth found that although a dominant allele underlies
the cause of polydactyly, the degree of polydactyly depends on the condition of adjacent
layered tissues in the developing limb; that is, the expression of genes in tissues surrounding
tissue that will become the toe determines the degree of polydactyly (Willier, 1974).

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 Gene Action: From Genotype to Phenotype

Expressivity
• Another example, the features of Marfan syndrome vary widely - some people have only
mild symptoms, such as being tall and thin with long, slender fingers, whereas others also
experience life-threatening complications involving the heart and blood vessels

• Although the features of Marfan syndrome are highly variable, all people with this disorder
have a dominant mutation in the gene coding for fibrillin 1, FBN1. However, it turns out that
the position of the mutation in the FBN1 gene is correlated with the severity of the Marfan
phenotype

• Researchers found that a mutation in one FBN1 position is prevalent in families with severe
symptoms, whereas a mutation in another position is prevalent in families with less severe
symptoms. These findings are an encouraging clue as to how specific defects in the fibrillin 1
protein can account for the variable expressivity in Marfan syndrome

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 Gene Action: From Genotype to Phenotype

• 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 between genes would occur. Bateson and Punnett
performed a classical experiment that demonstrated genetic interactions →they analysed
the three comb types of chicken known to exist at that time:

Rose Pea Single Walnut

Result: The F1 differed from both parents and two new phenotypes not seen in the
parents appeared in the F2.
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 Gene Action: From Genotype to Phenotype

A series of experiments demonstrated that the genotypes controlling the various

comb phenotypes are as follows.
Phenotypes Genotypes Frequency
Walnut R_P_ 9/16
Rose R_pp 3/16
Pea rrP_ 3/16
Single rrpp 1/16
It was later shown that the genotypes of the
initial parents were:
Rose = RRpp
Pea = rrPP

Therefore, genotypically the cross was:

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 Gene Action: From Genotype to Phenotype

• The development of any individual is obviously the expression of all the genes that are a
part of its genetic makeup

• Therefore, it is not an unexpected conclusion that more than one gene could be
responsible for the expression of a single phenotype

• Variations in the expression on one gene can be caused by modifier genes or

environmental effects

• Variation in expression of certain genes can make it difficult to figure out pedigrees
because Mendelian predictions alone cannot explain the inheritance pattern

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 Gene Action: From Genotype to Phenotype

Epistasis
Epistasis describes how gene interactions can affect phenotypes. Did you know that genes
can mask each other’s presence or combine to produce an entirely new trait?

• In Mendel’s dihybrid cross, each gene locus had an independent effect on a single
phenotype.
• Thus, the R and r alleles affected only the shape of the seed and had no influence on seed
color, while the Y and y alleles affected only seed color and had no influence on seed shape.
• In this case, there were two separate genes that coded for two separate characteristics.

• When two genes are involved in the outcome of one characteristic, a dihybrid cross
involving these genes can produce a phenotypic ratio very different from 9:3:3:1.

• Under these circumstances, there are more than two gene products affecting the same
phenotype, and these products may have complex hierarchical relationships. Any time two
different genes contribute to a single phenotype and their effects are not merely additive,
those genes are said to be epistatic.

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 Gene Action: From Genotype to Phenotype

Epistasis
• So, when two or more genes influence a trait, one of the allele may have a stronger effect
on the phenotype, hence this particular allele is said to be epistatic to the other genes that
are involved
• a mutant allele of one gene is epistatic to a mutant allele of another gene if it masks the
latter’s presence in the genotype

• epistasis is an interaction at the phenotypic level of organization

• the genes that are involved in a specific epistatic interaction may still show independent
assortment at the genotypic level

• in such cases, however, the phenotypic ratios may appear to deviate from those expected
with independent assortment

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 Gene Action: From Genotype to Phenotype

Example cross: sweet pea (Lathyrus odoratus) flower color

• In sweet peas, both of two genes must have a dominant allele to produce purple flowers
• C-P- gives purple flowers
• C-pp, ccP-, and ccpp give white flowers
• There are only two phenotypes
• The cross CcPp x CcPp produces a ratio of 9:7

• two independently assorting genes C and

P are responsible for anthocyanin
synthesis but each has a recessive allele
that abolishes pigment production

• each of the recessive alleles is epistatic

over the dominant allele of the other gene
• each dominant allele produces an
enzyme controlling a step in anthocyanin
synthesis from a biochemical precursor

• absence of a dominant allele blocks the

biosynthetic pathway
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 Gene Action: From Genotype to Phenotype

Example cross: snail shell colour

• Brown or white produced in 9:7 ratio
• A-B-, A-bb, aaB- produce one identical phenotype
• aabb produces a different phenotype

Can you provide the molecular

explanation for this pattern?

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 Gene Action: From Genotype to Phenotype

Example cross: squash fruit color

In squash, one gene is epistatic over the other in the dominant condition
• W-Y- and W-yy gives white fruit
• wwY- gives yellow fruit
• wwyy gives green fruit

There are three phenotypes; the cross WwYy x WwYy produces a ratio of 12:3:1

• 9/16 W-Y- : white Inheritance of fruit colour in squash through

• 3/16 W-yy : white interaction of two separate genes by dominant
• 3/16 ww Y- : yellow epistasis
• 1/16 ww yy : green

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 Gene Action: From Genotype to Phenotype

Pleiotropy
How can a mutation in one single gene cause a disease with a wide range of symptoms?
This situation is referred to as pleitropy, and it has been identified in a wide range of species,
even humans.
• Not only can a phenotype be influenced by many genes, but it is also true that one gene can
affect many phenotypes.

• Genes that affect multiple, apparently unrelated, phenotypes are thus called pleiotropic
genes.
• Pleiotropy should not be confused with polygenic traits, in which multiple genes converge
to result in a single phenotype.

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 Gene Action: From Genotype to Phenotype

Example - phenylketonuria (PKU)

• Primary phenotype is a lack of phenylalanine hydroxylase required for the metabolism of

phenylalanine
• When untreated, individuals have higher than normal levels of this amino acid

Other effects
• Lower IQ
• Smaller head size
• Rare compounds in the blood
• Lighter hair colour

• This array of phenotypic effects is typical for most genes and results between the different
biochemical and cellular pathways that the genes control

• These multiple affects make also sense when you consider that phenylalanine is a normal
constituent of all cells, so any many different cell types can be affected

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