Topic 3: Genetics → Inheritance

Gregor Mendel was an Austrian monk who developed the principles of inheritance by
performing experiments on pea plants
■ First, he crossed different varieties of purebred pea plants, then collected and
grew the seeds to determine their characteristics
■ Next, he crossed the offspring with each other (self-fertilization) and grew their
seeds to similarly determine their characteristics
■ These crosses were performed many times to establish reliable data trends (over
5,000 crosses were performed)

As a result of these experiments, Mendel discovered the following things:

1. When he crossed two different purebred varieties together the results were not a
blend – only one feature would be expressed
■ E.g. When purebred tall and short pea plants were crossed, all offspring
developed into tall growing plants
2. When Mendel self-fertilised the offspring, the resulting progeny expressed the
two different traits in a ratio of ~ 3:1
■ E.g. When the tall growing progeny were crossed, tall and short pea plants
were produced in a ratio of ~ 3:1

From these findings, Mendel drew the following conclusions:

■ Organisms have discrete factors that determine its features (these ‘factors’ are
now recognised as genes)
■ Furthermore, organisms possess two versions of each factor (these ‘versions’
are now recognised as alleles)
■ Each gamete contains only one version of each factor (sex cells are now
recognised to be haploid)
■ Parents contribute equally to the inheritance of offspring as a result of the fusion
between randomly selected egg and sperm
■ For each factor, one version is dominant over another and will be completely
expressed if present
Topic 3: Genetics → Inheritance

GOTTA KNOW THESE LAWS!

While there are caveats to Mendel’s conclusions, certain rules can be established:
1. Law of Segregation: When gametes form, alleles are separated so that each
gamete carries only one allele for each gene
2. Law of Independent Assortment: The segregation of alleles for one gene
occurs independently to that of any other gene*
3. Principle of Dominance: Recessive alleles will be masked by dominant alleles†

* The law of independent assortment does not hold true for genes located on the same
chromosome (i.e. linked genes → which we will discuss later)
†
Not all genes show a complete dominance hierarchy – some genes show
co-dominance or incomplete dominance

These ‘laws’ are now known to be due to key events that occur during meiotic division:
■ The law of segregation describes how homologous chromosomes (and hence
allele pairs) are separated in meiosis I
■ The law of independent assortment describes how homologous pairs align
randomly (as bivalents) during metaphase I
Through the elucidation of the process of meiosis, we now know that there are certain
exceptions to Mendel’s laws:
Topic 3: Genetics → Inheritance

■ Genes that are on the same chromosome (linked genes) will not undergo
independent assortment (unless recombination occurs)
■ Not all genes display a dominance hierarchy – certain traits may display
codominance or incomplete dominance

The Role of Meiosis in Mendelian Inheritance

Topic 3: Genetics → Inheritance

WHAT ARE HAPLOID GAMETES?

Gametes are haploid sex cells formed by the process of meiosis – males produce
sperm and females produce ova
■ During meiosis I, homologous chromosomes are separated into different nuclei
prior to cell division
■ As homologous chromosomes carry the same genes, segregation of the
chromosomes also separates the allele pairs
■ Consequently, as gametes contain only one copy of each chromosome they
therefore carry only one allele of each gene

Gametes are haploid, meaning they only possess one allele for each gene
When male and female gametes fuse during fertilisation, the resulting zygote will
contain two alleles for each gene
■ Exception: Males have only one allele for each gene located on a sex
chromosome, as these chromosomes
aren’t paired (XY)

For any given gene, the combination of alleles

can be categorised as follows:
■ If the maternal and paternal alleles are the
same, the offspring is said to be
homozygous for that gene
■ If the maternal and paternal alleles are
different, the offspring is said to be
heterozygous for that gene
■ Males only have one allele for each gene
located on a sex chromosome and are said to be hemizygous for that gene
Topic 3: Genetics → Inheritance

LET’S TALK ABOUT THE MODES OF INHERITANCE!

The gene composition (i.e. allele combination) for a specific trait is referred to as the
genotype
■ The genotype of a particular gene will typically be either homozygous or
heterozygous

The observable characteristics of a specific trait (i.e. the physical expression) is referred
to as the phenotype
■ The phenotype is determined by both the genotype and environmental influences

Complete Dominance
Most traits follow a classical dominant / recessive pattern of inheritance, whereby one
allele is expressed over the other
■ The dominant allele will mask the recessive allele when in a heterozygous state
■ Homozygous dominant and heterozygous forms will be phenotypically
indistinguishable
■ The recessive allele will only be expressed in the phenotype when in a
homozygous state

When representing alleles, the convention is to capitalise the dominant allele and use a
lower case letter for the recessive allele
■ An example of this mode of inheritance is mouse coat colour – black coats (BB or
Bb) are dominant to brown coats (bb)
Topic 3: Genetics → Inheritance

Co-dominance
Co-dominance occurs when pairs of alleles are both expressed equally in the
phenotype of a heterozygous individual
■ Heterozygotes therefore have an altered phenotype as the alleles are having a
joint effect

When representing alleles, the convention is to use superscripts for the different
co-dominant alleles (recessive still lower case)
■ An example of co-dominance is feathering in chickens – black (CB) and white
(CW) feathers create a speckled coat (CBCW)

POP QUIZ:

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Topic 3: Genetics → Inheritance

ANSWER: C

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Topic 3: Genetics → Inheritance

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Topic 3: Genetics → Inheritance

ANSWER: B

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Topic 3: Genetics → Inheritance

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Human red blood cells can be categorized into different blood groups based on the
structure of a surface glycoprotein (antigen)
■ The ABO blood groups are controlled by a single gene with multiple alleles (A, B,
O)

The A, B and O alleles all produce a basic antigen on the surface of red blood cells
■ The A and B alleles are co-dominant and each modifies the structure of the
antigen to produce different variants
■ The O allele is recessive and does not modify the basic antigenic structure

When representing blood group alleles, the letter I is used to represent the different
antigenic forms (isoantigens)
■ A allele = IA ; B allele = IB ; O allele = i (recessive)
Topic 3: Genetics → Inheritance

As humans produce antibodies against foreign antigens, blood transfusions are not
compatible between certain blood groups
■ AB blood groups can receive blood from any other type (as they already possess
both antigenic variants on their cells)
■ A blood groups cannot receive B blood or AB blood (as the isoantigen produced
by the B allele is foreign)
■ B blood groups cannot receive A blood or AB blood (as the isoantigen produced
by the A allele is foreign)
■ O blood groups can only receive transfusions from other O blood donor (both
antigenic variants are foreign)

The Consequence of an Incompatible Blood Transfusion

Topic 3: Genetics → Inheritance

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Topic 3: Genetics → Inheritance

ANSWER:
Hemophilia is a sex-linked recessive disorder carried by a recessive allele, Xh, on the X
chromosome. Since males only receive one copy of the X chromosome, a male with
hemophilia must carry the recessive Xh allele. A female without hemophilia could have
the genotypes XHXH, meaning she does not carry any copies of the recessive allele, or
XHXh, meaning she carries one dominant and one recessive allele. However, the
daughter must inherit her father’s recessive allele, so the daughter will have one Xh
allele (Statement II and Statement III). Since the daughter does not have hemophilia,
she must have inherited the XH allele from her mother (Statement II). Therefore, the
only possible genotype for the daughter is XHXh (Choice B).

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Topic 3: Genetics → Inheritance

ANSWER: A
Alleles are versions of a gene. Choice A shows 3 different alleles. Choice B shows
three blood groups (phenotypes). Choice C shows three genotypes, and Choice D
shows 3 blood groups (phenotypes).

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Topic 3: Genetics → Inheritance

ANSWER: D

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HOW DO WE MAKE Punnett Grids?

A monohybrid cross determines the allele combinations for potential offspring for one
gene only
Monohybrid crosses can be calculated according to the following steps:
■ Step 1: Designate letters to represent alleles (dominant = capital letter ;
recessive = lower case ; co-dominant = superscript)
■ Step 2: Write down the genotype and phenotype of the prospective parents (this
is the P generation)
■ Step 3: Write down the genotype of the parental gametes (these will be haploid
and thus consist of a single allele each)
■ Step 4: Draw a grid with maternal gametes along the top and paternal gametes
along the left (this is a Punnett grid)
■ Step 5: Complete the Punnett grid to determine potential genotypes and
phenotypes of offspring (this is the F1 generation)
Topic 3: Genetics → Inheritance

Overview of a Monohybrid Cross

The genotypic and phenotypic ratios calculated via Punnett grids are only probabilities
and may not always reflect actual trends
■ E.g. When flipping a coin there is a 50% chance of landing on heads – this
doesn’t mean you will land on heads 50% of the time

When comparing predicted outcomes to actual data, larger data sets are more likely to
yield positive correlations
■ Gregor Mendel performed over 5,000 crosses as part of his pea plant experiment
■ However many statisticians believe Mendel’s results are too close to the exact
ratios predicted to be genuine
Topic 3: Genetics → Inheritance

Mendel’s Pea Plant Experimental Data

Mendel crossed different varieties of pea plants and recorded the characteristics of
resultant offspring
■ Initially, he crossed purebred dominant and purebred recessive plants in order to
produce heterozygotes (F1 generation)
■ He then self-pollinated the heterozygotes to produce an F2 generation and
counted the dominant and recessive phenotypes
■ The expected ratio of dominant : recessive phenotypes was 3 : 1 – this ratio was
supported by the experimental data

LET’S TALK ABOUT Polygenic Traits!

Variation in phenotypes for a particular characteristic can be either discrete
(discontinuous) or continuous
■ Monogenic traits (characteristics controlled by a single gene loci) tend to exhibit
discrete variation, with individuals expressing one of a number of distinct
phenotypes
■ Polygenic traits (characteristics controlled by more than two gene loci) tend to
exhibit continuous variation, with an individual’s phenotype existing somewhere
along a continuous spectrum of potential phenotypes
Topic 3: Genetics → Inheritance

In the case of polygenic inheritance:

■ Increasing the number of loci responsible for a particular trait increases the
number of possible phenotypes
■ This results in a phenotypic distribution that follows a Gaussian (bell-shaped)
normal distribution curve

Monogenic → Polygenic Inheritance

Maize Grain Colour

An example of a polygenic trait is grain colour in maize (wheat), which is controlled by
three gene loci
■ Grain colour can range from white to dark red, depending on the amount of
pigment that is expressed

Each gene has two alleles, which either code for red pigment or white pigment
■ The most frequent combinations have an equal number of the two allele types
■ Conversely, combinations of one extreme or the other are relatively rare
■ The overall pattern of inheritance shows continuous variation
Topic 3: Genetics → Inheritance

Continuous Variation in Maize Grain Color →

Phenotypic characteristics are not solely determined by genotype, but are also
influenced by environmental factors
■ The added effect of environmental pressures functions to increase the variation
seen for a particular trait

One example of a polygenic trait that is influenced by environmental factors is human

height
■ Human height is controlled by multiple genes (polygenic), resulting in a
bell-shaped spectrum of potential phenotypes
■ Environmental factors such as diet and health (disease) can further influence an
individual human’s height

Another example of a polygenic trait that is influenced by environmental factors is

human skin colour
■ Skin colour is controlled by multiple melanin producing genes, but is also affected
by factors such as sun exposure
Topic 3: Genetics → Inheritance

POP QUIZ!

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Topic 3: Genetics → Inheritance

ANSWER: D
Two different colours show that there are two alleles for this characteristic (Choice D).
Polygenic inheritance results in continuous variation (Choice B). Two distinct colours
are an example of discontinuous variation. If there was co-dominance, there would be
three possible flower colour variations (Choice A). If there were genes at two loci that
controlled flower colour, then the trait would be a polygenic trait and show continuous
variation (Choice C).

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GENETIC DISEASES?!
Genetic diseases are caused when mutations to a gene (or genes) abrogate normal
cellular function, leading to the development of a disease phenotype
■ Genetic diseases can be caused by recessive, dominant or co-dominant alleles

An autosomal recessive genetic disease will only occur if both alleles are faulty

■ Heterozygous individuals will possess one copy of the faulty allele but not
develop disease symptoms (they are carriers)
■ An example of an autosomal recessive genetic disease is cystic fibrosis

An autosomal dominant genetic disease only requires one copy of a faulty allele to
cause the disorder
■ Homozygous dominant and heterozygous individuals will both develop the full
range of disease symptoms
■ An example of an autosomal dominant genetic disease is Huntington’s disease

If a genetic disease is caused by co-dominant alleles it will also only require one copy
of the faulty allele to occur
■ However, heterozygous individuals will have milder symptoms due to the
moderating influence of a normal allele
■ An example of a genetic disease that displays co-dominance is sickle cell
anaemia
Topic 3: Genetics → Inheritance

Cystic Fibrosis
■ Cystic fibrosis is an autosomal recessive disorder caused by a mutation to the
CFTR gene on chromosome 7
■ Individuals with cystic fibrosis produce mucus which is unusually thick and sticky
■ This mucus clogs the airways and secretory ducts of the digestive system,
leading to respiratory failure and pancreatic cysts
■ Heterozygous carriers who possess one normal allele will not develop disease
symptoms

Huntington’s Disease
■ Huntington’s disease is an autosomal dominant disorder caused by a mutation to
the Huntingtin (HTT) gene on chromosome 4
■ The HTT gene possesses a repeating trinucleotide sequence (CAG) that is
usually present in low amounts (10 – 25 repeats)
■ More than 28 CAG repeats is unstable and causes the sequence to amplify
(produce even more repeats)
Topic 3: Genetics → Inheritance

■ When the number of repeats exceeds ~40, the huntingtin protein will misfold and
cause neurodegeneration
■ This usually occurs in late adulthood and so symptoms usually develop
noticeably in a person’s middle age (~40 years)
■ Symptoms of Huntington’s disease include uncontrollable, spasmodic
movements (chorea) and dementia

There are over 4,000 identified single gene defects that lead to genetic disease, but
most are very rare
■ Any allele that adversely affects survival and hence the capacity to reproduce is
unlikely to be passed on to offspring

Recessive conditions tend to be more common, as the faulty allele can be present in
carriers without causing disease

Dominant conditions may often have a late onset, as this does not prevent reproduction
and the transfer of the faulty allele
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Topic 3: Genetics → Inheritance

Sex linkage refers to when a gene controlling a characteristic is located on a sex

chromosome (X or Y)
■ The Y chromosome is much shorter than the X chromosome and contains only a
few genes (50 million bp; 78 genes)
■ The X chromosome is longer and contains many genes not present on the Y
chromosomes (153 million bp ; ~ 2,000 genes)
■ Hence, sex-linked conditions are usually X-linked - as very few genes exist on
the shorter Y chromosome

Sex-linked inheritance patterns differ from autosomal patterns due to the fact that the
chromosomes aren’t paired in males (XY)
■ This leads to the expression of sex-linked traits being predominantly associated
with a particularly gender

As human females have two X chromosomes (and therefore two alleles), they can be
either homozygous or heterozygous

■ Hence, X-linked dominant traits are more common in females (as either allele
may be dominant and cause disease)

Human males have only one X chromosome (and therefore only one allele) and are
hemizygous for X-linked traits

■ X-linked recessive traits are more common in males, as the condition cannot be
masked by a second allele

The following trends always hold true for X-linked conditions:

Topic 3: Genetics → Inheritance

■ Only females can be carriers (a heterozygote for a recessive disease condition),

males cannot be heterozygous carriers
■ Males will always inherit an X-linked trait from their mother (they inherit a Y
chromosome from their father)
■ Females cannot inherit an X-linked recessive condition from an unaffected father
(must receive his dominant allele)

Inheritance of an X-linked Recessive Disease Condition

Red-green colour blindness and haemophilia are both examples of X-linked recessive
conditions
■ Consequently, they are both far more common in males than in females (males
cannot mask the trait as a carrier)

When assigning alleles for a sex-linked trait, the convention is to write the allele as a
superscript to the sex chromosome (X)
■ Haemophilia: XH = unaffected (normal blood clotting) ; Xh = affected
(haemophilia)
■ Colour blindness: XA = unaffected (normal vision) ; Xa = affected (colour
blindness)
Topic 3: Genetics → Inheritance

Haemophilia
Haemophilia is a genetic disorder whereby the body’s ability to control blood clotting
(and hence stop bleeding) is impaired
■ The formation of a blood clot is controlled by a cascade of coagulation factors
whose genes are located on the X chromosome
■ When one of these factors becomes defective, fibrin formation is prevented -
meaning bleeding continues for a long time
■ Different forms of haemophilia can occur, based on which specific coagulation
factor is mutated (e.g. haemophilia A = factor VIII)

Red-Green Colour Blindness

Red-green colour blindness is a genetic disorder whereby an individual fails to
discriminate between red and green hues
■ This condition is caused by a mutation to the red or green retinal photoreceptors,
which are located on the X chromosome
■ Red-green colour blindness can be diagnosed using the Ishihara colour test
Topic 3: Genetics → Inheritance

A gene mutation is a change to the base sequence of a gene that can affect the
structure and function of the protein it encodes
■ Mutations can be spontaneous (caused by copying errors during DNA
replication) or induced by exposure to external elements

AMAZING TEST QUESTION EXAMPLES: Examples of factors which can induce

mutations include:

■ Radiation – e.g. UV radiation from the sun, gamma radiation from radioisotopes,
X-rays from medical equipment
■ Chemical – e.g. reactive oxygen species (found in pollutants), alkylating agents
(found in cigarettes)
■ Biological Agents – e.g. bacteria (such as Helicobacter pylori), viruses (such as
human papilloma virus)

Agents which increase the rate of genetic mutations are called mutagens, and can lead
to the formation of genetic diseases
■ Mutagens which lead to the formation of cancer are more specifically referred to
as carcinogens

The nuclear bombing of Hiroshima and accident at Chernobyl are two examples of a
catastrophic release of radioactive material
■ The nuclear bombing of Hiroshima (and Nagasaki) occurred in August 1945,
during the final stages of World War II
■ The Chernobyl accident occurred in April 1986, when an explosion at the reactor
core caused the release of radioactive material

Of the two incidents, more people died from the nuclear bombing, but the meltdown
released far more radiation (~400×)

■ The Chernobyl meltdown involved far more fissionable material and produced
different isotopes with much longer half-lives
Topic 3: Genetics → Inheritance

■ The Hiroshima nuclear bomb was detonated above ground and radiation was
dispersed, resulting in less irradiation of the soil

Some of the long-term consequences of radiation exposure following these disasters

include:
■ An increased incidence in cancer development (with a strong correlation between
dose of radiation and frequency of cancer)
■ Reduced T cell counts and altered immune functions, leading to higher rates of
infection
■ A wide variety of organ-specific health effects (e.g. liver cirrhosis, cataract
induction, etc.)
Some of the consequences of radiation exposure are specific to the incident due to the
types and amounts of radiation released
■ Thyroid disease was a common consequence of the Chernobyl accident due to
the release of radioactive iodine
■ There was no significant increase in birth defects following the Hiroshima
bombing, but an estimated 250% increase in congenital abnormalities following
the Chernobyl meltdown

Whereas Hiroshima is still habitable and well populated, certain regions of Chernobyl
remain unsafe for human habitation
■ There is anecdotal evidence to suggest that radiation levels around Chernobyl
have caused variation to local flora and fauna
■ The presence of residual radiation in the environment can become concentrated
in organisms via bioaccumulation

Pedigree Charts:
A pedigree is a chart of the genetic history of a family over several generations
■ Males are represented as squares, while females are represented as circles
Topic 3: Genetics → Inheritance

■ Shaded symbols mean an individual is affected by a condition, while an

unshaded symbol means they are unaffected
■ A horizontal line between man and woman represents mating and resulting
children are shown as offshoots to this line
■ Generations are labeled with roman numerals and individuals are numbered
according to age (oldest on the left)

Autosomal Dominant
■ If both parents are affected and an offspring is unaffected, the trait must be
dominant (parents are both heterozygous)
■ All affected individuals must have at least one affected parent
■ If both parents are unaffected, all offspring must be unaffected (homozygous
recessive)
Autosomal Recessive
■ If both parents are unaffected and an offspring is affected, the trait must be
recessive (parents are heterozygous carriers)
■ If both parents show a trait, all offspring must also exhibit the trait (homozygous
recessive)

Determining X-Linked Inheritance

It is not possible to confirm sex linkage from pedigree charts, as autosomal traits could
potentially generate the same results
■ However certain trends can be used to confirm that a trait is not X-linked
dominant or recessive
X-linked Dominant
■ If a male shows a trait, so too must all daughters as well as his mother
■ An unaffected mother cannot have affected sons (or an affected father)
■ X-linked dominant traits tend to be more common in females (this is not sufficient
evidence though)

X-linked Recessive
■ If a female shows a trait, so too must all sons as well as her father
■ An unaffected mother can have affected sons if she is a carrier (heterozygous)
■ X-linked recessive traits tend to be more common in males (this is not sufficient
evidence though)
Topic 3: Genetics → Inheritance

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Topic 3: Genetics → Inheritance

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LET’S TAKE A MOMENT AND TALK ABOUT PHENOTYPE

The phenotype is the observable characteristics or traits of an organism
■ It is predominantly determined by the organism’s genotype (allele combination)
for each particular feature

However environmental factors may also influence the expression of characteristics

■ Hydrangeas change colour depending on the pH of the soil (acidic soil = blue
flower ; alkaline soil = pink flower)
■ Human skin colour is determined by the expression of melanin pigment, but
levels can change depending on sun exposure

WHAT ARE Lethal Alleles??

Topic 3: Genetics → Inheritance

Lethal alleles are alleles that cause an organism to die only when present in a
homozygous condition
■ The gene involved is considered an essential gene and the lethal allele may be
either dominant or recessive

An example of lethal alleles in humans is achondroplasia, a genetic condition which

causes dwarfism
■ The lethal allele is dominant and hence causes the death of the organism when
present in the homozygous state (AA)
■ Heterozygotes will possess a significantly shorter stature (dwarfism), while
homozygous recessive individuals will be normal size

By causing the death of one genotypic variant, lethal alleles create altered genotypic
and phenotypic ratios to the norm
■ Normally a cross of two heterozygotes will generate a 3 : 1 ratio (dominant :
recessive)
■ In achondroplasia, two dwarf heterozygotes are expected to generate a 2 : 1 ratio
(the homozygous dominant doesn’t survive)

WHAT’S Epistasis?!
Topic 3: Genetics → Inheritance

Epistasis describes a condition whereby one gene controls the expression of another
gene

In mice, the expression of a specific fur colour by one gene is dependent upon the
production of hair pigment by another gene
■ Black fur (B) is dominant to brown fur (b), but in the absence of hair pigment (cc)
mice will appear albino

In humans, the gene for baldness supersedes genes for hair colour and hence is
epistatic in nature

WHAT’S Pleiotropy!?
Topic 3: Genetics → Inheritance

Pleiotropy occurs when a single gene affects multiple traits – hence mutations will tend
to be severe and affect multiple systems
Pleiotropy can be observed in the multiple health issues arising from sickle cell
anaemia (mutation to the beta-globin gene)
■ The rapid breakdown of red blood cells causes anaemia, leading to increased
lethargy and higher risks of infection
■ The clotting of sickle cells in vessels can cause heart attacks and brain damage
(strokes and paralysis)
■ The accumulation of blood cells in specific organs can lead to loss of function
(e.g. liver or splenic failure, kidney damage, etc.)
■

ALL THE SINGLE LADIES ~

Topic 3: Genetics → Inheritance

X-inactivation is the process by which one of the two X chromosomes present in

females is inactivated
■ This ensures that females do not produce twice as many X-linked gene proteins
as males (who possess one X chromosome)

The silenced X chromosome is packaged as transcriptionally inactive heterochromatin,

forming a structure called a Barr body

■ Once an X chromosome is inactivated, it will remain permanently inactive in the

cell (and all cells derived from it)

X-inactivation occurs randomly in mammals, meaning both X chromosomes may be

active in different cells

■ This allows for a heterozygous phenotype to occur in the female as a whole

WHAT’S Mosaicism!? Mosaicism

Topic 3: Genetics → Inheritance

Mosaicism describes the presence of two populations of cells with distinct genotypes
within a single organism
■ It is caused when either mutation or division error creates two distinct cell types
which divide into separate cell lines

Mosaicism is more pronounced when errors occur in early embryo development and
thus affects a greater proportion of cells

■ X-inactivation in mammals creates a mosaic of genotypes linked to the X

chromosome only, and hence is not true mosaicism

LET’S TAKE A MOMENT TO DISCUSS Dihybrid Crosses

Topic 3: Genetics → Inheritance

According to the law of independent assortment, pairs of alleles are inherited

independently of one another if their gene loci are on separate chromosomes – these
genes are said to be unlinked
■ This is due to the random orientation of homologous pairs during metaphase I of
meiosis

The independent segregation of unlinked genes results in a greater number of potential

gamete combinations, as well as a greater variety of possible phenotypes
■ This also results in more complex inheritance patterns (e.g. monohybrid versus
dihybrid crosses)

A dihybrid cross determines the genotypic and phenotypic combinations of offspring for
two particular genes that are unlinked
■ Because there are two genes, each with two alleles, there can be up to four
different gamete combinations

The easiest way to work out potential gamete combinations in a dihybrid cross is to use
the FOIL method:
■ FOIL = First / Outside / Inside / Last
Topic 3: Genetics → Inheritance

How to Complete a Dihybrid Cross

The inheritance of dihybrid traits can be calculated according to the following steps:

Step 1: Designate characters to represent the alleles

■ Capital letter for dominant allele, lower case letter for recessive allele

Step 2: Write down the genotype and phenotype of the parents (P generation)
■ Always pair alleles from the same gene and always write capitals first (e.g. AaBb,
not ABab)

Step 3: Write down all potential gamete combinations for both parents
■ Use the FOIL method (or the claw) to identify all possible combinations

Step 4: Use a Punnett square to work out potential genotypes of offspring

■ Only include the different gamete combinations for each parent (e.g. AaBB has
two combinations = AB and aB)

Step 5: Write out the phenotype ratios of potential offspring

■ Phenotypic ratios reflect mathematical probabilities only and may not necessarily
reflect actual offspring ratios
Topic 3: Genetics → Inheritance

WHAT ARE LINKED GENES?!

A linkage group is a group of genes whose loci are on the same chromosome and
hence don’t independently assort
■ Linked genes will tend to be inherited together and hence don’t follow normal
Mendelian inheritance for a dihybrid cross
■ Instead the phenotypic ratio will be more closely aligned to a monohybrid cross
as the two genes are inherited as a single unit
■ Linked genes may become separated via recombination (due to crossing over
during synapsis in meiosis I)

Thomas Hunt Morgan provided a key contribution to our current understanding of gene
linkage by discovering non-Mendelian ratios in Drosophila melanogaster (fruit flies)
■ His breeding experiments involving fruit flies clearly demonstrated that linked
genes were not independently assorted
Topic 3: Genetics → Inheritance

Sex Linkage
When cross-breeding red-eyed wild
types with white-eyed mutants, he
discovered a clear sex bias in
phenotypic distribution
■ All female offspring of a
red-eyed male were
red-eyed, whereas all male
offspring of a white-eyed
female were also white-eyed
■ Morgan described this
distribution as 'sex-limited’
inheritance and inferred it
was caused by the gene for
eye colour being located on a
sex chromosome (i.e.
X-linked)

Gene Linkage
Morgan went on to identify a number of different traits in fruit flies that did not conform to
Mendelian ratios
■ Certain phenotypic combinations occurred in much lower frequencies than was to
be expected

Based on this data, Morgan made two key proposals:

■ The alleles for these traits were located on a shared chromosome (gene linkage)
and hence did not independently assort
■ Linked alleles could be uncoupled via recombination (crossing over) to create
alternative phenotypic combinations, but these new phenotypes would occur at a
much lower frequency

Morgan also observed that the amount of crossing over between linked genes differed
depending on the combination of traits
■ This led to the idea that crossover frequency may be a product of the distance
between two genes on a chromosome – genes with a higher crossover frequency
are further apart, whereas genes with a lower crossover frequency are closer
together
Topic 3: Genetics → Inheritance

■ Morgan used this concept to develop the first gene linkage maps that showed the
relative positions of genes on a chromosome

From the above diagrams it can be seen that:

■ Long aristae and red eyes are more likely to be separated via recombination
(high crossover frequency)
■ Long aristae and long legs are less likely to be separated via recombination (low
crossover frequency)

This indicates that the aristae and leg genes are located closer together, whereas the
eye gene is more distant
Topic 3: Genetics → Inheritance

WHAT ARE Recombinants?

Recombinants of linked genes are those combinations of genes not found in the
parents
■ Recombinants occur as a result of crossing over of genetic material during
prophase I of meiosis
■ If linked genes become separated by a chiasma, there will be an exchange of
alleles between the non-sister chromatids
■ This creates new allele combinations that are different to those of the parent

Identifying Recombinants from Genotype →

The frequency of recombinant phenotypes within a population will typically be lower

than that of non-recombinant phenotypes
■ This is because crossing over is a random process and chiasmata do not form at
the same locations with every meiotic division

The relative frequency of recombinant phenotypes will be dependent on the distance

between linked genes
■ Recombination frequency between two linked genes will be greater when the
genes are further apart on the chromosome
■ This is because there are more possible locations where a chiasma could form
between the genes

Recombinant phenotypes can be identified by performing a test cross (crossing with a

homozygous recessive for both traits)
Identifying Recombinants from Phenotype →
Topic 3: Genetics → Inheritance

TAKE A DEEP BREATH. Chi squared test:

It is possible to infer whether two genes are linked or unlinked by looking at the
frequency distribution of potential phenotypes

Offspring with unlinked genes have an equal possibility of inheriting any potential
phenotypic combination
■ This is due to the random segregation of alleles via independent assortment

Offspring with linked genes will only express the phenotypic combinations present in
either parent unless crossing over occurs
■ Consequently, the ‘unlinked’ recombinant phenotypes occur less frequently than
the ‘linked’ parental phenotypes
Topic 3: Genetics → Inheritance

Chi-Squared Tests
Chi-squared tests are a statistical measure that are used to determine whether the
difference between an observed and expected frequency distribution is statistically
significant

If observed frequencies do not conform to those expected for an unlinked dihybrid

cross, this suggests that either:
■ Genes are linked and hence not independently assorted
■ The inheritance of the traits are not random, but are potentially being affected by
natural selection

A chi-squared test can be applied to data generated from a dihybrid cross to determine
if there is a statistical correlation between observed and expected frequencies
A chi-squared test can be completed by following five simple steps:
■ Identify hypotheses (null versus alternative)
■ Construct a table of frequencies (observed versus expected)
■ Apply the chi-squared formula
■ Determine the degree of freedom (df)
■ Identify the p value (should be <0.05)
Topic 3: Genetics → Inheritance

A chi-squared table shows the distribution of critical values according to each degree of
freedom
■ This allows for an assessment to be made as to whether the data is statistically
significant (p<0.05) or not

For accurate data, the following conditions should be met:

■ All items in the group should be independent and collected on a random basis
■ No group should contain very few items (e.g. less than 10)
■ The total number of items should be large (e.g. more than 50)
Chi Squared Distribution Table
Topic 3: Genetics → Inheritance

EXTRA INFO
A centimorgan is a unit of measure used to approximate the distance between genes
■ Thomas Morgan demonstrated that genes that were further apart on a
chromosome were more likely to recombine
■ This is because there are more potential sites for crossing over to occur between
distant genes

One centimorgan (or genetic map unit / m. u.) is the equivalent to a recombination
frequency of 1%
■ A centimorgan is not a true measure of distance and will differ in equivalence
between species
■ In humans, 1 cM corresponds to approximately 1 million bp on average

While centimorgans may still be used to quantitate recombination frequencies, they are
no longer used to measure distance
■ Genome mapping has allowed scientists to determine specific distances between
genes in kilo bases (kb)
Topic 3: Genetics → Inheritance

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