Course: Medical Genetics

Code & No: CLS 483

Credits : 3(2+1)
Pre-requisite: CLS 476

By
Dr. Samir Al-Harbi
 Reference text book

• Emery's Elements of Medical Genetics

by Peter D. Turnpenny, Sian Ellard

• Essentials of Medical Genetics for Health

Professionals
by Laura M. Gunder.
 Lecture 1
History of genetics
 Heredity

• What is Heredity ?
• What genetic principles account for the
transmission of traits from parents to offspring?
• One possible explanation of heredity is a
“blending” hypothesis - The idea that genetic
material contributed by two parents mixes in a
manner analogous to the way blue and yellow
paints blend to make green
• An alternative to the blending model is the
“particulate” hypothesis of inheritance: the gene
idea - Parents pass on discrete heritable units,
genes
 Mid 1800’s Discoveries

• Four major events in the mid-1800’s led

directly to the development of modern
genetics.

• 1859: Charles Darwin publishes The

Origin of Species, which describes the
theory of evolution by natural selection.
This theory requires heredity to work.
• 1865: Gregor Mendel
Publishes experiments in
Plant Hybridization, which
lays out the basic theory of
genetics. It is widely
ignored until 1900.

• 1869: Friedrich Miescher

isolates “nucleic acid”
from pus cells.

• 1879: Walter Flemming

Described Mitosis
 1900’s Discoveries
• 1900: Robert Correns, Hugo de Vries, and
Erich von Tschermak rediscovery of Mendel’s
work by

• 1902: Walter Sutton Chromosom Theory of

Inheritance.
• 1902: Archibald Garrod discovers that
alkaptonuria, a human disease, has a genetic
basis.
• 1904: Gregory Bateson discovers linkage
between genes. Also coins the word
“genetics”.
• 1909: The word ‘gene’ coined by
Danish botanist Wilhelm Johannsen.

• 1911: Thomas Hunt Morgan proves

that genes are located on the
chromosomes (using Drosophila).

• 1918: R. A. Fisher begins the study of

quantitative genetics by partitioning
phenotypic variance into a genetic
and an environmental component.
• 1926: Hermann J. Muller shows that
X-rays induce mutations.

• 1944: Oswald Avery, Colin MacLeod

and Maclyn McCarty show that DNA
can transform bacteria,
demonstrating that DNA is the
hereditary material.
• 1953: James Watson and Francis
Crick determine the structure of the
DNA molecule, which leads directly
to knowledge of how it replicates.

• 1958 Crick proposes the ‘central

dogma’ for biological information
flow: that DNA makes RNA makes
protein
• 1966: Marshall Nirenberg solves the
genetic code, showing that 3 DNA
bases code for one amino acid.

• 1972: Stanley Cohen and Herbert

Boyer combine DNA from two
different species in vitro, then
transform it into bacterial cells: first
DNA cloning.
• 1977: Phillip Sharp and Richard
Roberts find that protein-coding genes
are carried in segments
•2001: initial results from the Human
Genome Project published
•2003: Completion of the Human Genome
Sequencing
 Gregor Johann Mendel
• Austrian Monk, born in what is now Czech
Republic in 1822
• Son of peasant farmer, studied
Theology and was ordained
priest Order St. Augustine.
• Went to the university of Vienna, where he
studied botany and learned the Scientific
Method
• Worked with pure lines of peas for eight years
• Prior to Mendel, heredity was regarded as a "blending"
process and the offspring were essentially a
"dilution"of the different parental characteristics.
• In 1866 he published Experiments in
Plant Hybridization, in which he
established his two Principles of
Inheritance

• Work was largely ignored for 34 years,

until 1900, when 3 independent botanists
rediscovered Mendel’s work.
• Mendel was the first biologist to use
Mathematics – to explain his results
quantitatively.
Tt Tt

• Mendel predicted Tt Tt
The concept of genes
That genes occur in pairs
That one gene of each pair is
present in the gametes
 Mendel’s peas
• Mendel looked at seven traits or
characteristics of pea plants:
 Antagonistic traits

Dominant

Recessive
 Genetic Vocabulary
• Genome – the entire set of genes in an organism

• Gene – a unit of heredity; a section of DNA

sequence encoding a single protein

• Alleles – two genes that occupy the same

position on homologous chromosomes and that
cover the same trait (like ‘flavors’ of a trait).

• Locus – a fixed location on a strand of DNA

where a gene or one of its alleles is located.
 Genetic Vocabulary
• Phenotype – observable characteristic of
an organism
• Genotype – pair of alleles present in an
individual
• Homozygous – two alleles of trait are the
same (YY or yy)
• Heterozygous – two alleles of trait are
different (Yy)
• Capitalized traits = dominant phenotypes
• Lowercase traits= recessive phenotypes
 Phenotype vs Genotype
Phenotype Genotype

Purple
PP
1
(homozygous)

Pp
3 Purple (heterozygous)

Pp
(heterozygous)
Purple

pp
1 White 1
(homozygous)

Ratio 3:1 Ratio 1:2:1

 Phenotype vs Genotype
Dominant & recessive alleles :
 Genetic Vocabulary
• Generations:
– P = parental generation
– F1 = 1st filial generation, progeny of the P
generation
– F2 = 2nd filial generation, progeny of the F1
generation (F3 and so on)
• Crosses:
– Monohybrid cross = cross of two different true-
breeding strains (homozygotes) that differ in a single
trait.
– Dihybrid cross = cross of two different true-breeding
strains (homozygotes) that differ in two traits.
 Genetic Vocabulary

• Dominant – the allele of a gene that

masks or suppresses the expression of
an alternate allele; the trait appears in the
heterozygous condition.
• Recessive – an allele that is masked by a
dominant allele; does not appear in the
heterozygous condition, only in
homozygous.
 Mendel’s Experimental Design

• In a typical breeding experiment Mendel mated

two contrasting, true-breeding varieties, a process
called hybridization
• The true-breeding parents are called the P
generation
• The hybrid offspring of the P generation are called
the F1 generation
• When F1 individuals self-pollinate the F2
generation is produced
 Mendel’s experimental design
• Mendel also made sure that he started his experiments
with varieties that were “true-breeding”

X X

X X

X X
 Mendel’s experimental design
• Statistical analyses:
– Worked with large numbers of plants
– counted all offspring
– made predictions and tested them
• Excellent experimentalist
– controlled growth conditions
– focused on traits that were easy to
score
– chose to track only those characters
that varied in an “either-or” manner
 First law : Law of Segregation

• Mechanism of gene transmission

Gametogenesis: Fertilization:
alleles segregate alleles unite
 Mendel’s Monohybrid Cross

White Purple
(pp) (Pp)

Gametes
Gametes
p p P p
Purple Purple
(PP) (Pp)

P P
Gametes Pp Pp PP Pp
Gametes
p
P

Pp
Pp Pp pp

F1 generation
All purple F2 generation
¾ purple, ¼ white
 Mendel’s Observations
• When Mendel crossed contrasting, true-breeding white and purple
flowered pea plants all of the offspring were purple
• When Mendel crossed the F1 plants, many of the plants had purple
flowers, but some had white flowers
• A ratio of about 3:1 purple to white flowers, in the F2 generation

EXPERIMENT: True-breeding purple-

flowered pea plants and white-flowered P Generation

pea plants were crossed (symbolized by
(true-breeding
). The resulting F1 hybrids were parents) Purple White
allowed to self-pollinate or were cross- flowers flowers

pollinated with other F1 hybrids. Flower

color was then observed in the F2
generation F1 Generation
(hybrids)

All plants had

purple flowers
RESULTS: Both purple-flowered plants
and white- flowered plants appeared in
the F2 generation. In Mendel’s F2 Generation
experiment, 705 plants had purple
flowers, and 224 had white flowers, a
ratio of about 3 purple : 1 white
 Mendel’s Rationale
• In the F1 plants, only the purple trait was
affecting flower color in these hybrids
• Purple flower color was dominant, and
white flower color was recessive
• Mendel developed a hypothesis to
explain the 3:1 inheritance pattern that he
observed among the F2 offspring
• There are four related concepts that are
integral to this hypothesis
 Heredity Concepts
1. Alternative versions of genes account for
variations in inherited characters, which are
now called alleles
Allele for purple flowers

Homologous
Locus for flower-color gene pair of
chromosom
es

Allele for white flowers

2. For each character an organism inherits
two alleles, one from each parent, A
genetic locus is actually represented
twice
3. If the two alleles at a locus differ, the
dominant allele determines the
organism’s appearance
4. The law of segregation - the two alleles
for a heritable character separate
(segregate) during gamete formation
and end up in different gametes
 The Law of Independent Assortment
• Mendel derived the law of segregation by following a
single trait
– 2 alleles at a single gene locus segregate when the
gametes are formed
– The F1 offspring produced in this cross were
monohybrids, heterozygous for one character

White Purple
(pp) (Pp)

Purple p p Purple P p
(PP) (Pp)
P P
gametes gametes
P p
 The Law of Independent Assortment
• Mendel identified his second law of inheritance
by following two characters at the same time

– Mendel was interested in determining

whether alleles at 2 different gene loci
segregate dependently or independently

– Crossing two, true-breeding parents differing

in two characters produces dihybrids in the
F1 generation, heterozygous for both
characters
 Dihybrid crosses
• Matings that involve parents that differ in two
genes (two independent traits)
For example, flower color:
P = purple (dominant)

p = white (recessive)

and stem length:

T = tall t = short
 Dihybrid cross: flower color and
stem length
TT PP  tt pp
(tall, purple) (short, white)

tp tp tp tp
T P and t p
TP TtPp TtPp TtPp TtPp
F1 Generation: All tall, purple TP TtPp TtPp TtPp TtPp
flowers (Tt Pp)
TP TtPp TtPp TtPp TtPp
TP TtPp TtPp TtPp TtPp
 Dihybrid cross: flower color
and stem length (shortcut)

TT PP  tt pp
(tall, purple) (short, white)

Possible Gametes for parents tp

TP tp Tt
TP
Pp

F1 Generation: All tall, purple flowers (Tt Pp)

 Dihybrid cross F2
If F1 generation is allowed to self
pollinate, Mendel observed 4
phenotypes: Tt Pp  Tt Pp
(tall, purple) (tall, purple)

Possible gametes: TP Tp tP tp
TP Tp t P tp TP TTPP TTPp TtPP TtPp
Tp TTPp TTpp TtPp Ttpp
tP TtPP TtPp ttPP ttPp
tp TtPp Ttpp ttPp ttpp
Four phenotypes observed
Tall, purple (9); Tall, white (3); Short, purple (3); Short white (1)
 Dihybrid cross

9 Tall purple
TP Tp tP tp
TP TTPP TTPp TtPP TtPp
3 Tall white Tp TTPp TTpp TtPp Ttpp
tP TtPP TtPp ttPP ttPp
tp TtPp Ttpp ttPp ttpp
3 Short purple

Phenotype Ratio = 9:3:3:1

1 Short white
 Dihybrid cross: 9 genotypes
9 Genotype : 4 Phenotypes:
1 TTPP
2 TTPp Tall, purple (9)
2 Tt PP
4 Tt Pp
Tall, white (3)
1 TTpp
2 Tt pp
1 tt PP
Short, purple (3)
2 tt Pp
1 tt pp Short, white (1)
 The Testcross

• In pea plants with purple flowers the

genotype is not immediately obvious
• A testcross
– Allows us to determine the genotype of
an organism with the dominant
phenotype, but unknown genotype
– Crosses an individual with the dominant
phenotype with an individual that is
homozygous recessive for a trait
 Test Cross
• To determine whether an individual with a dominant phenotype is
homozygous for the dominant allele or heterozygous, Mendel crossed
the individual in question with an individual that had the recessive
phenotype:

Alternative 2 – Plant with

Alternative 1 – Plant with
dominant phenotype is
Dominant
Phenotype
PP
? Dominant
? dominant phenotype is
heterozygous
homozygous
Phenotype
Pp
Gametes
Recessive Gametes
phenotype P P
P p
p Recessive
pp phenotype p
Gametes
Gametes
p pp p
 Test Cross
• To determine whether an individual with a dominant phenotype is
homozygous for the dominant allele or heterozygous, Mendel
crossed the individual in question with an individual that had the
recessive phenotype:

Alternative 1 – Plant with Alternative 2 – Plant with

dominant phenotype is
homozygous
Dominant
Phenotype
PP
? Dominant
?
dominant phenotype is
heterozygous

Phenotype
Pp
Gametes
Recessive Gametes
phenotype P P
P p
p Recessive
pp Pp Pp phenotype p Pp pp
Gametes
Gametes
p Pp Pp
pp p Pp pp

If all offspring are purple; If half of offspring are

unknown plant is white; unknown plant
homozygous. is heterozygous.
 The Testcross


APPLICATION An organism that exhibits a dominant
trait, such as purple flowers in pea plants, can be
either homozygous for the dominant allele or Dominant phenotype, Recessive phenotype,
heterozygous. To determine the organism’s genotype, unknown genotype: known genotype:
geneticists can perform a testcross. PP or Pp? pp

TECHNIQUE In a testcross, the individual with the

unknown genotype is crossed with a homozygous If PP, If Pp,
individual expressing the recessive trait (white flowers in then all offspring 1⁄
then 2 offspring purple
this example). By observing the phenotypes of the purple: and 1⁄2 offspring white:
offspring resulting from this cross, we can deduce the
genotype of the purple-flowered p p p p
parent.

P P
Pp Pp Pp Pp
RESULTS
P p
Pp Pp pp pp
Second law : Principle of Independent
Assortment
• Based on these results, Mendel postulated the
Principle of Independent Assortment:
“Members of one gene pair segregate
independently from other gene pairs during
gamete formation”

Genes get shuffled – these many combinations

are one of the advantages of sexual
reproduction
 Laws Of Probability Govern Mendelian
Inheritance
• Mendel’s laws of segregation and independent
assortment reflect the rules of probability
– The multiplication rule
• States that the probability that two or more
independent events will occur together is
the product of their individual probabilities
– The rule of addition
• States that the probability that any one of
two or more exclusive events will occur is
calculated by adding together their
individual probabilities
Laws Of Probability - Multiplication Rule
• The probability of two or more independent events
occurring together is the product of the probabilities that
each event will occur by itself

• Following the self-hybridization of a heterozygous purple

pea plants (Pp), what is the probability that a given
offspring will be homozygous for the production of white
flowers (pp)?

• Probability that a pollen seed will carry p: ½

• Probability that an egg will carry p: ½

• Probability that the offspring will be pp:

• 1/2 X 1/2 = 1/4
 Laws Of Probability - Addition Rule
• The probability of either of two mutually exclusive events
occurring is the sum of their individual probabilities

• Following the self-hybridization of a heterozygous purple

pea plant (Pp), what is the probability that a given
offspring will be purple?

• Probability of maternal P uniting with paternal P: 1/4

• Probability of maternal p uniting with paternal P: 1/4
• Probability of maternal P uniting with paternal p: 1/4

• Probability that the offspring will be purple:

• 1/4 + 1/4 + 1/4 = 3/4
 Probability In A Monohybrid Cross
• Can be determined using these rules

Rr  Rr
Segregation of Segregation of
alleles into eggs alleles into sperm

Sperm

1⁄ R 1⁄ r
2 2

R R
1⁄ R R r
2

1⁄ 1⁄
4 4
Eggs

r r
1⁄ r R r
2
1⁄ 1⁄
4 4
 Summary of Mendel’s Principles

• Mendel’s Law of Segregation:

– Recessive characters masked in the F1 progeny of two true-
breeding strains, reappear in a specific proportion of the F2
progeny.
– Two members of a gene pair segregate (separate) from each other
during the formation of gametes.

• Mendel’s Law of Independent Assortment:

– Alleles for different traits assort independently of one another.
– Genes on different chromosomes behave independently in
gamete production.
 Punnett square
• A useful tool to do genetic crosses
• For a monohybrid cross, you need a square divided by four
• Looks like a window pan, We use the Punnett square
to predict the genotypes and phenotypes of the offspring.
 Using a Punnett Square

STEPS:
1. determine the genotypes of the parent organisms
2. write down your "cross" (mating)
3. draw a p-square

Parent genotypes:

TT and t t

Cross

TT  tt
 Punnett square
4. "split" the letters of the genotype for each
parent & put them "outside" the p-square
5. determine the possible genotypes of the
offspring by filling in the p-square
6. summarize results (genotypes &
phenotypes of offspring)
T T
Genotypes:
t 100% T t
TTtt Tt Tt

t Phenotypes:
Tt Tt 100% Tall plants
 Monohybrid cross: F2 generation
• If you let the F1 generation self-fertilize, the
next monohybrid cross would be:
Tt  Tt
(tall) (tall)

T t Genotypes:
1 TT= Tall
2 Tt = Tall

T
1 tt = dwarf
TT Tt Genotypic ratio= 1:2:1
Phenotype:
t 3 Tall
1 dwarf
Tt tt
Phenotypic ratio= 3:1
 Secret of the Punnett Square
• Key to the Punnett Square:
• Determine the gametes of each parent…
• How? By “splitting” the genotypes of each
parent:

If this is your cross T T  t t

The gametes are: T T t t

Once you have the gametes…

T T  t t

t t

T Tt Tt

T
Tt Tt
 Shortcut for Punnett Square…
• If either parent is HOMOZYGOUS

T T  t t

t
T Genotypes:
Tt 100% T t

Phenotypes:
• You only need one box! 100% Tall plants
 Understanding the shortcut…

t t
t
T
=
Tt Tt
T Tt
T Tt Tt

Genotypes: Phenotypes:
100% T t 100% Tall plants
 If you have another cross…
• A heterozygous with a
homozygous
T t  t t

t Genotypes:
50% T t
You can still
use the T Tt
50 % t t
shortcut Phenotypes:
t t t
50% Tall plants
50% Dwarf plants