INTRODUCTION TO GENETIC

EPIDEMIOLOGY
 GENETIC EPIDEMIOLOGY
A hybrid science focusing on complex diseases (where both genetic &
environmental factors contribute to etiology of disease)

Genetics Epidemiology

Genetic Epidemiology

Parent sciences (genetics & epidemiology) share common goals but

they differ in their histories & perspectives.
 SUMMARIZING GENETIC HISTORY
Century 19th 20th 21st
Mendel Mendel DNA Human
Landmarks Redisc’d Structure Genome
Proj.

Rare Mendelian Multifactorial or Complex All?

Disease ?

Linkage (2 point  genome LD mapping &

Mapping wide) Sequencing
?

Genes Simple One gene, Models for One gene, >1 ?

genetic one protein complex proteins; Multiple
models (4) traits genes &
interaction
Gene Gene Gene Regulation
Gene defined by expression
?
Expression mutants (mRNA)
Neonatal Diagnostic Susceptibility
Testing Screening Testing
?

Public Health
applications
 LANDMARKS IN EPIDEMIOLOGY
Year Event
1832 Cholera epidemic in Britain prompted epidemiologic studies by
T. Proudfoot & H. Gaulter
1843 W. Farr develops epidemiologic concepts based on vital
statistics
1854 J. Snow defines transmission mechanism for cholera

1900’s As part of “bacteriologic revolution”, epidemiology evolves

from a descriptive to analytical science
1920’s Epidemiologic methods are applied to chronic diseases

1935 Descriptive studies of lung cancer patterns implicate cigarette

smoking
 LANDMARKS IN EPIDEMIOLOGY
Year Event
1948 Large cohorts established to study cardiovascular disease
(Framingham)
1950 Definitive case-control studies of lung cancer & smoking
published in US & UK
1960’s Large scale studies (both cohort & trials) develop statistical
tools for multiple risk factors
1979 Eradication of smallpox achieved

1980’s HIV emerges as major public health threat

2000- Epidemiology faces a new millenium: A mix of science,

public health practice & policy
 50 YEARS OF GENETIC
EPIDEMIOLOGY
MORTON (2006) J HUM GENET 51:269-277
1. Before DNA polymorphisms (1956-1979)
• Linkage analysis (LOD scores) began with very few markers
• Population genetics measured linkage disequilibrium (LD) by D’ & r2
• Heritability (h2) began with twin studies & evolved into path analysis with
genetic & non-genetic causal factors

2. Pre-genome period (1980-2001)

 Linkage analysis expanded to multipoint analysis
 Even for Mendelian diseases, peaks are hard to narrow
 With ‘complex’ phenotypes, it is worse
 Association studies proposed as alternative (Risch & Merikangas 1996
SCIENCE 273:1516-1517)
 Family based association tests are useful alternative
50 YEARS OF GENETIC
EPIDEMIOLOGY
(CONT’D)
3. Post-genome period (>2002)
 Sequence of the human genome allows greater
understanding of structure of genes, their physical
position & (maybe) their function
 HapMap offers virtually unlimited markers, but SNPs are
not equally polymorphic in all populations
 LD & haplotype blocks vary among populations
 Associated markers are only predictive, but can identify
causal genes
 Study design will be critical
 Is 500K always better than 100K?
 COMPARING GENETICS &
EPIDEMIOLOGY
Genetics Epidemiology

Origins Biologic science of Methodologic science of

inheritance Public Health
Breeding & Descriptive & Analytic
Experimental
Focus Mechanisms of Etiologic factors in disease
inheritance & gene & methods of control
expression
Often on rare Mostly on common
diseases diseases
 COMPARING GENETICS &
EPIDEMIOLOGY – (CONT’D)

Tools 1. Family Studies 1. Descriptive Studies

2. Laboratory Methods 2. Case/Control
3. Statistical Models 3. Cohort Designs
4. Population Models 4. Clinical Trials
Goals Understand mechanisms Understand disease
of inheritance etiology & distribution
Over- Diseases of interest (heart disease, cancer, diabetes)
lap Prevent/control disease
CENTRAL QUESTIONS IN
GENETIC EPIDEMIOLOGY

1. Does the trait cluster in families?

2. Can familial clustering be explained by genes or shared
environment?
3. What is the best model of inheritance?
4. Can we locate genes for complex diseases/traits?
5. How does the gene control risk of disease?
 STUDY DESIGNS FOR CENTRAL
QUESTIONS

1. Does the disease 1. Case-control studies;

cluster in families? familial correlation
2. Is this due to genes 2. Heritability &
or shared variance components
environments?
3. What is the best 3. Segregation analysis
model of inheritance?
 STUDY DESIGN FOR CENTRAL
QUESTIONS (CONT’D)

4. Can we locate causal 4. Linkage analysis &

genes for complex linkage disequilibrium
diseases? studies
5. How does the gene 5. Gene-environment
control risk? interaction
BASIC TERMINOLOGY
GENETICS

 The study of genes and the inheritance of traits

 The three main concepts of Genetics are

 Characteristic
 Trait
 Inheritance
 Characteristics:
The Features which are exhibited physically
Example: Color of our Eyes

 Traits:

Trait is the different versions of the characteristics

Example: Color of the eyes namely, brown,green or
blue
 Inheritance:
Occurs when trait are passed
down from parent to the
offspring.
Example: Color of the skin,
Hair type, etc.

 These information's are

carried over from one
generation to another through
Genes which is comprised of
a chemical substance called
DNA. These genes are carried
through chromosomes
MENDELISM
 GEORG MENDEL

Austrian monk
 born in 1822 in monastery known for

research and teaching

 after his death (1884)

acknowledgment of his discoveries in 1900

EXPERIMENTS WITH PEA PLANTS

1.Seed coat colour (Gray or White)

2. Seed shape (Round or Wrinkled)

3. Seed colour (Yellow or Green)

4. Pod colour (Green or Yellow)

5. Flower position (Axial or Terminal)

6. Pod shape (Inflated or Constricted)

7.Stem length (Tall or Dwarf)

 CROSS-POLLINATION OF PUREBREAD
PLANTS

- cross-pollination
between true breeding
green and yellow pods
- all F1 green

F1 Generation
Gg =
heterozygous
F2 GENERATION

- self-pollination of
green F1 plants
- ¾ in F2 green,
¼ yellow
- 3 : 1 ratio in pod
colour in F2

G = dominant = green
g = recessive = yellow

GG, gg = homozygous
SEED COLOUR

C = DOMINANT = yellow
c = recessive = green
INHERITANCE OF PEA COLOUR

phenotype:

genotype:
RESULTS FROM MENDEL'S
EXPERIMENTS

F2
Parental Cross F1 F2 Phenotypic Ratio
Ratio
Phenotype

Round x Wrinkled 5474 Round :

Round 2.96:1
Seed 1850 Wrinkled

Yellow x Green 6022 Yellow :

Yellow 3.01:1
Seeds 2001 Green

Axial x Terminal 705 Axial :

Axial 3.15:1
Flower Position 224 Terminal

l787 Tall :
Tall x Dwarf Plants Tall 2.84:1
227 Dwarf
 MENDEL‘S GENERALIZATION

1.Alternative versions of genes account for

variations in inherited characters
- concept of alleles (G=green, g=yellow)

2. For each character, an organism inherits two

genes, one from each parent
- two gametes form somatic cells
- one allele comes from the mother,
one from the father
 Mendel‘s Generalization
3. If the two alleles differ, then:
- dominant allele is fully expressed in the
organism's appearance (phenotype)
- recessive allele has no noticeable effect on the
organism's appearance (genotype)

4. The two genes for each character segregate

during gamete production
- ensures variation
LAW OF SEGREGATION
 The pair of alleles of each parent separate
and only one allele passes from each parent
on to an offspring
 Which allele in a parent's pair of alleles is
inherited is a matter of chance 
 Segregation of alleles occurs during the
process of gamete formation (meiosis)
 Randomly unite at fertilization
CHROMOSOMES
CHROMOSOMES
 Chromosomes are the rod-shaped, filamentous
bodies present in the nucleus, which become visible
during cell division.

 They are the carriers of the gene or unit of heredity.

 Chromosome are not visible in active nucleus due to

their high water content, but are clearly seen during
cell division.

 They were given the name chromosome (Chromo =

colour; Soma = body) due to their marked affinity
for basic dyes.
 Chromosomes are composed of thin chromatin threads
called Chromatin fibers.

 These fibers undergo folding, coiling and supercoiling

during prophase so that the chromosomes become
progressively thicker and smaller.

 Therefore, chromosomes become readily observable under

light microscope.

 At the end of cell division, on the other hand, the fibers

uncoil and extend as fine chromatin threads, which are not
visible at light microscope
NUMBER OF CHROMOSOMES
 Normally, all the individuals of a species have the same
number of chromosomes.
 Closely related species usually have similar chromosome
numbers.
 Presence of a whole sets of chromosomes is called
euploidy.
 It includes haploids, diploids, triploids, tetraploids etc.
 Gametes normally contain only one set of chromosome –
this number is called Haploid
 Somatic cells usually contain two sets of chromosome -
2n : Diploid
3n – triploid
4n – tetraploid

The condition in which the chromosomes sets are present in a

multiples of “n” is Polyploidy
When a change in the chromosome number does not involve
entire sets of chromosomes, but only a few of the
chromosomes - is Aneuploidy.

 Monosomics (2n-1)
 Trisomics (2n+1)

 Nullisomics (2n-2)

 Tetrasomics (2n+2)
Organism # chromosomes

Human 46
Chimpanzee 48
Dog 78
Horse 64
Chicken 78
Gold Fish 94
Fruit Fly 8
Mosquito 6
Round worm 2
 Chromosomes may differ in the position
of the Centromere, the place on the
chromosome where spindle fibers are
attached during cell division.

 In general, if the centromere is near the

middle, the chromosome is metacentric

 If the centromere is toward one end, the

chromosome is acrocentric or
submetacentric

 If the centromere is very near the end,

the chromosome is telocentric.
 Thecentromere divides the chromosome into two
arms, so that, for example, an acrocentric chromosome
has one short and one long arm,

 While, a metacentric chromosome has arms of equal

length.

 Human chromosomes include both metacentric and

acrocentric, but no telocentric
VARIATION IN STRUCTURE OF
CHROMOSOMES OR CHROMOSOMAL
ABERRATION
 The somatic (2n) and gametic (n) chromosome numbers of a species
ordinarily remain constant.

 This is due to the extremely precise mitotic and meiotic cell

division.

 Sometime due to mutation or spontaneous (without any known

causal factors), variation in chromosomal number or structure do
arise in nature. - Chromosomal aberrations.
Consider a normal chromosome with genes in
alphabetical order: a b c d e f g h i

1. Deletion: part of the chromosome has been

removed: a b c g h i

2. Dupliction: part of the chromosome is duplicated:

abcdefdefghi

3. Inversion: part of the chromosome has been re-

inserted in reverse order: a b c f e d g h i
ring: the ends of the chromosome are joined
together to make a ring
4. translocation: parts of two non-homologous
chromosomes are joined:
If one normal chromosome is a b c d e f g
h i and the other chromosome is u v w x y z,
then a translocation between them would be
a b c d e f x y z and u v w g h i.
DELETION OF CHROMOSOME
 Loss of a chromosome segment is known as deletion or deficiency
 It can be terminal deletion or interstitial or intercalary deletion
 Chromosome deletions are usually lethal even as heterozygotes, resulting in
zygotic loss, stillbirths, or infant death.
 Sometimes, infants with small chromosome deficiencies however, survive long
enough to permit the abnormal phenotype they express.

Cri-du-chat (Cat cry syndrome):

 The name of the syndrome came from a catlike mewing cry from small
weak infants with the disorder.
 Other characteristics are microcephaly (small head), broad face and
saddle nose, physical and mental retardation.
 Cri-du-chat patients die in infancy or early childhood.
 The chromosome deficiency is in the short arm of chromosome 5 .
DUPLICATION
 The presence of an additional chromosome segment, as compared to that
normally present in a nucleus is known as Duplication
 In a diploid organism, presence of a chromosome segment in more than
two copies per nucleus is called duplication.

 Four types of duplication:

1. Tandem duplication
2. Reverse tandem duplication
3. Displaced duplication
4. Translocation duplication
INVERSION
 When a segment of chromosome is oriented in the
reverse direction, such segment said to be inverted and
the phenomenon is termed as inversion.
 Inversion may be classified into two types:
 Pericentric - include the centromere
 Paracentric - do not include the centromere
TRANSLOCATION
 Integration of a chromosome segment into a
nonhomologous chromosome is known as translocation.
 Three types:

1. Simple translocation
2. Shift
3. Reciprocal translocation.
VARIATION IN NUMBER OF
CHROMOSOMES
 Organism with one complete set of chromosomes is said
to be euploid (applies to haploid and diploid organisms).

 Aneuploidy - variation in the number of individual

chromosomes (but not the total number of sets of
chromosomes).
 Nullisomy - loss of one
homologous chromosome
pair. (e.g., Oat )
 Monosomy – loss of a
single chromosome
(Maize).
 Trisomy - one extra
chromosome. (Datura)
 Tetrasomy - one extra
chromosome pair.
TRISOMY IN HUMANS

Down Syndrome
 The best known and most common chromosome related
syndrome.
 Formerly known as “Mongolism”
 1866, when a physician named John Langdon Down
published an essay in England in which he described a set
of children with common features who were distinct from
other children with mental retardation he referred to as
“Mongoloids.”
 Patients having Down syndrome will Short in stature
(four feet tall) and had an epicanthal fold, broad short
skulls, wild nostrils, large tongue, stubby hands
 Some babies may have short necks, small hands, and
short fingers.
 They are characterized as low in mentality.
 Down syndrome results if the extra chromosome is
number 21.
18TH TRISOMY
Chromosome Nomenclature: 47, +18
Chromosome formula: 2n+1
Clinical Syndrome: Trisomy-18
Estimated Frequency Birth: 1/8,000
Main Phenotypic Characteristics:
Multiple congenital malformation of many
organs, malformed ears, small mouth and nose with
general elfin appearance.
90% die in the first 6 months.
TURNER’S SYNDROME
Chromosome Nomenclature: 45, X
Chromosome formula: 2n - 1
Clinical Syndrome: Turner
Estimated Frequency Birth: 1/2,500 female
Main Phenotypic Characteristics:
Female with retarded sexual development,
usually sterile, short stature, webbing of skin in
neck region, cardiovascular abnormalities,
hearing impairment.
KLINEFELTER SYNDROME

Chromosome Nomenclature: 47, XXY, 48, XXXY,

48,XXYY, 49, XXXXY,
50, XXXXXY
Chromosome formula: 2n+1; 2n+2; 2n+2; 2n+3; 2n+4
Clinical Syndrome: Klinefelter
Estimated Frequency Birth: 1/500 male birth
Main Phenotypic Characteristics:
Pitched voice, Male, subfertile with small testes,
developed breasts, feminine, long limbs.
MOLECULAR GENETICS
NUCLEIC ACIDS
 The Nucleic acids, DNA & RNA, are macromolecules
(Polymers) composed of three types of units:
 Five carbon sugar (deoxyribose in DNA,ribose in RNA)
 A nitrogen containing base
 phosphate
DNA (DEOXY RIBOSE NUCLEIC ACID )
 Double polynucleotide
 Each nucleotide composed of
 Pentose sugar
 Phosphate functional group attached
to its 5’ carbon
 A nitrogenous base attached
to its 1’carbon
CONTD…
 DNA molecules carries in its biochemical structure the
genetic information that allows the exact transmission of
genetic information from generation to generation and
simultaneously specifies the amino acid sequence of the
polypeptide chains of proteins.
RNA
 Single stranded polynucleotide
 RNA is much shorter than DNA

 RNA carries coded information from DNA to ribosomal

sites of protein synthesis in cells.
 rRNA ribosomal RNA contains the bulk RNA and
transfers RNA (tRNA) attaches to amino acids.
WHY DNA STRUCTURE?
 Most organisms, the DNA Structure carries the genetic
information, whereas in some organisms such as viruses,
RNA carries the genetic information.
 The double helix of the DNA molecule resembles a
spiral staircase, with its two polynucleotide chains
running in opposite directions, held together by
hydrogen bonds between pairs of bases.
DNA REPLICATION AND
REARRANGEMENTS
 DNA Replicates when the cell divides itself.
 When the replication is not exact, it causes mutation of genes.

 The hydrogen bonds between the bases break during

replication which lead nucleotide chains of DNA to separate an
uncoil.
 Each nucleotide of separated chain attracts its complement
from the cell and forms a new nucleotide chain.
TRANSCRIPTION AND TRANSLATION
 The genetic information contained in the DNA is
transcribed into messenger RNA(mRNA).
 DNA Unfolds and one of the two strands acts as a
template for the synthesis of a sequence of nucleotides.
 The synthesis of mRNA proceeds in the 5’ to 3’
direction.
 Transcription occurs in 3 basic steps:
1. Initiation
2. Elongation
3. Termination
The synthesis of amino acids by using the information encoded
in the mRNA molecule is called translation.
This process involves mRNA, tRNA, and ribosomes
(composed of ribosomal RNA & proteins)
 tRNA contains anti codons and has a specific location on
mRNA.
 Translation happens in 3 step:

1. Initiation (Formation of Ribosomes/mRNA/initiator tRNA

is acheived)
2. Elongation (Synthesis of Polypeptide chain is done by the
formation of peptide bonds between amino acid)
3. Termination (dissociates the translation complex and
srelease the finished polypeptide chain)
GENETIC CODE
 The genetic information is stored in DNA by means of a
code in which three adjacent bases(a triplet) constitute a
codon, coding for a specific amino acid.
 For three bases there are 43 = 64 possible combination

 These 64 codons comprise the genetic code

 Thereare four common type of structural
aberrations:
1. Deletion or Deficiency
2. Duplication or Repeat
3. Inversion, and
4. Translocation
Genes are carried by Chromosomes
Two plant cells visualized by light
microscope, DNA stained with DAPI

Chromosome in Cells
DNA (deoxyribonucleic acid)
AGTC
Human 46 chromosomes
22 homologs, x, or x/y
Experimental procedures demonstrating that DNA is the genetic material
1940s
 The Structure and Function of DNA
 Genetic information is carried in the linear sequence of nucleotides in
DNA
 Genetic information contains instructions to synthesize proteins
 DNA forms double helix with two complimentary strands holding
together by hydrogen bonds between A-T (2 bonds) and G-C (3 bonds)
 DNA duplication occurs using one strand of parental DNA as template
to form complimentary pairs with a new DNA strand.
 DNA is in nucleus in eucaryotes
1953 Watson and Crick determined the
structure of DNA

DNA and its Building

Nucleotides: Guanine (G), Adenine (A),
Cytosine (C), Thymine (T).
Polarized strand, 5’->3’
Base inside, sugar outside
DNA and its Building
Antiparallel strands
DNA Pairs
A always pairs with T, and
G with C,
A-T two hydrogen bonds,
G-C three hydrogen bonds
DNA Double Helix
10.4 nucleutides/turn; 3.4 nm between nucleutides
DNA to Protein
Genome: the complete set of information in an organism’s DNA
Total length of DNA about 2 meters long in a human cell, encoding about 30000
proteins
To carry the genomic information to daughter cells
DNA Duplication
Using itself as template
Cell Nucleus, compartmentalized DNA
activity
Nuclear pores allow communication
Nuclear lamina and cytoskeleton
mechanically support the nucleus
SINGLE GENE & POLYGENIC
INHERITANCE
Polygenic traits – more than two alleles and
multiple genes control the expression of a
trait
 TWO TYPES OF TRAITS

Discrete or discontinuous traits: traits occur in distinct

categories: Trait is there or it is not (examples:
cystic fibrosis, Huntington’s disease) Mendelian inheritance,
single genes, complete dominance)

Continuous traits: Distribution of phenotypes in the population

varies along a continuum. Individuals differ by small degrees.
(examples include height, blood pressure, reaction time,
learning ability) Polygenic quantitative or multifactorial
inheritance. Genes act additively.
   SINGLE GENE INHERITANCE
            Genetic conditions caused by a mutation in a
single gene follow predictable patterns of inheritance
within families. Single gene inheritance is also referred
to as Mendelian inheritance as they follow transmission
patterns he observed in his research on peas. There are
four types of Mendelian inheritance patterns:
 Autosomal dominant
Autosomal recessive
 X-linked recessive
X-linked dominant
CONTD…
 Autosomal: the gene responsible for the phenotype is
located on one of the 22 pairs of autosomes (non-sex
determining chromosomes).
 X-linked: the gene that encodes for the trait is located on
the X chromosome.
 Dominant: conditions that are manifest in heterozygotes
(individuals with just one copy of the mutant allele).
 Recessive: conditions are only manifest in individuals
who have two copies of the mutant allele (are
homozygous).
AUTOSOMAL DOMINANT

            Dominant conditions are expressed in individuals who

have just one copy of the mutant allele. The pedigree on the
right illustrates the transmission of an autosomal dominant
trait. Affected males and females have an equal probability of
passing on the trait to offspring. Affected individual's have one
normal copy of the gene and one mutant copy of the gene, thus
each offspring has a 50% chance on inheriting the mutant
allele. As shown in this pedigree, approximately half of the
children of affected parents inherit the condition and half do
not.
EXAMPLE
 Autosomal Dominant Conditions:
 •  Huntington Disease
 •  acondroplasia (short-limbed dwarfism)
 •  polycystic kidney disease
AUTOSOMAL RECESSIVE

            Recessive conditions are clinically manifest only

when an individual has two copies of the mutant allele.
When just one copy of the mutant allele is present, an
individual is a carrier of the mutation, but does not
develop the condition. Females and males are affected
equally by traits transmitted by autosomal recessive
inheritance. When two carriers mate, each child has a
25% chance of being homozygous wild-type
(unaffected); a 25% chance of being homozygous mutant
(affected); or a 50% chance of being heterozygous
(unaffected carrier).
AUTOSOMAL RECESSIVE
DISEASES:

 Affected individuals are indicated by solid black

symbols and unaffected carriers are indicated by the half
black symbols.

 •  Cystic fibrosis
 •  Tay-Sachs
 •  hemochromatosis
 •  phenylketonuria (PKU)
X-LINKED RECESSIVE

 X-linked recessive traits are not clinically manifest when there

is a normal copy of the gene. All X-linked recessive traits are
fully evident in males because they only have one copy of the
X chromosome, thus do not have a normal copy of the gene to
compensate for the mutant copy. For that same reason, women
are rarely affected by X-linked recessive diseases, however
they are affected when they have two copies of the mutant
allele. Because the gene is on the X chromosome there is no
father to son transmission, but there is father to daughter and
mother to daughter and son transmission. If a man is affected
with an X-linked recessive condition, all his daughter will
inherit one copy of the mutant allele from him
X-LINKED RECESSIVE DISORDERS:

 •  Duchenne muscular dystrophy
 •  hemophilia A
 •  X-linked severe combined immune disorder (SCID)
 •  some forms of congenitaldeafness
X-LINKED DOMINANT

            Because the gene is located on the X

chromosome, there is no transmission from father to son,
but there can be transmission from father to daughter (all
daughters of an affected male will be affected since the
father has only one X chromosome to transmit). Children
of an affected woman have a 50% chance of inheriting
the X chromosome with the mutant allele. X-linked
dominant disorders are clinically manifest when only
one copy of the mutant allele is present
X-LINKED DOMINANT DISORDERS

 •  Some forms of retinitis pigmentosa
 •  Chondrodysplasia Punctata
 •  Hypophosphatemic rickets 
EXAMPLES OF DISCONTINOUS
POLYGENIC TRAITS
  Cardiac defects (most types)
  Cleft lip (alone)
  Cleft lip, with or without cleft palate
  Diaphragmatic hernia
  Hip dislocation
  Limb reduction defect (most forms)
  Neural tube defects (anencephaly, spina bifida)
 
Characteristics of polygenic inheritance:

1. A substitution at one locus usually produces the

same effect on the phenotype as a substitution at
another.

2. Many loci with small, additive effects.

3. Tall parents can produce a short child, tall child or

in between, with limits.

4. Average parents can produce a tall, average

or short child
Why are the traits continuous?
Because of the environment.

In height, for example, nutritional differences

can play a major role in variation

For skin color, exposure to sun can modify

the phenotype

How do we know how much of the variability

we see among people is due to genetic differences
between them as opposed to environmental
differences?
 Fig 14.12 Polygenic inheritance of skin tone

3 loci: each has two possible alleles: A,a B,b C,c,

each capital allele adds one unit of darkness
each lower case allele adds nothing

Parents with intermediate tone

AABBCC
aabbcc

Offspring can have tone darker or lighter than either

parent.
Can two light toned people have a darker child?
ANOTHER EXAMPLE OF A
POLYGENIC TRAIT:

 Hair Color
 Hair color is controlled by
alleles on chromosomes 3,
6, 10, and 18.
 The more dominant alleles
that appear in the
genotype, the darker the
hair!
 Hypothetical mechanism for determination of eye color in Humans

Gene for melanin production B (produce) dominant to b (none)

2 Modifier loci affect amount of pigment deposited
CC’ and DD’ each non prime allele contributes one unit of deposition

G’type at B Modifier loci Phenotype

B_ CCDD Dk brown (+4)
B_ CCDD’ Med. Brown (+3)
B_ CC’DD’ Lt Brown (+2)
B_ CC’D’D’ Hazel (+1)
BB C’C’D’D’ Green
Bb C’C’D’D’ Greenish blue
bb any g’type Blue
   MULTIFACTORIAL INHERITANCE
 Most diseases have multifactorial inheritance patterns.
As the name implies, multifactorial conditions are not
caused by a single gene, but rather are a result of
interplay between genetic factors and environmental
factors. Diseases with multifactorial inheritance are not
genetically determined, but rather a genetic mutation
may predispose an individual to a disease. Other genetic
and environmental factors contribute to whether or not
the disease develops.
CONTD…
 Numerous genetic alterations may predispose individuals
to the same disease (genetic heterogeneity). For instance
coronary heart disease risk factors include high blood
pressure, diabetes, and hyperlipidemia. All of those risk
factors have their own genetic and environmental
components. Thus multifactorial inheritance is far more
complex than Mendelian inheritance and is more
difficult to trace through pedigrees
 A typical pedigree from a family with a mutation in the BRCA1
gene. Fathers can be carriers and pass the mutation onto offspring.
Not all people who inherit the mutation develop the disease, thus
patterns of transmission are not always obvious.
MITOCHONDRIAL INHERITANCE
 Mitochondria are organelles found in the cytoplasm of
cells. Mitochondria are unique in that they have multiple
copies of a circular chromosome. Mitochondria are only
inherited from the mother's egg, thus only females can
transmit the trait to offspring, however they pass it on to
all of their offspring. The primary function of
mitochondria is conversion of molecule into usable
energy. Thus many diseases transmitted by
mitochondrial inheritance affect organs with high-energy
use such as the heart, skeletal muscle, liver, and kidneys
PEDIGREE
 In this family, the father is affected as is the first born
daughter. The mother, son and twin girls are not affected.
This couple is pregnant with another child.
 This pedigree shows three generations. The proband is the affected
woman in the second generation. Her father (now deceased) had the
disease, her mother is unaffected and still living. She has two
siblings; neither is affected. She has three children from a previous
marriage, two are affected and she is currently pregnant with a new
partner.
PEDIGREE ANALYSIS IN HUMAN GENETICS:
INHERITANCE PATTERNS

 http://education-portal.com/academy/lesson/pedigree-
analysis-in-human-genetics-inheritance-patterns.html
GENETIC DISORDERS: PENETRANCE &
PHENOTYPIC VARIABILITY
 http://education-portal.com/academy/lesson/genetic-
disorders-penetrance-phenotypic-variability.html
WHAT IS HEMOPHILIA? - SYMPTOMS, GENETIC CAUSE &
TREATMENT

 http://education-portal.com/academy/lesson/what-is-
hemophilia---symptoms-genetic-cause-treatment.html
HARDY WEINBERG
EQUILIBRIUM
KEY CONCEPT
Hardy-Weinberg equilibrium provides a framework for understanding
how populations evolve.
HARDY-WEINBERG EQUILIBRIUM DESCRIBES
POPULATIONS THAT ARE NOT EVOLVING.
 Biologists use models to study populations.
 Hardy-Weinberg equilibrium is a type of model.
HARDY-WEINBERG EQUILIBRIUM DESCRIBES
POPULATIONS THAT ARE NOT EVOLVING.
 Genotype frequencies stay the same if five conditions are met.
 very large population: no genetic drift
 no emigration or immigration: no gene flow
 no mutations: no new alleles added to gene pool
 random mating:
no sexual selection
 no natural selection:
all traits aid equally
in survival
HARDY-WEINBERG EQUILIBRIUM DESCRIBES
POPULATIONS THAT ARE NOT EVOLVING.
 Real populations rarely meet all five conditions.
 Real population data is
compared to a model.
 Models are used to
studying how populations
evolve.
THE HARDY-WEINBERG EQUATION IS USED TO
PREDICT GENOTYPE FREQUENCIES IN A
POPULATION.
 Predicted genotype frequencies are compared with actual
frequencies.
 used for traits in simple dominant-recessive systems
must know frequency of recessive homozygotes
p2 + 2pq + q2 = 1

"The Hardy-Weinberg equation

is based on Mendelian genetics.
It is derived from a simple
Punnett square in which p is the
frequency of the dominant allele
and q is the frequency of the
recessive allele."
 Genetic drift changes allele frequencies due to chance alone.
 Gene flow moves alleles from one population to another.
 Mutations produce the genetic variation needed for evolution.
 Sexual selection selects for traits that improve mating success.
 Natural selection selects for traits advantageous for survival.
 In nature, populations evolve.
– expected in all populations most of the
time
– respond to changing environments
INBREEDING
INBREEDING
 When the population is finite, and mating is random, and
there is some probability of mating with a relative.
 Effects of small population size, mating with related
individuals are similar.
 Drift, inbreeding, population subdivision reduces within
population genetic variance.
 Consequence is assortative mating over entire genome
deviations from expected heterozygosity (vs.HWE
expectstions)over all genes.
GENETIC DRIFT AS A CAUSE OF
INBREEDING
INBREEDING RESULTS FROM DRIFT
SEGREGATION ANALYSIS
INTRODUCTION
 ™ Segregation analysis is a test of Mendel’s
first law, the law of segregation in human.
 ™ A method to determine whether a trait is

genetic by testing whether the transmission

pattern in human families is consistent with
 Mendelian expectations (i.e., dominant,

recessive, or codominant).
CONTD…
 ™ Statistical detection of Mendelian ratios in human
sibships.
 ™ Statistical methodology used to determine from

family data the mode of inheritance of a articular

 phenotype, especially with a view to elucidating

single gene effects.

 ™ Can be used to classify individuals with respect to
their genotypes.
 ™ User data on one or more groups of related

individuals: sibships, nuclear families (parents and

children), or more extensive pedigree data.
PROBLEMS
•™ In contrast to animal experiments, there
are problems in conducting segregation
analysis in human data:
•Families are not large enough
•Matings cannot be controlled
•Ascertainment of families varies
•Inaccurate diagnoses
•Genetic heterogeneity
•Inaccurate family history; non-paternity;
•incomplete families, etc
SEGREGATION RATIO TEST
 Segregation ratio: A/(A+N)
 A: affected offspring; N: normal offspring

 In general, segregation ratio of recessive trait is

 expected to be ¼ (Aa X Aa)

 In general, segregation ratio of dominant trait is

The detection of Mendelian ratios for
 Rare diseases

 Dichotomous phenotypes

 Sibships

 Assumes a single mating type for all sampled

sibships
FREQUENT MODELS TESTED
1. Most saturated (General) model
2. Sporadic model
3. Environmental model
4. Polygenic model
5. Major gene model
 Mendelian dominant model
 Mendelian recessive model
 Mendelian codominant model

6. Multifactorial model
7. Other restricted models
SUMMARY
 ™ Segregation analysis is a basic statistical
test to expose the genetic component of a disease or trait.
 ™ Segregation analysis is best done on

population based pedigrees.

 ™ Segregation can reveal predictive model

for subjects with a specified trait.

 ™ Segregation analysis affords the initial

estimates of parameters needed in the

following linkage analysis or others
TWIN STUDIES
TWIN STUDIES
Using correlational research to establish a genetic
argument for the origin of human behaviour
CORRELATION
Correlations show the relationship
between two variables. There is no
manipulation of an IV, so cause and effect
are not established.
A correlation of +1.0 means as x increases,
y increases. -1.0 means that x increases, y
decreases.
In twin research, we expect to find a
higher correlational than when comparing
a child to someone outside of the family.
WHAT IS INHERITED?
 Which of the following do you think might be inherited? Why?
Intelligence
Depression
Risk-taking behaviour
Homosexuality
Problem solving skills
Agoraphobia
TECHNIQUES
Comparing Monozygotic twins (MZ) with
Dyzygotic twins (DZ). Since MZ twins
have identical DNA, there should be a
higher concordance rate.
Comparing MZ twins reared together vs.
MZ twins reared apart. Why might this be
better than the first technique?
STRENGTHS OF TWIN STUDIES

 Twin studies have produced a great deal of data in support of biological roots of
disorders; this has helped psychologists to stress prevention for those who are
vulnerable to such disorders.
 There is a high cross-cultural reliability of concordance levels.
LIMITATIONS OF TWIN STUDIES

 MZ twins are rarely separated at birth and raised in a totally different environment, yet
this is really necessary to substantiate claims. MZ twins reared together share many of
the same experiences. DZ twins reared together may not share the same experiences
due to levels of attractiveness or temperament.
WRIGHT’S INBREEDING
COEFFICIENT F
POPULATION SUBSTRUCTURE
 Many species naturally subdivide themselves
into herds, flocks, colonies, schools etc.
 Patchy environments can also cause subdivision

 Subdivision decreases heterozygosity and

generates genetic differentiation via:
Natural selection
Genetic drift
STEP 1: CALCULATE MEAN
HETEROZYGOSITIES AT EACH
POPULATION LEVEL
 Heterozygosity = mean percentage of heterozygous
individuals per locus
 Assuming H-W, heterozygosity (H) = 2pq where p and q
represent mean allele frequencies
 H = sum of all subpopulation heterozygosities divided
S
by the total number of subpopulations
WRIGHT’S FIXATION INDEX
 Equals the reduction in heterozygosity expected with
random mating at one level of population hierarchy
relative to another more inclusive level.

FST = (HT – HS)/ HT

HIERARCHICAL STRUCTURE OF A
DESERT PLANT (FROM WRIGHT 1943)
Subpopulations Regions Total

Region Allele Frequency H Avg. Allele Frequency H Avg. Allele Frequency H

W 0.573 0.4893
0.717 0.4058
0.504 0.5
0.657 0.4507
0.302 0.4216
0.339 0.4482 0.5153 0.5

C 9 x 0.00 0
0.032 0.062
0.007 0.0139
0.008 0.0159
0.005 0.01
0.009 0.0178
0.005 0.01
0.01 0.0198
0.068 0.1268
0.002 0.004
0.004 0.008
0.126 0.2202 0.0138 0.027

E 0.106 0.1895
0.224 0.3476
0.411 0.4842
0.014 0.0276 0.1888 0.306 0.1374 0.237

Average Heterozygostiy Hs = .1424 Hr = .1589 Ht = .2371

EXAMPLE CALCULATION- DESERT
PLANT
 FST = (0.2371 – 0.1424)/ 0.2371 = 0.3993

 Overall reduction in average H is close to 40% of the

total heterozygosity
 Subpopulations in this species are highly differentiated
INTERPRETING FST
 Can range from 0 (no genetic differentiation) to 1
(fixation of alternative alleles).
 Wright’s Guidelines:

 0 - 0.05, little differentiation

 0.05 – 0.15, moderate

 0.15 – 0.25, great

 > 0.25, very great

FST FOR VARIOUS ORGANISMS

Organism Number of Populations Number Loci Ht Hs Fst

Human (major races) 3 35 0.13 0.121 0.069

Yanomama Indian Villages 37 15 0.039 0.036 0.077

House mouse 4 40 0.097 0.086 0.113

Jumping rodent 9 18 0.037 0.012 0.676

Fruit fly 5 27 0.201 0.179 0.109

Horseshoe crab 4 25 0.066 0.061 0.076

Lycopod plant 4 13 0.071 0.051 0.282

GENETIC EPIDEMIOLOGY
MODELS