Autosomal Inheritance

Autosome
• Non-sex chromosome
• Same in both sexes
• 22 pairs of autosomes in humans
(the other will be the sex-
chromosome X or Y)
 Fields of genetics
• Transmission genetics – how traits are
passed
• Molecular genetics – how hereditary
material controls expression of genes
(and thus traits)
• Population genetics – genetic
variation
 Mendelian inheritance
• Experiments on monohybrid crosses
(where one characteristic differs)
revealed the law of segregation
• Reciprocal crosses disproved the
notion of one parent contributing
more to the offspring
• Used pure lines
– Parental generation = P
– First filial generation = F1
– Intercrossed F1s => 2nd filial generation
(F2)
 Mendel’s hypothesis
• Hereditary factor (gene) is necessary for
displaying particular traits
• Each ‘parent’ has a pair of this type of gene
• Alleles = variants of the gene
• Each gamete only contains one member of
each gene pair – Mendel’s first law
• These gametes fuse RaNdOmLy at fertilization
to form the ZYGOTE
• Zygote = first cell that develops into a progeny
individual

• Genes do not act in a vacuum; they depend on

the environment for their effects
 Some terms y0
• Haplosufficiency – one ‘dose’ of the wild-
type allele is enough to allow full expression
• Homozygote – plant with a pair of identical
alleles
– Homozygote dominant (Y/Y)
• Heterozygote – plant in which the alleles of
the pair differ
– Heterozygote for one gene is sometimes
referred to as ‘monohybrid’
– Heterozygous (Y/y)
– Heterozygous recessive (y/y)

Note: Y/Y, Y/y, y/y are all GENOTYPES

 Autosomal dominant
inheritance
• Males and females equally affected
• Affected people are heterozygous for
the abnormal allele
• Transmission by both sexes to both
sexes
– I.e. Huntington disease
(neurodegenerative disease)
 Autosomal recessive
inheritance
• Rare
• Skips in generation
• Males and females equally affected
• Occur in individuals who are
homozygous for a particular gene
mutation
• Common for parents to be related
(consanguineous)
– Cystic fibrosis
– Albinism
– Sickle cell anaemia
Monohybrid – 3:1
Dihybrid – 9:3:3:1

Allowed Mendel to infer

that gene pairs on
different chromosome
pairs assort
independently during
gamete formation
Dihybrid – 9:3:3:1

Allowed Mendel to infer

that gene pairs on
different chromosome Mendel’s 2
nd

Law
pairs assort
independently during
gamete formation
 Example 1
• Albinism is an autosomal recessive disorder. Two heterozygous
parents are expecting a baby. A/a . A/a

– Probability that the baby is affected? 0.25

– Probability that the baby is a homozygote? 0.50

– Probability that this baby is affected, and they then have a

second baby who is unaffected? 0.19

– If they have 5 children, what is the probability that the children

will have the following phenotypes in the order stated; 1.
unaffected, 2. albino, 3. albino, 4. unaffected, 5. unaffected?
0.026
 Example 2
• A male of genotype Aa:Bb and a
female of genotype Aa:bb decide to
have children (the two traits are
autosomal)
What is the probability of obtaining a
child of the genotype aa:bb?
Probability is ¼ for aa
Probability is ½ for bb
Overall probability is ¼ x ½ = 1/8
 Example 3
• Plants of the genotype Aa:bb ; Cc:Dd
and Aa:Bb; Cc:dd are crossed.
What is the probability of obtaining a
progeny plant of the genotype aa; bb;
cc; dd?
Probability of aa = ¼
Probability of bb = ½
Probability of cc = ¼
Probability of dd = ½
Product of these values gives us: 1/64
Sex-linked Inheritance
 Sex-linked Inheritance
• Regularly shows different phenotypic
ratios in the two sexes of progeny, as
well as different ratios in reciprocal
crosses
• X-linked traits do not give same results
with reciprocal crosses
• w = recessive mutant allele; w+ =
dominant wild-type allele
• Males are HEMIZYGOUS for X-lines
genes
• I.e. they only have one allele of a gene
rather than the usual two – just 1 ‘X
 X-linked recessive
inheritance
• Males usually affected
– Only need ONE copy of the mutant allele in order to
exhibit mutant phenotype; they can only be HEMIzygous
– Females would require BOTH parents to bear the allele
in order to inherit it i.e. (X^A . X^a) x (X^a . Y)
• Transmitted through unaffected females
• Females affected through affected fathers
• No male to male transmission
– Father’s X chromosome isn’t inherited

• Hemophilia (failure of blood to clot)

• Colour Blindness
• Duchenne Muscular Dystrophy
• Fragile-X syndrome (x-linked mental retardation)
 X-linked dominant
inheritance
• Rare
• Both genders affected
• Females less severely affected than males (due
to X inactivation)
• Affected heterozygous females married to
unaffected males pass the condition to half
their sons and daughters
• Affected males transmit to all daughters but not
sons
– Because sons don’t receive the X chromosome
from the father

• Hypophosphatemia (vit-D resistance rickets)

• Rett Syndrome (neurodevelopmental disorder)
 Y-linked inheritance
• Very rare
– VLittle genetic information on Y
chromosomes
• Only males affected
 Molecular basis of
dominance/recessiveness
of alleles
• Dominance is a result of interactions
between genes at the SAME locus
• Dominance does not affect the way
in which genes are inherited; it only
influences the way genes are
expressed
• Dominance/recessiveness depends
on the FUNCTION OF THE GENE and
the EFFECT that the mutation has on
this function
• Recessive mutant alleles
– Most new mutations cause LOSS OF
FUNCTION of the gene
– Complete loss of function = NULL
mutation
• I.e. ALBINISM (protein simply doesn’t
function)
• Dominant mutant allele
– Rare
– Haploinsufficiency = loss of function mutation. 1
wild-type dose (50%) is NOT enough to achieve
normal levels of function 
• I.e. Tailless mice
• Dominant-negative mutations
– Loss of function mutation
– Protein made but non-functional
– Mutant allele inhibits function of normal protein in
heterozygotes
• ‘Spoiler’ polypeptide distorts or interferes with the
function of the wild-type polypeptide

Gain function mutations

- New function of the gene product
- Protein always active
- Increased levels of expression
- Inappropriate expression
Extensions to Mendelian
Inheritance
 Extensions to Mendel for
single genes
Recall –
Complete dominance is
the interaction between
alleles on a single gene in a
heterozygote whereby a
single copy of a dominant
allele hides the recessive
allele. 50% of the gene
product is enough to produce
wild-type phenotype.

Transmission of many traits

doesn’t produce Mendelian
ratios however, Mendelian
Variations on Dominance
• Arise from different types of
interaction between alleles
• Incomplete dominance

• Co-dominance
Variations on Dominance
• Arise from different types of
interaction between alleles
• Incomplete dominance

• Co-dominance
 Incomplete Dominance
• The occurrence of an intermediate
phenotype observed (between the
corresponding homozygotes)
• Phenotypic ratio = genotypic ratio
i.e. 1:2:1
Each wild-type allele
produces a set dose of its
protein product. The
number of doses of the wild-
type allele determines the
concentration of a chemical
made by the protein, i.e.
PIGMENT.

Genes – code for enzymes

Alleles – determines total
level of the enzyme in the
cell/organism
Each wild-type allele
produces a set dose of its
protein product. The
number of doses of the wild-
type allele determines the
concentration of a chemical
made by the protein, i.e.
PIGMENT.

Genes – code for enzymes

Alleles – determines total
level of the enzyme in the
cell/organism
Each wild-type allele
produces a set dose of its
protein product. The
number of doses of the wild-
type allele determines the
concentration of a chemical
made by the protein, i.e.
PIGMENT.

Genes – code for enzymes

Alleles – determines total
level of the enzyme in the
cell/organism
Incomplete
dominance can be
observed on the
microscopic level
with peas ->
 Codominance
• Expression of both alleles of a heterozygote, i.e.
blood type AB, where I^A and I^B alleles are co-
dominant because both transferases are active
and both antigens are present
– Blood type is determined by the types of
polysaccharide antigen present on the RBC
surface
– In blood, all individuals have the O (aka.
Substance H) surface antigen on the RBC
surface Universal
Donor

Univers
al
Recipie
nt
 Codominance
• Expression of both alleles of a heterozygote, i.e.
blood type AB, where I^A and I^B alleles are co-
dominant because both transferases are active
and both antigens are present
– Blood type is determined by the types of
polysaccharide antigen present on the RBC
surface
– In blood, all individuals have the O (aka.
Substance H) surface antigen on the RBC
surface Universal
Donor

Protein made by that Univers

immune system that al
Recipie
is capable of binding nt
to a stimulating
molecule (antigen)
null-
mutation
Agglutination is
undesirable as it BLOCKS
blood vessels and the
recipient of the transfusion
may go into shock and
may die. We see, A can’t
accept blood from B.
So…? More than 2 alleles may be present within a group of
individuals, although each diploid individual still only has two
alleles at that locus
Bear in mind…

Variations in dominance do not negate

Mendel’s law of segregation. They reflect the
differences in the way GENE PRODUCTS
control the production of PHENOTYPES and the
effect of the mutant allele on protein function
 Lethal alleles
• Usually recessive
– Generally cause death in homozygotes
– Can be dominant, where heterozygotes
don’t survive
• Capable of causing the death of an
organism
– Mutation of an essential gene
– Manx cat (a homozygote, tailless cat)
• May produce ratios that deviate from
Mendelian ratios
• Pleiotropic – A gene that affects
multiple traits
 Penetrance
• Penetrance – percentage of individuals
with a given allele who exhibit the
phenotype associated with that allele
• Incomplete penetrance – phenotype
expected from a particular genotype is
not expressed
• Phenotype may not be expressed due
to
– Environmental factors i.e. a person
genetically predisposed to lung cancer
may not get it if he/she doesn’t smoke;
temperature; chemicals
 Expressivity
• Expressivity – degree to which a trait
is expressed
• Quantifies the modification of gene
expression by varying environment
and genetic background
 Sex-influenced and sex-
limited traits
• Sex-influenced trains – gender
governs inheritance pattern. Allele is
dominant in one sex and recessive in
another
– I.e. Males have a greater propensity to
baldness if this autosomal trait is passed
onto them as they only require a single
allele

• Sex-limited traits are limited to one

And then…
 Extensions to Mendel –
Gene Interation
• Most traits are genetically
heterogeneous – controlled by
multiple genes (and often the
environment too)
– Thalassemia
– Deafness
 Complementation test
• Can determine whether two mutations with
the same phenotype affect the same gene
or different gene
– Determines whether or not mutations occur at
the same locus
• Applied only to recessive mutations
• Two homozygous mutant lines are crossed
to produce a heterozygous mutant line
• When organisms homozygous for mutations
that show the same phenotype and are in:
– Different genes -> Wild-type observed,
mutations complement one another
– Same gene -> mutant, fail to complement
Two genes controlling a single
trait give rise to novel
phenotypes in the F2
• When two genes affect the same
phenotypic trait, we get a novel
phenotype (a double homozygous
mutant)
 Complementary gene
action
• Dominant allele from both genes
required to produce the trait
• 9:7 ratio in the F2 generation is
observed when a homozygous
mutation in either or both of two
different genes results in the same
mutant phenotype.
• i.e. In sweet peas, genotypes that
are C- for the C gene and P- for the P
gene have purple flowers
 Two individuals
heterozygous for two
loci are crossed
• Let’s say, pigement (compound C) is
produced ONLY after compound A
has been converted to compound B
by enzyme I and after compound B is
converted to compound C by enzyme
II…
 At least one
dominant Enzyme I
allele A at the
first locus
 At least one dominant
allele B at the second
locus
At least one
dominant Enzyme I Enzyme II Compound
allele A at the C
first locus
 At least one dominant
allele B at the second
locus
At least one
dominant Enzyme I Enzyme II Compound
allele A at the C
first locus

So, if there are two recessive alleles at the first locus. i.e. aaB_ = no
pigementation
A_bb = no pigmentation
Aabb = no pigmentation
 Epistasis
• Masking of the expression of one gene
by another gene at a different locus
(unlike ‘dominance’ where masking occurs at the same
locus)
– Masking gene = epistatic gene
• Can be dominant or recessive
• Can mask when recessive homozygous
– Masked gene = hypostatic gene
• Normally occurs because genes act in
the same pathway for producing a
phenotype
• F2 ratio is 9:3:4 [3pist4sis (9 letters)]
“Golden Labrador
retrievers are
homozygous for the
recessive e allele.
Because this ee
genotype masks the
effects of the B coat
color gene, golden
retrievers may be of
any genotype—BB,
Bb, or bb—at this
other gene. In E-
dogs, a B- genotype
produces black and a
bb genotype
produces brown”
 Individual can
still pass on IA or
IB allele

Omg, no substance H! – needed for

addition of A / B sugars at the
surface of the RBC
 Suppression
• A suppressor is a mutant allele of a
gene that reverses the effect of a
mutation of another gene and
restores the corresponding wild-type
phenotype
• Only 2 phenotypes segregate (unlike
3 as in epistasis)
• Implies that gene products normally
interact
 Non-Mendelian
Inheritance
• Extranuclear inheritance
• Maternal effect (nuclear genes)
• Imprinting
– Expression of a gene is influenced by
the sex of the parent who transmits the
gene to the offspring.
 Extranuclear inheritance
• Inheritance of genetic material not located
within the nucleus (aka. Cytoplasmic
inheritance)
• Main organelles – mitochondria and chloroplasts
– Uniparental inheritance
– Each mitochondria contains approx. 15,000
nucleotides that encode for 37 genes
– Nuclear DNA contains some 3 billion nucleotides
encoding for 35,000 genes
• Contain circular chromosomes, resemble
smaller versions of bacterial chromosomes
• Rely largely on nuclear genes for their function
• Replicate autonomously
• Encode products which function within the
organelles
• Multiple chromosome per organelle
:P
 Extranuclear inheritance
continued…
• Mitochondria is inherited from the mother in
most cases
• Variegation in plants is caused by mixture of
chloroplasts (heteroplasmic vs
homoplasmic)
– White leaves caused by mutations in
chloroplast genes that control the production
and deposition of chlorophyll
– White-leaved plants cannot live
• During somatic cell division, organelles
separated more or less evenly into daughter
cells
• Paternal (and biparental) inheritance is
much rarer as the egg is the larger gamete
and is able to provide far more cytoplasm to
 Mutations in
mitochondrial DNA
• Often in genes that code for the
components of the electron-transport
chain, which generates most of the ATP
in aerobic cellular respiration
• Disease only inherited maternally
• Can cause disease that are chronic
degenerative disorders affecting the
brain, kidneys, heart and other high
energy requiring tissue
– Myopathy
– Leber’s Hereditary Optic Neuropathy
• Affects cells in the optic nerve, leading to loss of
vision
• Point mutation in the gene encoding NADH
 Maternal effect
• PHENOTYPE of the offspring
determined by GENOTYPE of mother
• Genes inherited from BOTH parents
(unlike in cytoplasmic inheritance)
• Phenotype is not affected by the
genotypes of the father, and of the
offspring themselves
– Expression is too late in embryogenesis
 Maternal effect

Snail-shell coiling

Sinistral coiling is recessive

Direction of the coiling is

determined by the nuclear
genotype of the mother and
NOT the snail itself or by
extranuclear inheritance

Obviously no Medelian
inheritance patterns here…
 Maternal effect

Snail-shell coiling –
closer look

The direction of coiling is affected by the way in

which the cytoplasm divides soon after
fertilization, which in turn is predetermined by a
substance produced by the mother and passed
to the offspring in the cytoplasm of the egg
 Errors in
mitosis ->
cancer Change in
Accidents in number of
Defective cell division chromosom
control of cell -> es that can
cycle -> cancer aneuploidy lead to
chromosom
al
abnormality

Cell division and

chromosome theory

Errors in
meiosis ->
developmental
defects and
mental
retardation
 Chromosomes
• Singular piece of DNA constituted by genes,
regulatory elements and other nucleotide
sequences
• Linear structures in eukaryotes
– Highly folded and condensed
– Packed around histone proteins
– Consist of a centromere, a pair of telomeres and
origins of replications
• Most eukaryotes are DIPLOID (contain two
similar sets of chromosomes, one is maternal
and the other paternal), each chromosomes is a
member of a pair called HOMOLOGUES. They
each carry copies of the same genes but are
NOT identical to each other
• Our gametes are HAPLOID
Also participate
in limiting cell
division and
play important
roles in aging
and cancer
 Cell division
• Mitosis: Same number and types of
chromosomes as the original mother cell
(genetically identical) i.e. diploid cells
• Meiosis: Half the number of chromosomes
as the mother cell, one member of each
chromosome pair. I.e. haploid cells
• Division occurs via CELL CYCLE, alternates
between
– Interphase
• DNA replication that produced an identical pair of
sister CHROMATIDS which are to end up in daughter
cells
• Sister chromatids become visible at the beginning of
mitosis
– Mitosis (the phase of actual division)
• Resulting daughter cells have the same genomic
 More annoying terms…
• Dyad = replicate (two) sister
chromatids
• Bivalent = pair of synapsed dyads
• Tetrad = 4 chromaTIDS that make up
the bivalent
Major events of cell cycle
Major events of cell cycle

Doubling of the
genome

Halving of the
genome
Major events of cell cycle
Synthesis (of DNA)
10 – 12 hours

Nuclear
division
-Anaphas
Mitosis
e

-Telophas 30 mins
Cytoplasmice division
Chromosome
segregation

Cell division
 Phases of the cell cycle
• Gap phases G1 and G2
allow time for the cell to
grow and double their
mass of proteins and
organelles

• They also provide time for

the cell to monitor the
internal and external
environment to ensure
that conditions are
suitable and preparations
and complete before the
cell commits itself to the S
phase or mitosis

• Cell growth does not occur

during mitosis
 Cell-cycle control system
• Operates much like a timer or oscillator that triggers the events of
the cell cycle in a set sequence
• Control system is independent of the events in controls but does
utilize sensors to detect the completion of processes and will delay
progression of the cycle if for example DNA damage occurs
• Highly adaptable and can be modified to suit specific cell types or
to respond to specific intracellular or extracellular signals
• Triggers cell-cycle progression at 3 major regulatory transition
(checkpoints).
- 1st checkpoint @ Start(restriction point), late in G1
- 2nd checkpoint @ G2/M where the control system triggers early
mitotic events that lead to chromosome alignment on the specific
spindle in the metaphase
- 3rd checkpoint @ metaphase-to-anaphase transition where the
control system stimulates sister-chromatid separation ->
completion of mitosis and cytokinesis
Cell-cycle control system
Cell-cycle control system

Feedback signals are

received at checkpoints

Checkpoints allow the cell-

cycle control system to
receive information about
the environment

If damage is irreversible,
apoptosis will be
triggered
 Checkpoints
• Signals that arrest the cycle usually occur
at G1

• During infection of T-cells with HIV-1,

signal is arrested at G2 – this allows for
greater virus production!
 Interphase
• DNA is being synthesized
• RNA and proteins are being produced

• G1 (gap 1) – material required for

survival and growth is made
• S – chromosomes replicated to form
sister chromatids
• G2 (gap 2) – synthesis of proteins
needed for divison
– i.e. microtubules, centrosomes etc…
 Mitosis
• Separation of sister chromatids to provide a complete set of
genetic information for each of the resulting cells
• Involves 6 stages
– Prophase
– Prometaphase
– Metaphase
– Anaphase
– Telophase
– Cytokinesis
 Mitosis
• Separation of sister chromatids to provide a complete set of
genetic information for each of the resulting cells
• Involves 6 stages
– Prophase
– Prometaphase
– Metaphase
– Anaphase
– Telophase
– Cytokinesis
 Mitosis
• Separation of sister chromatids to provide a complete set of
genetic information for each of the resulting cells
• Involves 6 stages
– Prophase
– Prometaphase
– Metaphase
– Anaphase
– Telophase
– Cytokinesis
 Mitosis
• Separation of sister chromatids to provide a complete set of
genetic information for each of the resulting cells
• Involves 6 stages
– Prophase
– Prometaphase
– Metaphase
– Anaphase
– Telophase
– Cytokinesis
 Mitosis - Prophase
• Chromosomes condense and become
visible
• Each chromosomes possesses two
chromatids
– Each pair of chromatids is the product of
the duplication of one chromosome in the S
period of the interphase
– Chromatids are held together at the
centromere by cohesin
• The mitotic spindle (a bipolar bundle of
microtubules that move the
chromosomes in mitosis) forms
– Nuclear envelope disintegrates
 Before we move to Prometaphase…

Centrosome
• Regulator of the cell-cycle progression

• Centrosomes surround the centrioles which organize the

mitotic spindles and are involved in the completion of
cytokinesis

• They form the two poles of the mitotic spindle which serve
to pull two sets of sister chromatids to opposite ends of the
cell during the anaphase

• Eukaryote cells must duplicate its centrosome to provide

one for each of its two daughter cells

• Must replicate only once per cell cycle to ensure that the
cell enters mitosis with only 2 copies. Incorrect number of
centrosomes could lead to defects in spindle assembly and
thus errors in chromosome segregation
 Mitosis - Prometaphase
• Spindle microtubules which have thus
far been outside the nucleus, enter the
nucleus
• The ends of certain microtubules make
contact with the chromosome and
anchor to the kinetochore of one of the
sister chromatids
• A microtubule from the opposite
centrosome then attaches to the other
sister chromatid and so each
chromosome is anchored to both of the
centrosomes
• The microtubules lengthen and shorten,
 Mitosis - Metaphase
• Both sister chromatids attached to
kinetochore microtubules and
chromosomes line up on the
metaphase plate
• Basically, this metaphase plate is an
imaginary plane that’s equidistant
from the two poles of the mitotic
spindle where all the kinetochores lie
on
• Chromosomes reach their maximum
contraction on this plate
 Anaphase
• Centrosomes divide
• Each sister chromosome moves to
opposite poles of the spindle and
regarded as a separate chromosome in
its own right
• Chromosome movement results in part
from progressive shortening of the
kinetochores attached to the
centromeres
• This movement is mediated by
KINESINS (motor proteins) which and
results in chromosomes being pulled
 Telophase
• Chromosomes at poles begin to
decondense
• Spindle disappears
• Nuclear envelope forms around each
compact group of chromosomes -> 2
nuclei
• Chromosomes decondense until
they’re no longer visible as discrete
entities
 Cytokinesis
‘Cytoplasm division’

• Fiber ring composed of actin around

the center of the cell contracts
pinches the cell into two daughter
cells
• Important organelles (i.e. ribosomes,
mitochondria) are divided between
daughter cells
Summary
 Meiosis
• Introduces GENETIC VARIATION
– If we all reproduced mitotically, we’d essentially be
clones of one another and would not evolve
– Cells produced by meiosis are genetically different from
one another and the parental cell
• Longer process than mitosis – spans for several days
or even weeks
• Only one member of each pair of chromosome is
present in the premeiotic cell
• Consists of two successive nuclear divisions (meiosis I
and meiosis II) that lead to four HAPLOID cells
– Meiosis I: the homologous chromosomes disjoin =
reductive division
– Meiosis II: the sister chromatids separate (similar to
mitosis BUT there is no chromosome replication)
• Occurs during GAMETE formation in GERM CELLS
• Diploid chromosome number re-established at
fertilization (23 in gamete, 46 in zygote)
 More on meiosis…
• Independent assortment of maternal and
paternal chromosomes, and cross-over of
genetic material between homologous
chromosomes – Mendel’s law of independent
assortment
• Begins after cells have progressed through G1,
S and G2 phases of the cell cycle, thus
chromosomes have been replicated
• The cells enter meiosis containing pairs of sister
chromatids
• Major differences occur during prophase I
(prophase of meiosis I):
– Homologous chromosomes pair
– Exchange between non-sister chromatids
 Prophase I
• Leptotene ‘thin thread’ – chromosomes begin to condense
(become visible)
• Zygotene ‘paired threads’ – pairing (or synapsis) of the
homologous chromosomes
– Recall! Each pair of synapsed homologous chromosome is
referred to as a ‘bivalent’ or ‘tetrad’
• Pachytene ‘thick thread’ – condensation of the chromosome
continues
– Crossing over occurs – physical exchange of chromosome
segments (genetic info)
– Site of crossing-over is called CHIASMA which is formed by a
breakage and rejoining by non-sister chromatids
• Diplotene ‘double thread’ and diakinesis ‘moving apart’ –
homologous chromosomes move apart, except at segments
connected by chiasmata (cross-over points)
• At the end of diakinesis, the formation of a spindle is
initiated, and the nuclear envelope breaks down
Exchange of genes
between non-sister
chromatids generates
even more diversity
 Metaphase I
• Homologous pairs of chromosomes
align along the metaphase plate
• Arrangement of chromosomes within
this double row is RANDOM
– 50-50 chance for daughter cells to get
either the mother’s or father’s
homologue for each chromosome
• A microtubule from one pole
attaches to one chromosome of a
homologous pair
 Anaphase I
• Homologous chromosomes separate
from each other and migrate to
opposing poles
• Centromeres and sister chromatids
still intact with each other
• Alignment of chromosomes in
metaphase I ensures each daughter
cell receives a RANDOM assortment
of maternal and paternal
chromosomes
 Telophase I
• The chromosomes arrive at the
spindle poles
• Spindle breaks down and the
cytoplasm divides (this overlaps with
the short INTERKINESIS stage)
• Chromosomes enter phase II of
mitotic division after only a limited
uncoiling
 Meiosis II
• Similar to mitosis, except half the
number of chromosomes are
invovled
– In mitosis, we have 46 chromosomes,
containing 92 sister chromatids joined
into 46 pairs
– In meiosis II, we have 46 sister
chromatids joined as 23 pairs
 Stages of Meiosis I
Simplified Version

• Prophase I - Chromosomes condense,

homologous pairs of chromosomes synapse,
crossing over takes place, nuclear envelope
breaks down, and mitotic spindle forms
• Metaphase I - Homologous pairs of
chromosomes line up on the metaphase plate
• Anaphase I - The two chromosomes (each with
two chromatids) of each homologous pair
separate and move toward opposite poles
• Telophase I - Chromosomes arrive at the
spindle poles
• Cytokinesis The cytoplasm divides to produce
two cells, each having half the original number
of chromosomes
• Interkinesis In some cells the spindle breaks
down and chromosomes relax
 Stages of Meiosis II
Simplified Version

• Prophase II - Chromosomes condense, the

spindle forms, and the nuclear envelope
disintegrates
• Metaphase II - Individual chromosomes line
up on the metaphase plate
• Anaphase II - Sister chromatids separate
and migrate as individual chromosomes
toward the spindle poles
• Telophase II - Chromosomes arrive at the
spindle poles; the spindle breaks down and
a nuclear envelope re-forms
• Cytokinesis The cytoplasm divides
 Genetic variation
• Crossing-over
• Random distribution of chromosomes
Crossing-over
Random distribution of
chromosomes
 Chromosome theory
Chromosome theory of inheritance
states that genes are located on
chromosomes. The two alleles of a
genotype segregate during ANAPHASE I
of meiosis, when homologous
chromosomes separate. The alleles
may also segregate during anaphase II
of meiosis if crossing over has taken
place

Btw, in drosophila, sex is determined by

number of X chromosomes. 1 = male, 2
Gene mutation and Gene
Function
 Yay, even more
definitions…
• Forward mutation = Change from WT ->
mutant
• Reverse mutation = Change back to WT
• Spontaneous mutation
– Natural changes to DNA structure
– Very rare
– Arise from altered base structures and from
wobble base pairing
– Small insertions and deletions may occur
through strand slippage in replication and
through unequal crossing over
– Depurination / deamination -> alter pairing
properties of bases
• Mutagen = substance that increases rate of
mutation; causes point mutation
 Luria and Delbruck
experiment
• TonR = resistance mutants
• The hypothesis:
– If an ADAPTIVE RESPONSE let to tonR – we’d
expect resistance only when the cells are
exposed to the adverse agent
– If RANDOM MUTATION let to tonR – we’d
expect that the mutation could occur any time
in the growth of the culture
• Results: Large variation in number of T1
resistance colonies between the 20
individual cultures
• Conclusion: Heritable variants are produced
by mutations occurring spontaneously at
random
– Specific mutations are not responses to the
 Function of a gene
• Genes encode RNAs (and not
proteins)
• Chemical synthesis in cells is by
pathways of sequential steps
catalyzed by enzymes
• The genes encoding the enzyme of a
specific pathway constitute a
functionally interacting subset of the
genome
 Types of mutation – levels of
mutation
The following types are stably
inherited:
• Changes to the genome – changes in
chromosome number. i.e. Down
syndrome, trisomy etc…
• Changes to a chromosome –
structural changes in chromosomes
• Single gene mutations – relatively
small changes within a particular
gene
 Types of mutation – What
can a single gene mutation
do?
• Mutation within the coding sequence
– May or may not affect AA sequence
– Effect on protein function depends on the
role of the altered amino acid(s) in the
protein
• Mutations in non-coding regions
– Promoter region – mutation may result in
an increase or a decrease of gene
transcription
– Splice recognition sites – pre-mRNA may
not be spliced correctly – similar result to a
frameshift mutation
– Alteration in ability of mRNA to be
translated
 Types of mutation –
Mutation can occur in
•
germ-line or somatic cells
Mutations are the primary tools of genetic
analysis
• Most mutations seen are GERM-LINE (cells that
produce gametes) mutations which can be
inherited
• Somatic mutations = mutation in the somatic
cells; not passed from parent to offspring, but
will be passed from cell to cell during cell
division
– Cells with somatic mutations that that stimulate
cell division can increase in number and spread
• Basis for all cancers!
• Only dominant mutations will affect the
phenotype of cells within a somatic mutant
clone
• Genetic mosaic = individual who has a
 How does genotype affect
phenotype?
• Effect ranges from trivial -> lethal
• Depends on function of gene in the cell
• Depends on effect of the mutation on
the gene product

• Deleterious - i.e. disease genes

• Beneficial – enhances survival of
organism and is favored by evolution
• Conditional – mutations affect
phenotype only under defined
conditions
 How does genotype affect
phenotype?
Loss of gene function vs. gain of gene
function
• Loss of gene function mutations
– Alteration of the gene product most often
leads to loss of wild-type function
– Null mutation = total loss of function
– HYPOMORPHIC mutation = partial loss of
function
– I.e. cystic fibrosis, albinism
– Normally recessive as 50% of gene product
is often enough
– Can be dominant
• Haploinsufficiency (50% not enough)
• Dominant-negative – mutant protein is non-
function and interferes with function of normal
protein in heterozygotes
 How does genotype affect
phenotype?
Loss of gene function vs. gain of gene
function
• Gain of gene function mutations
– Relatively uncommon
• Mutant protein has a new function
• Mutant protein is always active
• Mutant gene is expressed at increased
levels or in different areas
– Generally dominant
 Using mutations to understand
gene function
• Forward genetics
– Phenotype first – DNA sequence later
• Reverse genetics
– DNA sequence first – phenotype later
 Population and
Quantitative Genetics
 Population genetics
• Is concerned with the distribution
patterns of alleles and the factors
that alter or maintain their
frequencies
• Application of genetic principles to
entire populations of organisms

• The gene pool of a population can be

described by the frequencies of
genotypes and alleles in the
population
Genotype frequencies
depend on allele
frequencies
 Genotype frequencies
depend on allele
-
frequencies
Can be calculated from a
random sample of genotypes
- AA = 60, Aa = 30, aa = 10
- P = freq (A) = (twice no.
homozygotes + no. of
heterozygotes) / (total no. of
alleles sampled) = [(2x60) +
30] / (2x100) = 0.75

- I.e. allele frequency of A =

0.6 and allele frequency of a
is 0.4

Hardy-Weinberg principle –
these frequencies result
from random mating for a
gene with two alleles
Principles of Hardy-Weinberg Equilibrium are
founded on
6 key assumptions
• The population is sufficiently large that the
frequencies of alleles do not change from
generation to generation because of chance
• Allelic frequencies of the population are not
affected by natural selection, migration and
mutation(no gene flow)
• Mutation does not occur
• Mating is random; there are no
subpopulations that differ in allele
frequency
• All the genotypes are equal in viability and
fertility; selection does not operate
• Allele frequencies are the same in males
and females
 Hardy-Weinberg Equilibrium
2 predictions
• The allelic frequencies of a population do
not change
• The genotypic frequencies stabilize after
one generation [in the proportions p2 (the frequency of AA),
2pq (the frequency of Aa), and q2 (the frequency of aa), where p
equals the frequency of allele A and q equals the frequency of allele a]

• So… when these assumptions are met,

reproduction alone does not alter allelic or
genotypic frequencies and the allelic
frequencies determine the frequencies of
genotypes
• A population cannot evolve if it meets the
Hardy-Weinberg assumptions since
evolution consists of change in allelic
frequencies of a population
i.e. when q = 0.01, aa =
1/10,000
 Calculating carrier
frequencies for rare
recessive gene defects
• I.e. Cystic fibrosis affects 1 in 2,500 live
births = 0.0004
• Q^2 = 0.0004, Q = 0.02
• Since p + q = 1, p = 0.98
• Almost 4% of
the population!
= 0.0392 (almos

1 in a million disease, we’d have q^2 = 1 x

10^-6, q = 0.001, p = 0.999
2 x 0.001 x 0.999 = 0.001998, about 1 in
How to check if a gene in a
population is in Hardy-
Weinberg equilibrium?
• Use the known allele frequencies
to predict the genotype
frequencies for a population in
the H-W equilibrium
• Compare these to the known
genotype frequencies
• Use chi-squared test to see if
excepted frequencies =
observed frequencies
 Genetic drift
(sampling error)

• The random, undirected changes in

allele frequency that occur by chance
in all populations, but particularly in
small ones
• Amount of change in allelic
frequency due to genetic drift is
inversely related to the effective
population size
• Effective population size decreases
when there are unequal numbers of
males and females
 Bottlenecks
• Temporary Founder effect that can
have long-lasting effects
– Founder effect: establishment of a
population by a small number of
individuals
• I.e. Cheetahs, elephant seals
 Therefore, allele has
reached frequency
of 1

Loss of an
allele =
reduction in
genetic
diversity

Risks:
- Higher incidence of rare genetic disease
- All individuals may be susceptible to an infectious disease
- Individuals may have reduced fitness because of ‘inbreeding
 Assortative mating
• Bias towards choosing a similar mate
– positive assortative mating
– Increases the homozygosity of the
population
• Bias towards choosing a dissimilar
mate – negative assortative mating
– I.e. short people mating with tall people
 Inbreeding
• Non-random mating between related
individuals
– Alters the frequency of the genotypes but
not the frequency of the alleles
• Decreases proportion of heterozygotes
– Boosts the probability that deleterious and
lethal recessive alleles will combine to
produce homozygotes with a harmful trait
• When inbreeding occurs, the genotypic
frequency will be:
– F(A,A) = p^2 + Fpq
– F (A,a) = 2pq – 2Fpq
– F (a,a) = q^2 + Fpq
 Mutation in population
genetics
• Mutations create VaRiAtioN
– Can influence the rate at which one genetic
variant increases at the expense of another
• Mutation rate = µ = probability of mutation
to a different allele per gene per generation;
mutation rates are around 10^-5 to 10^-8
• Mutation is extremely slow at changing
allele frequencies, and so cannot account
for rapid genetic changes
– Very few mutations are favorable for the
organism and contribute to evolution
– If mutation rates were very high, a species
would suffer excessive genetic damage due to
preponderance of harmful mutations
 Migration (gene flow)
• Influx of genes from
other populations
causing change in
allelic frequency;
causes gene pools from
two populations to
become more similar
• Prevents genetic
divergence between
populations
• Increases genetic
variation within
populations
• I.e. I^B allele of ABO
blood groups is highest
in frequency in Eastern
 Natural Selection
• Changes allelic frequencies
– Direction and magnitude depends on the intensity of the
selection, dominance relations among the genotypes
and the allelic frequencies
– Environmental factors can also influence selection
pressure
• Selection works on GENOTYPES (not alleles)
• Alleles that give more fit genotypes, will be
represented in higher frequencies in the following
generation
– Fitness (relative reproductive success of a genotype)
measured from 0 (none) to 1 (maximum)
– Fitness of 1 = selection of 0
– Fitness of 0 = selection of 1
– This selection coefficient (s) measures the relative
intensity of selection against the genotype
– I.e. People with achrondroplasia produce only about 74%
as many children as those without it, so fitness of people
without achrondroplasia averages 0.74, selection
 Frequency of single-gene
disorders
Mutation – selection balance
• Mutation and natural selection act as
opposing forces on detrimental
alleles
– Mutations tend to increase frequency
– Natural selection tends to decrease
frequency
– Equilibrium formed
Heterozygote (overdominance)
advantage
• Heterozygote has higher fitness than
homozyogetes…
• Explains why some gene disorders
have much higher incidence
• In some cases, natural selection
works to maintain a deleterious
phenotype
– I.e. Cystic fibrosis, incidence much
higher in Europeans due to heterozygote
advantage
 Quantitative genetics
• A character which is
continuous over a
range
– I.e. height, weight,
color, metabolic rate
etc...
• Many genes
contribute to one trait
= polygenic
inheritance, i.e. height
• Trait can be affected
by environment, i.e.
 Heritability of a
quantitative trait
• Heritability = proportion of
phenotypic variance that is due to
genetic variance
• A trait is heritable if some of the
variation can be accounted for by the
genetics of the system
• Narrow heritability = h^2 = measure
of how heritable a trait is, using
family data = (additive genetic
variance ÷ phenotypic variance)
• Familial = trait shared by a family,
even if they do not share the same
genotype
• Heritable = trait shared by people
with the same genotype
Regression analysis
Regression analysis
 Identifying the genes that
affect a qualitative trait
• Educated guess
• Quantitative trait loci (QTL) mapping
using DNA markers
– QTL = genes that control polygenic
characteristics
Autosomal Chromosomal
Disorders
Changes in chromosome
number
 Human cytogenetics
• Cytogenetics = study of the genetic
implications of chromosome
structure and behavior
– Can be performed on blood, amniotic
fluid, placental tissue, bone marrow
aspirates etc…
 Karyotype
• Karyotype = complete set of
chromosmes
• In a standard karyotype,
chromosomes are arranged
according to:
– Position of the centromere
– Size
Karyotype nomenclature
• Normal male – 46, XY
• Normal female – 46, XX
• Female trisomy 21 – 47, XX + 21
• P = short arm of the chromosome
– 13p = short arm of chromosome 13
• Q = long arm of the chromosome
 Chromosomal
abnormalities
• Responsible for a large proportion of
spontaneous miscarriage and childhood
disabilities
• Types
– Chromosome number i.e. aneuploidy,
polyploidy
– Mixed cells i.e. mosaicism, chemerism
– Chromsome structure i.e. translocations,
deletions
– [Diagnostic tools i.e. FISH, chromosome
paint]
– Abnormalities of autosomes
 Changes in chromosome number
Polyploidy
• The presence of more than two genomic sets of
chromosomes
– Normal karyotype (46 chromosomes)
– Triploidy (69 chrmosomes)
– Tetraploidy (92 chromsomes)
– Pentaploidy (115 chromosomes)
• Caused by failure of meiotic division during
formation of ovum or sperm or by fertilization of
an ovum by two sperm
• Phenotype – very severe
– Polyploid individuals almost always die mid-
pregnancy
– Polyploidy is a common cause of spontaneous
miscarriage
– Polyploid individuals never survive beyond birth
 Changes in chromosome number
Aneuploidy
• Loss or gain of one or more entire
chromosome (not sets of
chromosomes!)
– Monosomy – loss of one chromosme
– Trisomy – gain of one chromosome
– Tetrasomy – gain of two chromosomes
• Usually caused by non-disjuction
• More than one aneuploid mutation may
occur in the same individual
• Phenotype – relatively mild to severe
– Depends on which chromosome
Learn to draw this!
Failure of separation of a pair of homologous chromosomes

Failure of a pair of sister chromatids to separate

 Monosomy
One chromosome missing

• Missing a copy of one of the

chromosomes
• Monosomy of an autosome – severe
– Usually do not survive to term
(miscarriage)
• Monosomy of sex chromosomes -
milder
• Monosomy uncovered deleterious
recessive alleles
• Some genes are haploinsufficiency
• Small deleterious effects of incorrect
 Trisomy
One extra chromosome

• Trisomy of an autosome – moderate

to severe
– Three trisomies can survive to term
• Patau syndrom (trisomy 13)
• Edwards syndrome (trisomy 18)
• Down syndrome (trisomy 21)
– Survival perhaps due to fewer genes on
affected chromosomes
• I.e. chromosome 21 is thought to contain
less than 300 genes of a total 30,000-35,000
for the entire genome
• Trisomy of sex chromosomes – mild
Patau Syndrome and Edwards
Syndrome
• Incidence of 1 in 5000
• Increased incidence with maternal age
• Phenotype – severe
– Very poor prognosis (most infants die in a
few days)
– Long term survivors suffer severe learning
difficulties and cardiac abnormalities

• Cleft palate, harelip, polydactyly

• Growth failure, skull elongation
 Down Syndrome –
Trisomy 21
• Caused by nondisjunction
– 1 gamete will contain two copies of chromosome 21 and the
other will carry none
– If this gamete with two copies participates in fertilization, then
we’ve got ourselves a zygote with trisomy 21
• 1 in 700
• 80% spontaneously lost in pregnancy
• Increased incidence with maternal age
– For some unknown reason, nondisjunction of chromosome 21
is more likely to occur in oogenesis than in spermatogenesis
• Most common and least detrimental of the autosomal
trisomies
• Phenotype – moderate
– Low IQ
– Usual life expectancy (if no cardiac defect)
– Most adults develop Alzheimer’s disease
• APP gene affected
 Clinical features of Down
syndrome
Can also be caused by:
- Translocation - Movement of a chromosome segment to a
nonhomologous chromosome or region of the same chromosome
- Mosaicism - regions of tissue with different chromosome
constitutions

Upward sloping
palpebral
fissures, small
ears

Atrial and ventral Small middle

septal defect – phalanx of 5th
results in early finger
death in 15-20% of
 Clinical features of Down
syndrome
Can also be caused by:
- Translocation - Movement of a chromosome segment to a
nonhomologous chromosome or region of the same chromosome
- Mosaicism - regions of tissue with different chromosome
constitutions
 Diagnostic tools for chromosomal
disorders
Fluorescent in situ hybridization
(FISH)cytogenetics
• Diagnostic tool combining
(karyotype) with molecular genetics
• Allows us to determine the chromosomal
location of a particular gene
• We need to now the sequence of a gene to
make a probe
[1] Make a single-stranded DNA probe – designed
so it binds only to the target sequence – labeled
with a fluorophore
[2] Hybridize the DNA probe to chromosomes in a
metaphase spread
[3] The area of the chromosome with the target
sequence will fluoresce under a fluorescent
microscope
Allows us to detect the presence or absence of
A fluorophore is a chromosome-specific DNA probe that contains
fluorescent dyes. It anneals with its complementary target sequence
wherever it is located on a metaphase spread
 Different types of FISH
• Centromere probes and telomere
probes
– Useful for identification of the whole
chromosome
– Ideal for rapid diagnosis of aneuploidy
syndromes
• Whole chomosomes probes
(chromosome paint)
– Ideal to identify translocations
– Induces different color images of each
chromosome pair
• Locus-specific probes to show just one
 Different types of FISH

Multiplex-FISH (M-FISH) uses multiple colors

- Only 5 different colour fluorophores are required to label all
the chromosomes differently
-A CCD camera can generate a composite image of each
chromosome in a pseudocolor visualized by appropriate
software
- Ideal for detecting subtle chromosome rearrangements i.e.
 Physical chromosomal
mapping
• Genetic maps reveal the relative positions of
genes on a chromosome on the basis of
frequencies of crossing over, but they don’t
provide information that can allow us to place
groups of linked genes on a particular
chromosome
• Due to these limitations, physical mapping, that
don’t rely on rates of crossing over was
developed
• Physical mapping of a gene is an essential first
step in its identification and cloning
• Identification will enable an understanding of
the developmental basis of the disease with the
prospect of the possibility of therapeutic
interventions
• All that needs to be known is the DNA sequence
 Types of physical
chromosomal mapping
• Somatic cell hybridization
– Involves the fusion of cell from two different
species(a process facilitated by the Sendai virus
which alters plasma membranes )
– Requires gene product to be identifiable in cell
culture and different in the two species
– After fusion, the cell possesses two nuclei and is
called a heterokaryon
– The two nuclei eventually fuse, generating a hybrid
cell that contains chromosomes from both cell lines
– The hybrid cell eventually begins to lose
chromosomes as they divide and chromosomes
from one of the species are lost preferentially
• I.e. in the human-mouse somatic-cell hybrid, the human
chromosomes tend to be lost
• The presence of “extra” human chromosomes in the
mouse genome makes it possible to assign human
genes to specific chromosomes
 Types of physical
chromosomal mapping
• Radiation hybrids
– Human cell cultures are irradiated with
lethal levels of X-rays, which causes many
chromosome breaks
– This cell is fused to a rodent cell
– The fragments of broken chromosomes join
up with the mouse chromosomes, stay as
mini chromosomes, or are lost
– Panel of hybrids is produced, each carrying
a small proportion of the human genome
– Genes are ‘mapped’ to each hybrid cell by
PCR identification
Autosomal Chromosome
Disorders
(structural)
 Structural abnormalities in
chromosomes
• Caused by breakage followed by reunion in a
different configuration
• OR crossing over between repetitive
(duplicated) regions
• Only survive meiosis if abnormal chromosome
still has one centromere and two telemores
• Can be balanced or unbalanced
• Balanced
– No gain or loss of genetic material
– Chromosome complement is complete
– Generally harmless unless breakpoint disrupts via a
vital gene
– Carriers at risk of producing offspring with an
unbalanced complement
• Unbalanced
– Clinically serious
Four basic types of
rearrangement
 Translocation
• Transfer of genetic material from
between two chromosomes or even the
same chromosome
• Can affect a phenotype
– Create new linkage relations that affect
gene expression, as in… genes
translocated to new locations may come
under the control of different regulatory
sequences or other genes that affect their
expression
– Chromosomal breaks that bring about
translocations may take place within a
gene and disrupt its function
 Types of translocation
• Reciprocal
– Breakage of at least two chromosomes with exchange of
material
– Chromosome number usually remains unchanged
– Indentified by high resolution banding studies or FISH
– Usually does not cause clinical signs
• Non-reciprocal
– Genetic material moves from one chromosome to another
without any reciprocal exchange
• Robertsonian
– Specific type of reciprocal translocation
– Breakpoints are located at / close to centromeres of two
acrocentric chromosomes
– Generates a metacentric chromosome and another
chromosome with two short arms
– This small chromosome fails to segregate, leading to an overall
reduction in chromosome number
– Functionally balanced translocation, with an incidence of 1 in
1000
– 6 possible games: 1 normal, 1 balanced, 4 unbalanced
Robertsonian translocation
Can also happen in chromosome 13, 15,
21 and 22
 Pachytene quadrivalent
in meiosis
• At meiosis, incorrect segregation can
generate significant chromosome
imbalance
– Early pregnancy loss
– Infant with multiple abnormalities
• Chromosomes with translocations
cannot pair properly to form normal
bivalents
• Cluster to form a pachytene
quadrivalent
Formation of a pachytene
quadrivalent
Formation of a pachytene
quadrivalent
Robertsonian translocation
is one cause of Down
syndrome
• Robertsonian translocation can predispose
to birth of babies with Down syndrome – 3
copies of long arm of chromosome 21
– 2 copies of normal chromosome 21 + 14/21
translocation
• 2/3 cases – translocation is de novo – has
occurred only in the gamete that gave rise
to the child
• 1/3 of the cases – parent is the carrier of the
translocation
– Parents have high risk of having further
affected children or spontaneous abortion due
to other chromosomal abnormalities
 Chromosome deletions – large
or small
• Loss of part of a chromosome resulting in monosomy for that
segment
• Phenotypic consequences depend on which genes are located
in the deleted region
• If the deletion includes the centromere, the chromosome will
not segregate in meiosis or mitosis and will usually be lost
• Generally deletions larger than 2% of total haploid genome will
be lethal
• Defects due to haploinsufficiency of genes
• In individuals heterozygous for a deletion, the normal
chromosome loops out during prophase I of meiosis. Deletions
do not undergo reverse mutation. They cause recessive genes
on the undeleted chromosome to be expressed and cause
imbalances in the gene product
• Large chromosomal deletions
– Karyotyping
– Wolf-Hirschhorn and Cri du chat syndromes
• Microdeletions
– Detectable by FISH
– Cause of Prader-Willi and Angelman syndromes
– Even more sensitive technique – CGH (comparative genomic
 Wolf-Hirschhorn and Cri
• Very rare du chat
• Visible deletions of tips of chromosomes 4 and
5 respectively
• Mortality rate of 34% as infants, usually due to
heart defect, pneumonia, infection or seizure
• Cause severe growth, statomotoric and mental
retardation
• ‘Cry of the cat’
• 10% mortality rate as infant, due to heart
defects
• Causes severe and variable mental retardation
• Poor concentration between extent of deletion
and phenotype
Microdeletion syndromes
• Detectable with high-resolution karyotyping
or FISH
• May result in loss of only a few genes at
adjacent loci-contiguous gene syndromes
• Usually presents with characteristics facial
features, aortic stenosis (narrowing of the
aorta), growth retardation and impaired
mental development
• I.e. WAGR (Wilm’s tumour, Aniridia –
absence of colored part of iris,
Genitourinary abnormalities and
Retardation of growth and development),
DiGeorge syndrome
 Chromosome insertions
• Segment of one chromosome becomes
inserted into another chromosome
• Balanced
– Inserted material has moved from elsewhere in
another chromosome (deletion-insertion
rearrangment)
– Breakpoints can disrupt important genes
– Carriers have 50% risk of producing
unbalanced gametes (random chromosome
segregation at meiosis will result in 50% of the
gametes inheriting either the deletion or the
insertion but not both)
• Unbalanced
– Likely to be clinically severe
 Chromosome inversions
with or without the centromere
• A segment of a chromosome in which the order of the genes is the
reverse of the normal order
• No gain/loss of genetic material
• Chromosome must break in two places for inversion to take place
• Paracentric (para means ‘next to’) inversion = inversions that do
not include the centromere
• Pericentric (peri means ‘around) inversion = inversions that
include the centromere
• In heterozygotes for a chromosome inversion, the chromosomes
form loops in prophase I of meiosis
• When crossing over takes place within the inverted region,
nonviable gametes are usually produced, resulting in a depression
in observed recombination frequencies.
• Balanced
– Breakpoints can disrupt important genes, one part can move to a new
location and destroying the function of that gene – phenotypic effects arise!
– Many genes are regulated in a position-dependent manner; if their positions
are altered by an inversion, they may be expressed at inappropriate times
or in inappropriate tissues
– Carriers of inversions have a variable risk of producing unbalanced gametes
 In both cases,
individual has one
inverted
chromosome and
one normal
chromosome
 Paracentric inversions:
crossovers in inversion can cause
inviable gametes
• Crossover in the inverted segments
results in recombinant chromosomes
that are either acentric or dicentric
• Acentric (chromosome fragment, no
centromere)
– Cannot attach a spindle – randomly
segregate at meiosis, but cannot segregate
at mitosis
– Usually early pregnancy loss
• Dicentric (two centromeres)
– Forms a dicentric bridge during meiosis,
which breaks as the two centromeres are
pulled further apart
– Usually early pregnancy loss
 Pericentric inversions:
crossovers in inversion can cause
inviable gametes
• Crossover within inversion loop results in
recombinant chromosomes with
complementary duplications / deletions
• No acentric fragments or dicentric bridges
produced
• Recombinant chromosomes have too many
copies of some genes and no copies of
others; so gametes that receive
recombinant chromosomes cannot produce
viable progeny
• The larger the inversion, the more likely
crossovers will occurs, leading to gametes
with duplication/deletion
 Ring chromosomes – rare
and severe
• Break occurs on each arm of a
chromosome leaving two sticky ends
that reunite as a ring
• Often involves the loss of the
chromosome ends (two deletions)
• Very unstable during mitosis
• Survivors have severe mental
retardation
 Iso-chromosomes: lose one arm
and duplicate the other – usually
the X
• Loss of one arm of a chromosome and duplication
of the other
– Unbalanced duplication / deletion
• Accounts for 15% of cases of Turner’s syndrome

Mixoploidy – Mosaicism
A mix of two genotypes
• Mosacism – presence of two or more cell types
differing in genetic composition but derived
from a single zygote
• Usually caused by non-disjunction in an early
embryonic mitotic division
• Accounts for 1-2% of all cases of Down
The earlier the occurrence of disjunction, the more severe
the effects
 Mixoploidy – Chimerism
A mix of two embryos
• Presence of two different cell lines
derived from fusion of two zygotes
• Dispermic chimeras
– Double fertilization
– If zyogotes are different sexes, a true
hermaphrodite forms! (XX / XY karyotype)
• Blood chimeras
– Exchance of blood cells between non-
identical twins via placenta
– This can happen because immune system
hasn’t fully developed at that stage
 Stuff I’ve missed…
• In reciprocal translocation
– 2:2 segregation = normal, balanced,
unbalanced, unbalanced
– 3:1 segregation = unbalanced, tertiary
trisomy
Sex chromosome
disorders
 Sex chromosomes
• Presence of SRY gene on the Y chromosome causes human
embryo to develop as a male
– SRY gene encodes a protein that binds to DNA and causes a sharp bend in
the molecule. This alteration of DNA structure affects the expression of
other genes that encode testis formation
– There have been rare cases of XX males with the SRY gene attached to one
of the X chromosomes! (also XY females who lack the SRY gene in their Y
chromosome)
• X and Y share small homologous pseudoautosomal regions
required for chromosome pairing which contains some genes
• Genes in pseudoautosomal regions are not subject to X
inactivation
 X chromosome inactivation
Dosage compensation
• X chromosomes have approx. 1000 genes
• Dosage imbalance is corrected by dosage
compensation
– Otherwise, females would be producing twice as
much gene product and protein concentration
(which plays a critical role in development) would
be affected
• Achieved by random inactivation of one of two
X chromosomes in each cell early in female
development
• Inactive state is propagated to all progeny cells
• Inactivated chromosome is called a Barr body
– Darkly stained, highly condensed structure
• Most genes on the inactivated chromosomes
are silenced
 If a female is heterozygous for a recessive allele X-linked
disorder, she will be mosaic for the disorder (may reduce
severity) and can make the disorder harder to diagnose

Cells that have inactivated the normal allele may have a

selective advantage, and not be 50:50
i.e. Duchenne Muscular Dystrophy

Female cell
w/
Barr body

Male cell w/o Barr

body
 The Tortoise
Shell Cat

Once an X chromosome becomes inactive in a cell, it

remains inactivated and is inactive in all somatic cells
that descend from the cell. Thus, neighboring cells
tend to have the same X chromosome inactivated,
producing a patchy
pattern (mosaic) for the expression of an X linked
characteristic.
I regret not attending The particular
this lecture because X chance
I missed the rare that remains activefame
of getting ephemeral is afor correcting a
matter of chance
lecturer 
Lecturer says “when you see this type of cat, you can impress people at parties by saying, if a cat looks like
this , it MUST be a female”
 Some regions on the X
chromosome are not
•
inactivated
Approx. 200 X chromosome genes remain active
– It’s probably because of these that patients with say Turner
syndrome differ from normal females even despite the dosage
compensation… or something might be happening in the short
period of development where all X chromosomes are active
• XIST (X inactive-specific transcript) gene required for
inactivation
– Mechanism not fully understood, but entails the addition of
methyl groups (-CH3) to the DNA
– Only one copy is expressed, and it continues to be expressed
during inactivation
– XIST does not encode a protein; it produced an RNA molecule
that binds to the inactivated X chromosome – this prevents the
attachment of other proteins that participate in transcription
• Genes in the pseudoautosomal region (also found on Y)
• Genes for which gene dosage is not an issue (may be genes
which feminize)
 Klinefelter Syndrome
(47,XXY – male)
• Can also be XXXY, XXXXY, XXYY
– More Xs -> greater degree of mental
retardation
• Arises by non-disjunction, thus the
additional X chromosome is equally likely to
be maternally or paternally derived
• Phenotype
– Individuals are slightly taller than average
– Sterile
– Slightly lower IQ
• Testosterone treatment can improve 2nd
degree sexual characteristics
 Turner Syndrome (45,X or
45,XO – female)
• Generally arises from meiotic non-disjunction
• High fetal mortality rate
• Infertile (unless they have the mosaic 46XX/45X – mitotic
non-disjunction)
• Slightly lower IQ
• Estrogen treatment can improve 2nd degree sexual
characteristics and prevent osteoporosis
• IVF treatment with donor cell may allow patient to conceive
as they still have a normal womb
• Phenotype
– Immature secondary sex characteristics
– Shorter than normal
– Broad chest
– Folds of skin on the neck
– Coarction of the aorta
 XXX females (47,XXX) and XYY
males (47,XYY)
• Caused by extra
chromosome from non-
disjunction
• Phenotype
– Occasional behavioral
problems
– Mild reduction in IQ
• Normal fertility as
additional chromosomes
does not pair during
meiosis, is subsequently
lost and therefore the
condition is not passed
on
 XXX and dosage
compensation
• In triploidy (69,XXX), cells randomly
contain 1 or 2 Barr bodies
• Autosome: X ratio is abnormal and
variable – lethal

• In trisomy (47,XXX), cells contain 2

Barr bodies
• Autosome: X ratio is normal –
phenotype is very mild
Trinucleotide Repeat Disease /
Disorder
• Changes to a gene i.e. missense mutations are stably
inherited
• Structural alterations to the chromosome are
sometimes stably inherited
• Trinucleotide repeat expansions are NOT stably
inherited
– Several genes are known to contain regions of
trinucleotide repeats. The number of repeats varies from
person to person in the general population, but within
the normal range, these repeats are stably repeated.
When the number of repeats is increased beyond the
normal range, this region becomes unstable with a
tendency to increase in size when transmitted to
offspring
– In some conditions, there’s a clear distinction between
normal and pathological alleles. In others, the expanded
alleles may act either as premutations (no phenotypic
effects) or as full pathological mutations
– Premutations can -> Mutations as they can increase in
 Fragile X syndrome
A trinucleotide repeat disorder

• Caused by a mutation in a single gene

on the X chromosome
• Phenotype
– High forehead, large jaw, learning
difficulties
• Female carriers sometimes show some
facial features
• A fragile X contains a ‘fragile site’ at
Xq27-Xq28 that tends to break in
cultured cells that are starved for DNA
precursors, such as nucleotides
• Mutation causes trinucleotide
expansion of CGG nucleotide repeat in
Linkage, Recombination
and Genetic Mapping
 Crossing over produces recombinant
chromosomes
• Linkage can be altered during gamete
formation by crossing over
• New combination of alleles generated – genetic
recombination
• Same allele combination as parents (of the F1)
= parental gametes
• New combination of alleles = recombinant (or
non-parental) gametes
– Involves a physical exchange between homologous
chromosomes
• If two genes lie close together on the same
chromosome, they do not assort independently,
therefore independent assortment ratios will
not be observed
 Recall

Crossing over takes place in meiosis

and is responsible for recombination
– it breaks up associations of genes
imposed by linkage
Linkage between genes causes them to be inherited
together and reduces recombination; crossing-over breaks
up the association of such genes. In a testcross for two
linked genes, each crossover produces two recombinant
gametes and two non-recombinant gametes.
The frequency of recombinant gametes is half the frequency
of the crossing over, and the maximum frequency of
recombinant gametes is 50%

Crossing over produces half non-recombinant games and half

recombinant gametes
 With linked genes and some crossing over,
we observe inheritance patterns that deviate
from Mendel’s 2nd law

• Was Mendel wrong? Nah

– Recombination is the sorting of alleles
into new combinations.
– InTERchromosomal recombination,
produced by independent assortment, is
the sorting of alleles on different
chromosomes into new combinations
– InTRAchromosomal recombination,
produced by crossing over, is the sorting
of alleles on the same chromosome into
 Physical basis of recombination
Creighton and McClintock’s study on
corn
Studied the inheritance of two traits in corn
determined by genes on chromosome 9: at one
locus, a dominant allele (C) produced colored
kernels, recessive alleles (c) produced colorless
kernels
Wx – starchy kernels ; wx – waxy kernels

Homozygous for
colorless and
heterozygous for waxy
 Gene mapping with Recombination
Frequencies
• Physical distance between genes on a chromosome are
related to the rates of recombination
– The further apart the genes are, the more likely they are to
crossover
• Genetic maps = chromosome maps calculated by using
recombination frequencies
– Distances on genetics maps are measured in centimorgans
(cM) or map units (m.u. 1 cM = 1 m.u.)
• Genetic distances measured with recombination rates are
approximately additive
– i.e. if the distance from gene A to gene B is 5 m.u. and the
distance from gene B to gene C is 10 m.u., the distance from
gene A to gene C is 15 m.u. (= recombination frequency of
15%)
or
Double crossovers make long distances
inaccurate
• A double crossover arises when two separate
crossover events take place between the same
two loci
– Single crossover just switches the alleles on the
homologous chromosome, producing combinations
of alleles that were not present on the original
parental chromosomes
• The further apart the two loci are, the fewer the
recombinants observed compared with the
number expected
– Genes very far apart on the same chromosome act
as though they’re on separate chromosomes,
hence appear to segregate independently
• The second crossover between the same two
genes reverses the effects of the first, restoring
the original parental combination of alleles
– This is why recombination frequencies will be
underestimated
– Makes it harder to distinguish it between progeny
 Why generate genetic
maps
• Allows us to determine whether
human mutations affect different
genes or not
• We can identify genes using their
map position
– i.e. Cystic fibrosis gene
• It can enhance our ability to predict
inheritance patters
• Generating a high res. Genetic map
is the first step in sequencing a
genome
Gene mapping in humans
• Humans have 1-2 recombination events per pair of
chromosomes in meiosis I, total approx. 40
• 1 cM approx. = 1000kb
• Relationship between map units and physical distance is
not entirely linear
• Recombination events are rare close to centromeres ;
occurs more often in female meiosis

• Genetic mapping in human genes hampered by the inability

to perform desired crosses and the small number of
progeny in most human families
• Geneticists are restricted to analyses of pedigrees
– Have to combine data from many families and calculate the
odds of linkage (LOD score – calculation of the most likely
degree degree of linkage)
• Make use of molecular markers, mostly consisting of RFLPs
(restriction fragment length polymorphisms)
– Cosegregation of two or more markers is studied and map
distances are based on the rates of recombination between the
Genetic linkage and
mapping
 Trihybrid crosses
• A more efficient mapping technique than
dihybrid crosses
– Numerous dihybrid crosses must be carried out to
establish the order of genes and because double
crossovers are missed
• For each locus, two types of progeny will be
produced: progeny that are heterozygous,
displaying the dominant trait, and progeny that
are homozygous, displaying the recessive trait
– With two classes of progeny possible for each of the
three loci, there will be 2^3 = 8 classes of
phenotypes possible
• In test-cross progeny, phenotypes reflect
genotypes of gametes of F1 parent (two most
numerous phenotypes will be that of the
parents’)
3 types of crossover can take place among three
linked loci

Non-
Recombinant
Recombinant
Recombinant
Non-
Recombinant
 Determining gene order
• Method 1
– Consider two genes at a time and determine
the map distance between them
– Divide number of recombinants from all
crossovers (smaller numbers) by the total
number of progeny tested
– i.e. 10% recombinant frequency corresponds to
map distance of 10 m.u. (cM)
– Map distance between the two outer loci may
be less than the sum of the two internal
regions, this is due to double crossovers
– Double the map distance for double crossovers
(usually smallest numbers) to resolve this
 Determining gene order
• Method 2
– First determine which progeny are the non-recombinants, they will be
the two most numerous classes of progeny
– Identify the double crossover progeny, almost always the least-
numerous phenotypes (because the probability of a double crossover is
always less than the probability of a single crossover)
– The locus with differing gene in the double crossover progeny is the
locus in the middle
– i.e. our double crossover recombinants have the following:
(st+ e+ ss) and (st e ss+)
Three possible gene orders and the types of progeny produces by the
double crossover are:
 Determining gene order
• Method 2
– First determine which progeny are the non-recombinants, they will be
the two most numerous classes of progeny
– Identify the double crossover progeny, almost always the least-
numerous phenotypes (because the probability of a double crossover is
always less than the probability of a single crossover)
– The locus with differing gene in the double crossover progeny is the
locus in the middle
– i.e. our double crossover recombinants have the following:
(st+ e+ ss) and (st e ss+)
Three possible gene orders and the types of progeny produces by the
double crossover are:
Probability of double
crossover = (st-ss
recombination frequency) x
(ss-e recombination
frequency)
Here’s our gene order!
 Interference messes with double
recombination
• Interference: degree to which one crossover
interferes with additional crossovers in the
same region
– 1 minus coefficient of coincidence
– i.e. a value of 0.4 tells us that 40% of the double
crossover progeny expected will not be observed
because of interference. Value of 1 would indicate
that no double crossover progeny are observed
– A value of say -0.3 means that more double-
crossover progeny appear than expected, which
happens when a crossover increases the probability
of another crossover occurring nearby (coefficient
of coincidence > 1) – negative interference is rare
• Coefficient of coincidence: ratio of observed
double crossovers to expected double
crossovers
 Q and A 2 from Griffiths

Just draw a Punnett square and you’ll see…

 Chromosomal inversions
affect recombination and
fertility
• Heterozygote carriers of inversions have
reduced fertility due to effect of crossing over
within the inversions
– Homozygotes are fertile
• Crossing over within a pericentric (exchange
over centromere) inversion – duplications and
deletions
• Crossing over within a paracentric inversion –
dicentric and acentric chromosomes
• For genes within the inversions, no
recombinants will ever be seen in the progeny
• There is no looping in meiosis, crossing over
occurs normally and all gametes carry the
inverted chromosme
Molecular Mapping
 Molecular markers can be
used for linkage mapping
• Facilitates examination of variations
in DNA itself (even if it is not a gene)
• Genetic mapping of the loci of genes
using classical mapping requires
alleles that give phenotypic
differences
 Single Nucleotide
Polymorphisms (SNPs)
• Simples variant of a DNA sequence is a one base pair
difference (SNP)
– Polymorphic DNA marker
• Sometimes it will create a difference in ability of a
restriction enzyme to cut the surrounding sequence
– Even if only one base is different, the sequence is not
cut
• Good for mapping because an SNP occurs about once
every 100bp in a human genome
– Can generate high resolution genetic maps
• When a SNP is physically close to a disease-causing
locus, it will tend to be inherited along with the
disease-causing allele. Thus the SNP marks the
location of a genetic locus that causes the disease
• A SNP can also be useful for determining family
relationships—most SNPs are unique within a
population, having arisen only once by mutation. Thus
the presence of the same SNP in two persons often
indicates that they have a common ancestor
 Restriction Fragment
Length Polymorphisms
•
(RFLPs)
RFLPs are polymorphisms in the patterns of
fragments produced when DNA molecules are
cut with the same restriction enzyme
• Provide a large number of genetic markers that
can be used in mapping
• If DNA from two persons is cut with the same
restriction enzyme and different patterns of
fragments are produced, these persons must
posses differences in their DNA sequence
• RFLPs are detected restriction enzymes (RE)
digestion followed by Southern Blot OR by
polymerase chain reaction (PCR) amplification
followed by RE digestion and agarose gel
electrophoresis
• If the disease and the RFLP are inherited
together, they must be physically linked
Recall
 (a) Restriction fragment length polymorphisms can be
used to detect linkage

In this pedigree, the father and half of the children are affected (red circles and
squares) with Huntington disease (autosomal dominant disease). The father is
heterozygous (Hh) and will pass the chromosome with the Huntington gene to
approximately half of his offspring. The father is also heterozygous for RFLP alleles A
and C; each child receives one of these two alleles from the father. The mother is
homozygous for RFLP allele B, so all children receive the B allele from her
(a) In this case, there is no correspondence between the inheritance of the RFLP
allele and inheritance of the disease—children with the disease are just as likely to
carry the A allele as they are the C allele. Thus the disease gene and RFLP alleles
segregate independently and are not closely linked
(b) In this case, there is a close correspondence between the inheritance of the RFLP
alleles and the presence of the disease—every child who inherits the C allele from
 Simple Sequence Length
Polymorphisms (SSLPs)
• A variable number of copies of a short
sequences occurring in tandem repeats
• Used commonly in DNA fingerprinting to
detect genetic differences among people
• Also called Mini- and Micro- satellite
markers
– Mini-satellite markers are based on variation in
the number of tandem repeats of a repeating
unit from 15 – 100 nucleotides long
– Micro-satellite markers based on even simpler
sequence, usually dinucleotide repeats (VNTR)
• Detected by gel electrophoresis followed by
Southern hybridization, using the repeat as
a probe OR PCR, using sequences on each
side of the repeat as primers followed by gel
Human pedigree showing segregation of VNTR
alleles. Six alleles (1–6) are present in the pedigree,
but any one person can have only one allele (if
homozygous) or two alleles (if heterozygous)
 Why are SSLPs good for
mapping?
• Satellites scattered throughout the
genomes, occurs once every
10,000bp in humans (so roughly 3
million SNPs in the human genome)
• Can often identify both alleles of an
individual
• Ideal for DNA profiling
• Downside is that there are not as
many SSLPs as SNPs
How DNA markers are used
in human gene mapping
• Can test of DNA markers are linked to
each other
• Can generate a genetic map
– the human one has 100s of 1000s of DNA
markers
• Can use these markers to map human
disease genes – using multiple
pedigrees to gain sufficient information
• I.e. Huntingtons Disease
– Mapped using molecular markers, found to
be closely linked to a marker on 4p. 10
years later the gene was cloned
 How are DNA markers
made / discovered?
• Detection is by trial and error
• Process:
– Isolate genomic DNA from many
members of a population and run on a
Southern blot
– Probe with many different random
probes (i.e. from a genomic library); by
chance, some will detect a
polymorphism
– OR, try many different random PCR
primers; by chance, some will detect a
SNP or satellite polymorphism
 Using molecular mapping to clone
human genes
• If a gene is known only by its
mutant phenotype, the next
stage is to identify the gene:
– In chromosome walking, a
gene is first mapped in
relation to a previously cloned
gene. A probe made from one
end of the cloned gene is
used to find an overlapping
clone, which is then used to
find another overlapping
clone. In this way, it is
possible to walk down the
chromosome to the gene of
interest
– The candidate is the gene of
interest if it is
• Never separated from the
disease phenotype by crossing
over
• Expressed in tissues affected
 Applications of genetic
mapping
• High res. Genetic map of DNA
markers is the essential starting
point for a genome sequencing
project
• A gene is defined by its map position
which can be used to determine
whether a disorder is caused by the
one gene, or by different genes in
different pedigrees
DNA profiling
 DNA fingerprinting
• Involves profiling the individual’s genetic
information from DNA test results of genetic
markers, placed in highly variable regions of the
genome, in order to locate characteristics
unique to the individual
• Most commonly used in forensics and criminal
investigation
– PCR can be used to amplify the DNA if there’s too
little for testing
– PCR is extremely sensitive and will amplify intact
DNA; degraded DNA will not amplify
• Identical twins are monozygotic and fraternal
twins are dizygotic
• Possible because:
– DNA sequence is stable and sequence remains the
same
– All progeny have the same DNA (unless mutations
 DNA fingerprinting
Basically… each DNA sample is cut with one or more restriction
enzymes, and the resulting DNA fragments are separated by gel
electrophoresis. The fragments in the gel are denatured and
transferred to nitrocellulose paper by Southern blotting. One or
more radioactive probes is then hybridized to the nitrocellulose
and detected by autoradiography. In a crime scene, the patterns
of bands produced by DNA from the sample is then compared
with patterns produced by DNA from the suspects
 Genetic diversity in
humans
• 3 billion base pairs in the human
genome
– Individuals are 99.9% identical at the
DNA sequence level
• Differences occur in both coding
(some which can be observed at the
phenotypic level) and non-coding
regions (require specialized
techniques to detect them)
 DNA Polymorphisms
• Difference in DNA sequence at the same
locus
– Variation occurs too frequently to be labeled as
a mutation
– >1% of the population
– When studied using the Southern blot, we may
see restriction fragments complementary to a
probe that differ in size among individuals.
These differences arise from differences in the
location of restriction sites along the DNA
• Single nucleotide polymorphisms (SNPs)
• Mini- and Micro-satellites
• Insertions and deletions
 DNA Polymorphisms
• Simple sequence length polymorphisms (SSLPs)
• Microsatellite (CA repeats)
– 2-10 bp repeats
– Simple sequence repeats
– Difference in number of microsatellites at any one site
between individuals in highly polymorphic and these have
shown to be inherited in a Mendelian codominant manner
• Minisatellite
– 10 – 100 bp repeats
– Clustered repeats of specific DNA sequences
– Variable Number of Tandem Repeats (VNTR)
• This same repeat of around 10bp is usually in many places in the
genome
• Highly polymorphic compared to RFLPs, which is due to the presence of
variable number of tandem repeats over a short DNA sequence that
has been inherited in a Mendelian fasion
• Many different alleles and lots of polymorphisms
• Co-dominant
 Problems with DNA
fingerprinting (multi locus)
using minisatellites
• Southern blot requires large amounts
of DNA
• DNA must be intact
• Cannot tell which pairs of bands
represent alleles
 Potential sources of
error
• False inclusion
– Relatives likely to share alleles
– Some alleles more frequent in specific
populations
• False exclusion
– Contamination or mixed source of DNA
– Technical problem such as ‘allele drop-
out’
 Multilocus
Single locus
Cannot determine which allele comes from
Partially degraded DNA can be used
which locus
 Polymorphisms in
mitochondrial DNA and Y
chromosome DNA
• Y chromosome DNA
– Passes to male children from father only
– No recombination
– Polymorphisms can be followed through
many generations
• Mitochondrial DNA
– Passed to children from mother only
– No recombination
– Polymorphisms can be followed through
many generations
 Developmental Genetics
Content in this lecture was straightforward, the notes are mostly
copied off lecture notes
 Dysmorphology
Study of congenital birth defects that alter the shape of one or more
body parts

• Malformation, primary structural defect of

an organ or part of an organ. Their presence
suggests that the early development of a
particular tissue or organ has been arrested
or misdirected
• Intrinsic genetic abnormality
• Common examples of malformations
include congenital heart disease, cleft lip
and neural tube defects (i.e. anencephaly)
• Most malformations involving only a single
organ show multi-factorial inheritance,
implying an interaction of many genes with
environmental factors
 Dysmorphology
Study of congenital birth defects that alter the shape of one or more
body parts

• Deformation, defect which results

from an abnormal mechanical force
which distorts an otherwise normal
structure, i.e. dislocation of the hip
which can be caused by lack of
amniotic fluid or intra-uterine
crowding due to twinning or a
structurally abnormal uterus
• Usually occur late in pregnancy
• Generally resolved soon after birth
 Dysmorphology
Study of congenital birth defects that alter the shape of one or more
body parts

• Disruptions, abnormal structure of an

organ or tissue as a result of external
factors (such as ischemia – restriction of
blood supply, infection and trauma)
disturbing the normal developmental
process
• Not genetic, although occasionally,
genetic factors can predispose to
disruptive events
– I.e. small proportion of amniotic bands are
caused by an underlying, genetically
determined defect in collagen which
weakens the amnion, making it more liable
to tear or rupture spontaneously
 Major causes of
malformations
• 25% autosomal trisomies
• 20% single gene mutation
– i.e. achondroplasia
• 50% multifactorial
– I.e. cleft lip, congenital heart defects
• 5% environmental teratogens
– Drugs, infections, chemicals, radiation
 Plieotropy
• Single underlying cause results in
abnormalities in more than one system
of the body
• A syndrome – multiple abnormalities in
parallel
– Branchial arch defects and renal defects
• A sequence – only one organ system is
affected, with secondary pleiotropic
effects
– I.e. Robin sequence, where the mutant
collagen causes primary defect in jaw
Developmental Genetics
• Study of the cellular processes
– Division
– Migration
– Differentiation
– Apoptosis
 Mosaic development
• Later in development, some cells
have already developed distinct fates
– the embryo only appears to be
homogenous
• Loss of part an embryo after this
point could lead to failure of
development
• Conjoined twins – if cleavage occurs
after progression from regulative
mosaic development, two fetuses
share body structures / organs
 Fate, specification and
determination
• Differentiation – process where cells
undergo a series of discrete steps (acquiring
distinct functions / attributes) until they
reach a final fate
– Stepwise acquisition of a stable cellular
phenotype of gene expression
• Specification – cell acquires specific
characteristics, but it can still be influenced
by environmental cues such as signaling
molecules, neighboring cells, positional
information
• Determination – cell has irreversibly
committed to acquire final traits / attributes
– i.e. nerve cells making synaptic proteins, RBCs
making hemoglobin
 Homeobox (HOX) gene
system
Plays a crucial role in early morphogenesis
• These genes were shown to be transcription
factors that determine segment identity and
developmental fate along an axis
• In drosophila, mutations in these genes
have resulted in major structural
abnormalities, such as development of a leg
instead of an antenna
• 38 HOX genes in mammals; most mutations
are lethal
– I.e. mutation in HOXD13 will result in
synpolydactylyl, resulting in an extra digit
• Order of the HOX gene parallels:
– Position in the embryo in which that gene is
expressed
– The time in development when it is expressed
 Antennapedia, left is the normal
fruit fly, right is the antennapedia
mutant
Pattern – positional cues
• Cell-to-cell communication conveys positional information
– Can be direct or via short/long-range signals
– In a concentration dependent manner, Hedgehog proteins play
a major role in the development of the ventral neural tube with
loss-of-function mutations resulting in a serious and often
lethal malformations
• Signaling cells produce ligands which bind to the cell
surface receptors leading to transmission of a signal in the
receiving cell
– i.e. fibroblast growth factors (receptors) FGF(R)
– 23 known human FGFs – mutation causes diseases such as
achondroplasia

Arrows indicate the location of mutations that lead to

achondroplasia
 Signaling Centers
• Diffusible ligands / signals produced
at signaling centers act as sources of
positional information
• Cells can detect how far from the
signal source they are and which
direction the signal source lies
 Immunogenetics
Content in this lecture was straightforward, the notes are just copied
of lecture notes
 The immune system
• Protection mechanisms:
– Physical barriers
• skin, mucous membranes, respiratory cilia
– Immediate general response – innate immune
response
• Inflammation, phagocytes, cytokines
– Specific acquired defense that identifies self-
antigens from foreign antigens
• Antigens – substances that elicit immune
reaction – proteins or parts of proteins often on
the surface of bacteria, viruses, pollens etc…
• Reacts against a foreign substance, destroying
it
• Remembers a foreign substance and responds
more strongly to a later exposure
 Acquired immune
•
response
Third line of defense
• Slow to respond as it must be stimulated
• Macrophages – large lymphocytes that engulf and digest foreign
substances
• B-cells – produce antibody proteins and are activated by T-cells in the
humoral immune response
– Antibodies are proteins that circulate in the blood and other body
fluids, binding to specific antigens and marking them for destruction by
phagocytic cells
• T-cells
– After a pathogen such as a virus has infected a host cell, some viral
antigens appear on the cell surface. Proteins, called T-cell receptors, on
the surfaces of T cells bind to these antigens and mark the infected cell
for destruction. T-cell receptors must simultaneously bind a foreign
antigen and a self-antigen called a major histocompatibility complex
(MHC) antigen on the cell surface. Not all T cells attack cells having
foreign antigens; some help regulate immune responses, providing
communication among different components of the immune system
– Killer T-cells – do not make antibodies, but destroy antigen carriers by
direct cell-to-cell contact
 Antibodies
IgM IgD IgE IgG IgA

• Immunoglobulins (Ig), consisting of four

polypeptide chains
– two identical heavy chains liked by
disulfide bonds + two identical light chains
– Each chain has a constant region and a
variable region (where there are variations
in amino acid sequence)
– The variable regions of both heavy and
light chains make up the antigen-binding
region and specify the type of antigen that
the antibody can bind
 Variable regions of
Antibodies
• Amino acids in the variable regions of
different amino acids differ from
each other
– Variation is restricted to a few
subregions called the hypervariable
regions
– These regions form the antigen binding
cavity
– Different antibodies are characterized
by their antigen-binding characteristics
 Generation of antibody
diversity
Immune system capable of making 10^15 antibody molecules, yet human
genome only contains 3 x 10^9 base pairs, how’s this possible?
• Antibody GENES are composed of
segments. There are a number of
copies of each type of segment, each
differing slightly from the others. In the
maturation of a lymphocyte, the
segments are joined to create an
immunoglobulin gene. The particular
copy of each segment used is random
and, because there are multiple copies
of each type, there are many possible
combinations of the segments. A
limited number of segments can
therefore encode a huge diversity of
antibodies.
 Generation of antibody
diversity
Immune system capable of making 10^15 antibody molecules, yet human
genome only contains 3 x 10^9 base pairs, how’s this possible?

• Somatic recombination
– Permanent change at DNA level
– B and T cells use alternate RNA splicing
and somatic recombination to generate
diversity
– Diversity generated by changing the
pieces of these genes
– Heavy chains have 4 sections, V, D, J
and C regions
– Kappa and lambda light chains have 3
sections V, J and C
Somatic recombination producing variation in the
heavy chain
 Immature B-cells
Clonal theory
• Each B cell makes one type
of antibody
• Contains a heavy chain and
either a kappa or lambda
chain
• C region of the heavy
region determine antibody
class
• Variable regions of
antibody determine antigen
specificity…
• Each cell has different
arrangement of V-(D)-J
 Preprogrammed B-cells
• If antigen is present:
– It binds to the antibody and is taken up by
cells
– Antigen is processed and peptide displayed
on cell surface (with MHC protein)
– Altered MHC is recognized by T cells
• The MHC genes encode proteins that provide
identity to the cells of each individual organism.
To bring about an immune response, a T-cell
receptor must simultaneously bind both a
histocompatibility (self) antigen and a specific
foreign antigen
– T cells stimulates B cell to differentiate
causing clonal expansion of the antibody
secreting cell
Antibody diversity by class
switching
• Class switching generates the
different classes of antibody, all with
the same variable domains as the
original antibody generated by V(D)J
recombination, but with distinct
constant domains in their heavy
chains
• Naïve mature B-cells produce both
IgM and IgD with identical antigen
binding regions
 Classes of antibody
Defined by heavy chain C region

• IgA – Milk, saliva, urine

– protects against pathogens at point of
entry into cell
• IgD - on B cells in blood
– stimulates B cells to make other types of
antibodies
• IgE - in secretion with IgA and in mast
cells
– cause mast cells to secrete allergy
mediators
• IgG - blood plasma (can pass to fetus)
– especially involved in secondary immune
response
 Antibody diversity by somatic
hypermutation
• V-(D)-J recombination (+ alternate
splicing) creates initial antibody
diversity allowing recognition of various
antigens
• Base substitutions occur at high rate in
V-(D)-J DNA during differentiation of
activated B cells to plasma cells
• Especially high mutation rate in
hypervariable regions
• Process leads to variant antibodies with
an enhanced ability to recognize and
bind a specific foreign antigen
 T cell response
• Involved in cell-mediated responses
• Important for combating viral
infections
• Allows recognition of self from non-
self

• T cell receptors
– Structurally similar to
immunoglobulins
– Like the genes that encode
antibodies, the genes for the T-cell-
receptor chains consist of segments
that undergo somatic
recombination, generating an
enormous diversity of antigen-
binding sites
– Don’t undergo somatic
hypermuation
 Major Histocompatibility
Complex (MHC)
• Important for recognizing
self from non-self
• Required for presenting
antigen on B cells
• Required for stimulating
T cells
• Important antigens in
transplantation
– Rejection of donor tissue
due to non-self antigens