Genetics notes - MED 103 - Alaa Al Hurini

CDK —> Protein + phosphate to it

What do they check for? And controlled by what?

G1 checks for:
cell size
Nutrients
Growth factors
DNA damage
Controlled by:
G1 Cdks-cyclin (their levels vary with the cycle)

G2 checks for:
Cell size
DNA damage

Controlled by:
Maturation promoting factor (MPF)
CDK + Cyclin make Actv. MPF

MPF Works by:

Phosphorylating + activating proteins involved in

M checks for:
Chromosome attachment to spindle

What regulates the cell cycle and how?

Protein kinases. Cycle dependent kinases

 Internal protein regulators if there is damage or issue:

p53—> blocks cell cycle if DNA damaged, if severe then leads to apoptosis.
(Tumour suppressor gene)
p27—> Binds to cyclin + CDK blocks entry into S phase.

Four classes of cyclins :

I. G1-cyclins
II. G1/S-cyclins
III. S-cyclins
IV. M-cyclins

External protein regulators:

Will signal to stop or speed up growth. Growth factors most IMP external regulators. Also,
when a neighbour cell has a molecule on surface it will cause cells to slow or stop cycle.

Mitosis
Interphase:

• Chromatin and nucleus visible

Prophase:

• Chromatin condenses
• Spindle fibers grow
• Centrioles migrate to opposite ends.

Metaphase:

• Chromosome on the equator.

• Spindle fibers attached to centromeres pf chromosomes
• Nuclear membrane disappeared.

Anaphase:

• Centromeres split
• Sis chromatids separate to each pole.

Telophase:

• Chromosome thin, long, faded low-key

• Nuclear membrane reforms
• Neucleolus reappears
• Cell division almost done

Ends with Cytokinesis—> Cytoplasmic division

 4 sperm cells are produced

from each primary
spermatocyte.
Okay on to Meiosis now
Meiosis I: Reduces number of chromosomes to half.
Difference between Meiosis I and II will be listed down below.
- Prophase I is the longest an most complex and is further divided into 5 phases
- Metaphase I is the shortest
I. Leptotene: Chromosomes condense
II. Zygotene: Chromosomes super close and pair—>form synapsis
III. Pachytene: crossing-over. Expected crossing over is when they cross in
syneptonemal complexes areas.
IV. Diplotene: Formation of Chiasmata, which is the site of crossing over
V. Diakinesis: Terminalisation of the chiasmata. Maximal condensation.

Metaphase I: independent assortment will occur when tetrad line up of the

Tetrad
metaphase plate. Formula 2^n=4

Non-disjunction is when the chromosomes fail to separate. This leads to

Aneuploidy

- Chromosomes are not seen in an active nucleus because of their high water
content but they are seen in cell division.
- Anaphase chromosomes are seen as smallest but metaphase they are
seen as very thick, quite short and well spread. Dis why chromosomes
measurements are taken during mitotic metaphase.

Identifying a chromosome:
• Size stoic
• Giemsa - the banding pattern (G-
banding)
• Shape - position of centromere:

The centromere is sometimes

called the “primary constriction”

Acrocentric chromosomes have a

secondary constriction where there are thin strands of chromatin coming out with
non coding DNA That is called chromosomal satellites. The secondary constriction
contains the loci for the ribosomal RNA (rRNA) genes, (the Nucleolar Organizing
Region).

 A 1-3
Largest
Metacentric + Submetacentric
B4-5
Large
Submetacentric

C 6 -12 & X
V similar
Medium + arranged in decreasing size
Submetacentric

D 13 -15
Medium
Acrocentric + satellites

E 16 -18
Smaller
Metacentric + Submetacentric

F 19 - 20
Smaller
Metacentric + submetacentric

G 21-22 & Y
Smallest
Acrocentric + satellites (Y no satellites)

- Staining gives us chromosomal bands. Dark it hetero, Light is Euchro

Euchro
Rich in G and C
Active genes
Replicate in early S phase

 Hetero
two groups:
Constitutive: Permanent in hetero.
Facultative: euchromatin taking stain and characteristics of hetero
during some phase dvlpmnt.
Rich in: A and T bases
Few active genes

- Centromeres for segregation of chromatids during meiosis and mitosis

- Telomeres for terminal stability and survival.

Karyotype: a standard arrangement of chormosome pairs in decreasing length.

Levitsky——> said Karyotype is phenotypic appearance of somatic chromo

Idiotype: a diagram representing karyotype of a species, shows all morphology of

chromo.

Trisomies:
Patau’s syndrome
Karyotype: 47,XX,+13 Translocation type der(13;14)(q10;q10)
Incidence: 1/15,000
Symptoms:
Cleft lip + palate
Microcephaly
Microphthalmia (eye small or abnormal)
Polydactyly (more fingers)
Rocker-bottom foot
Umbilical hernia
Renal + heart defects

Edward’s syndrome
Karyotype: 47,XX,+18
Incidence: 1/8000 80% in females
Symptoms:
Failure to thrive
Low set ears
Micrognathia (small jaw)

 Short neck
Overlapping fingers
Prominent occiput
Rocker-bottom foot
Limited hip abduction
Renal malformations + heart defects

Down’s syndrome
Advanced maternal age is grave risk factor (nondisjunction type)
Karyotype:
95% 47,XX,+21.
4% of dem Translocation: (14;21) OR (21,22) rare
(one part usually mom carries the translocation)
1% mosaic
Incidence: 1/700 live births, 1/25 live births mothers >45
Symptoms:
Epicanthic folds (eye fold)
Flat facial profile
Lots of neck skin
Single palmar crease (One line seen on top of palm)
Umbilical hernia
Intestinal stenosis (narrowing) + heart defects
Gap between 1st and 2nd toe.

Kleinfelter’s syndrome
Karyotype: 47,XXY,+23. OR 48,XXXY,(MALE) Cause: non disjunction of
XX homologue
Incidence: 1/500
Symptoms:
Taller than average
Facial hair -ve
Body hair -ve
Gynaecomastia (breasts)
Feminine fat distribution
Osteoporosis
Testicular atrophy

Monosomy:
Turner’s syndrome

 Karyotype: 45,X0
Incidence: 1/2500
Symptoms:
Low hair line POST
Webbed neck
Broad chest + Nipples spaced out
Cubitis valgus
Infertility + amenorrhea
Coarctation of aorta (narrowing)
Pigmented nevi
Peripheral lymphedema at birth

Polyploidy two forms in humans: Tri and tetra (3 & 4)

Triploidy
happens in:
1% conceptuses
20% spontaneous abortions + chromosomal abnormalities.
Few survive to term but die quickly.

(Diploid/triploid mosaics longer survival.)

Autosomal aneuploidy incidence: 1/500

Approximately 27-30% spontaneous abortions
Profound loss of genetic material and lethal
Except a few trisomies (13,18, 21) survive but severe abnormalities.

Sex chromosome aneuploidy incidence: 1:500 live births

They are less severe + compatible with life
Reasons for this: Inactivation of all additional X chromo + small no. of
genes on Y chromo.

Causes of aneuploidy?
1. Nondisjunction (Failed division) in mitosis & Meiosis II ——> mosaicism
Mosaic individuals will manifest phenotypic abnormalities intermediate
of the cell populations.
2. Anaphase lag: 1 homologous chromo or chromatid lags and is left of
nucleus ——> 1 cell monosomy + 1 cell normal

 3. Nondisjunction in meiosis II: homologous pair fails to disjoin.

Xist lyonises or inactivates C chromo

1 X active other is hyperpyknotic
Inactivation random in blastocyst (16th day)

Greater X chromosome the greater likelihood of mental retardation.

Fragile X Syndrome
Mental retardation in
80% of males who carry the abnormal chromosome
Only 30% of females (perhaps due to preferential
inactivation of the abnormal X chromosome).
Unusually large number of repeat nucleotide triplets close to the
tip of the long arm of the X chromosome (Xq27).
Growth abnormalities may occur + severe retardation.
The frequency
1:1000 in males and 1:2000 in females

Mosaicism in sex chromo more common

Turner’s
Early error in mitosis 45,X / 47,XXX mosaic
Later error 45,X/ 46,XX/ 47,XXX

Hardy-weinberg equilibrium

1. Define gene pool

It’s the complete set of unique alleles of every living member of that
species or population.

Large gene pool ——> genetic diversity

Small gene pool——> Low genetic diversity (inbreeding)

 2. Describe Hardy-Weinberg equilibrium formula and its uses.

f(Dom)=p f(Rec)=q —> these are allele frequency P+q=1

The gene frequency and genotype frequency do not change from

generation to generation.

In founding population if frequency A is p and frequency of a is q

then after one generation of random mating (GENOTYPE FIXED)

p 2 (AA) + 2 p q (Aa) + q 2 (aa)

Then:

Cause (a+b)2 OR (p+q)2 = 12

Assumptions of the equilibrium:

I. Large population

II. Random mating

III. No recurrent mutations effecting it

IV. No selection against any phenotype

V. Population does not have in or out migration.

VI. Autosomal locus

3. Calculate gene pool and frequency of genes/alleles in a

population

(2 x homozygote frequency (A or a)) + (1 x heterozygote frequency)

2 x population
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 The frequency of the allele is different than the frequency of the

genotype.

4. Calculate carrier rate using the Hardy-Weinberg equilibrium

formula

p2=AA (carrier) q2= aa 2pq = Aa

5. Explain factors violating the Hardy-Weinberg equilibrium

(balance) leading to changing gene frequency

I. Non random mating

Assortive mating ——> like with like

Inbreeding ——> Close relatives

II. Natural selection

Evolutionary process where fav traits become more common in

generations, and unfav traits become less common.

If these phenotypes have a genetic basis; the genotype for the

fav pheno. Will increase in freq.

III. Mutation (beneficial or random)

Beneficial —-> ability to adapt and evolution.

Random —-> not helpful usually + Dom mut. Are lethal in

utero.

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 IV. Heterozygote advantage

If harmful in homo then maybe advantageous in carrier. E.g.

Thalassemia + Hbs ——protection against malaria

V. Genetic drift and founder effect

Genetic drift ——> changes in frequencies of alleles by

chance rather than Natural selection.

- Seen in isolated population.

- New region may develop new disease OR

express old disease at higher freq.

Founder effect ——> new colony formed by small no.

so loss of genetic variation.

6. Describe the general principles of Mendelian disorders.

They are determined by two copies of same gene, called
alleles, located at same locus on 2 homo chromo.

I. Autosomal gene on 22 autosomes, sex linked gene

located on 23 chromo.

II. Dominant phenotypic trait requires exp. of 1 of alleles.

III. Recessive phenotypic trait demands exp. of both alleles.

IV. Co-dom refers to a situation which both alleles are fully

expressed in a heterozygote. E.g. blood group and
histocompatibility antigens.

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 V. Pleiotropism: single mutant gene with MANY clinical effects

w/ different systems of body. E.g. Marfan syndrome and
sickle cell anaemia.

Marfan syndrome

Mutations ——> FBN1 affects fibrillin 1 (glycoprotein

major component of microfibrils found in the ECM)

Symptoms like:

- Scoliosis OR kyphoscoliosis with kyphosis

- Enlarged aorta (aneurysm)
VI. Genetic heterogeneity: mutations at several loci produces 1
trait or abnormality. E.g. Childhood deafness results from 16
types of AR (autosomal recessive) mutations and Retinitis
pigmentosa.

VII. Polymorphism: Lotta allelic forms from a single gene. E.g.

Blood group and histocompatibility antigens.

7. Classify Mendelian disorders.

Autosomal dominant disorders

Autosomal recessive disorders

X linked disorders —> Recessive or dominant.

8. Explain briefly the transmission of disease/trait in Mendelian

disorders.
Autosomal dominant disorders
HETEROZYGOUS STATE

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 Vertical inheritance
M&F
Affected marries unaffected child has 50% being affected
Autosomal recessive disorders (Largest category of mendelian dis.)
HOMOZYGOUS RECESSIVE
Parents both hetero but normal
Child 1/4 chance being affected. Ratio affected to normal is
1:3
Proband comes usually from a consanguineous marriage.

X-linked disorders
HOMOZYGOUS OR HETERO
Females can be hetero or homo
Males hv 1 X so hemizygous
Most are X-linked recessive
Recessive. E.g. Color blindness

FEW EXCEPTIONS BUT MOSTLY M

An affected M does NOT give to sons but gives ALL

daughters.

Affected Female V rare mum has to be carrier and dad

affected.

Dominant E.g. Vit D resistant rickets

Females affected 2x than males

Affected Hetero F give half of children

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 Affected M give ALL daughters but not sons

9. Enumerate examples of autosomal dominant disorders.

Nervous —> Huntington’s dis

Myotonic dystroph
Neuro bromatosi
Tuberous sclerosis
Urinary —> Polycystic kidney dis
GIT —> Familial polyposis col
Hemopoietic —> Hereditary spherocytosis
Von Willebrands diseas
Skeletal —> Marfan synd
Osteogenesis imperfect
Achondroplasia
Metabolic —> Familial hypercholesterolemi
Acute intermittent porphyria

10. Enumerate examples of autosomal recessive disorders.

Metabolic —> Cystic brosi

14
fi
s

fi
.

 Phenyl ketonuri
Galactosemi
Lysomal storage disorders
Wilson’s dis
Hemopoietic —> Sickle cell anaemia
Thalassemi
Endocrine—> Congenital adrenal hyperplasi
Skeletal —> Ethlers Danlos syndr

Nervous —> Neurogenic muscular atrophies

Friedreich ataxi
Spinal muscular atroph

11. Enumerate examples of X-linked recessive disorders.

Duchene muscular dystrophy Hemophilia A & B
Chronic granulomatous disease. G6PD deficiency
Agammaglobulinemia Wiscot-Aldrich synd.
Diabetes insipidus Lesch-Nyhan synd.
Fragile X syndrome

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.

12. Biochemical and molecular mechanisms

Single gene alter. ——> Abnormal protein OR reduction in
output of protein.
Mutations affect diff stages in protein synthesis
Phenotypic effects of mutation may result directly pr indirectly
in abn. In protein synthesis
Mechanisms of single gene:
1. Defcts in enzyme protein and functions
2. Defcts in membrane receptors and trnsprt protns
3. Alt. in structure, func, and trnsprt protns.
4. Mutations resulting in unusual reaction to drugs.
13. Define the following terms and give examples:
• Penetrance : Likelihood of a characteristic manifesting itself
- Non penetrance can cause a phenotype to skip a
generation. Problems arise from this because a normal
phenotype can possibly have a mutated genotype.
-
• Variable expressivity: a family that has the same disorder may
present with different features. E.g. Neurofibromatosis Type 1.
(Presence of two or more of the various features)
Multiple tumours on the skin and multiple skeletal
deformities

Anticipation: Tendency of some genetic disorder to manifest at an

early age or to increase in severity in the succeeding generations.
E.g. Huntington dis. (Coding) Myotonic dystrophy (Non Cod)
, and fragile X syndr. (Non Cod)

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 - Usually caused by a mutation called a trinucleotide repeat

expansion. E.g. CTG repeat in myotonic dystrophy.
- In some cases the TriN may expand until the gene stops
functioning, this is called complete mutation.
- This expansion causes features of some disorders to
become more severe + age onset decrease with each
successive generation.
- The degree of amplification increases during
gametogenesis ——> influence pattern of inheritance +
Phenotypic manifestations.
FRAGILE X SEEN AS DISCONTINUITY OF STAINING.
Macro-orchridism most apparent symptom.

Parental imprinting (SILENCING) —> indicates that one of

the parental gene copies is inactive while the other is active.
Maternal imprinting > Maternal inactive and paternal
active.
Paternal imprinting > Paternal inactive and maternal
active.
It occurs in the ovum or sperm.

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 Prader-Willi & Angelman syndromes

Del (15)q 11 q13
Prader-willi — paternal deletion

Angelman — Maternal deletion

De Novo mutations: NEW! Some patients with AD disorders do

not have an affected parent. New mutations occur in egg or
sperm. MANY occur in the germ cells of older fathers.
Mosaicism (somatic mosaicism; confined placental mosaicism)
Genetic heterogeneity:

Clinical heterogeneity. MUT in same gene = different disorders

Allelic heterogeneity Multiple MUT in same allele cause disorder
Locus heterogeneity. MUT >1 locus produce phenotype
E.g breast carcinoma. BRCA 1 , BRCA 2

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 Phenocopy: Enviromentally induced non hereditary CLOSELY

resembles a genetically trait.
E.g. Breast cancer BRCA 1 & 2 in fam BUT a member develops
without the mutations.
Parent-of-origin effect: Unusual! Both copies of chromosome 15
are from 1 parent.

COMPLEX DISEASES

• Explain polygenic inheritance in complex

diseases
Many genes, each making only a small contribution to the
final phenotype. E.g. Skin colour

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 • Explain multifactorial disease

Disease controlled by inheritance of many genes with
small additive effects + environmental effects.
The genes and environmental factors affecting a multi-
factorial trait may vary among different individuals
No dom or rece.
Increases the risk of occurrence of same sex relatives and
siblings

• Explain Threshold model with examples

All individuals genetic and environmental factors
(disease related) considered together make a liability.
When the individuals’ liabilities exceed a certain
threshold value, they will have the disease.
Shift of curve to right- more frequency (number) to
the right of the curve
Important model in Qualitative: diseased- not
diseased
Eg. Achondoplasia, cleft palate

• Explain Modifier genes with examples

Genes that have small quantitative effects on the level of
expression of another gene.
E.g. 1. in mice: coat colour controlled by B gene.
B allele conditions black colour and is
dominant to the b allele that produces a brown
coat.

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 Intensity of colour controlled by D gene. At this

gene, Dom D allele controls full colour whereas d
allele controls dilute or faded expression The d
gene does not mask effect of b gene rather
modifies its expression.
E.g. 2. Melanocortin-1 receptor (MC1R) gene
variant- role in skin cancer melanoma. 60% in
Australia heterozygous for MC1R variants
3. Cyclin dependent kinase inhibitor (CDKN2A)-
role in skin cancer melanoma. (50%risk of melanoma)
4. Individuals who are hetero zygotes for both-
together have 85% risk of melanoma
5. Melanocortin-1 receptor (MC1R) gene is
considered to be a low penetrance melanoma gene
as well as a modifier gene for CDKN2A
• State examples of complex disorders
• Adult onset: Hypertension, Diabetes, Epilepsy,
Glaucoma, Ischemic heart disease, Manic depression,
schizophrenia.
• Congenital: Cleft lip/palate, heart defects, dislocation of
hip, Pyloric stenosis, Talipes

PREVENTION
Identification of individuals with genetic susceptibility to
Multifactorial diseases may lead to disease prevention by
manipulation of the non-genetic factors

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