INTERNATIONAL UNIVERSITY FOR
SCIENCE & TECHNOLOGY
GENETICS lecture course
Office N. IUST: 6116
E-mail: a.rahmo@gmail.com
Website:
http://groups.google.com/group/genet
ics-dentistry-iust?hl=ar
Dr. A. Rahmo
PhD. Biochemistry and Molecular biology USC
GENETICS COURSE LECTURES
1- INTRODUCTION
2- MONOGENIC INHERITANCE (ONE GENE)
3- MONOGENIC INHERITANCE (TWO GENES)
4- PEDIGREE ANALYSIS
5- BEYOND CLASSICAL (MENDELIAN) GENETICS
6- EXAM
7-POLYGENIC INHERITANCE
8- CYTOGENETICS
9- MOLECULAR GENETICS OF PROCARYOTES
10- MOLECULAR GENETICS OF EUCARYOTES
11- ONCOGENETICS
12- EXAM
13- TESTING & TREATMENT OF GENETIC DISEASES
14- POPULATION GENETICS
15- REVIEW
MONOGENIC TRAITS
Classical (Mendelian) Genetics
Inheritance of one gene
Genetic Information
• Gene – basic unit of genetic
information. Genes determine the
inherited characters.
• Genome – the collection of genetic
information.
• Chromosomes – storage units of
genes.
• DNA - is a nucleic acid that contains
the genetic instructions specifying the
biological development of all cellular
forms of life
٤
Chromosome Logical Structure
• Locus – location of a gene/marker on
the chromosome.
• Allele – one variant form of a
gene/marker at a particular locus.
Different versions of the
same gene are called
alleles.
Locus1
Possible Alleles: A1,A2
Locus2
Possible Alleles: B1,B2,B3
٥
Human Genome
Most human cells
contain 46 chromosomes:
• 2 sex chromosomes (X,Y):
XY – in males.
XX – in females.
• 22 pairs of chromosomes
named autosomes.
٦
Normal
Male
Normal
Female
Autosomes and Sex Chromosomes
• Chromosomes that determine
gender are called sex chromosomes;
all other chromosomes are called
autosomes.
• Autosomes are homologous pairs.
• Sex chromosomes can be
homologous or non-homologous
pairs .
Sex determination in humans
• Human females have two X
chromosomes, and all their gametes
contain one X chromosome.
• Human males have one X and one Y
chromosome; half their gametes
contain an X chromosome, and the
other half contain a Y chromosome.
• The chromosome carried by the
sperm determines sex in humans.
• Genetic anomalies such as XY
females and XX males can occur
because of chromosomal mutations.
Genotypes
Phenotypes
• At each locus (except for sex chromosomes) there are 2
genes. These constitute the individual’s genotype at
the locus.
PP = homozygous dominant (Capital letter)
Pp = heterozygous
pp = homozygous recessive (small letter)
• The expression of a genotype is termed a phenotype.
For example, hair color, weight, or the presence or
absence of a disease (outward appearance of an
individual).
١٠
Mendel’s 1st Law
Two members of a gene pair segregate from each other into
the gametes, so half the gametes carry one member of the
pair and the other half carry the other member of the pair.
Y/y
y/y
all y
½ y/y
Gamete
production
½y
½ Y/y
½Y
١١
Gamete
production
Principle of Segregation
Two alleles for a gene
segregate during
gamete formation
and are rejoined at
random, one from
each parent, during
fertilization.
SEGREGATION
GAMETES
1n
fertilization
2n
In the diagram above, the dominant allele is represented by _Ţ__and the recessive allele is
represented by _ţ_ .
We can look at which genes may be passed onto
offspring. We do this using a PUNNETTE SQUARES
FATHER
25%
25%
25%
25%
MOTHER
Each square represents a possible offspring. Each PUNNETTE
square is worth 25%. This is because there are 4 squares, and 4
times 25 is 100. We use this to describe the chances of offspring
being a carrier, diseased or normal.
One Locus Inheritance
Female
A|A
Male
Heterozygote: two
different alleles
heterozygote
١٤
1
A|a
2
a|a
3
A| a
4
5
6
a|a
a | a Homozygote: two
identical alleles
homozygote
gene: information for a trait
passed from parent to
offspring.
alleles: alternate forms of a
gene.
homozygous: having 2 of the
same allele.
heterozygous: having 2 different
alleles.
Individuals
carry two
alleles of each gene.
15
Genotype
Mutations in single
genes (often causing loss
of function)
Male
Variants in genes causing
alteration of function
Chromosomal imbalance
causes alteration in gene
dosage
PHENOTYPE APPARENT
Dominant
Heterozygotes with one copy of the altered gene
are affected
Recessive
Homozygotes with two copies of the altered gene are
affected
X-linked recessive
Males with one copy of the altered gene on the
X-chromosome are affected
Male
Dominant vs. Recessive
A dominant allele
is expressed even if
it is paired with a
recessive allele.
A recessive allele is
only visible when
paired with another
recessive allele.
١٨
Monogenic / Polygenic traits
Some human traits are controlled by a single gene
Pedigree analysis:
used to track
inheritance patterns
in families.
19
Mendelian traits
• Some human diseases segregate in families following Mendel’s
principles
• Characteristics of classical Mendelian traits;
-Single gene
-Clear pattern of inheritance
-Complete penetrance
•OMIM: Online Mendelian Inheritance in Man
•> 12,000 Mendelian traits known in humans
a comprehensive, authoritative, and timely compendium
of human genes and genetic phenotypes. contain
information on all known mendelian disorders . OMIM
focuses on the relationship between phenotype and
genotype http://www.ncbi.nlm.nih.gov/sites/entrez?db=omim
5 basic Mendelian pedigree patterns
o Autosomal dominant
o Autosomal recessive
o X-linked recessive
o X-linked dominant
o Y-linked
Autosomal dominant disorders
(neurofibromatosis, tuberous sclerosis, polycystic
kidney disease, familiar polyposis coli, hereditary
spherocytosis, Marfan syndrome, osteogenesis
imperfecta, achondroplasia, familiar
hypercholesterolemia)
Autosomal recessive disorders (cystic fibrosis,
phenylketonuria, homocystinuria,
hemochromatosis, sickle cell anemia,
thalassemias, alkaptonuria, neurogenic muscular
atrophies)
X-linked disorders (glucose-6-phosphate
dehydrogenase deficiency)
Autosomal Inheritance of Single-Gene Mutations
• Several thousand human genetic disorders are inherited
as recessive characters, most of which are caused by
recessive mutations of genes on autosomes .
• For genetic disorders caused by a recessive allele (a),
only homozygous (aa) individuals get the disease.
• Heterozygous individuals (Aa) are called “carriers”
because they have one copy of the disease-causing allele
but do not get the disease.
• If two carriers of a recessive genetic disorder (Aa) mate,
there is a 25 percent chance that their offspring will get
the disease.
• If a genetic disorder is dominant (A), then AA and Aa
individuals are symptomatic for the disease.
Punnett Square
Punnett squares can be used to
predict and compare the genetic
variations that will result from a
cross.
Autosomal recessive
•
•
The disease appears
in male and female
children of
unaffected parents.
e.g., cystic fibrosis
٢٤
Autosomal recessive inheritance (AR)
• Recessive character: both alleles needed to cause the
phenotype (homozygous)
– Affects both sexes equally
– A child of unaffected carrier
parents has 25% risk of disease
– Few affected, usually only in one
generation (skips generations)
– Increased probability of parental
consanguinity
Carrier female
Symbols explanation:
Affected male
Normal male
Normal female
Autosomal dominant
• Affected males and females
appear in each generation of
the pedigree.
• Affected mothers and fathers
transmit the phenotype to
both sons and daughters.
• Both sexes transmit the trait
with equal frequency.
• e.g., Huntington disease.
٢٦
Autosomal dominant inheritance (AD)
• Dominant character: only one allele needed to cause the
phenotype (heterozygous)
– Successive generations are affected.
– Affected have at least one affected parent, unless incomplete penetrance.
– Transmission stops after a generation in which no one is affected
– A child of an affected and an unaffected has 50% risk of disease
Codominant inheritance
• Two different versions
(alleles) of a gene can be
expressed, and each version
makes a slightly different
protein
• Both alleles influence the
genetic trait or determine
the characteristics of the
genetic condition.
• E.g. ABO locus
٢٨
Sex-Linked Inheritance of Single-Gene
Mutations
• Genes located on the X or Y chromosome are called
“sex-linked.”
• Genes on the X chromosome are called “X-linked.”
• Males inherit one X chromosome from their
mothers; therefore, genes on sex chromosomes have
different patterns of inheritance than genes on
autosomes (see Figure 13.8).
• Males are more likely than females to have recessive
X-linked genetic disorders, because they need to
inherit only one copy of the disease-causing allele to
be affected.
X-linked recessive
• Many more
males than
females show
the disorder.
• All the
daughters of
an affected
male are
“carriers”.
• None of the
sons of an
affected male
show the
disorder or
are carriers.
• e.g.,
hemophilia
٣٠
X-linked recessive
X-linked recessive inheritance (XR)
– Affects almost exclusively men
– Affected men born from carrier mother, with 50% risk of disease
– No male to male transmission
X-linked dominant
• Affected males
pass the disorder
to all daughters but
to none of their
sons.
• Affected
heterozygous
females married to
unaffected males
pass the condition
to half their sons
and daughters
• e.g. fragile X
syndrome
٣٣
X-linked dominant inheritance (XD)
--Much more severe effects in males
– High rates of miscarriage due to early lethality in males
– More females than males
– All daughters of affected males are affected, but no sons
– A child of an affected female has 50% risk of disease
Some single gene disorders
The Scientific Process: Tracing the Inheritance of
a Disease Gene
• The inheritance
pattern of
congenital
generalized
hypertrichosis
(CGH) is
illustrated with a
pedigree
diagram.
• CGH is an Xlinked dominant
genetic disorder.
EXAMPLES For Self testing:
Hemophilia
Blood clotting impaired
Recessive allele, h
carried on X cms
X-linked recessive trait
More common in males
Albinism
• Lack of pigment
– Skin
– Hair
– Eyes
Autosomal recessive
a
A
Amino Acids
Enzyme
AA = Normal
pigmentation
Aa = Normal
pigmentation
aa = Albino
(a)
DISFUNCTIONAL
ENZYME because
of a mutation
Melanin Pigment
Phenylketonuria (PKU) Disease
• Phenylalanine excess
• Mental retardation if
untreated
• Autosomal recessive
Molly’s Story
p
P
Phenylalanine
Enzyme
PP = Normal
Pp = Normal
pp = PKU
(p)
DISFUNCTIONAL
ENZYME because
of a mutation
Tyrosine
A man & woman are both carriers
(heterozygous) for albinism. What is
the chance their children will inherit
albinism?
AA = Normal
pigmentation
Aa = Normal
pigmentation
(carrier)
Man = Aa
Woman = Aa
aa = Albino
A
A
EGGS
SPERMS
a
a
PUNNET squares
A
a
A
AA
Aa
a
Aa
aa
Genotypes
AA
Aa
1 AA, 2Aa, 1aa
Phenotypes
Aa
aa
3 Normal
1 Albino
Probability
25% for albinism
A man & woman are both carriers
(heterozygous) for PKU disease. What
is the chance their children will inherit
PKU disease?
PP = Normal
Pp = Normal
(carrier)
P
pp = PKU disease
P
p
p
PP
Pp
Pp
pp
Genotypes
PP
Pp
1 PP, 2Pp, 1pp
Phenotypes
3 Normal
Pp
pp
1 PKU disease
Probability
25% for PKU disease
A man with sickle cell anemia marries a
woman who is a carrier. What is the
chance their children will inherit sickle
cell anemia?
SS = Normal
Ss = Normal
(carrier)
S
ss = Sickle Cell
s
s
s
Ss
ss
Ss
ss
Genotypes
Ss
ss
2 Ss, 2ss
Phenotypes
Ss
ss
2 Normal (carriers)
2 Sickle cell
Probability
50% for Sickle cell
A man with heterozygous dwarfism
marries a woman who has normal
height. What is the chance their
children will inherit dwarfism?
Dwarfism is dominant.
DD = Dwarf
Dd = Dwarf
dd = Normal
d
D
d
d
Dd
Dd
dd
dd
Genotypes
Dd
Dd
2 Dd, 2dd
Phenotypes
dd
dd
2 Normal
2 Dwarfs
Probability
50% for Dwarfism
X-linked Recessive Traits
• Alleles are on the X chromosome
• Inheritance pattern different in males and
females
XH XH = Normal Female
XH Xh = Normal Female
(Carrier)
Xh Xh = Hemophilic Female
XHy = Normal Male
Xhy =
Hemophiliac Male
A man with hemophilia marries a
normal woman who is not a carrier.
What is the chance their children will
inherit hemophilia? Hemophilia is Xlinked recessive.
Xh XH = Normal Female
XH Xh = Normal Female
(Carrier)
Xh Xh = Hemophilic Female
XHy = Normal Male
Xhy =
XH
Hemophiliac Male
XH
Xh
XH Xh
XH Xh
y
XHy
XHy
XH
XH
Genotypes
Xh
XH
Xh
XH
Xh
2
XH Xh, 2XHy
Phenotypes
2 Carrier Females
y
XHy
XHy
2 Normal Males
Probability
O% for Hemophilia
A normal man marries a normal woman
who is a carrier for hemophilia. What is
the chance their children will inherit
hemophilia?
Xh XH = Normal Female
XH Xh = Normal Female
(Carrier)
Xh Xh = Hemophilic Female
XHy = Normal Male
Xhy =
XH
Hemophiliac Male
Xh
XH
XH XH
XH Xh
y
XHy
Xhy
Xh
XH
Genotypes
XH
XH
XH
XH
Xh
XH XH , XH Xh, XHy, Xhy
Phenotypes
2 Normal Females
y
XHy
Xhy
1 Normal Males
1 Male Hemophiliac
Probability
50% for Male Hemophilic
0% for Female Hemophilic
MORE DETAILLES on Genetic Diseases
• Cystic fibrosis – disease affecting the mucus lining of the lungs,
leading to breathing problems and other difficulties
• Huntington disease - or Huntington's chorea is an inherited
disorder characterized by abnormal body movements called
chorea, and loss of memory. There also is evidence that doctors
as far back as the Middle Ages knew of this devastating disease.
The incidence is 5 to 8 per 100,000. It takes its name from the
New York physician George Huntington who first described it
precisely in 1872.
• Hemophilia-illness that impair the body's ability to control
bleeding.
• Fragile X syndrome - is a genetic condition that causes a range of
developmental problems including learning disabilities and
mental retardation. Usually males are more severely affected by
this disorder than females. In addition to learning difficulties,
affected males tend to be restless, fidgety, and inattentive.
Affected males also have characteristic physical features that
become more apparent with age.
X-Linked Recessive
COLOUR BLINDNESS
• Red-green colour blind is the most common
• Blue-Yellow is also possible
• Altered genes affect receptors for these colours in the eye
• Who is more likely to be affected by this?? Males or
Females?? Why????
HEMOPHILIA A or B
• Absence of Clotting factor VIII (A) or IX (B)
• Cant stop bleeding
• Absence of genes coding for clotting factors on the X
chromosome
X-Linked DOMINANT
Hypophosphatemic Rickets
Impairs kidneys ability to reabsorb PHOSPATE
HYPO= LOW
PHOSPHATE
Emic = Blood
LOW BLOOD PHOSPHATE levels
Phosphate is needed for bone growth
Phosphate deficiency disrupts bone growth
Bones Bend and disfigure
RICKETS
From the word Wrick that means TWIST
For curiosity: BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in structural proteins
Marfan syndrome
A disorder of the connective tissues of the body, manifested principally
by changes in the skeleton, eyes, and cardiovascular system.
Ehlers-Danlos syndromes
A clinically and genetically heterogeneous group of disorders that result
from some defect in collagen synthesis or structure (other disorders
resulting from mutations affecting collagen synthesis include
osteogenesis imperfecta, Alport syndrome, epidermolysis bullosa)
BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in receptor proteins
Familiar hypercholesterolemia
A disease that is the consequence of a mutation in the gene encoding the
receptor for low-density lipoprotein (LDL), which is involved in the transport and
metabolism cholesterol. More than 150 mutations, including insertions, deletions,
and missense and nonsense mutations, involving the LDL receptor gene have
been identified. These can be classified into five groups: Class I mutations uncommon, they lead to a complete failure of synthesis of the receptor protein.
Class II mutations - common, they encode receptor proteins that accumulate in
the endoplasmic reticulum because they cannot be transported to the Golgi
complex. Class III mutations - affect the LDL-binding domain of the receptor. Class
IV mutations - encode proteins that are synthesized and transported to the cell
surface efficiently, they bind LDH normally, but the bound LDL is not internalized.
Class V mutations - encode proteins that are expressed on the cell surface, can
bind LDL, and can be internalized, however, the acid-dependent dissociation of
the receptor and the bound LDL fails to occur.
BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in enzymes
Lysosomal storage diseases: Lysosomes contain different types of hydrolytic
enzymes, which can cleave various substrates in the acid milieu and can be
secreted. With an inherited deficiency of a functional lysosomal enzyme,
catabolism of its substrate remains incomplete, leading to the accumulation of
the partially degraded insoluble metabolite within the lysosomes. These
organells become large and numerous giving rise to the lysosomal storage
disorders. These disorders result exclusively from mutations that lead to reduced
synthesis of lysosomal emzymes There are also other defects: Synthesis of a
catalytically inactive proteins that cross-react immunologically with normal
enzymes, so the enzyme level appear to be normal.,.defects in post-translational
processing of enzymes (example is a failure of mannose-6-phosphate receptor),
lack of an enzyme activator or protector protein, lack of a substrate activator
protein, lack of transport protein. The lysosomal storage disorders can be divided
into (1) glycogenoses, (2) sphingolipidoses (lipidoses), (3)
mucopolysaccharidoses, and (4) mucolipidoses. Examples follow:
BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in enzymes
Tay-Sachs disease – GM2 gangliosidosis, hexosaminidase α-subunit
deficiency,GM2 ganglioside accumulates in heart, liver, spleen etc.,
destruction of neurons, proliferation of microglia and accumulation of lipids
in phagocytes within the brain.
Niemann-Pick disease – types A and B, two related disorders with lysosomal
accumulation of sphingomyelin, deficiency of sphingomyelinase, 80% of all
cases repreents type A – the severe infantile form with neurologic
involvement, visceral accumulation of sphingomyelin and early death within
the first 3 years of life.
Gaucher disease – a cluster of autosomal recessive disorders resulting from
mutations in the gene encoding glucocerebrosidase, the most common
lysosomal storage disorder, accumulation of glucocerebrosides, types I-III, the
glucocere¨brosides accumulate within phygocytes (Gaucher cells) throughout
the body – spleen, liver, bone marrow, lymph nodes, tonsils thymus etc.
BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in enzymes
Mucopolysaccharidoses (MPS) – the deficiencies of lysosomal enzymes
involved in the degradation of mucoplysaccharides (glycosaminoglycans),
several clinical variants classified from MPS I (Hurler syndrome) to MPS VII,
each resulting from the deficiency of one specific enzyme, all the MPS except
one are autosomal recessive disorders, the exception (Hynter syndrome) is an
X-linked recessive disorder, involvement of multiple organs including liver,
spleen, heart, blood vessels, joint stiffness, mental retardation.
Glycogen storage diseases – resulting from a hereditary deficiency of one of
the enzymes involved in the synthesis or sequential degradation of glycogen,
3 forms: hepatic, myopathic, miscellaneous (deficiency of α-glucosidase and
lack of branching enzymes, type II – Pompe disease and type IV, death early in
life.
BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in enzymes
Alkaptonuria (Ochronosis) – an autosomal recessive disorder in which the lack
of homogentisic oxidase blocks the metabolism of phenylalanine-tyrosine at
the level of homogentisic acid, homogentisic acid accumulates in the body, it
selectively binds to collagen in connective tissues, tendons, and cartilage,
these tissues have a blue-black pigmentation (ochronosis) most evident in
the ears, nose, and cheeks, the deposits of the pigment in the articular
cartilages cause the cartilage to lose its normal structure and function
resulting in osteoarthritis.
BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in proteins that regulate
cell growth
Neurofibromatosis: types 1 and 2 – two autosomal dominant
disorders, neurofibromatosis type 1 previously called von
Recklinghausen disease, neurofibromatosis type 2 previously called
acoustic neurofibromatosis. Although there is some overlap in clinical
features, these two entities are genetically distinct.
BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in proteins that regulate
cell growth
Neurofibromatosis-1: The neurofibromatosis 1 gene (NF-1) has been mapped to
chromosome 17q11.2. It encodes a protein called neurofibromin, which downregulates the function of the p21ras oncoprotein. NF-1 therefore belongs to the family
of tumor-suppressor genes. Three major features of disorder – multiple neural tumors
(neurofibromas) dispersed anywhere on or in the body, numerous pigmented skin
lesions, and pigmented iris hamartomas, also called Lisch nodules. A wide range of
associated abnormalities has been reported in these patients – skeletal lesions like
erosive defects, scoliosis, intraosseous cystic lesions, subperiosteal bone cysts,
pseudoarthrosis of the tibia. Patients have also a twofold to fourfold greater risk of
developing other tumors (Wilm´s tumor, rhabdomyosarkoma, meningioma, optic
glioma, pheochromocytoma, chronic myeloid leukemia). There is also tendency for
reduced intelligence. Whem neurofibromas arise within gastrointestinal tract,
intestinal obstruction or bleeding may occur. A frequency about 1 in 3000.
BIOCHEMICAL BASIS OF GENETIC DISORDERS
Disorders associated with defects in proteins that regulate
cell growth
Neurofibromatosis-2: an autosomal dominant disorder in which patients
develop a range of tumors – bilateral acoustic schwannomas, multiple
meningiomas, gliomas, ependymomas of the spinal cord, and/or nonneoplastic lesions – nodular ingrowth of Schwann´s cells into the spinal cors,
meningiomatosis, glial hamartia. Pigmented (café au lait) spots like NF-1 are
present, but Lisch nodules are not found. The NF-2 gene, located on
chromosome 22q12, is also a tumor-suppressor gene, the product of this gene
called merlin shows structural similarity to a series of cytoskeletal proteins,
but is function remains uncertain. An frequency about 1 in 45,000.