LEC.1
Dr. Roaa S. Mahdi
24/11/2015
Human Genetics
Structure of nucleic acids:DNA&RNA
Nucleic acid is composed of a long polymer of individual molecules called nucleotides. Each nucleotide
is composed of a nitrogenous base, a sugar molecule and a phosphate molecule.
The nitrogenous bases fall into two types, purines and pyrimidin, the purines include adenine and
guanine; the pyrimidines include cytosine, thymine and uracil.
There are two different types of nucleic acid, ribonucleic acid (RNA), which contains the five carbon
sugar ribose, and deoxyribonucleic acid (DNA), in which the hydroxyl group at the 2' position of the
ribose sugar is replaced by a hydrogen (i.e. an oxygen molecule is lost, hence 'deoxy').
DNA and RNA both contain the purine bases adenine and guanine and the pyrimidine cytosine, but
thymine occurs only in DNA and uracil is found only in RNA.
RNA is present in the cytoplasm and in particularly high concentrations in the nucleolus of the nucleus.
DNA is found mainly in the chromosomes.
The DNA molecule is composed of two chains of nucleotides arranged in a double helix. The backbone
of each chain is formed by phosphodiester bonds between the 3' and 5' carbons of adjacent sugars, the two
chains being held together by hydrogen bonds between the nitrogenous bases , which point in towards the
center of the helix.
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The chain end terminated by the 5' carbon atom of the sugar molecule is referred to as the 5' end,
and the end terminated by the 3' carbon atom is called the 3'end.
In the DNA duplex the 5' end of one strand is opposite the 3'end of the other,they have opposite
orientation and are said to be antiparrellel.
The arrangement of the bases in the DNA molecule is not random. A purine in one chain always pairs
with a pyrimidine in the other chain, with specific pairing of the base pairs: guanine in one chain always
pairs with cytosine in the other chain, and adenine always pairs with thymine, so that this base pairing
forms complementary strand.
How genetic information is transmitted from one generation to the next
During nuclear division the two strands of the DNA double helix separate through the action of enzyme
DNA helicase, each DNA strand directing the synthesis of a complementary DNA strand through specific
base pairing, resulting in two daughter DNA duplexes that are identical to the original parent molecule
when cells divide, the genetic information is conserved and transmitted unchanged to each daughter cell
,this process is called replication.
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Gene structure
The original concept of a gene as a continuous sequence of DNA coding for a protein , Human genome
has approximately 25000 genes, which are the individual unit of heredity, that consist of coding regions
called exons that encode the amino acids sequence of a protein and intervening segments called introns
which are non coding regions whose DNA not represented in the finished protiens .The genes are
organized into long segments of DNA, which, during cell division are compacted into intricate structures
with proteins to form chromosomes.
Transcription
The process whereby genetic information is transmitted from DNA to RNA is called transcription.
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The information stored in the genetic code is transmitted from the DNA of a gene to messenger
RNA( mRNA), every base in the mRNA molecule is complementary to a corresponding base in the DNA
of the gene, but with uracil replacing thymine in mRNA. mRNA is single stranded, being synthesized by
the enzyme RNA polymerase, which adds the appropriate complementary ribonucleotide to the
3' end of the RNA chain.
RNA processing
Before the primary mRNA molecule leaves the nucleus it undergoes a number of modifications, or what
is known as mRNA processing, this is involves splicing, capping and polyadenylation.
***mRNA splicing
After transcription, the non-coding introns in the primary mRNA are excised, and the non-contiguous
coding exons are spliced together to form a shorter mature mRNA before its transportation to the
ribosomes in the cytoplasm for translation, this process is known as mRNA splicing.
***5'capping
Shortly after transcription, the nascent mRNA is modified by the addition of a methylated guanine
nucleotide to the 5'end of the molecule by an unusual 5' to 5' phosphodiester bond, the so-called 5' caping,
the 5' cap is thought to facilitate transport of the mRNA to the cytoplasm and attachment to the
ribosomes, as well as to protect the RNA transcript from degradation by endogenous cellular
exonucleases .
***Polyadenylation
The cleavage of the 3' end of the mRNA molecule from the DNA involves the addition of approximately
200 adenylate residues ,this called polyadenylation .
Translation
Translation is the transmission of the genetic information from mRNA to protein, newly processed
mRNA is transported from the nucleus to the cytoplasm, where it becomes associated with the ribosomes
which are the site of protein synthesis. Ribosomes are made up of two different sized subunits, which
consist of four different types of ribosomal RNA (rRNA) molecules and a large number of ribosomal
specific proteins. Groups of ribosomes associated with the same molecule of mRNA are referred to as
polyribosomes or polysomes ,in the ribosomes, the mRNA forms the template for producing the specific
sequence of amino acids of a particular polypeptide.
Post translation modification
Many proteins, before they attain their normal structure or functional activity , undergo post-translational
modification, which can include chemical modification of amino-acid side-chains (e.g. hydroxylation,
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methylation), the addition of carbohydrate or lipid moieties (e.g. glycos-vlation) or proteolytic
cleavage of polypeptides (e.g. the conversion of proinsulin to insulin).
Structure of chromosome
A chromosome is very much wider than the diameter of a DNA double helix. In addition, the amount
of DNA in the nucleus of each cell in humans means that the total length of DNA contained in the
chromosomes, if fully extended, would be several meters long .
Under the electron microscope chromosomes can be seen to have a rounded and rather irregular
morphology, however , most of our knowledge of chromosome structure has been gained using light
microscopy and are best seen during cell division, when the chromosomes are maximally contracted and
the constituent genes can no longer be transcribed.
Each chromosome can be seen to consist of two identical strands known as chromatid , These chromatids
can be seen to be joined at a primary constriction known as the centromere. Centromeres consist of
several hundred kilobases of repetitive DNA and are responsible for the movement of chromosomes at
cell division. The tip of each chromosome arm is known as the telomere, which play a crucial role in
sealing the ends of chromosomes and maintaining their structural integrity.
Morphologically chromosomes are classified according to the position of the centromere. If this is located
centrally, the chromosome is metacentric, if terminal it is acrocentric, and, if the centromere is in an
intermediate position the chromosome is submeatcentric.
The mitochondria contain their own unique genome. The mitochondrial chromosome consist of a
double-stranded circular piece of DNA, which contains 16,568 base pairs(bp) of DNA . All mitochondria
are maternally derived because sperm do not usually carry mitochondria into fertilized eggs.
The mutation:
refers to permanent changes in the DNA, Those that affect germ cells are transmitted to the progeny and
may give rise to inherited diseases. Mutations in somatic cells are not transmitted to the progeny but are
important in the causation of cancers and some congenital malformation.
Types of mutations :
•Point mutation: result from substitutions of a single nucleotide base by a different base ,resulting in the
replacement of one amino acid by another in the protein product, the best example of point mutation is
sickle cell anaemia ,such mutations are sometimes called missense mutations. In contrast certain point
mutations may change the an amino acid codon to a chain termination codon or stop codon, this type of
mutations are called nonsense mutation which interrupt translation and the resultant protein is rapidly
degraded.
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• frame shift mutations: occurs when the insertion or deletion of one or two base pairs alters the
reading frame of DNA strand.
• Trinucleotide repeat mutations: these mutations are characterized by amplifications of a sequences of 3
nucleotides , all affected sequences share the nucleotides guanine (G) and cytocine (C ), e.g: fragile X
syndrome in which there are 200-4000 repeats of the sequence CGG with in a gene.
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LEC.2
Dr. Roaa S.Mahdi
8/12/2015
Classifications of genetic disorders:
There are three major categories of genetic diseases:
1-those related to mutant genes of large effects, which some times referred to as mendelian disorders
,includes many uncommon conditions such as storage diseases and inborn errors of metabolism, all
resulting from single-gene mutations of large effect.
2-diseases with multifactorial (polygenic inheritance) implies that both genetic and environmental had a
role in the expression of diseases such as hypertension and diabetes mellitus.
3-Disorders that are a consequence of numeric and structural abnormalities in the chromosomes.
A pedigree provides a graphic depiction of a family's structure and medical history. The person
providing the information is termed the proband. A three generations-pedigree should be obtained.
consanguinity is relationship by descent from a common ancestor. First degree relatives, such as,
parents, full sibling, or child, share 1/2 their genetic information on average; first cousins share 1/8.
Disorders caused by single gene defects (mednelian disorders)or (unifactorial)
These are divided in (Autosomal Recessive (AR), Autosomal Dominant (AD), X-Linked Recessive
(XLR), X-Linked Dominant (XLD).
(a) Autosomal Recessive Disease: -It involves mutations in both copies of a gene.
It is characterized by: 1) ♂ & ♀ affected equally, though some traits exhibit different expression in males and
females ( ovarian cancer and hypospades).
2)
The affected individual should be homozygous for the affected gene.
3)
If both parents are heterozygous the chance of having affected child is 25%.
4)
If the affected person married from normal person, all the children will be
heterozygous.
5)
If affected person married from a heterozygous person the children will be: 
50% affected.

50% heterozygous (carrier).
It is called Pseudodominant inheritance, which refers to the observation of apparent
dominant ( parent to child) transmission of a known AR disorder. It is most likely to
occur for relatively common traits, such as sickle cell anemia.
6)
The affected cases are almost always born in only one generation (sister, brother or
cousins…), this is called horizontal inheritance.
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7)
Increased frequency of consanguinity, particularly for rare traits. The risk of a genetic
disorder for the offspring of a first-cousin marriage (6-8%) is about double the risk in
general population (3-4%)
examples of autosomal recessive disorder:
Haemopoitic : sickle cells anaemia and thalassemias.
Metabolic : cystic fibrosis , phenyle ketonuria ,galactosemia,homocystenuria,lysosomal storage disease,
Wilson disease, haemochromatosis, glycogen storage disease.
Endocrine : congenital adrenal hyperplasia.
Nervous: spinal muscular atrophy.
(b) Autosomal Dominant Disease: -It is characterized by: 1)
The transmission occurs from one parent to the child .
2)
The responsible mutant gene can arise by spontaneous mutant gene.
3)
The affected cases in multiple generation, which is called vertical or perpendicular
inheritance (grand parent-parent-child).
4)
♂ & ♀ affected equally.
5)
The recurrence risk is 50%.
6)
The finding of male-to-male transmission essentially confirms AD inheritance.
7)
For many patients with AD disorder there is no history of an affected family member,
which could be explained by:
a- New mutation.
b- Incomplete penetrance:- not all the individuals who carry the mutation have
phenotypic manifestations, which may appear as skipped generation in such family we
see that affected grand parent-normal (Skipped) parent-affected child.
c- Variable expression: manifestations of the disorder in different degrees.
d- Somatic mutations: the mutation occur not in the egg or sperm that forms a child but
in the cell of an developing embryo. The phenotypic manifestations are usually milder
than if all cells contain the mutation .
8)
It is of (2) types: 
Mild: - there is no effect on longevity of life or reproduction
♦ cleido cranial dystosis: - in which there is failure of development of clavicle, short
stature & delayed teething,

♦porphyria.
Severe: - which forms the majority of Autosomal Dominant (AD) cases, either the
fertility is affected or the patient die before age of reproduction so the disease is extinct
in affected families and kept only by fresh mutation
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♦Achondroplasia: - (short trunk & extremities, large head, early hypotonia & later on
develop normal tone, normal IQ).
Examples of autosomal dominant disease :
Nervous: tuberous sclerosis .
Urinary : polycystic kidney .
Gastrointestinal : familial polyposis .
Haemopoitic : hereditary spherocytosis, von willebrand disease.
Skeletal : marfan syndrome ,achondroplasia.
Metabolic : familial hypercholestrolemia
(c)
X-Linked Recessive Disease: -The disease carried on X-chromosome, it is characterized
by: 1)
Males are more commonly and more severely affected than females.
2)
Female carriers are generally unaffected, or if affected, they are affected more
mildly than males.
3)
4)
Only the ♂ is clinically affected via carrier ♀.
If the carrier ♀ married from normal ♂
 50% of sons affected.
 50% of daughters are carrier.
So the chance of affected son is 25%.
5)If affected ♂ married from normal ♀
 All daughters will be carriers.
 All sons will be normal.
So no ♂ to ♂ transmission but grand son can be affected by carrier ♀.
6) Don’t forget to ask about affected uncles from mother side or affected sons of sisters
because the disease is transmitted in indirect vertical descent.
7) The ♀ can be affected in:  She is a product of carrier ♀ & affected ♂.
 Turner syndrome (XO).
 Lionization (Lion hypothesis, X chromosome inactivation): in which only one X
chromosome is active in each cell.
Initially both X-chromosome of ♀ zygote are active. Random inactivation of portion of one
X-chromosome in each cell occur early in fetal development which replicated later than the
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active X-chromosome, so this protect the carries ♀ from the effect of X-Linked
Recessive (XLR) mutant gene because there is 50% chance that the X-chromosome that carry
the mutated gene will be inactivated, so the carrier express the affect of mutant gene in 50% of
her cells, so the ♀ carrier of classic hemophilia have decreased level of factor VIII activity but
not as low as her brother.
Examples of X-linked recessive :
Haemopoitic : G6PD , Hemophilia A, B .
Muscloskeletal: Duchene muscular dystrophy .
Immune : wiskott –alderich syndrome
Metabolic : diabetes insipidus.
Nervous : fragile X syndrome.
(d) X-Linked Dominant Disease: - it is characterized by: 1)
Both ♂ & ♀ affected, but the disease is more severe in ♂.
2)
The disease transmitted from one generation to another.
3)
The affected ♀ transmit the disease to 50% of her daughters & 50% of her sons.
4)The affected ♂ transmit the disease to all his daughters but to
non of his sons, so the disease appears more common in ♀.
5) The pedigree shows only affected females.
(e.g.) Vit.D resistant Ricket’s, incontentia pigmenti.
Multi factorial inheritance: - it is due to genetic and environmental factors.
Some times it is difficult to differentiate it from Autosomal Dominant (AD) with reduced Penetrance.
It is characterized by: 1) The recurrence risk among first-degree relatives is (3-5%).
2) The recurrence risk related to the incidence of the disease.
3) Some diseases have sex predilection( e.g.):
 Pyloric stenosis are common in ♂.
 CDH are common in ♀.
And the recurrence risk is higher for relatives of an index case in which the sex is less common.
(e.g.) The recurrence risk to the son of an affected ♀ with pyloric stenosis is 18% which the
recurrence risk to the son of an 7affected ♂ with pyloric stenosis is 5%.
4) The identical twins affected in <100%, usually (21-63%), with the same disorder.
5) The recurrence risk increased when multiple family members affected (e.g.) recurrence risk
of unilateral Cleft lip & palate is 4% with one affected child, but increased to 9% when there
is 2 affected children.
6) The recurrence risk increased when the disease is more severe, (e.g.) Long Segment
Hirschsprung disease.
Autosomal: the gene responsible for the phenotype is located on one of the 22 pairs of autosomes (non-sex
determining chromosomes).
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X-linked: the gene that encodes for the trait is located on the X chromosome.
Dominant: conditions that are manifest in heterozygotes (individuals with just one copy of the
mutant allele).
Recessive: conditions are only manifest in individuals who have two copies of the mutant
allele (are homozygous).
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Autosomal Dominant
Dominant conditions are expressed in individuals who have just one copy of the
mutant allele. The pedigree on the right illustrates the transmission of an autosomal
dominant trait. Affected males and females have an equal probability of passing on the
trait to offspring. Affected individual's have one normal copy of the gene and one
mutant copy of the gene, thus each offspring has a 50% chance on inheriting the mutant
allele. As shown in this pedigree, approximately half of the children of affected parents
inherit the condition and half do not.
Autosomal Dominant
Conditions:
• Huntington Disease
• acondroplasia (short-limbed
dwarfism)
• polycystic kidney disease
Autosomal Recessive
Recessive conditions are clinically manifest only when an individual has two
copies of the mutant allele. When just one copy of the mutant allele is present, an
individual is a carrier of the mutation, but does not develop the condition. Females and
males are affected equally by traits transmitted by autosomal recessive inheritance.
When two carriers mate, each child has a 25% chance of being homozygous wild-type
(unaffected); a 25% chance of being homozygous mutant (affected); or a 50% chance
of being heterozygous (unaffected carrier).
Affected individuals are
indicated by solid black
symbols and unaffected
carriers are indicated by the
half black symbols.
Autosomal recessive diseases:
• Cystic fibrosis
• Tay-Sachs
• hemochromatosis
• phenylketonuria (PKU)
X-linked Recessive
X-linked recessive traits are not clinically manifest when there is a normal copy
of the gene. All X-linked recessive traits are fully evident in males because they only
have one copy of the X chromosome, thus do not have a normal copy of the gene to
compensate for the mutant copy. For that same reason, women are rarely affected by
X-linked recessive diseases, however they are affected when they have two copies of
the mutant allele. Because the gene is on the X chromosome there is no father to son
transmission, but there is father to daughter and mother to daughter and son
transmission. If a man is affected with an X-linked recessive condition, all his daughter
will inherit one copy of the mutant allele from him.
X-linked Dominant
Because the gene is located on the X chromosome, there is no transmission from
father to son, but there can be transmission from father to daughter (all daughters of an
affected male will be affected since the father has only one X chromosome to transmit).
Children of an affected woman have a 50% chance of inheriting the X chromosome
with the mutant allele. X-linked dominant disorders are clinically manifest when only
one copy of the mutant allele is present.
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X-linked Recessive Disorders:
• Duchenne muscular
dystrophy
• hemophilia A
• X-linked severe combined
immune disorder (SCID)
• some forms of congenital
deafness