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GENETICS AND DISEASE
By MWAKYOMA, HA
MD
THE NUCLEUS
•
The nucleus consists of an outer nuclear
membrane enclosing nuclear chromatin
and nucleolus
1. NUCLEAR MEMBRANE.
 Is the outer envelope
 It consists of 2 layers (double membrane
separated by a 40-70 nm wide space
 The outer membrane is studded with
ribosomes.
The nuclear membrane cont- There is an existence of pores
 There is perinuclear space or cistern which
communicates with channels of endoplasmic
reticulum (ER i.e. – RER) which perticipates in
the formation nuclear membrane.THUS, the
nucleus has 2 channels.
The pores which provide passage ways directly
into the cytoplasmic colloidal matrix and
The communication between the perinuclear
cistern (space) and the lamina of ER
Nuclear membrane cont-There is abundant evidence that the 3
types of RNA,tRNA, mRNA and rRNA are
synthesized within the nucleus and pass to
the cytoplasm of the cell where they
participate in protein synthesis.
NUCLEAR CHROMATIN
• The main substance of nucleus is
comprised of the nuclear chromatin.
• The chromatin contains chromosomes
• There are 2 types of chromatin:EUCHROMATIN:Are finely divided or filamentous (threadlike) structures, called CHROMOSOMES.
Euchromatin cont-- Are generally ACTIVE than heterochromatin
HETEROCHROMATIN: Occur in clumps or flakes
 Usually most abundant about the nuclear
membrane
 Are INACTIVE and are mainly found in female
cells which contain dense clumps of
heterochromatin known as BARR BODY (Sex
chromatin) characteristically attached to the
nuclear membrane.
CHROMOSOMES:
• The chromatin contains chromosomes
• There are 23 pairs (46 chromosomes), of these
22 pairs (44) are called AUTOSOMES and
1pair(2) chromosomes are called SEX
CHROMOSOMES, either XX (female) or XY
(male)
• Each chromosome is composed of 2
CHROMATIDS connected to each other at
CENTROMERE to form “X” configuration having
variation in location of centromere
Classificatio of Chromosomes.
•
Depending on centrometric location the
23 pairs of chromosomes can be
classified as follows.
1. METACENTRIC CHROMOSOMES: The centromere is exactly in the middle
 The chromosomes 1, 3, 9, and 10 fall
into this group
Classification of chromosomes
cont-2. SUBMETACENTRIC CHROMOSOMES:
In this group, the centromere is off the
centre
The centromere divides the chromosome
into a short arm (p) and long arm (q)
Classification of chromosomes
cont-3. ACROCENTRIC CHROMOSOMES:
In this group the centromere is near the
end of the pair
The centromere has very short arm or
stalks and satellites giving a “V”-shaped
appearance
included in this group are chromosomes
13, 14, 15, 21, and 22.
Classification of chromosomes
cont-4. TELOCENTRIC CHROMOSOMES:
The centromere is terminally located
This type of chromosome is found in many
animal species but NOT in man
Classification of chromosomes
cont-• Depending on both the LENGTH of a
chromosome and CENTROMETRIC
location, 23 pairs of chromosomes are
categorized (classified) into 7 groups A to
G according to DENVER classification
(adopted at a meeting in Denver, USA).
A = 1-3
B = 4-5
Denver classificatioin cont--C =(6-12) + X chromosome
D =13-15
E =16-18
F =19-20
G =(21-22) + Y chromosome
The chromosome cont-• The chromosome is composed of 3 components each
with distinctive function.
 DNA – comprising of 20%
 RNA – comprising of 10%
 Nuclear proteins – comprising of 70% that includes a
number of basic proteins and acidic proteins.
• DNA of a cell is largely contained in the nucleus
• The only other place in the cell that contains small
amount of DNA is MITOCHONDRIA
• Nuclear DNA carries the genetic information that is
passed via RNA into the cytoplasm for manufacture of
proteins.
3. NUCLEOLUS
• The nucleus may contain one or more
rounded bodies called nucleolus
• It is involved in synthesis of rRNA
NB: Cells involved in protein synthesis,
particularly ACTIVE DIVIDING cells, tend
to have large nucleoli and may have more
than a single nucleolus.
THE CELL CYCLE:
• HAS 4 STAGES
G1phase – a stage when messenger RNAs for
proteins required for DNA and DNA polymerase
are synthesized
S phase – involved in replication of nuclear DNA
G2 phase – messenger RNA (mRNA) required
for mitosis are synthesized.
M phase – process of mitosis to form 2 daughter
cells is completed. This occurs in 4 sequential
steps. The stages include the following:-
M phase sequential steps:PMAT:
•
Prophase – each chromosome is divided into 2
CHROMATIDS which are held together at the
centromere
•
Metaphase – the microtubules become arranged
between 2 centrioles forming spindles while the
chromosome line up at the equatorial plate of the
spindle
•
Anaphase – the centromere divide and each set of
separated chromosome moves towards the opposite
poles of the spindle.
- cell membrane begins to divide.
Sequential steps of Metaphase
cont-4. Telophase – there is formation of nuclear
membrane around each set of
chromosome and reconstitution of the
nucleus.
- the cytoplasm of the two
daughter cells completely separates.
Genetics and disease
OVERVIEW:
 Human development depends on genetic
and environmental factors.
 A person’s genetic composition (genome)
is established at conception
 The genetic information is carried in the
DNA of the chromosome and mitochondria
Genetics and disease overview
cont- Most diseases probably have some
genetic component, the extent of which
varies.
 Environmental factors may alter genetic
information or other structural alteration
and can affect classic genetic disorders.
 DNA’s capacity to replicate constitutes the
basis of hereditary transmission.
Genetics and diseases overview
cont- DNA also provides the genetic code which
determines cell development and
metabolism by controlling RNA synthesis
 The sequence of elements (Nucleotides)
that comprise DNA and RNA determines
protein composition and thus its function.
 Genes (between 60,000 and 100,000 in
humans) are carried by chromosomes.
Genetics and disease overview
cont- In humans, SOMATIC (non-germ) cells normally have 46
chromosomes, occuring as 23 pairs.
 Each pair of chromosome consists of ONE chromosome
from the MOTHER (maternal) and ONE from the
FATHER (paternal).
 ONE pair the set SEX, women have TWO X
chromosomes, whereas men have ONE X and ONE Y
chromosome (i.e. heterologous chromosomes)
 The X chromosome carries genes responsible for many
hereditary traits
 The small, differently shaped Y chromosome carries
genes that initiate male sex diffrentiation or
determination.
Genetics and disease overview
cont- The remaining 22 chromosome pairs, the
AUTOSOMES, are usually Homologous (i.e.
identical shape and position and number of
genes).
 Germ cells (egg and sperm) undergo MEIOSIS,
reducing the number of chromosome to 23
(HAPLOID number)- half that of somatic cells
(46), so that when an egg is fertilized by a sperm
at conception, the normal number of
chromosomes is reconstituted.
Genetics and disease overview
cont- In MEIOSIS, the genetic information
inherited from a person’s mother and
father is combined through crossing over
or exchange between the homologous
chromosomes.
GENETIC DISORDERS:
• There are 3 types of genetic disorders:Mendelian or Single gene mutations are
inherited in recognizable patterns.
Multifactorial conditions involve more than
one gene and
Chromosomal abnormalities which include
Structural defects
Deviation from the normal number
(Numerical abnormalities).
CHROMOSOMAL
ABNORMALITIES:
These can be of 2 types;
 Abnormality in the number (Alteration in
number)
- Errors in cell division
 Abnormality (Alteration)in the structure
- Breakage and reunion of DNA
ALTERATION IN NUMBER:
• This may involve;
Autosomes or
Sex chromosomes
Alteration is either an ADDITION (+) or an
ABSENCE (-) of a chromosome. This is
called ANEUPLOIDY, as the cells do not
contain an exact multiple of the Haploid
number.
Alteration in the number cont-EUPLOIY:1. Haploid (n)= 23
2. Diploid (2n)= 46
3. Triploid (3n)= 69
4. Tetraploid (4n)= 92
5. polyploid
ANEUPLOIDY
1. Hypoploid (2n-1, -2)- monosomy
2. Hyperploid (2n +1, +2 etc) – trisomy
 Numerical chromosomal abnormalities
arise primarily from NONDISJUNCTION.
NONDISJUNCTION: Is a failure of paired chromatid to
separate and move to opposite poles of
the mitotic spindle at anaphase
NONDISJUNCTION cont-Occurs during mitosis or meiosis.
It leads to aneuploidy if only one pair of
chromosome is involved and
polypoid if the entire set fails to divide and
all the chromosomes are segregated in a
single daughter cell.
Nondisjunction may involve autosomes or
sex chromosomes.
ANEUPLOIDIES:
AUTOSOMES: Monosomy.
Absence of an autosome is almost
invariably lethal, resulting in ABORTIONS.
 Trisomy .
An addition of a chromosome cause
severe effect e.g. MENTAL
RETARDATION or deficiency
TRISOMY:Example of trisomy:
TRISOMY 21 (TRISOMY G).
 DOWN’S SYNDROME
 47XY, 21+ for male and 47XX, 21+ for female
(Mongolism).
 Maternal age is important
 It increases with maternal age above 35 years
 Genetic counselling is required
ANEUPLOIDY cont-OTHERS:Trisomy 13 syndrome (Patau’s)
Trisomy 18 syndrome (Edward’s)
SEX CHROMOSOME: Monosomy.
Examples:Turner’s syndrome (45X0, Ovarian
dysgenesis)
Turner’s syndrome cont-A sex chromosomal abnormality in which
there is complete or partial absence of one
or two sex chromosomes, producing
PHENOTYPIC FEMALE
Occurs in about ¼,000 live births
98% of 45X0 conception are miscarried.
80 of live born newborns with monosomy
X have loss the PATERNAL X.
Turner’s syndrome cont-There is gonadal dysgenesis (Failure to go
through puberty, develop breast tissue).
- Presence of hypoplastic ovaries (No
germinal follicles)
- Patients have primary infertility
- Have primary amenorrhoea
- Failure to develop secondary sex
characteristics
- Barr body are absent.
Aneuploidy of sex chromosomes
cont-Trisomy:
 The triple X syndrome (47,XXX).
 A sex chromosomal abnormality in which there
are 3 X chromosomes resulting in
PHENOTYPIC FEMALE.
 Sterility and menstrual irregularity sometimes
occur
 Mild impaired intellect with IQ score average just
below 90 and associated with school problems
occur when compared with siblings.
Triple x syndrome (47,XXX) cont-Advanced maternal age increases the risk
The extra X chromosome is usually
maternally derived.
 Klinefelter’s syndrome (47,XXY).
A sex chromosomal abnormality in which
there are two or more X chromosomes
and one Y, resulting in PHENOTYPIC
MALE.
klinelfelter’s syndrome cont- Occurs in about 1/1000 live male births.
 The extra X chromosome is maternally derived
in 60% of cases
 Stigmata:- an apparent male with
gynaecomatsia
 Infertility (no or low sperm count)
 High pitched voice
 Small testis
 Increased levels of urinary excretion of FSH.
 Barr body present
STRUCTURAL CHROMOSOMAL
ABNORMALITY:
I: GENERAL:• Structurally abnormal chromosomes aris during
cell division (mitosis or meiosis).
• In dividing somatic cells, these abnormalities
usually are of No consequences or can lead to
lethal traits that cause extinction of the abnormal
cell clone.
• Some structural chromosomal abnormalities are
pathologically related to some form of cancer.
Structural chromosomal
abnormality-General cont-• Much more from embryological point of
view are the structural abnormalities that
originate during gametogenesis because
these are transmitted to all somatic cells
and result in hereditary transmissible
traits.
STRUCTURAL CHROMOSOMAL
ABNORMALITY:
Alteration in structure of chromosomes
may involve either;
 Autosomes or
 Sex- chromosomes
 AUTOSOMES:During cell division,meiosis of homologous
chromosome pair form bivalents.
Their chromatids are broken and crossing
of portions of chromatids normally occurs.
AUTOSOMES Cont-- Exchange of fragmented chromatids during the
first meiotic division also occur between
Nonhomologous chromosome,a process that
results in TRANSLOCATION: a fragment of
chromatid is transferred (reciprocally into
another.)
 TYPES of Translocations:
 Reciprocal translocation: A centric segment of a chromatid from one
chromosome is exchanged for a similar segment
from a heterologous chromosome.
Translocations
Types of translocations cont- Robertsonian transilocation: Is a centric fusion which involves the centromere
 Two acrocentric chromosomes, broken near the
centromere exchange TWO ARMS and form
new, large, metacentric chromosome and small
fragments.
 The segment is devoid of a centromere and is
usually lost during subsequent division
 If there is no loss of genetic material this
translocation is called BALANCED
Robertsonian translocation cont- Individual with such abnormalities are usually
NORMAL but may suffer from INFERTILITY.
- When fertile, they have a higher risk of giving
birth to MALFORMED children.
- Apparently, the translocation that was
BALANCED, in the cells of a parent may
become UNBALANCED, and may be
transmitted in haploid gamete and is paired with
new set of genes from the other parent.
Translocation cont- The overall risk for the development of
cancer because of translocation in
somatic cells lineage are associated with
increased risk of tumour formation.
 Best examples of translocation are:1. TRANSLOCATIONS between
chromosomes.
 8 and 14 t(8;14) = Burkitt’s lymphoma
Examples of translocations cont- 9 and 22, t(9;22) = chronic granulocytic leukemia
 Robertsonian translocation of chromosome 21 to
14 = hereditary DOWN’S syndrome t(14;21).
 This type of Down’s syndrome is NOT
related to increasing maternal age
 Children are usually born from young mothers
 It can be inherited
 Counseling is very important.
DELETION SYNDROMES:
• Meiotic disturbances of single BREAKS of
chromatids in somatic fragment that are
NOT incorporated into any of the 46
chromosomes and may be LOST is
subsequent cell division.
• This loss of genetic material is called
DELETION and involves either the
terminal or middle portion of a
chromosome.
Types of deletions
Examples of deletion syndromes:
• The best examples of deletion syndromes
are:5p Deletion (Cri du chat syndrome):This involves deletion deletion of part of
the short arm (46XY, 5p or 46XX, 5p)
It is characterized by a high pitched
mewing cry, closely resembling the cry of
a kitten.
Deletion syndromes cont-13q-deletion (hereditary retinoblastoma
There is deletion of long arm of
chromosome 13 (46XY, 13q or 46XX, 13q)
11p-deletion (Wilm’s tumour-aniridia
syndrome)
This involves deletion of a short arm of
chromosome 11.
ISOCHROMOSOMES
• These are X-chromosomes
• They are formed by faulty division of the
centromere during mitosis
• Normally, the centromere division occurs in a plane
parallel to the long axis of the chromosome, leading
to the formation of two identical hemichromosomes
• If the centromere divides transversely to the long
axis, pairs of isochromosomes are formed
- One pair corresponding to the short arm attached to
the upper portion of the centromere and the other
to the long arms attached to the segment.
An isochromosome
An isochromosome
Isochromosomes cont-• The most important clinical condition involving
isochromosome is TURNERS SYNDROME
(45X0) in which approximately 15% of the
affected have isochromosomes of the X
chromosome
• Has abnormal chromosome composed of long
arms of the X-chromosome and is monosomic
for genes located at missing short arm i.e. the
other isochromosome is lost during meiotic
division.
Isochromosomes cont-• There is no genetic information for the
short arm:-the individual does posses a Barr body and
46 chromosomes
- Is monosomic for the short arm of X
(carrier of short arm)
INVERSION:
• The break of a chromosome at TWO points
followed by inversion of the INTERMEDIATE
SEGMENT and REUNION results in the
formation of chromosomes with rearranged
distribution of genes in the restructured
chromatid
• Inversion are called PERICENTRIC and
PARACENTRIC depending on whether the
rotation occurs around the centromere or on
only the centric portion of the arm.
Structural changes
INHERITANCE OF SINGLE GENE
DEFECTS (ABNORMALITIES):
• Single genes that encode identifiable
traits, segregate sharply within families
and transmit according to the classic laws
of inheritance outlined by GREGOR
MENDEL and are called “MENDELIAN”
LAWS.
Single gene defects:
• Each mendelian trait is specified by two variants
of the same gene called ALLELES, which are
located at the same LOCUS of two homologous
chromosomes
• Genetic make-up of an individual is called
GENOTYPE
• The effect produced by the genetic make-up is
known as PHENOTYPE.
• MUTATION:- is an inheritable change in a gene
CLASSIFICATIONS OF GENES:
Genes are classified as: AUTOSOMAL-if located on an autosome or
 SEX-LINKED – if located on X and/or Y
chromosomes
 Genes that are expressed ONLY when they are
present in IDENTICAL form on both
chromosomes (i.e. double dose),the individual is
HOMOZYGOUS for that pair of genes and are
called RECESSIVE.
Classifications of genes cont-Genes that require ONLY ONE COPY-that
is genes that are expressed in
HOMOZYGOUS and HETEROZYGOUS
form are called DOMINANT
EXAMPLES:Rhesus Blood Group “D” may be considered
as Dominant and “d” as Recessive
Rhesus Blood group-as example:
GENOTYPE
PHENOTYPE
DD
D
Dd
D
Dd
d
• It is evident that if the phenotype is known, only
in case of group “d” can the genotype be
inferred.
• A person group “D” may be homozygous (DD) or
heterozygous (Dd). The actual genotype can be
deduced only by investigating the whole family.
Classifications of genes cont- Each individual has double chromosomal set
(PATERNAL and MATERNAL) and therefore
posseses two copies of the gene at every
LOCUS (with exception of genes at X
chromosome in male).
DOMINANT GENE (TRAIT).
 Is one which produces its effect whether
combined with a similar dominant alleles or a
recessive one.
 It is fully expressed in heterozygous(i.e. even if
only one copy of the allele determining it is
present)
DOMINANT GEN cont- Thus a dominant disease will affect every
individual possessing a single copy of a mutant
allele.
RECESSIVE GENE(TRAIT):
 Produces their effect only in homozygous
condition (i.e. double dose of the allele MUST BE
PRESENT for the recessive trait to appear).
 A recessive disease affects only those having two
copies of a mutant allele i.e. Homozygous.
 Individuals who are heterozygous for a recessive
allele will nevertheless be CARRIERS, in the
genetic sense of the trait
X-CHROMOSOMES
• Exceptions exists for mutant genes on the Xchromosomes
• Recessive X-linked genes will always be expressed in
MALES even though only one copy is present because:- The Y chromosome does not carry any gene
homologous to those on the X-chromosome.
- The male is said to be HEMIZYGOUS for genes on Xchromosome.
- Because of this different pattern of expression on the Xlinked genes, it is usual to divide the single gene
diseases into two:-
DOMINANTor RECESSIVE
diseases:
AUTOSOMAL: (Dominant or recessive).
X-LINKED (Dominant or Recessive).
Sex-liked dominant traits are rare and of
little practical significance.
AUTOSOMAL DISORDERS: Dominant disorders.
The salient features of autosomal dominant
traits are as follows
Autosomal dominant disorderssalient features:1. The gene is located on an autosome
2. The gene produces its effect in both
homozygous and heterozygous states.
3. The trait transmitted by the gene appears
in every generation
4. Unaffected member of the family do not
transmit the trait to their offsprings.
Examples of Autosomal Dominant
diseases:1.Connective tissue disease –e.g. Marfan’s
syndrome
2. Adult polycystic kidney disease
3. Haemoglobinopathies – e.g. sickle cell
anaemia, thalassemia
4. Familial hypercholesterolaemia – impared
metabolism of cholesterol
5. Familial tumours –e.g. Familial polyposis
coli, Neurofibromatosis
AUTOSOMAL RECESSIVE
DISORDERS:
The characteristic pattern of this inheritance are as
follows:1. The gene is located on an autosome
2. The effect on the gene are obvious only in the
homozygous state
3. Both parents are usually heterozygous for the
trait and are clinically unaffected
4. Symptoms appear in ¼ of the offsprings
5. ½ of siblings are heterozygous for the trait and
are thus asymptomatic
6. Males and females are equally affected.
Examples of autosomal Recessive
diseases:1. Inborn errors of metabolism: Phenylketonuria
 Alkaptonuria
 Albinism
2. Lysosomal storage diseases: Glycogenosis
 Lipidoses
SEX-LINKED DISORDERS:
•
1.
2.
3.
4.
5.
6.
The principles of X-linked recessive inheritance follow the
following pattern:The gene is located on X-chromosome
The recessive traits are fully expressed in heterozygous
males and rarely in homozygous females
A trait is usually transmitted by asymptomatic females.
Each son of heterozygous female carrier has a1in 2
chance of being affected (50%).
Unaffected males do not transmit
Affected males do not transmit the trait to their sons, but to
daughters. These daughters can become asymptomatic
carriers.
Examples of X-linked diseases:
1. Haemophilia A (Factor VIIIC, classic
haemophilia)
2. G-6PD deficiency
3. Diabetes insipidus
4. Red/Green colour blindness etc
MULTIFACTORIAL INHERITANCE
• These are inherited NEITHER as
dominant NOR as recessive mendelian
characteristics
• It is a combination of many genetic and
non genetic factors:Systemic hypertension
Diabetes mellitus
Cleft lip and palate
Congenital pyloric stenosis.