Unit 2 - Molecular and genetic factors in disease
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Lecture 1 - Introduction
Molecular medicine
Is a broad field, where physical, chemical, biological and
medical techniques are used to:
Describe molecular structures and mechanisms
Identify molecular and genetic errors of disease
Develop molecular interventions to correct them. The
molecular medicine perspective emphasizes cellular and
molecular phenomena and interventions rather than the
previous conceptual and observational focus on patients
and their organs
Classification of Human diseases
1) Those that is genetically determined.
2) Those that is almost entirely environmentally determined.
3) And those to which both nature and nurture contribute.
About 1% of all newborn infants possess a gross
chromosomal abnormality.
Approximately 5% of individuals under age 25 develop a
serious disease with a significant genetic component
The human genome
The gene is the most important unit of genetics.
The estimated total number of genes is about 30000-
35000, the gene has an average 1400 base pairs,only 1.5%
of the genome reprsents primary coding sequence
There are 3×10
9
(3000 megabase) base pairs of deoxy-
ribonucleic acid (DNA) present In the human genome.
DNA forms a double stranded helical structure with only
two type of base pairing are possible G-C and A-T, the
double stranded DNA unit of two nucleotides is referred
as a (BASE PAIR (bp))
The double stranded DNA helix is coiled around
chromosomal protein called histone to form nucleosomes
then these also adopt a coiled structure to form a
chromatin fibre which on more coiling forms the
chromomosome
DNA contains all of the genetic information required for
the development of cells into tissue & organs
Human cells contain 46 chromosomes:
22 pairs of autosomes and 1 pair of sex chromosome
One chromosome of each pair is derived from each
parent; these 46 chromosomes are the diploid number
seen in somatic cells.
Only germ cells (sperm &ova) have the haploid number
of 23 chromosome (22 autosomes and either an X or Y)
The genetic code is a 3 nucleotides unit which specify
certain aminoacid to be inserted into protein ,only a very
small fraction of the human genome codes for protein;
a Locus refers to any area of the genome ,
not all the DNA code for protein
sequences within the gene include coding
regions(exons),noncoding regions(introns)and regulatory
sequences
The conversion of DNA sequence to protein is mediated
by RNA
Most of the natural variation in DNA sequence occurs in
the noncoding region and have no effect on development
and function ,
variations that occur in the coding region leads to change
in protein sequence and possibly the function
If DNA variation results in sufficient impairment of
protein function to bring a harmful effect then A
GENETIC DISEASE may result.
When the genetic abnormality is mild, the genetic disease
can be recognized, but sometimes the genetic abnormality
may impair more vital process to such an extent that
embryogenesis cannot continue.
X inactivation
Is a special property of the X chromosome in the female
one of the two X chromosome in a cell is inactive, so in a
similar manner to male ,females only express one copy of
genes on the X chromosomes and this process of
inactivation is random ,
This can have a bearing on the expression of diseases
which are due to mutations in genes on the X
chromosome as either the normal or the mutant gene may
be inactivated.
Genotype: is the genetic makeup of an individual (the
sequences of their gene)
Phenotype: is any aspect of structure or development of
an individual (is the "outward, physical manifestation" of
the organism)
Genomic imprinting
• It means that the effect of a gene depends on whether its
inherited from the mother or father
• If an imprinted gene carries a mutation then the
manifestation of the disease will vary according to which
parent transmitted the mutation.
• For example a certain region on chromosome 15 contain
several genes in which only the paternal or maternal allel
Unit 2 - Molecular and genetic factors in disease
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is transcriptionally active so deletion of these gene on the
paternal chromosome cause a syndrome called (prader
willi syndrome) while deletion of maternal chromosome
causes a different syndrome(angelman's syndrome)
Polymorphism
It represents a small change in DNA sequence that does
not result in overt diseases this can happen if:
The change occurs in the noncoding DNA.
Do not alter the amino acid inserted in a given protein.
Result in an amino acid which is able to perform the same
function as the original.
We all share genome sequence that are 99.9% identical,
the remaining 0.1% is therefore responsible for all genetic
diversity between individuals.
Genetic factors in common diseases
Susceptibility to many common diseases is influenced by
genetic factors, this is recognized by an increased
incidence of the diseases in first degree relatives of
affected individuals but not in a pattern typical of
classical single gene disorders
Asthma,hypertention,diabetes,atopy , and ischemic heart
diseases and many infectious diseases show this pattern
Genes that act together with environmental influences
giving rise to this susceptibility are of interest
Penetrance and expression
Individuals who inherit a specific disease mutation do not
show an identical phenotype since they may not share the
other genetic or environmental factors that predispose or
unmask the full effect of the mutation.
Penetrance is the proportion of individuals who develop
the diseases phenotype.
Fully penetrant mutation: if all individual who inheret it
Develop the associated disease phenotype.
If additional environmental factors are needed the gene
may show late onset pentrance
Non –pentrant mutation if the individual is not exposed
to sufficient additional factors
Disease Expression describes the degree to which the
severity of the disease phenotype varies.
Genetic counseling
Genetic counseling is providing information about the
medical and family implications of a specific disease.
Aims of Genetic counseling is to:
Help individuals make decisions about planning a family
Taking part in screening program
Accepting prophylactic therapies.
Specific problems encountered in genetic counseling
include:
Accurate assessment of genetic risk
Identification of children at risk of genetic disorders
The increase in genetic risks associated with
consanguinity
Non-paternity as an ncidental finding in DNA diagnostic tests
Indication of genetic counseling
One or more birth defects
A genetic disorder or chromosome abnormality
Intellectual Development Disorder or developmental delay
Neuromuscular abnormalities
Unexplained metabolic problems
Congenital or familial hearing loss or blindness
Abnormal growth patterns
Abnormal sexual development
Prenatal exposure to drugs or medications
Cancer