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Dr.Mohammed Alhamdany
Molecular and genetic factors in disease
Almost all diseases have a genetic component, and many
disorders that cause long-term morbidity and mortality.
All human cells are derived from the zygote (the fertilized
ovum), a single totipotent stem cell capable of producing all cell
types. During development, organs and tissues are formed by
the integration of four closely regulated cellular processes:
1-cell division
2- migration.
3-differentiation.
4-programmed cell death.
These processes continue in adult life by small populations of
stem cells capable of self-renewal. These cells can also
differentiate to maintain and repair the tissues.
DNA, chromosomes and chromatin
The nucleus is a membrane-bound compartment found in all
cells, with the exception of erythrocytes and platelets. In
humans, the nucleus contains 46 chromosomes, each of which
comprises a single linear molecule of deoxy-ribonucleic acid
(DNA), which is intimately complexed with proteins in the form
of chromatin. The basic (structural) unit of chromatin is the
nucleosome, which is a structure of approximately 147 base
pairs (bp) of DNA bound round a complex of four different
histone proteins.
Each nucleus contains two copies of the genome and thus
humans are diploid organisms. The diploid status is present as
22 identical chromosomal pairs—the autosomes—named 1–22
and two sex chromosomes (XX in females and XY in males).
Each DNA strand consists of a linear sequence of four bases—
guanine (G), cytosine (C), adenine (A) and thymine (T)—
covalently linked by phosphate bonds. The sequence of on
strand of double-stranded DNA determines the sequence of the
opposite strand because the helix is held together by hydrogen
bonds between adenine and thymine or guanine and cytosine.
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Genes and transcription
Genes are functional units of the chromosome that result in a
flow of information from the DNA template via the production
of messenger ribonucleic acid (mRNA) to the production of
proteins. The human genome contains an estimated 21 500
different genes. Genes may be silent or active; genes that are
active undergo transcription which requires binding of an
enzyme called RNA polymerase II to a segment of DNA at the
start of the gene termed the promoter. Once bound, RNA
polymerase II proceeds along one strand of DNA, producing an
RNA molecule which is complementary to the DNA template. A
DNA sequence close to the end of the gene, called the
polyadenylation signal, acts as a signal for termination of the
RNA transcript. The activity of RNA polymerase II is regulated
by transcription factors (promoters and enhancers)
Alterations of the DNA sequence within promoters and
enhancers can cause disease for example, alpha-thalassaemia.
Epigenetic: The histone proteins associated with chromatin can
also be methylated, phosphorylated or acetylated at specific
amino acid residues in a pattern that reflects the functional state
of the chromatin; this is called the histone code. Such
modifications are termed epigenetic, as they do not alter the
primary sequence of the DNA code but do have biological
significance in chromosomal function. Abnormal epigenetic
changes are increasingly recognized as important events in the
progression of cancer, allowing re-expression of genes which
are normally silenced during development to support cancer cell
dedifferentiation.
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RNA splicing:
Transcription produces an RNA molecule that is a copy of the
whole gene, termed the primary or nascent transcript.
RNA differs from DNA in three main ways:
• RNA is single-stranded.
• The sugar residue within the nucleotide is ribose, rather than
deoxyribose.
• Uracil (U) is used in place of thymine (T).
The nascent RNA molecule then undergoes a process called
splicing , to generate an mRNA molecule which provides the
template for protein production.
Following splicing, the mRNA molecule is exported from the
nucleus and used as a template for protein synthesis.
Most mRNA molecules contain a segment called the open
reading frame (ORF), which contains the code that directs
synthesis of a protein product. This code comprises a contiguous
series of three sequential bases (codon), which specifies that a
particular amino acid should be incorporated into the protein.
There are 64 different codons; 61 of these specify incorporation
of one of the 20 amino acids, whereas the remaining three
codons (stop codons)—cause termination of the growing
polypeptide chain.
There are various categories of non-coding RNA (ncRNA),
including 1-transfer RNA (tRNA), 2-ribosomal RNA (rRNA),
and 3-microRNA (miRNA). There is increasing evidence to
suggest that miRNAs play a role in normal development, cancer
and common degenerative disorders by regulating the stability
of other RNA molecules.
Translation and protein production
Following splicing and export from the nucleus, mRNAs
associate with ribosomes, which are the sites of protein
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production. During translation, tRNA binds to the ribosome.
The tRNAs deliver amino acids to the ribosome so that the
newly synthesized protein can be assembled in a step-wise
fashion. Individual tRNA molecules bind a specific amino acid
and ‘read’ the mRNA ORF via an ‘anticodon’(that found on
tRNA) of three nucleotides that is complementary to the codon
in mRNA.
Proteins synthesised on these ribosomes are translocated into the
lumen of the ER, where they undergo folding and processing.
From here the protein may be transferred to the Golgi apparatus,
where it undergoes post-translational modifications, such as
glycosylation, to form the mature protein that can be exported
into the cytoplasm or packaged into vesicles for secretion.
Cellular signalling
Cells communicate with one another directly through gap
junctions, and indirectly by release of hormones, cytokines and
growth factors which bind to receptors on the target cell.
Transmembrane receptors can be grouped into:
1- ion channel-linked receptors (e.g. glutamate and the nicotinic
acetylcholine receptor)
2- G protein-coupled receptors (e.g. olfactory receptors,
parathyroid hormone receptor)
3- receptors with intrinsic enzyme activity (e.g. insulin receptor,
growth factor receptors)
4- receptors which do not have intrinsic enzymatic activity, but
which recruit other proteins with kinase activity (TNF receptor,
interleukin (IL)-1 receptor).
Cell death, apoptosis and senescence
With the exception of stem cells, human cells have only a
limited capacity for cell division. The molecular nature of
‘biological clock’ is of great interest in the study of the normal
ageing process, and the study of rare human diseases associated
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with premature ageing has been very helpful in identifying the
importance of DNA repair mechanisms in senescence.
apoptosis, or programmed cell death which is an active process
that occurs in normal tissues and plays an important role in
development, tissue remodelling and the immune response. The
signal that triggers apoptosis is specific to each tissue or cell
type. This signal activates enzymes, called caspases, which
actively destroy cellular components, including chromosomal
DNA.
Necrosis is a pathological cell death process in which the
cellular environment loses one or more of the components
necessary for cell viability. Hypoxia is probably the most
common cause of necrosis.
Genetic Disease and Inheritance
Meiosis
Meiosis is a special form of cell division that only occurs in the
postpubertal testis and the fetal and adult ovary. Meiosis differs
from mitosis in two main ways:
Firstly, there is extensive swapping of genetic material between
homologous chromosomes, a process known as recombination,
before the first of the two meiotic cell divisions. As a result of
recombination, each chromosome that a parent passes to his or
her offspring is a mix of the chromosomes which the parent
inherited from his or her own mother and father.
Secondly, the cells that are produced as the result of meiosis
(sperm and egg cells) are haploid, in that they each have only 23
chromosomes: one of each homologous pair of autosomes and a
sex chromosome.
The sperm determines the sex of the offspring, since 50% of
sperm will carry an X chromosome and 50% a Y chromosome,
with each egg cell carrying an X chromosome.
In females, meiosis begins in fetal life but does not complete
until after ovulation. In males, meiotic division does not begin
until puberty and continues throughout life.
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