Medical Genetics
Genetic: Search for life
What
is a Gene?
Gene functions?
What is mutation?
Mutation types:
Can something in your genes cause disease?
What causes some genes to be recessive and other genes to be dominant?
Dominant or recessive?
X-linked inheritance.
Mithochondrial inheritance.
Genetic:
Search for life
The role of genetic factors in diseases is the core of modern medicine. Discovery
of electron microscopy, recombinant DNA technology, and modern analytical instrument
help the study of genes gains popularity and make this field of medicine better
understood. The science of genetics is based on work carried out in the 1860s
by Gregor
Mendel. Experimenting with a variety of garden pea (Pisum
sativum), Mendel discovered that the inheritance of traits was due to the transmission
of specific units of inheritance. This was the first sighting of "genes",
a discovery that revolutionized biology and laid the foundations for modern
biomedical research.
What
is a Gene?
Is it a template for life? Is it a chemical component that is bound together
by physical and chemical forces? Or is it the life itself? Before we get into
the examining the specifics of a gene's componenets, lets take a broader look
at its basic components and the way it functions. The first thing one needs
to know is that DNA (deoxyribounucleitide) comes in four chemical forms: Adenine,
Cytosine, Guanine, and Thymine. A-T and C-G and always paired together. A gene
looks like a very long thread made up of a large number of DNA. These DNA like
any other macromolecule found in nature are bound together in a particular arrangement.
The makeup of a gene include a covalent bond, hydrogen bond, and electronegativity
of oxygen and nitrogen. The elements that make DNA are carbon, oxygen, hydrogen
and phosphate. Only by this form are we able to exist. Just imagine if DNA had
one different component. Humans would have a completely different shape, function
and mechanism!
With a few exceptions, every cell in the human body has 3 billion pairs of these
A-T C-G, forming 46 chromosomes (23 pair; 22 pairs of autosomes and one pair
of X and Y). The chromosomes come in different shapes and sizes and each pair
are joined in the middle.
Each chromosomes contains over a 1000 genes containing several thousands of
DNA, each with its own specific function. The rest of the DNA are dormant (not
active). We carried these dormant DNA with us when we were in "primordial
soup".
Gene
functions:
The major function of genes is to produce protein, the basic block of all functions
in the body. Body structure, color of your eye, enzymes to digest the food we
take, neurotransmitters which determine our way of thinking, hormones for growth,
sex, metabolism and many more. Therefore, it is important to have the right
kind and the right amount. If the gene is defective even by one DNA missing
or displaced, the right protein will not be made and the structure will either
be defective and won't work at all or there won't be enough to maintain the
function and cause medical problems. The inactive genes(Introns), if triggered
by for example, sun light, virus (HIV, Human Papilloma Virus), radiation, or
other chemicals, start functioning abnormally and lead to problems. Before we
get to genetic diseases there is one more item we need to discuss: mutation.
What is mutation (change, permanent gene transformation)?
In the human genome,
there are many mechanisms of mutation. Keep in mind that mutation is not bad
all the time; after all, it is due to mutation, that as humans, we can communicate
through speech and differentiate ourselves from all other species. These mutations
may affect and alter the function of the gene and hence, its protein making
ability.
Every time a cell divides these entire DNA (3 billion of them) have to duplicate
themselves. The cell has it own mechanism to correct any error that may happened
(proof reading), but statistically one in very billion will be missed and will
make up a new gene. Now suppose, mutation happens during the division of an
egg which is formed in females in the first few months of conception and that
this mutation is compatible with life; then we have a new species.
Here is an example: it is been known since 1980 that some people with HIV do
not go on to develop Aids. It is now found that the immune cells of these patients,
called CD8 T cells, produce some unidentifiable factors which inhibited HIV
cells from replicating. These patients share the same genes as every one else,
but during their developmental stages, some of their stem cells (cells capable
of forming any organism in the embryonic stage) mutated to cells that produce
special protein that inhibit the HIV growth. Now suppose, AIDS was an airborne
virus! Only that small population with mutant cells would survive, wiping out
the remaining population. An new race of humans would follow; the mutants offspring
would become the norm!
A-Major gene rearrangement
1. Deletion, absence or altered size of a DNA fragment is uncommon in human
except for a few diseases,
" a-Thalassemia
" Growth hormone deficiency
" Familial hypercholesterolemia
2. Duplications
" Duplication of DNA sequences are common in evolution and may be caused
by mispairing between homologous DNA sequences in close proximity.
3. Insertion
" Insertions are rare cause of mutation in human. However, transposition
(transfer from one point to another location) is not uncommon. This mutation
disrupts a gene and a defect may result. Hemophilia is an example.
B-Point mutation
(single nucleotide substitutions)
Similar to bacteria and viruses, point mutation is the most common cause of
mutagenesis in human genome. Disorders that have clearly shown to be causes
by this type of mutations are b-thalassemia, cystic fibrosis, phenylketonuria
(PKU), and Tay-Sachs disease.
Mutations during protein production (translation, transcription) are other form of mutation that resulted in non-functional protein or no protein production at all.
Can
something in your genes cause disease?
Can you really inherit the risk for developing a disease if other people in
your family are diagnosed with the syndrome? We never know except when the gene
is dominant or recessive and then we can only predict the risk of transmitting
the disease to the offspring.
What
causes some genes to be recessive and other genes to be dominant?
As mentioned before, chromosomes (collation of genes) come in pairs; one pair
is paternal and one pair is maternal; each parallel genes called allele. As
you may recall, the function of these genes is to make functional proteins.
In a normal person both of these genes are active. If the gene for the protein
is structural, then it's important to have the right kind and the right amount.
If the gene is defective, the right protein will not be made and the structure
will either be defective and won't work at all or there won't be enough to maintain
the structure. Sometimes you need both genes (allele) to be working to get enough
of the structure. So a homozygous person (an individual with both genes from
maternal and paternal working) will have the strongest structure. A heterozygote
would have one gene that is working and may produce enough of the protein to
maintain the structure, but maybe not. So in some cases, just having one copy
of the dominant (working) gene is enough (this person is now carrier of the
disease. If it is a trait for something like eye color, this is not going to
cause a defect, just a difference. In this case, being heterozygous or homozygous
for the dominant trait produces the same color of eye. In the case of sickle
cell anemia, the recessive gene changes the protein structure of the shape of
the red blood cell. If you have one good copy and one bad copy of the gene,
some of your cells will be normal and some will be sickle cells. One good copy
of the gene gives you enough normal red blood cells to stay healthy. But if
you don't have a normal copy, all of your cells have the capability to sickle
under certain conditions and this can be fatal.
So think of dominant effect if the body cannot produce enough of the gene product if only one allele is functioning normally. Familial hyperchlostremia is one example. Other mutant genes exert a dominant effect because they produce an abnormal product that interferes with the normal allele's product. This type of mutation is called Dominant Negative mutation. An example of this type of mutation is dominantly inherited isolated growth hormone deficiency, a mutation of one allele produce a protein that binds to the normal protein produce from normal gene, which prevents the growth hormone from being secreted and thus hormonal deficiency.
Dominant
or recessive?
Dominant or recessive depends on the function of the gene. The term is mostly
used for genetic diseases. Look at it this way. If a gene responsible to making
a protein, hormone or factor that is needed in whatever amount, the lack of
a portion of that protein would not be disastrous. So if one of the two genes
present in a diploid cell would be mutated, but the other one is in tact, the
cell or organism would still be healthy. However when both gene copies are damaged,
the cell would suffer from disease. That is a recessive gene. When a gene product
and it's amount is essential, and a mutant form would cause damage to the cell
or the organism, even one copy of a mutated gene would cause damage: the healthy
second copy of that gene could not prevent this. That gene is causing a disease
that is inherited in a dominant form.
x-linked inheritance
can be either recessive or dominant, although in patiendts with a recessive
X-linked condition, the effect is usually only observed in the make. X-linked
inheritance is suspected when several relatives in the female line of a family
are affected. Because male have only one X chromosom, they are hemizygous, not
heterozygous, for X-linked genes.
Fragil X syndrom, ocular albinism, and Duchenne Muscular Dysrophy (DMD) are
among the example of X-linked inheritance.
Mithochondrial
inheritance
Mithochondrial inheritance, human cells have hundreds of mitochondria (powe
plant) dispresed throughout the cytoplasm, each containing a nymber of circular
DNA. The role of these DNS is just to cause diseases. Their origin is thought
to be from the time where prokaryote cells (simple cells like bacteria) were
evalvint into eukaryote cells (advanced cells capapable of forming organismes).
Kearns-Sayre syndrome and Lebre's optic neuropathy are two examples of mithocondrial
inheritance.
Author: Mansour
Nooshmehr MD, MS, MSc.
drnoush@medfamily.org
Genetics