Topic 3.

1 - Genes
What is a Gene?

Genes are commonly thought of as part of a DNA molecule that controls a particular characteristic,
such as the gene for eye colour in humans or the coat colour of a mouse. In the sections on
transcription and translation (protein synthesis) we learned that the way a gene controls such
characteristics is by coding for a protein. In the case of eye (also skin and hair) colour the protein
encoded is an enzyme that controls the production of the pigment melanin.

A definition of a gene is then a sequence on a DNA molecule that codes for a polypeptide.
Remember it may take more than one polypeptide to produce a functional protein.

Since genes are part of the DNA they can be passed from one generation to the next they can be
inherited.

How many genes are present (required to code for) different species?

Examine the table in your textbook (page 142) and answer the following questions:

1. Compare the number of genes in the Prokaryotes to all other members in the table and
suggest an explanation?

2. Does the data support the conclusion that multicellular organisms require more genes than
unicellular organisms? Explain.

3. Is there a clear trend amongst the animals that suggests greater complexity requires more
genes?

4. Suggest why plants (on average) have more genes than animals?

5. (HL) Humans are estimated to have 23,000 genes, but it is likely that we produce many more
proteins than this number, explain how?
What is an Allele?

If we return to the example of human eye colour and consider the situation of blue and brown eyes
(although this is a simplification as there are other genes involved that account for the other eye
colours) we can understand the concept of alleles. There are two forms of the gene that controls the
blue versus brown eye colour, the alternative forms of a gene (often two, sometimes many) are
called alleles.

We denote the brown eye allele by the letter B and the blue eyed allele by the letter b.

These two versions of the eye colour gene differ in their sequences and therefore produce different
polypeptides / proteins that give rise to the two different colours.

The differences between the two alleles may result from changes of single bases at particular points
in the sequence; these are called Single Nucleotide Polymorphisms or SNPs (pronounced snips).
They account for >90% of all human DNA polymorphisms.

Complete the activity Cytochrome Oxidase

Complete the data based question from p145 of your textbook COX-2, smoking and
stomach cancer.

Alleles arise by mutation

A mutation is a change in the structure or amount of DNA in an organism. A gene mutation or point
mutation is a change that occurs within the DNA sequence of a single gene.

The differences that we see between alleles of a particular gene arise as a result of mutation. One of
the most common ways in which gene mutation occurs is as an error of DNA replication. When a
mutation occurs in a gene, there are three possible outcomes: (i) The mutation changes the protein
that is encoded and has a negative effect on the organism, (ii) The mutation does not affect the
protein sequence, due to the degeneracy of the genetic code, as thus is a neutral mutation and (iii)
The mutation changes the protein encoded in such a way that it improves the survival chances of the
organism. The third option is certainly the least likely since the genes in most organisms are the
results of millions of years of evolution.
Types of gene mutation include:

Substitution one or more nucleotides are replaced by alternatives, changing the DNA
sequence. This may or may not change the protein product since the genetic code is
degenerate.
Deletion and Insertion in these two cases one or more nucleotides are either removed
from the sequence or added to the sequence. This results in a changed sequence and an
altered protein product. If multiples of 3 nucleotides are not added or deleted then the
reading frame of the gene is changed.

Sickle Cell Anaemia

Haemoglobin molecules are made up of four polypeptide chains known as globins. Each globin chain
is attached to an iron-containing haem molecule, which is the part that carries oxygen.
Intermolecular attractions between amino acids in adjacent globin chains hold the four chains
together in the quaternary structure. Under conditions of high concentration of oxygen, such as in
the lungs, haemoglobin associates readily with oxygen. In the body tissues, where oxygen
concentrations fall, the affinity of haemoglobin for oxygen is much less and oxygen is released.

Adult haemoglobin (HbA) has two alpha () globin chains associated with two beta () globin chains
as in the diagram below:

globin

globin

Haem group

A section of the -globin gene is shown below with the template strand uppermost:

---TGTGGGCTCCTTTTT---

---ACACCCGAGGAAAAA

This would be transcribed to form the following mRNA:

---ACACCCGAGGAAAAA---

The mRNA would be translated into the following sequence of amino acids:

---thr---pro---glu---glu---lys---

This forms part of the -globin protein that is used to form haemoglobin and packaged into
erythrocytes (red blood cells)
Sickle cell anaemia is a genetic disease that results from a gene mutation in the globin gene. There is
a single base substitution of a T (thymine) for an A (adenine). In the following diagram the nucleotide
that has been changed is marked.

The DNA sequence for the same section of the globin gene after substitution is now:

---TGTGGGCACCTTTTT---

---ACACCCGTGGAAAAA---

Substitution

The transcribed mRNA would now read:

---ACACCCGUGGAAAAA---

The mRNA would be translated into the following amino acid sequence:

---thr---pro---val---glu---lys---

The single base substitution resulted in the polar amino acid glutamic acid being replaced by the
non-polar amino acid valine. Consequently, sickle cell haemoglobin (Hb-S) replaces normal adult
haemoglobin (Hb-A) in the red blood cells. This apparently trivial alteration to the -globin gene
alters the quaternary structure of haemoglobin, which has a profound influence on the physiology,
and well-being of an individual. Haemoglobin S (Hb-S) is less efficient at carrying oxygen than normal
haemoglobin. It is also much less soluble and begins to crystallise as the oxygen concentration falls,
as it does in the capillaries of the tissues. The Hb-S molecules polymerise, arranging themselves in
long, parallel fibres within the red blood cells. These fibres are stabilised by interactions between the
substituted valine and hydrophobic regions on adjacent Hb-S molecules. This causes the red blood
cells to become sickle, or crescent, shaped.

In their lifetime's passage of about 100 miles around the body, the red blood cells go through a cycle
of sickling and desickling, eventually becoming irreversibly sickled. Unavoidable damage is caused to
the red blood cell membrane resulting in lysis of these fragile cells after a lifespan of merely a few
days (compared with the normal lifespan of 120 days). Chronic haemolytic anaemia is the result.
Sickled cells are also relatively inflexible and rigid and tend to form aggregates, so increasing the
viscosity of the blood. Small capillaries become blocked, which deprives tissues of their blood supply
and leads eventually to death of the tissue. Almost any organ can be involved in this process, which
may be excruciatingly painful, although bones are particularly susceptible. If the blood vessels
supplying the brain are affected, this can cause a stroke, or if the sickle cells sequester in vessels of
the lungs, this can lead to a gradual deprivation of oxygen, which places a severe strain on the heart.
Secondary infections frequently follow repeated blockage of blood vessels.
 Why does such a lethal allele persist at relatively high levels in some populations?

In sickle cell anaemia there are genetically determined morphs.

What is a Genome?

Text Genotype Phenotype Condition Malaria

The Human Genome project Normal red blood cells, no

A A Susceptible
Hb Hb Normal anaemia. Healthy
Text

Sickled red cells at low O2

levels. Anaemia from
Sickle cell Susceptible
HbS HbS destruction of sicked red
Anaemia
blood cells. Lethal.

Normal red blood cells, no

Sickle cell Resistant
HbA HbS anaemia. Healthy
Trait

Given that the recessive genotype is lethal you might expect that the frequency of the HbS
-allele would gradually be reduced in the gene pool. However, in some parts of Africa,
notably those where malaria is endemic, the frequency of this allele is higher than
expected and relatively stable. The reason for this is that there is a heterozygote
advantage; the HbA HbS genotype confers normal blood cells and resistance to malaria.
Therefore there are two selection pressures acting on the frequency of the HbS -allele. One
is a negative pressure, the lethality of HbS HbS, and the other a positive pressure, the
heterozygote advantage enjoyed in areas where malaria is common. These two pressures
balance each other out and a stable situation, of steady gene frequencies, is achieved.

Activity complete the Biozone worksheet Sickle cell anaemia

Genome

The Genome is defined as the genetic information of an organism, which is comprised of all the
nucleotide sequences of all the DNA molecules in the cell of an organism.

In the case of eukaryotic organisms the genome includes the DNA found inside the mitochondrion
and chloroplast. In the case of mitochondria they are inherited through the egg and so the
mitochondrial genes inherited are always of maternal origin (not 50:50 from both parents as with
most genes).

In the case of prokaryotes the genome is the circular loop of DNA plus any plasmids that may be
present.

Note that the genome does not just refer to the genes that code for proteins, but ALL of the DNA,
including the non-coding DNA (junk DNA) that makes up around 97% of the DNA.

Refer back to the term Proteome and compare the definitions.

The Human Genome project

The Human Genome Project (HGP) was the international, collaborative research program whose
goal was the complete mapping and understanding of all the genes of human beings.

The HGP has revealed that there are probably about 20,500 human genes. The completed human
sequence can now identify their locations. This ultimate product of the HGP has given the world a
resource of detailed information about the structure, organization and function of the complete set
of human genes. This information can be thought of as the basic set of inheritable "instructions" for
the development and function of a human being.

The International Human Genome Sequencing Consortium published the first draft of the human
genome in the journal Nature in February 2001 with the sequence of the entire genome's three
billion base pairs some 90 percent complete. A startling finding of this first draft was that the
number of human genes appeared to be significantly fewer than previous estimates, which ranged
from 50,000 genes to as many as 140,000.The full sequence was completed and published in April
2003.

The sequence published was just one example of the human genome; a major undertaking is now
underway to sequence many different human genomes in order to study the variation that exists
within the human population.

The link below provides an interesting perspective of the past, present and future of the HGP:

http://report.nih.gov/NIHfactsheets/ViewFactSheet.aspx?csid=45&key=H#H