Genetics I A guide to the Human Genome for Clinicians

Question 1

How can you get a disease?

Answer 1

A combination of the environment and through your genetic variation causes you to get a disease.

Question 2

What is the concept of precision/personalised medicine?

Answer 2

The object is to use a test (it could be a genetic or a non-genetic test) to determine who will respond to a treatment and who will not, and find those who will not respond a different treatment.
Genetic testing is one of the tools for determining treatment.

Question 3

What is the proportion of genetic predisposition to environment in common diseases?

Answer 3

For common diseases most is caused by the environment with a little genetic predisposition.

Question 4

What is the structure of DNA?

Answer 4

Strands of DNA pair up and bond in an antiparallel fashion.
DNA is replicated and read always in the 5’ -3’ direction.
DNA is an information molecule.
The sugar backbone is made of 2-deoxyribose (ribose in RNA).
The bases are ACGT (in RNA the bases are ACGU).

Question 5

Where is the information in DNA held?

Answer 5

In the sequence of the bases which are held on a sugar/phosphate backbone.
Thymine (T) always pairs with Adenine (A) and Guanine (G) with Cytosine (C).

Question 6

How many chromosomes does a normal person have?

Answer 6

46

Question 7

How is a chromosome formed?

Answer 7

The DNA strand associates with proteins (including histones) and is wound into a structure called a chromosome.

Question 8

Why is cell division important?

Answer 8

Genes must be replicated.

Question 9

What happens during DNA replication?

Answer 9

(In some diseases, DNA replication is the bases of the disease)….

Question 10

How is DNA damaged and repaired?

Answer 10

DNA strand breaks e.g. BRC1, for breast cancer.
UV or Chemical crosslinking e.g. Xeroderma Pigmentosa can be used to repair single strands of DNA.
Mismatched bases e.g. Hereditary colorectal cancer can damage the DNA.
DNA can be damaged during replication.
Repair mechanisms exist.
Defects in these repair mechanisms cause disease.

Question 11

What is the process of mitosis?

Answer 11

(You can get

mutations in cells during mitosis that can cause cancer)

Question 12

In mitosis what does one diploid parent cell become?

Answer 12

Two identical diploid daughter cells

Question 13

In meiosis what does one diploid parent cell become?

Answer 13

One diploid parent cell becomes 4 haploid daughter cells (one chromosome to each cell).

Question 14

In meiosis sometimes crossing over occurs, what is crossing over?

Answer 14

Crossing over is where genes segregate independently, even if on the same chromosome.
This occurs in gamete formation.

Question 15

What are the differences between ribonucleic acid (RNA) and DNA?

Answer 15

Same primary structure as DNA except:
Single stranded.
Ribose in backbone not deoxyribose.
Uracil (U) is used instead of Thymine (T).

Question 16

How does a gene become a protein?

Answer 16

DNA undergoes transcription to become pre mRNA. This is spliced (where the introns are removed) and becomes mRNA. It is then translated and becomes a protein where 3 bases encode for 1 amino acid or a stop. Protein is modified and moved round the cell.

Question 17

How many bases encode an amino acid?

Answer 17

3 bases encode 1 amino acid.

However different combinations of bases can code for the same amino acid.

Question 18

How is the amount of protein produced determined?

Answer 18

Rate of transcription (manufacture of Pre-mRNA).
Rate of splicing to mRNA.
Half life of mRNA.
Rate of processing of polypeptide.

Question 19

Why is every copy of the human genome different?

Answer 19

There are sequence variations within a gene

There are also sequence changes in the DNA between genes.

Question 20

During what phase of the cell cycle does DNA replication exist?

Answer 20

S phase.

Question 21

What is the process of meiosis?

Answer 21

Meiosis is divided into 2 phases: meiotic division 1 and Meiotic division 2. During meiotic division 1 DNA replication and recombination occurs. Cell division 1 then takes place. Meiotic division 2 then takes place and cell division 2 is carried out forming 4 gametes with unique genetic information.

Question 22

What are the different types of sequence variations that can occur within a gene?

Answer 22

Changes in the promotor sequence.
Changes in the exon sequence.
- Ones that change an amino acid
- Sequence changes that do not change the amino acid coded for.

Question 23

What are the different types of sequence changes that can occur in the DNA between genes.

Answer 23

Single nucleotide polymorphisms (SNPs)

Larger deletions or duplications

Question 24

What are the 2 definitions of polymorphs?

Answer 24

Any variation in the human genome that has a population frequency of greater than 1%.
OR
Any variation in the human genome that does not cause a disease in its own right. It may however, predispose to a common disease.

Question 25

What are the 2 definitions of a mutation?

Answer 25

A gene change that causes a genetic disorder (a disease causing mutation)
OR
Any heritable change in the human genome.

Question 26

Where does variation come from?

Answer 26

Variation arises because DNA replication is not perfect causing each copy of the genome to be slightly different.
This would explain in part why you don’t all look the same.
Because of crossing over at meiosis, these variants all segregate independently of each other (unless they are very close together on the chromosome).

Question 27

What is the results of DNA replication being imperfect?

Answer 27

Everyone has new genetic variants that their parents don’t.

Every cell in your body has mutations that have been acquired during mitosis.

Question 28

What are the 2 major phases of the cell cycle and what is a brief oversite of what happens in each?

Answer 28

The stages of the cell cycle are divided into 2 major phases: interphase and the mitotic (M) phase. During interphase the cell grows and makes a copy of it’s DNA.
During the mitotic phase, the cell separates it’s DNA into 2 sets and divides it’s cytoplasm, forming 2 new cells.

Question 29

What are the stages within interphase and what happens during each?

Answer 29

G1 Phase.
During this phase, also called the first gap phase, the cell grows physically larger, copies organelles and makes the molecular building blocks it will need in later steps.
S Phase
The cell synthesizes a complete copy of the DNA in it’s nucleus. It also duplicates a microtubule-organizing structure called the centrosome. The centrosomes help separate DNA during M phase.
G2 Phase
During the second gap phase, or G2 phase, the cell grows more, makes proteins and organelles, and begins to reorganize its contents in preparation for mitosis. G2 phase ends when mitosis begins.
The Interphase takes place between one mitotic (M) Phase and the next.

Question 30

What happens during the M (mitotic) Phase?

Answer 30

The cell divides it’s copied DNA and cytoplasm to make new cells. M phase involves 2 distinct division-related processes: mitosis and cytokinesis.
In mitosis, the nuclear DNA of the cell condenses into visible chromosomes and is pulled apart by the mitotic spindle, a specialized structure made out of microtubules. Mitosis takes place in 4 stages:
Prophase (sometimes divided into early prophase and prometaphase),
Metaphase
Anaphase
Telophase.
In cytokinesis, the cytoplasm of the cell is split in 2, making 2 new cells. Cytokinesis usually begins just as mitosis is ending, with a little overlap. importantly, cytokinesis takes place differently in animal and plant cells.
In animals, cell division occurs when a band of cytoskeletal fibres called the contractile ring contracts inward and pinches the cell in 2, a process called contractile cytokinesis. The indentation produced as the ring contracts inward is called the cleavage furrow. Animal cells can be pinched in 2 because they’re relatively soft and squishy.

Question 31

What happens during cell cycle exit and G0?

Answer 31

What happens to the 2 daughter cells produced I 1 round of the cell cycle? This depends on what type of cells they are. Some types of cells divide rapidly, and in these cases, the daughter cells may immediately undergo another round of cell division. For instance, many cell types in an early embryo divide rapidly, and so do cells in a tumour.
Other types of cells divide slowly or not at all. These cells may exit the G1 phase and enter a resting state called G0 phase. In G0, a cell is not actively preparing to divide, its just doing it’s job. For instance, it might conduct signals as a neuron (like the one in the drawing below) or store carbohydrates as a liver cell. G0 is a permanent state for some cells, while others may re-start division if they get the right signals.

Question 32

How long does the cell cycle take?

Answer 32

Different cells take different lengths of time to complete the cell cycle. A typical human cell takes 24 hours to divide.

Question 33

What is the process of chemical crosslinking?

Answer 33

Chemical crosslinking is the process of linking polymer chains by covalent bondings, forming tridimensional networks which reduce the mobility of the structure and usually enhance it’s mechanical and barrier properties and it’s water resistance.

Question 34

What is mismatched bases?

Answer 34

This is a DNA defect occurring when 2 non-complementary bases are aligned in the same base-pair step of a duplex DNA.

Question 35

What is the process of mitosis?

Answer 35

Mitosis consists of 4 basic phases:
Prophase (this can be broken down into an early phase-prophase and a late phase-prometaphase
Metaphase
Anaphase
Telophase
Cytokinesis - The process of dividing the cell contents to make 2 new cells starts in anaphase or telophase. PMAT
A cell right before it begins mitosis is in interphase (late G2 phase) and has already copied it’s DNA, so the chromosomes in the nucleus each consist of 2 connected copies, called sister chromatids. You can’t see the chromosomes very clearly at this point, because they are still in their long, stringy, decondensed form.
This animal cell has also made a copy of its centrosome, an organelle that will play a key role in orchestrating mitosis, so there are 2 centrosomes.

Question 36

What happens during prophase?

Answer 36

In early prophase, the cell starts to break down some structures and build others up, setting the stage for division of the chromosomes.
The chromosomes start to condense (making them easier to pull apart later on).
The mitotic spindle begins to form. The spindle is a structure made of microtubules, strong fibres that are part of the cell’s “skeleton”. Its job is to organize the chromosomes and move them around during mitosis. The spindle grows between the centrosomes as they move apart.
The nucleolus, a part of the nucleus where ribosomes are made, disappears. This is a sign that the nucleus is getting ready to break down.
In late prophase (sometimes also called prometaphase), the mitotic spindle begins to capture and organize the chromosomes.
The chromosomes finish condensing, so they are very compact.
The nuclear envelope breaks down, releasing the chromosomes.
The mitotic spindle grows more, and some of the microtubules start to “capture” chromosomes.

Question 37

What happens during metaphase?

Answer 37

The spindle has captured all the chromosomes and lined them up at the middle of the cell, ready to divide.
All the chromosomes align at the metaphase plate (not a physical structure, just a term for the plane where the chromosomes line up).
At this stage, the 2 kinetochores of each chromosome should be attached to microtubules from opposite spindle poles.
Before proceeding to anaphase, the cell will check to make sur that all the chromosomes are at the metaphase plate with their kinetochores correctly attached to microtubules. This is called the spindle checkpoint and helps ensure that the sister chromatids will split evenly between the 2 daughter cells when they separate in the next step. If a chromosome is not properly aligned or attached, the cell will halt division until the problem is fixed.

Question 38

What happens during anaphase?

Answer 38

The sister chromatids separate from each other and are pulled towards opposite ends of the cell.
The protein “glue” that holds the sister chromatids together is broken down, allowing them to separate. Each is now it’s own chromosome. The chromosomes of each pair are pulled towards opposite ends of the cell.
Microtubules not attached to chromosomes elongate and push apart, separating the poles and making the cell longer.
All of these processes are driven by motor proteins, molecular machines that can “walk” along microtubule tracks and carry a cargo. In mitosis, motor proteins carry chromosomes or other microtubules as they walk.

Question 39

What happens during telophase?

Answer 39

The cell is nearly done dividing, and it starts to re-establish it’s normal structures as cytokinesis (division of the cell contents) takes place.
The mitotic spindle is broken down into it’s building blocks.
2 nuclei form, one for each set of chromosomes. Nuclear membranes and nucleoli reappear.
The chromosomes begin to decondense and return to their “stringy” form.

Question 40

What happens during Cytokinesis?

Answer 40

The division of the cytoplasm to form 2 new cells, overlaps with the final stages of mitosis. It may start in either anaphase or telophase, depending on the cell, and finishes shortly after telophase.
In animal cells, cytokinesis is contractile, pinching the cell in 2 like a coin purse with a drawstring. The “drawstring” is a band of filaments made of a protein called actin, and the pinch crease is known as the cleavage furrow. Plant cells cant be divided like this because they have a cell wall and are too stiff. Instead, a structure called the cell plate forms down the middle of the cell, splitting it into 2 daughter cells separated by a new wall.