Mutations (Prof London)

Question 1

What is a mutation?

Answer 1

A mutation is a change in DNA sequence.

Question 2

What can cause a mutation?

Answer 2

DNA replication errors made during cell division (mitosis and meiosis)
Exposure to ionising radiation (a mutagen)
Exposure to chemicals (chemical mutagens)
Infection by virus’

Question 3

Broadly speaking, what are are two types of mutation?

Answer 3

Germ line mutations and somatic mutations

Germ line mutations (genetic or hereditary) occur in the eggs or sperm. They affect all cells in the body and can be passed in to the offspring
A somatic mutation occurs in a body cell. This is not passed onto the offspring.

Question 4

Why are errors in DNA transcription and RNA translation fairly common?

Answer 4

Errors are not uncommon because RNA polymerase don’t proofread like DNA polymerases.

Question 5

Why will the long term effects of an error in transcription or translation be less severe to an error in the genome?

Answer 5

It will not be as bad because the cell will be making multiple copies of the same RNA and it is unlikely that this exact mutation will occur again.
Also, RNAs are quickly degraded so the mutated RNA will be quickly removed.
Lastly, RNA is not an inherited molecule that is passed down from generation to generation. So, making an incorrect copy of an RNA molecule is not going to have as big of an effect as making a change in the genome, which is lasting and permanent.

Question 6

Can mitochondrial DNA suffer mutations?

Answer 6

Yes! Mitochondrial DNA can suffer both germ line and somatic mutations. These mutations are carried down the mothers line.

Question 7

What kind of organs and tissues are the effects of mitochondrial disease (germ line mutations of mitochondria) most prevalent? What features are frequently observed?

Answer 7

The effect of mitochondrial mutations (mitochondrial disease) are most prevalent in tissues and organs that require a lot of energy. For example, the heart brain and muscles. This is because the mitochondria and the powerhouse of the cell.
Frequently observed features of mitochondrial disease include muscle weakness and wasting, problems with movement, diabetes, kidney failure, heart disease, dementia, hearing loss, vision abnormalities.
It is said that 1 in 200 children have mitochondrial disease.

Question 8

What are the effect of mitochondrial somatic mutations?

Answer 8

Mitochondrial DNA has a limited ability to repair when damaged so, mutations tend to build up over time. This build up of somatic mutations has been associated with some forms of cancer and an increased risk of age related disorders such as heart disease, Alzheimer’s and Parkinson’s.
Also, research suggests that the progressive accumulation of these mutations over time may play a role in the normal process of ageing.

Question 9

What would happen if a spontaneous mutation occurred in a germ cell?

Answer 9

Although the majority of germ line mutations are inherited, the first was spontaneous.
If the spontaneous mutation causes an autosomal dominant disorder (eg achondroplasia) then the child will have the disease and neither parent will. This phenomenon is how scientists know that the mutation is spontaneous.
In the cause of an autosomal recessive disorder (eg cystic fibrosis), for an individual to get the disease spontaneously, the spontaneous mutation must occur in exactly the same place on both chromosomes. This is very unlikely! Only 5 cases of spontaneous cystic fibrosis have ever been recorded. However, a spontaneous mutation does common affect one gene (eg 1 in 25 Caucasians for cystic fibrosis) producing a heterozygote.

Question 10

How does mitosis produce a chromosomal mutation?

Answer 10

A chromosomal mutation occurs when the duplicate chromosomes do not line up properly at the metaphase plate. This means that the pair will not move properly to each pole during anaphase (anaphase lag) which results in one cell having two copies of the chromosome and the other having none.

Question 11

What effect does a chromosomal mutation have on the daughter cell lacking a copy of a chromosome?

Answer 11

This type of mutation is usually fatal daughter cells lacking a copy of a chromosome.

Question 12

What effect does a chromosomal mutation have on the cell receiving two copies of a chromosome?

Answer 12

The cell receiving two copies of a chromosome will have an increase in expression of genes contained on the extra chromosome.
If the gene functions to slow growth then the extra copy may be fatal to to the cell. However, if the genes promote growth then the cell may grow uncontrollably leading to cancer. Other effects will depend on the nature of the additional gene.

Question 13

What are the four broad phases of gametogenesis?

Answer 13

1. The origin of the primordial germ cells and migration to the gonads
2. Increase in the number of germ cells by mitosis
3. Reduction in chromosomal number by meiosis
4. Structural and functional maturation of eggs and spermatozoa.

Question 14

What is a primordial follicle?

Answer 14

This is a primary oocyte surrounded by flattered epithelial cells.

Question 15

How many primary oocytes are there
At birth?
Puberty?
That will be ovulated?

Answer 15

Birth : 800,000
Puberty: 40,000
Ovulated: 500

Question 16

Why do primordial germ cells only begin to differentiate into spermatozoa at puberty?

Answer 16

Because they are only needed when oocytes are available to fertilise.

Question 17

What is the current model as to why so many oocytes are made and then lost during early development?

Answer 17

Despite there being many other theories, the current theory is that oocyte loss helps to individualise the surviving oocytes.
Eg one oocyte of a large cyst dies and this separates the cyst into two. This process is repeated until there are a few single oocytes.
This is supported by the fact that dying oocytes are found where new basement membrane is forming souring follicle assembly.

Question 18

What is the mutation rate in male gametes compared to female gametes? Why is this?

Answer 18

The mutation rate in male gametes is approximately 5 times higher than females.
This is because the number of germline divisions in spermatogenesis vastly exceeds that in oogenesis. Also, spermatogonal germ cells are continually active in adult men and the male mutation rate increases with age. (Male fertility decreases and miscarriage rate increases with age)

Question 19

Why do make and female gametocyte mutations increase with age?

Answer 19

Male - spermatozoa are continually made so older men’s spermatozoa have been exposed to mutagens / radiation for a longer time.
Females - scientists believe it is because they have spend longer in meiosis arrest.

Question 20

Would you expect the IVF embryo aneuploidy rate to over or under estimate the in vivo rate?

Answer 20

Overestimate. This is because, in natural fertilisation, the sperm have to ‘swim’ to the egg and compete to fertilise it. Only healthy spermatozoa will be able to do this. However, in IVF, the sperm do not have to ‘swim’ to fertilise the egg so, it is more likely to be fertilised by a mutated sperm.

Question 21

What percentage of pregnancies end in the first trimester?

Answer 21

60%

Question 22

What percentage of clinically recognised pregnancies end in miscarriage?

Answer 22

15%

Question 23

What percentage of clinically recognised pregnancy loss results from either structural or numerical chromosomal abnormalities?

Answer 23

75%

Question 24

When a successfully fertilised oocyte / zygote cleaves, what does it form?

Answer 24

A Morula

Question 25

What could happen if there was a mitosis chromosomal mutation in one of the cells at the 2 cell stage? 4 cell stage?

Answer 25

Mosaicism would occur. This is when the adult contains a mixture of two different genetic codes. The proportions of each type would depend when in the differentiation process this mutation occurred.

Question 26

What are the possible outcomes if a very early embryo was exposed to radiation?

Answer 26

Death / aborted
Teratogenesis (congenital malformation)
Cancer when born

Question 27

What features would allow a germ cell mutation to be inheritable?

Answer 27

It would not be lethal to gametes
It would not impure gamete function
It would not be lethal at fertilisation
It would allow the production of a viable adult with normal reproductive capacity.

Question 28

What observations have been made about the effect recessive mutations often have?

Answer 28

In general, it ha been observed that recessive mutations cause a loss of function and often affect biochemical pathways.

Question 29

What observations have been made about the effect dominant mutations often have?

Answer 29

In general, dominant mutations cause increased function and often cause structural abnormalities.

Question 30

What effect can mutations have on drug treatments?

Answer 30

This may lead to the drug having no effect, reduced effect, increased effect, side effects or an allergic reaction. (Basically, it can jut completely change the effect of the drug in any way). There are 1000s of different examples and they lead to exciting possibilities for precision medicine.

Question 31

What are somatic mutations?

Answer 31

These are errors in mitosis. They can be genetic (where an error in DNA replication has occurred) or, less commonly, chromosomal. The affected cell will produce 2 affected cells.
If the mutation is not lethal, does not affect mitosis and is not recognised as ‘foreign ‘ by the immune system then a clone will develop. This clone may produce a benign tumour or a malignant tumour. (Tumour means swelling).

Question 32

What can cause somatic mutations?

Answer 32

Mutations (eg soot and scrotal cancer, bladder cancers and an aniline dyes, smoking products…)
Radiation
Viruses