Spontanous Mutations - Early Gametogenesis

Question 1

Which cell type is the common origin of spermatozoa and oocytes?

Answer 1

• Primordial Germ Cells (PGCs)

- Start in gut mesentery and migrate to gonads during embryogenesis.

Question 2

How many PGCs do we have at birth as a result of mitosis?

Answer 2

~ 1 million in females (develop 7 million but die by apoptosis)
~ 4 million in males

Question 3

Describe the process of oogenesis.

Answer 3

1. PGCs migrate from gut mesentery to female foetal gonads.
2. PGCs differentiate into oogonia and undergo mitosis.
3. Majority remain in mitosis, some enter prophase of meiosis I and arrest cell division - primary oocytes.
4. At birth, ~ 800,000 primary oocytes but many degenerate.
5. At puberty, ~ 40,000 primary oocytes (<500 will be ovulated).
6. 1 oocyte/month continues meiosis to become a secondary oocyte (arrests in metaphase II) + polar body.
7. Meiosis only completes upon fertilisation (total of 1 ovum and 3 polar bodies).

Question 4

What is a primordial follicle?

Answer 4

Layer of flattened epithelial cells around primary oocyte.

Question 5

Suggest a reason for the generation of so many oocytes during embryogenesis, only to lose them after.

Answer 5

• Oocyte loss helps individualise the surviving oocytes: 1 oocyte of a large cyst dies, separates cyst into 2. Process repeated until only a few oocytes remain.
• Supporting idea: dying oocytes found where new basement membrane is forming during follicle assembly.
• Dying cells may serve as nurse cells for surviving oocytes.

Question 6

Why is much mitosis required in spermatogenesis?

Answer 6

Human male produces 100 million sperm/day - need to maintain cell pool.

Question 7

Why do males produce so many sperm?

Answer 7

Survival of the fittest, many obstacles to reach egg?

Question 8

Is the gametophyte mutation rate higher in males or females and why?

Answer 8

• 5x higher in males
• Because:
  1. Number of germline divisions in spermatogenesis vastly exceeds that in oogenesis.
  2. Spermatogonial germ cells are continually active in adult men - male mutation rate increases with age (although survival of fittest sperm enables selection against these mutations).

Question 9

What is the estimated aneuploidy rate in morphologically normal embryos?

Answer 9

50%

Question 10

What is the effect of germ-line mutations on pregnancy loss?

Answer 10

• 60% of all conceptions end within 1st trimester
• 15% of all clinically recognised pregnancies end in miscarriage
• At least 75% of clinically recognised pregnancy loss results from chromosomal abnormalities.

Question 11

Why do gametophyte mutations increase with age?

Answer 11

• Male: spermatozoa are continually made. Older men’s spermatogonia have been exposed to mutagens/radiation for a longer time.
• Female: longer in meiosis arrest?

Question 12

What is mosaicism?

Answer 12

Individual contains cells of 2 genetically different types as a result of mitotic chromosomal mutations early in embryogenesis (morula stage).

Question 13

What are the possible outcomes of very early embryo exposure to radiation (mutagen)?

Answer 13

1. Death/aborted
2. Teratogenesis (congenital abnormality caused by mutagen)
3. Cancer when born

Question 14

What are the features required for a germ cell mutation to be inheritable?

Answer 14

1. Not lethal to gamete
2. Does not impair gamete function
3. Not lethal at fertilisation
4. Allows production of a viable adult with normal reproductive capacity

Question 15

In general, what are the molecular/physiological effects of recessive and dominant mutations?

Answer 15

• Recessive: cause loss of function, affect biochemical pathways (e.g. CF).
• Dominant: cause increased function, structural abnormalities (e.g. Achondroplasia)

Question 16

Give 2 reasons why is a given mutation much more likely to be inactivating rather than introducing a new function.

Answer 16

1) As there are many ways to deactivate or inactivate a proteins but it is much more difficult to introduce an activating mutation.
2) Failure of 1 allele to produce a protein can be compensated for by the normal allele if heterozygous, but overproduction by a single allele in heterozygotes will not be ‘compensated for’ by the normal allele and will therefore produce an effect - hence will be dominant.