2. Chromosome structure and organisation in humans

Question 1

Describe the structure of a chromosome

Answer 1

Chromatin (DNA + protein complexes) folded/coiled into compact arrangement.

Constricted at centromere - creates p (small) and q (long) arms

Question 2

What are the 3 types of chromosome?

Answer 2

Metacentric - p and q equal length

Submetacentric - p and q unequal length

Acrocentric - p present but very small (13, 14, 15, 21, 22)

Question 3

What is the centromere formed of?

Answer 3

Constitutive heterochromatin, consisting of repetitive DNA

Flanked by pericentric heterochromatin - facilitates sister chromatid cohesion

Question 4

What is the role of the centromere?

Answer 4

Provides foundation for kinetochore assembly

Mediates interactions between DNA and spindle fibres

Serves as site for sister chromatid attachment

Essential for correct chromosome segregation - defects in regulatory pathways lead to aneuploidies, chr instability - common in cancer

Question 5

What is the kinetochore?

Answer 5

Multiprotein complex, point of attachment for spindle fibres

Inner and outer sections, only assembled and functional during cell division

Formed in late prophase, 1 on each sister chromatid

Question 6

Give an examples of a disorder where centromere function is impacted

Answer 6

1. Roberts syndrome (ESCO2):
   - Encodes acetyltransferase involved in holding centromere together
   - LoF variants –> delayed cell division and cell death
   - Metaphases show premature centromere separation
2. Mosaic variegated aneuploidy syndrome (BUBR1, CEP57, TRIP13):
   - IUGR, microcephaly, dysmorphism, risk of malignancies
   - some cells have trisomies/monosomies
   - genes involved in spindle fibre organisation and stabilisation

Question 7

What is a neocentromere?

Answer 7

New centromere formed at non-centromeric location due to disruption of normal centromere

Form on acentric chromosome (those lacking a centromere, i.e. markers) - stop them being lost at cell division

Question 8

What are telomeres?

What are their role?

Answer 8

Highly conserved, gene-poor DNA-protein complexes at ends of chromosomes

1. Maintain structural integrity
2. Prevent shortening with each round of cell division
3. Aid chromosome pairing

Question 9

Describe the structure of telomeres

Answer 9

Tandem TTAGGG repeats associated with proteins, telomere associated repeats, chromosome specific DNA

End has single strand overhang due to difficulty replicating

Question 10

Give an example of a telomeropathy

Answer 10

1. Dyskeratosis congenita - mutations in telomerase holoenzyme complex –> decreased telomerase stability –> shorter telomeres –> premature ageing
2. Cri-du-chat syndrome - deletion of telomerase reverse transcriptase which maintains telomere ends