Lecture 3: Hox genes

Question 1

What happens when hox genes mutate?

Answer 1

• Bithorax mutation is LOF. Causes the entire third thoracic segment to be transformed into a second thoracic segment. This gives 4 wings instead of 2. This is a loss of hox gene.
• Tab is a dominant mutation. This is a GOF mutation that transforms part of the second thoracic segment into the sixth abdominal segment.
• Antennapedia mutations are GOF mutations. This transforms an antenna into a leg. The hox mutation is enough to activate a cascade of events.
• It shows that you can have quite extreme changes from just one mutation (e.g. extra wings).
• A ground state would be where all HOX genes are expressed in all segments.

Question 2

What are homeodomain proteins?

Answer 2

• The hox genes encode TFs called homeodomain proteins.
• They are 60aa protein domains which bind DNA.
• Hox genes bind DNA regulatory elements of their target genes in a specific combination so that the expression pattern in each of the different segments is unique.
• In vitro, HDs have broad binding specificity.
• One idea was the co-factor hypothesis. There are a few that has been found (extradenticle aka EXD and homothorax aka HTH).
• You can generate cooperativity.
• The homeodomain recognises 6 bases, around TATA.
• It has 3 helix-turn-helix motifs.
• The recognition helix is in a different position in the groove.
• Direct interaction with asparagine 51.

Question 3

How do hox genes work in other animals?

Answer 3

• It was first thought that hox genes were just for fruit flies.
• However, it became apparent that they are highly conserved. Animals essentially have the same basic building blocks and regulatory devices.
• Mice mutant knockout for HoxC8 in mice gives ribs duplication and clenched-fingers phenotype.

Question 4

How do Hox genes evolve?

Answer 4

• Duplication of genes or whole clusters (mammals) by unequal crossing over.
• Following duplication the coding and regulatory sequences can diversify.
• Changes (rare) in coding sequences can occur. This has occurred in Ubx.
• Changes in Hox target expression.