Lecture 6 - Evolution of Vertebrate Signaling

Question 1

1R-WGD and 2R-WGD:

Answer 1

WGD = Whole Genome Duplication

Two rounds of whole genome duplication.

Question 2

Ohnologues:

Answer 2

One of a pair of paralogous sequences that result from complete genome duplication.

Question 3

391 human protein kinases (66% of kinome) belong to 14-3-3-binding 2R-protein families
TRUE OR FALSE

Answer 3

TRUE

Question 4

What is the 2R-WGD?

Answer 4

Two rounds of whole genome duplication (1R and 2R) occurred early in the evolution of the vertebrates. During these events one gene became two, then two became four.

Question 5

What happened to the quadrupled genes after the 2R-WGD?

Answer 5

In most cases, 1-3 of the 4 gene copies produced by this process were subsequently lost. Therefore only ~25% of the human genome comprises families of between 2 and 4 2R-ohnologues.

Question 6

What is amphioxus?

Answer 6

The marine chordate amphioxus (Branchiostoma floridae) diverged from the vertebrate lineage before these gene duplication events, and is perhaps the best living proxy for the ancestral invertebrate, since its genome generally contains a single pro-orthologue for each family of vertebrate 2R-ohnologues, and amphioxus are not so ‘derived’ as sea squirts.

Question 7

How can 2R-ohnologues be recognized?

Answer 7

Criteria to assign paralogous vertebrate genes as 2R-ohnologues are:

1. They are typically on different chromosomes, in blocks called paralogons that retain the gene content [and order] of the ancestral region from which they derive (ie. sister paralogons share synteny);
2. There should be a single pro-orthologue in amphioxus in a chromosomal region showing evidence of synteny with up to four corresponding vertebrate paralogons;
3. The phylogenetic tree should have a symmetrical topology because the 1R generated two precursor genes, which in turn were both duplicated simultaneously in the 2R to generate four vertebrate genes relative to a single invertebrate gene
4. The paralogues (aka 2R-ohnologues) generally share similar domain architectures.

NB: Due to the 500 million years of genome losses, rearrangements and mutations since the 2R occurred, few 2R-ohnologue families fit these criteria perfectly.

Question 8

How did the 2R-WGD and subsequent events affect cell signalling?

Answer 8

The few thousand families of 2R-ohnologues retained in modern-day vertebrates are highly enriched in genes encoding regulatory proteins, including cytokines, growth factors, ion channels, receptors, G proteins, regulated metabolic enzymes, transcription factors, protein kinases, and many of these are also 14-3-3-binding phosphoproteins.

One implication of this is that the 2R-WGD provided an evolutionary leap in cellular communication; quadrupling of the signalling pathways available to our last common invertebrate ancestor may have enabled the great increase in complexity and variety of vertebrates that followed.

Question 9

2R-WGD Evolutionary leap:

Answer 9

Linear control pathways endowed our invertebrate chordate ancestor with binary “on/off” phenotypes

2R-WGD Evolutionary leap ——–>

Activating different routes through the quadruplex 2R-networks generates vertebrate complexity and variety

Question 10

Lynchpin hypothesis:

Answer 10

14-3-3 dimer binding to lynchpins gives other sites freedom to evolve

14-3-3 dimers facilitated evolutionary diversity among members of a 2R-ohnologue family.

i.e. “Lynchpin site” remains the same/similar (facilitating 14-3-3 binding), other sites evolve

Question 11

14-3-3-binding phosphoproteins are enriched in 2R-ohnologues.
TRUE OR FALSE

Answer 11

TRUE