Lecture 4 Flashcards
dN/dS =
- A metric to measure evolution, this controls for lineage effects (taxa) and regional mutation biases.
dN =
Changes per non-synonymous site
dS =
Changes per synonymous site
dN is usually less than dS, why?
- Synonymous sites are evolving faster, because there is more purifying selection acting on non-synonymous sites
- Synonymous site rates show less variance because there is less heterogeneity in selective constraint
dN < dS
- Purifying selection
dN = dS
- Neutrally evolving
dN > dS
2
- Diversifying selection (a type of adaptive selection)
- More aa site changes that synonymous site changes.. eg) parts of the MHC complex, viral coat proteins, mating associated loci.
Homolgy:
Similarity between two sequences due to that fact that they arose from the same ancestral sequence
Paralogs:
Genes who lineages diverged at a gene duplication event
Orthologs:
Genes whose lineages divgered at a speciation event.
Gene dupication events arise via:
- Unequal crossing-over
- Retrotransposition
- Duplication of a whole genome
Unequal crossing over:
Genetic material between non-sister chromatids during the prophase I of meiosis.
Retrotransposition:
- dsDNA gene is transcribed to a primary transcript with introns spliced out and poly-A tail is attached. Sometimes reverse transcription occurs, and the transcript is randomly integrated back into the genome.
How can you identify retrocopies?
- Long poly-A tail
- Randomly found in the genome
- No introns
Ohno’s model of gene duplication:
- A gene is duplicated and mutations can occur where ever in the new gene, as it is an extra, unnecessary copy
- A mutation that inactivates the sequence may occur, or a beneficial mutation may occur with a positive function
How can you tell if an extra copy of a gene is a pseudogene:
- After a certain level of divergence frameshift/nonsense mutations start arising
- dN/dS ratio of 1
Jingwei - the reincarnated princess:
An Adh-like sequence in flies not interupted by introns - maybe a pseudogene arisen by retrotransposition
- Polymorephic and divergent sites are mainly at ‘synonymous sites’ so dN<dS
- Three upstream exons
- This function formed a novel chimeric gene
Neofunctionalization:
- A possible fate of a duplicated gene due to the addition of a beneficial mutation
Neofunctionalisation in columbine monkeys:
A gene duplication event in RNASE, a gene present in the pancrease and small intestine
- The ancestral copy digests dsRNA in lots of tissues with a pH optima of 7.4
- The new copy is expressed in the small intestine with a pH optima of 6.3, due to mutations optimising the new RNASE1B gene.
Subfunctionalistion:
- An ancestral gene with multiple functions splits into specialised functions after a gene duplication event.
- Complementary degenerative mutations eg) in regulatory elements, which are often modular
- Increase the maintenance of duplicates.
Subfunctionalisation in Zebra fish:
- gng1 gene expressed in pectoral buds, and eng1b is expressed in spinal neurons
- In mice ancestor this gene is expressed in both places.
Saccharomyces gene duplicates of Sir3P and ORC1:
Sir3p and ORC1 are paralogs, not functionally equivalent.
- Adding an ancestral sequence rescues for knockouts of either gene.
- The ancestral sequence has both functions, and the gene duplication event lead to subfunctionalisation
Sir3p:
- Mutants viable but sterile
- Part of a similar complex that silence mating-type loci
ORC1:
- Essential for viability
- Part of the origin of replication complex
Paralogs in a nematode genome:
- Plotting substitutions/replacement site vs. substitutions/silent site
- If everything is evolving neutrally we would expect everything to lie on the line of 1.
- The further you go in evolutionary time, the more functions have derived and more purifying selection occurs
Humans and chimps have diverged by:
- 1% in align-able regions
- 60 000 amino acids
