Structural vs regulatory mutation Flashcards
Pre-2007, most scientists believed adaptive mutations were mostly…
structural
Post-2007, many scientists will argue that adaptive mutations are largely…
regulatory
Why was there such an increase in support for regulatory mutations post-2007?
Due to advances in sequencing technology
What is the regulatory hypothesis?
What kind of regulation is it referring to?
Adaptations are due to mutations in regulatory sequences
cis-regulation
What is cis-regulation?
CREs encode binding sites for TSFs and thus regulate nearby genes
Give 3 arguments for the regulatory hypothesis.
- Diversity in cell types is caused by changes to regulation (regulation can bring about vastly different phenotypes in the same area)
- Changes in the expression of genes underlie morphological traits (so is plausible new regulation could create a new trait)
- Pleiotropy constrains coding sequence, regulatory mutations do not have this problem
What is pleiotropy?
When a single gene has multiple seemingly unrelated effects
Why is pleiotropy difficult in adaptation?
If the same gene has different functions in multiple tissues, then a mutation that is beneficial in one area is likely to be detrimental somewhere else
Who thinks that both regulatory and structural are important in adaptation, not just one or the other? There are two examples.
Stern and Orgogozo, 2008
Hoekstra and Coyne, 2007
What did Stern and Orgogozo (2008) say about our understanding of both regulatory and structural mutations?
Recent advances in genome technology have made it easier to detect regulatory
Most adaptive mutations after 2007 found are regulatory, suggests our knowledge of structural is saturated
Give to examples of regulatory mutations.
- Stickleback pelvic spines
2. Mouse coat colour
Who studied spine morphs in sticklebacks?
What is the latin name for the threespine stickleback?
Shapiro et al., 2004
G. aculeatus
Shapiro et al., 2004
Why do sticklebacks have different spine morphs?
Marine species need them for predator defence
Freshwater species do not need them for predator defence plus it allows faster growth and storage of overwinter fat reserves
Shapiro et al., 2004
Why is it less costly for marine sticklebacks to produce spines?
Because the Ca2+ in the water allows calcification
Shapiro et al., 2004
In QTL mapping, what did they cross to produce the F1?
What did they observe in the F1? What does this indicate?
What did they observe in the F2? What did they do?
What did QTL mapping implicate in spine morph?
A marine (spined) female and a freshwater (non-spined) male
All F1 had spines, indicating spines are dominant/no spines is recessive
F2 had a range of spine sizes, scored these for analysis
1 major chromosome and 4 minor chromosomes as QTLs for spines
Shapiro et al., 2004
Major QTL contained which gene?
What is this gene involved in?
Pitx1, member of the homeobox family
Important in limb formation
Shapiro et al., 2004
What does Pitx1 encode?
How do we know spine formation is regulatory?
A TSF
It is a pleiotropic gene, expressed in both the mouth/jaw and pelvis. Silencing of Pitx1 in freshwater species had no effect on jaw formation; if the mutation was in the coding region the jaw would be abnormal
Who studied coat colour in mice?
What is the latin name for the species studied?
Steiner et al., 2007
P. polionotus (the oldfield mouse)
Steiner et al., 2007
What are the two morphs in mice? Why are they adaptive?
Mainland = dark
Beach = light
Provides crypsis against avian and mammalian predators
Steiner et al., 2007
What did they do?
What did they find?
What was the condition in the light morph? How is this a regulatory mutation?
QTL mapping
2 major QTLs; Mc1r and agouti
Light morphs produced (a faulty Mc1r receptor) increased levels of agouti mRNA
mRNA is produced in transcription, indicates an up-regulation of transcription. Also there was NO CHANGE to the coding sequence of agouti.
Who described the function of agouti?
What does it do?
Nachman et al., 2003
Agouti is the antagonist of Mc1r. It binds Mc1r and reduces cAMP production, producing phaeomelanin or light pigment
What is the structural hypothesis?
Adaptations are due to changes in AA sequences of proteins
Muts are IN THE CODING REGION
Give 2 arguments for the structural hypothesis.
- Duplication is a common process and solves the pleiotropy problem as duplicates can take on new functions (neofunctionalisation)
- There is lots of empirical evidence e.g. all the pre-2007 data
Give two examples of structural mutations.
- Stickleback armour
2. Coat colour in mice
Who studied armour in sticklebacks, G. aculeatus?
Why do sticklebacks need armour?
Colosimo et al., 2004
Marine = predator defence Freshwater = do not need for predator defence, can grow larger and accumulate more fat reserves for overwinter storage, can reach sexual maturity younger
Colosimo et al., 2004
What did they do?
What did they find?
QTL mapping and complementation experiments
A major QTL and several minor; major QTL contained the gene EDA
Colosimo et al., 2004
What does EDA do?
How did they know EDA is a structural mutation?
How many alleles of EDA were found?
Ectodysplasin; important in teeth, hair, bone development
Mutation in the coding region has produced multiple alleles (structurally different proteins)
2
Who performed a phylogenetic analysis on sticklebacks?
What did they find about EDA?
What does this suggest?
Colosimo et al., 2005
That the EDA sequence for reduced armour showed individuals were clustered together, regardless of geography
Suggests convergent evolution as low plate allele has arisen independently multiple times as marine species have entered freshwater
Who proved that the low-plate allele in sticklebacks was adaptive?
What did they do?
What did they find? How was the L allele found to be adaptive?
Barrett et al., 2008
Put 182 marine sticklebacks with armour that were heterozygous at the EDA locus (CL) in 4 artificial freshwater ponds. Thus the allele frequency at the start was known.
Allele frequency of L increased over time. This was initially due to higher overwinter survival, adaptive
Barrett et al., 2008
What 4 qualities did L individuals display?
Were larger
Were heavier
Had higher fecundity
Grew more quickly on the same amount of food
Who studied coat colour in P. polionotus?
What did they do?
What did they find?
What was the condition in the light morph?
How was this a structural adaptation?
Steiner et al., 2007
QTL mapping
2 major QTLs identified, Mc1r and agouti
Light morph displayed a structural change in the Mc1r receptor
Mutation in the coding region produced a faulty protein
Who described how Mc1r works?
How does it work?
Thus what was happening in the light morph?
Nachman et al., 2003
Mc1r is bound by alpha-MSH, which increases cAMP production and produces eumelanin, dark pigment
alpha-MSH could not bind the receptor and so eumelanin is not produced
Who showed that the light morph in P. polionotus is adaptive? How?
Vignieri et al., 2010
Tested predation on plasticine models of light and dark morphs
Who discussed regulatory vs structural mutations?
Hoekstra and Coyne, 2007
Hoekstra and Coyne, 2007
What was their overall conclusion?
What did they find in whole genome studies?
What did they find in single locus studies?
Adaptation is largely attributable to structural mutation, contrary to belief in evo devo biology
There are more adaptive mutations in coding regions (structural), including in TSFs
That single-locus studies focus on cis-regulatory LOSS of function mutations, yet to find regulatory gain of function mutations
Hoekstra and Coyne, 2007
What did the authors have to say about speciation?
Most studies show that hybrid sterility/inviability leading to reproductive isolation is caused by positive selection on mutations in coding regions
Stern and Orgogozo, 2008 and Hoekstra and Coyne, 2007 both say that adaptation is likely to be attributed to a combination of regulatory and structural mutations. How do your examples show this?
Sticklebacks; spines are regulatory and armour is structural, both contribute to defensive phenotype
Mice; agouti expression is regulatory, Mc1r is structural, both contribute to light colour morph
Stern and Orgogozo, 2008:
What percentage of known adaptive mutations are regulatory?
22% of 331
not that many
Where are sticklebacks found?
In the northern hemisphere
