Transcript HIV-1 as a model organism to study epistasis

Evidence for Positive Epistasis in HIV-1
Sebastian Bonhoeffer, Colombe Chappe, Neil T. Parkin, Jeanette M. Whitcomb, Christos J. Petropoulos
Evolutionary basis for sexual reproduction and recombination
• Population theories based on effects of fitness interactions
between alternate allelles at different loci to control a single
phenotype (epistasis)
• In a two-locus, two-allele model, it is defined as:
E = wab + wAB – waB – wAb
where a/A and b/B are the alternative alleles at the two loci and
w** is the log fitness of the corresponding genotype
• Measures deviations from multiplicativity of the fitness effect
caused by individual mutations
Positive and negative epistasis
Synergistic
beneficial
mutations;
antagonistic
deleterious
mutations
Antagonistic
beneficial
mutations;
synergistic
deleterious
mutations
Michalakis and Roze, Science 306: 1492-1493, 2004
Evolutionary basis for sexual reproduction and recombination
•In negative epistasis, beneficial mutations interact
antagonistically (increase fitness less than multiplicatively) and
detrimental mutations act synergistically (decrease fitness more
than multiplicatively)
• Increases efficiency in selection
•Appeal of negative epistasis is that recombination can
efficiently eliminate deleterious mutations, thus providing a
strong selective advantage
• No clear evidence for an overall predominance of positive or
negative epistasis due to inherent difficulties
Why use HIV-1 as a model organism to study epistasis
• Reproductive cycle is a primitive form of sexual reproduction
• Retroviruses pack two full-length copies of the RNA genome
• After infection, RT engages one copy and converts it to DNA
• RT carrying nascent DNA may disengage from the first
template and switch over to the next
• If the RNA genomes are heterozygous, this may lead to a
recombinant proviral DNA
• Common occurrence when host cells are infected by distinct
proviruses
• RT switches RNA templates approximately 10 times per
replication (about 1 recombination event for 1000 NBP)
HIV-1 as a model organism to study epistasis
• 9466 virus samples from HIV-1 patients
• Only PR and most of RT inserted into a HIV-1 clone that can
undergo only one round of replication
• Fitness assay quantifies the total production of infectious
progeny virus, and measured in absence of drug, relative to
ability of the clone
HIV-1 as a model organism to study epistasis
• Plot log fitness as a function of the number of mutations
• Less than linear decrease suggests positive epistasis
• Could be due to bias in data set against sequences with low
fitness
HIV-1 as a model organism to study epistasis
• Measure fitness interactions between pairs of alternative amino
acids (“alleles”) at different positions (“loci”) where all four
possible combinations are observed (103,826 pairs)
•Average log fitness values used to calculate E
• Mean of distribution is 0.052; different from random; mean for
those that significantly affect fitness is 0.109
What’s going on here
• Most isolates are lower in fitness than the clone, suggesting
antagonism between deleterious mutations (positive epistasis)
• Not consistent with current genetic theories of sexual
reproduction and recombination
• May not be extrapolatable to higher eukaryotes
• Might be a mechanism to repair single stranded breaks in the
RNA genome that is susceptible to degradation
What’s going on here – a structural perspective
• Analysis done on two enzymes; positive epistasis makes sense
for isolates that have high fitness from a protein structure
stability perspective
• Complementary beneficial mutations that increase stability
more than multiplicatively, like two near oppositely charged
residues on the surface replacing polar ones
• Strong evidence for positive epistasis of beneficial mutations:
What’s going on here – a structural perspective
• Positive epistasis makes less sense for isolates that have a low
fitness from a protein structure stability perspective, but still
possible
• Deleterious mutations that decrease stability due to
environment compensate each other
•Strong evidence for positive epistasis of deleterious mutations: