l21 genome evolution 15
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203.341!Genome Evolution!
Lectures 21-22!!
Nielsen, 2005 Annual Review of Genetics 39:197-218!
Austen Ganley, October 5th, 2015
Genome Evolution • Different parts of the genome can undergo
three different types of evolutionary behaviour:!• Positive selection!• Negative selection!• Neutral evolution!
• What are these, and importantly, how do we figure out which is at play?!
• We are looking at genome evolution (i.e. evolution at the DNA level)!
Positive selection • Where a region of the genome has been
selected for mutations that provide an advantage for the organism!
• Positive selection is usually associated with adaptation!
• If an organism that is not perfectly adapted to an environment happens to get a mutation that makes it more adapted, it will be more likely to contribute to the next generation!
Positive selection
• The mean of the population for a certain trait shifts as a result of positive selection for an adaptive mutation!
• Involves the adaptive allele sweeping to fixation in the population!
• Normally, this happens on an ongoing basis!
Negative selection • Where deleterious mutations compromise
the organism, therefore making it less likely to contribute to the next generation!
• Negative selection is usually associated with maintenance of a useful function!
• The more serious the effects of a non-permissible mutation, the stronger the selective effect against it!
Negative selection
• Residues essential for organism survival will not tolerate mutations, and thus will be selected against!
• Will manifest as highly conserved sites when comparing between species!
Neutral evolution • Where mutations have neither a beneficial
nor a detrimental effect on the likelihood of contributing to the next generation!
• Because neutral mutations are “unseen” by selection, they can either increase or decrease in frequency in a population!
• Therefore, their frequency in a population is governed by genetic drift – chance dictates whether they increase or decrease in frequency!
Neutral evolution • Neutral alleles
rise and fall in frequency through generations!
• This is governed by chance – an individual may leave more or fewer offspring for reasons other than the neutral allele!
Other forms of selection
• Stabilizing selection – where selection favours a narrow value for the trait and selects against individuals at either extreme (by negative selection)!
Other forms of selection
• Disruptive selection – where selection favours extreme values for the trait over intermediate values, making populations with two distinct groups (also called diversifying selection)!
Other forms of selection
• Balancing selection – where selection simultaneously favours both extreme values for the trait, thus maintaining multiple alleles. Usually occurs where there is heterozygous advantage!
Coef!cient of selection • Different mutations have different
consequences – from very severe to very mild!
• Therefore, we can think of mutations as falling on a continuum between 1 (lethal), 0 (completely neutral) and -1 (100% favoured)!
• This is the coefficient of selection – how strongly, and in what direction, a mutation affects the fitness of individuals that have it!
Population size • The size of the population dramatically affects
the strength of selection!• Somewhat counter-intuitively, selection is much
more effective in large populations!• The reason is that drift dominates in small
populations – chance events have a relatively large effect!
• The smaller the population size, the greater the selection coefficient has to be to overcome genetic drift!
Selection effect • The relationship between
population size (Ne) and the selection coefficient (s) can be graphed!
• Above the line, selection rules for a mutation; below the line drift rules!
Detecting evolutionary history in the genome
• A major goal of comparative genomics is to understand the evolutionary history of various parts of the genome!
• This helps us to understand why things are the way they are!
• The different forms of selective leave different patterns, and these help us determine what has happened!
• We will look at ways of determining what selective force has been operating!
Detecting negative selection • We will look at three methods for detecting
negative selection:!• Unexpected abundance of low-frequency
polymorphisms (Tajima’s D)!• Fewer non-synonymous than
synonymous mutations (Dn/Ds ratio)!• Phylogenetic footprinting!
Low-frequency of polymorphisms • If a region is under negative selection, we
expect to see fewer mutations in the population than a region that is not!
• Therefore, relative to neutral regions, we are only likely to see occasional mutations that are present in few members of the population!
• Tajima’s D is a measurement of the number of sites that are polymorphic and how polymorphic they are!
Low-frequency of polymorphisms
Limitations of Tajima’s D • Tajima’s D is not specific to negative
selection – any force that results in such a shift in allele frequencies will be detected!
• Importantly, positive selection has the same effect, so Tajima’s D only tells us that selection is important, not which type!
• This pattern of reduced polymorphism is also expected when a population undergoes a rapid increase in size!
Codon Table
Synonymous to non-synonymouse mutation ratio
• Therefore, based on this principle, we can use the ratio of non-synonymous to synonymous mutations to find evidence of negative selection!
• This is called the dN/dS ratio (sometimes also the Ka/Ks ratio)!
• The lower the ratio the more it suggests negative selection has removed non-synonymous mutations!
Calculating dN/dS ratio • To calculate the dN/dS ratio, first you need at
least two DNA sequences (e.g. from two different species)!
• These are aligned, and organised into codons!• dN is the number of differences between the
two sequences per non-synonymous site!• dS is the number of differences between the
two sequences per synonymous site !• A ratio less than 1 suggests negative
selection!
Limitations of dN/dS ratio • Only works on protein-coding regions of the
genome!• Has limited sensitivity – if only a few sites
are undergoing negative selection, but the rest are not, the negative selection is very difficult to detect!
• Need to take bias in mutations into account – not all mutations occur with equal frequency, and these can lead to an overestimate of dN!
Phylogenetic footprinting • As we have seen, one hallmark of negative
selection is conservation of bases through evolution!
• A way to reveal this is by phylogenetic footprinting!
• For this, sequences (e.g. from several different species) are aligned, and the level of sequence conservation is plotted!
• The regions undergoing negative selection stand out as “footprints” of sequence conservation!
Sequence Alignment
Phylogenetic Footprinting
Phylogenetic Footprinting
• The evolutionary divergence of the species used is critical to success!
• This in turn depends on the region being analysed!
Phylogenetic footprinting limitations
• Relies on having sequences of your region of interest available for multiple species of the right evolutionary distances!
• Detects regions, not individual bases, so has limited resolution (in the order of 10 bp)!
• Measures relative conservation: if your region as a whole has anomalous conservation, you may be misled in your interpretations!