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POPULATION STRUCTURE, GENETIC MECHANISMS OF EVOLUTION AND GENOMIC…

- - - - isolates get trapped in separate niches/hosts
        
        over time strains diversify
      - completely random
      - in an entirely neutral model multiple lineages freely colonise both hosts and expand to occupy the niches
      - in a neutral model modulated by transmission barriers strains differentially colonise the hosts and give rise to multi-host and single-host lineages
    - - a bit old fashioned
      - in the ecotype model genomes that acquire a host adaptive trait (X) cause a selective sweep and strains containing the adaptation out-compete other colonising strains
      - in a divided-genome model multiple colonising genotypes can acquire an adaptive trait (X) which causes a horizontal genetic sweep and genomic convergence at that lotus in divergent genomic backgrounds
- - - - novel protein isoforms that may have novel function
      - insertion/deletions (indels) and frameshift that interrupt protein translation
        
        associated with genome degradation
        
        associated with reductive evolution
    - - nucleotide substitution (coding sequence)
        
        novel protein isoforms increase population phenotype variation and can promote adaptation
      - indel (coding sequence)
        
        loss of function is associatied with reductive evolution and may streamline the genome
      - nucleotide substitution (intergenic region)
        
        variation in gene expression caused by changes to promoter sequence. RNA polymerase activity or transcription is associated with adaptation
      - nucleotide substitution (phase variable region)
        
        variation caused by activation or inactivation of gene expression is associated with adaptation
  - - - lung infections in patients with CF are caused by hypermutator phenotypes in P. aeruginosa and Burkholderia dolosa
      - maximum-parsimony phylogeny of 29 isolates from the same sputum sample shows the coexistence of diverse sub-lineages separated by many single nucleotide mutations accumulating since the last common ancestor (LCA) of patient
      - very useful to be able to mutate quickly
- - - - HOMOLOGOUS RECOMBINATION
        
        replacement
        
        novel alleles increase in phenotypic variation and can promote adaptation
        
        inversion
      - NON HOMOLOGOUS RECOMBINATION
        
        insertion
        
        novel genes increase phenotypic variation and can promote adaptation
        
        bringing SNPs together into the same genomes (disrupting LD) may promote adaptation
        
        deletion
        
        altered gene function may streamline the genome during adaptation
        
        duplication
        
        production of new/more gene products promotes adaptation
  - - - virus that infect bacteria, often phage DNA gets incorporation and sometimes other bacterial DNA
- - - - what makes a pathogen pathogenic?
    - - epidemiology/transmission dynamics
    - - can we predict/detect early emerging pathogens
  - - - recent host-switch events are often associated with horizontal gene acquisition, including mobile genetic elements that might confer a specific advantage
      - more ancient events might exhibit signatures of reductive evolution, optimisation through loss of redundant function and positive selection
  - - - a dN/dS<1 is associated with negative or purifying selection which surpasses protein changes (that is, it imposes genetic constraints)
      - a dN/dS>1 is associated with positive selection which promotes changes in the protein sequence
      - these estimates have been used to investigate selective forces in bacterial adaptation, particularly to human hosts
      - limitations of dN/dS
        
        although dN/dS estimates have been useful for quantifying adaptation in bacterial genomes, there are limits to their utility
        
        selection operates not only to maintain protein-coding sequence but also on features such as gene order, distribution of coding sequences on leading and lagging strands, GC skew and codon usage, none of which would necessarily affect dN/dS
        
        complex traits such as host adaptation will involve multiple genes and most likely interactions at multiple levels of genome arrangement, which are not likely detectable by analysing dN/dS ratios
        
        eg polymorphisms can be in strong LD with other loci owing to common ancestry; all variants linked within a haplobloack would be associated with host adaptation and may have similar dN/dS whether they conferred a direct functional advantage or not
        
        frameshift and incorrect interpretation of start codons can lead to non-synonymous SNPs being interpreted as synonymous leading to inaccurate dN/dS estimates and non-detection of positive selection
        
        dN/dS estimates are not accurate if polymorphisms are not fixed between independent lineages, and segregating variation in the population is likely weakly deleterious and destined to be purged in the future
        
        for example isolates from different physically separated populations may have segregating polymorphisms that were inherited from the respective founding strains, and the effect of selection on dN/dS will not necessarily be identical in each, making population-wide estimates error prone