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Selection and Recombination (Haplotypes (Recombination (Principles…

- - - - dominance effects the speed of fixation of a beneficial allele
    - - Frequency dependent
        
        fitness is related to its frequency -pathogens
        
        MHC
      - Heterozygote advantage- allele finds an equilibrium between 0 and 1
      - overdominance
      - sickle cell and malaria
    - - with drift, dominance affects the probability of loss of a deleterious allele
    - - homozygotes have the highest fitness
      - may be important for sympatric speciation
  - - - Tajima's D
        
        Significantly different from 0 means not neutral
        
        D> 2= balancing selection
        
        Uses the pairwise differences and the segregating sites
      - Fu and Li's H statistic
        
        Takes into account the ancestral variants
        
        under neutrality there should only be a few excess variants
        
        number of singletons and segregating sites
        
        (+) values mean balancing selection- (-)= positive selection
      - Mismatch distribution- modal distribution could show positive selection
    - - compare the expected and observed numbers of haplotypes
      - haplotype diversity high under balancing selection
      - Low diversity under selective sweeps
    - - Compare the dn/ds ratios
        
        HKA Test
        
        Like MK but at two or more loci
        
        used in tb1 and in FOXP2
        
        Can use a sliding window
        
        MK Test
        
        amount of change with the ratio within species and between species- should be equal under the neutral theory
        
        weakly deleterious mutations can reduce the power
        
        FOXP2- 3 amino acid different between humans and mice
        
        Value of D and H were slow- selective sweep
        
        Selection
        
        Type of Selection
        
        Assessed through orthologues aligned protein sequence
        
        Phylogenetic tree
        
        Amino acid level
        
        synonymous (silent) dN # # #
        
        nonsynonmous (replacement) dS # # # #
        
        Positive: pressure for the genotype to improve
        
        dN/dS >1
        
        Neutral: non advantageous genetic drift occuring
        
        dN/dS= 1
        
        Purifying: Pressure to retain current genotype
        
        dN/dS<1
  - - - absolute fitness
      - relative fitness
        
        reference genotype is the fittest
        
        selection coefficient gives value in relation to selection coefivient
        
        h=0, A1 dominant, A2 recessive
        h=1, A2 dominant, A1 recessive
        0<h<1, incomplete dominance
        h<0, overdominance (heterozygote advantage) h>1, underdominance (homozygote advantage)
        
        take away heterozygous effect too
      - Mean fitness of each genotype using HW
- - - - reduces LD
        
        will decrease each generation
      - randomize genotypes at one locus
      - determines how big the haplotypes are that we see in a population
      - throughout the genome- some areas more common
    - - novel combinations
      - increases the efficiency of natural selection
      - infer population history
      - locate genes of interest
    - - recombination hotspots
      - low rate around centromeres
      - not only simply distance- also the area
    - - small populations will have tightly linked sites= low recombination
  - - - tb1 gene
      - 39% nucleotide diversity is maintained
      - only 3% maintained in the promoter region
    - - Lewotins D
        
        D=Pab- Pa xPb
        
        += relative association
        
        -=relative disassociation
      - Admixture
        
        Hybrids show high LD after first mixing
      - Selection
        
        Positive selection and hitch-hiking
        
        Long Range haplotype test
        
        EHH
        
        Proabability that two randomly chosen sequences with the core haplotype are identical be descent
        
        1= complete linkage= greatest LD
        
        Measures the effects of selection and linkage= quanitfiable
        
        Genome wide studies of selection
        
        SLC45
        
        solute carrier
        
        selective advantage for derived change leading to lighter skin tone
        
        Beneficial allele will rise in frequency and fix- taking linked alleles with it- reduction in diversity is the selective sweep
        
        Background selection
        
        Differences between selective sweeps and background selection
        
        negative selection and reduced recombination
        
        Neutral expectation - neutral coalescent
        
        slow and steady process
        
        Outbreeding depression
        
        Arabian oryx
        
        co-adapted gene complexes
        
        Breaks fitter haplotypic combinations
      - Tendancy of alleles at separate loci to be coinherited because of reduced recombination between them
      - Study the patterns of disease with family histories- use a high level of signficance
    - - The frequency of B on chromosomes carrying allele A is equal to the frequency of B on chromosome carrying A
      - The frequency of any chromosome haplotype can be calculated by multiplying the frequencies of constituent alleles
      - D=0
  - - - population scale genome
      - four poulations
      - 300 - 600 thousand SNPs