Inferring recent or ongoing selection http://popgen.dk/albrecht/BAG2017/web/ Anders Albrechtsen
Introduction Signatures of recent/ongoing selection Recent selection within species / using shared variation
Introduction Signatures of recent/ongoing selection Sorry about the Human-centric talk Good candidates for genes under recent selection
Introduction Signatures of recent/ongoing selection Methods is applicable for most organisms Examples of organisms with DNA
Introduction Signatures of recent/ongoing selection Discrete time Write-Fisher Model Figure: 5 generations • We will sample with replacement to fill up the next jar. • We assume the total number of marbles in the jar stays constant • We are interested in the number of blue marbles at time t • Let f n blue = frequency of blue marbles at time n • P[ no. blue marbles at time = n +1 | no. blue marbles at time = n]
Introduction Signatures of recent/ongoing selection haploid view of selection based on the Wright fisher model fitness and allele frequency changes (Expected) selection coefficient w A N A f n +1 = A w a w A = 1 − s w A N A + w a N a w A f n f n +1 N A = f n +1 A = A N A +(1 − s ) N a A w A f n A + w a f a A n f n A = f n A + w a / w A f a A n
Introduction Signatures of recent/ongoing selection Selection over time (expectations) Figure: generations given f 0 A = 0 . 01 s = 0 . 01
Introduction Signatures of recent/ongoing selection Selection in diploid (expectations) Diploid selection w Aa = 1 − S Aa w AA w aa = 1 − S aa w AA Additive s aa = 2 s Aa Dominant s Aa = s aa Recessive s Aa = 0
Introduction Signatures of recent/ongoing selection Allele frequency trajectory Alleles frequency over time - what kind of selection? Figure: time
Introduction Signatures of recent/ongoing selection Allele frequency trajectory neutral - drift - starting frequency 1/2N
Introduction Signatures of recent/ongoing selection Probability of fixation
Introduction Signatures of recent/ongoing selection strong positive selection 7 of 50 simulations reach fixation
Introduction Signatures of recent/ongoing selection Weak positive 2 / 50 simulation reach fixation
Introduction Signatures of recent/ongoing selection Weak negative 1 of 50 simulation reach fixation
Introduction Signatures of recent/ongoing selection Neutral selection Alleles can be removed,polymorphic or fixed figure from Matteo Fumagalli
Introduction Signatures of recent/ongoing selection strong negative selection alleles can be removed or be polymorphic
Introduction Signatures of recent/ongoing selection Strong positive selection Alleles can be removed, polymorphic or fixed
Introduction Signatures of recent/ongoing selection Balancing selection Alleles can be removed, polymorphic or fixed
Introduction Signatures of recent/ongoing selection Summary selections effect on alleles Neutral/weak removed, polymorphic or fixed Strong negative removed or polymorphic Strong positive removed, polymorphic or fixed Balacing removed, polymorphic or fixed Strong selection Depends on the population size Conclusion Allele frequency is (almost always) not enough to determine selection
Introduction Signatures of recent/ongoing selection Need for additional information Option 1 use information from the genomic region Option 2 Use information from mulitple species/populations Options 3 selection experiments External information • Candidate genes/biological knowledge • Functional categories • Association to phenotypes
Introduction Signatures of recent/ongoing selection Common methods used to detect selection
Introduction Signatures of recent/ongoing selection Signature of selection • Neutral locus • Lots of variability
Introduction Signatures of recent/ongoing selection Signature of selection • Mutation enters the population
Introduction Signatures of recent/ongoing selection Signature of selection • Negative selection removed the allele
Introduction Signatures of recent/ongoing selection Signature of selection • Mutation enters the population
Introduction Signatures of recent/ongoing selection Signature of selection • Mutation enters the population • Mutation increases in frequency due to positive selection
Introduction Signatures of recent/ongoing selection Signature of selection • Increases LD • Affects the variability
Introduction Signatures of recent/ongoing selection Signature of selection • Increases haplotype similarity
Introduction Signatures of recent/ongoing selection Signature of selection • Increases differences with other populations in the whole region
Introduction Signatures of recent/ongoing selection What is the site frequency spectrum Ind 1 1 T C G T C T C A A T 1 2 T C G T C T C C A G 2 1 A G G T C G C C A T 2 2 A C G T G G T C A T 3 1 A C T A G G C C T T 3 2 A C T A G G T C A T # Minor 2 1 2 2 3 2 2 1 1 1 Number of minor alleles (folded) η = (0 . 4 , 0 . 5 , 0 . 1) 0.4 Density 0.2 0.0 1 2 3 Number of minor alleles
Introduction Signatures of recent/ongoing selection What is the site frequency spectrum Ind 1 1 T C G T C T C A A T 1 2 T C G T C T C C A G 2 1 A G G T C G C C A T 2 2 A C G T G G T C A T 3 1 A C T A G G C C T T 3 2 A C T A G G T C A T Outgroup A C T T C T C C A G # Derived 2 1 4 2 3 4 2 1 1 5 polarized SFS (unfolded) η = (0 . 3 , 0 . 3 , 0 . 1 , 0 . 2 , 0 . 1) 0.30 0.20 Density 0.10 0.00 1 2 3 4 5 Number of minor alleles
Introduction Signatures of recent/ongoing selection Frequency spectrum gives information about selection and demography
Introduction Signatures of recent/ongoing selection Thetas are based on the frequency spectrum Watterson θ W = a − 1 � n − 1 i =1 η i , where a = � n − 1 i =1 1 / i � − 1 � n − 1 � n Tajima θ T = i =1 i ( n − i ) η i 2 Tajima’s D θ T − θ W √ D = Var ( θ T − θ W ) under a neutral model* θ T = θ W
Introduction Signatures of recent/ongoing selection Theta are based on the frequency spectrum Watterson θ W = a − 1 � n − 1 i =1 η i , where a = � n − 1 i =1 1 / i � − 1 � n − 1 � n Tajima θ T = i =1 i ( n − i ) η i 2 4 diploid individuals 0.6 tajimas 0.39 tajimas 0.39 0.4 watterson 0.39 watterson 0.39 0.2 0.0 η 0.39 0.19 0.13 0.1 0.08 0.06 0.06 i(n−i) = 0.25 0.43 0.54 0.57 0.54 0.43 0.25 Ση 1 1 1 1 1 1 1
Introduction Signatures of recent/ongoing selection Theta are based on the frequency spectrum Watterson θ W = a − 1 � n − 1 i =1 η i , where a = � n − 1 i =1 1 / i � − 1 � n − 1 � n Tajima π = θ T = i =1 i ( n − i ) η i 2 4 diploid individuals 0.6 tajimas 0.39 tajimas 0.39 tajimas 0.32 tajimas 0.32 0.4 watterson 0.39 watterson 0.39 watterson 0.39 watterson 0.39 0.2 0.0 η 0.66 0.17 0.07 0.04 0.03 0.02 0.01 η 0.39 0.19 0.13 0.1 0.08 0.06 0.06 i(n−i) = 0.25 0.43 0.54 0.57 0.54 0.43 0.25 Ση 1 1 1 1 1 1 1
Introduction Signatures of recent/ongoing selection Thetas are based on the frequency spectrum Watterson θ W = a − 1 � n − 1 i =1 η i , where a = � n − 1 i =1 1 / i � − 1 � n − 1 � n Tajima π = θ T = i =1 i ( n − i ) η i 2 Fu & Li θ FL = η 1 � − 1 � n − 1 � n i =1 i 2 η i Fay & Wu θ H = 2 � n − 1 1 Zeng, Fu,Shi and Wu θ L = i =1 i η i n − 1 general ˆ θ = � n i =0 α i η i Test statistics √ θ 1 − θ 2 D = Var ( θ 1 − θ 2 ) under a neutral model* θ 1 = θ 2 Difference weighting schemes for the SFS
Introduction Signatures of recent/ongoing selection Why does selection affect the SFS
Introduction Signatures of recent/ongoing selection Frequency spectrum gives information about selection and demography
Introduction Signatures of recent/ongoing selection How to assess significance slides stolen from Matteo Fumagalli
Introduction Signatures of recent/ongoing selection How to assess significance
Introduction Signatures of recent/ongoing selection How to assess significance
Introduction Signatures of recent/ongoing selection How to assess significance
Introduction Signatures of recent/ongoing selection How to assess significance
Introduction Signatures of recent/ongoing selection How to assess significance
Introduction Signatures of recent/ongoing selection How to assess significance
Introduction Signatures of recent/ongoing selection How to assess significance
Introduction Signatures of recent/ongoing selection How to assess significance
Introduction Signatures of recent/ongoing selection Exercises Let see how variability π and Tajimas D performs on famous examples of human adaptation. go to http://popgen.dk/albrecht/BAG2017/web/ Graphics When you will run analysis on the server you will need graphic (see above link)
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