Tracking signatures of response over 20 generations of selection - - PowerPoint PPT Presentation

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Tracking signatures of response over 20 generations of selection - - PowerPoint PPT Presentation

Feb 18, 2023 665 likes •1.08k views

Tracking signatures of response over 20 generations of selection for long leg length in mice Layla Hiramatsu Postdoc with Frank Chan Friedrich Miescher Laboratory Max-Planck Campus, Tbingen, Germany How do small populations respond to

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Tracking signatures of response

  • ver 20 generations of selection

for long leg length in mice Layla Hiramatsu

Postdoc with Frank Chan Friedrich Miescher Laboratory Max-Planck Campus, Tübingen, Germany

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How do small populations respond to selection?

  • Selection vs. genetic drift
  • Hard vs. soft sweeps
  • Allelic interactions
  • How many genes
  • Effect sizes
  • How repeatable is the response

Replicated, controlled, pedigreed selection experiments

Quantitative genetics Population genetics

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Longshanks selection experiment for long tibiae

Three lines of CD-1 outbred mice, 16 pairs per generation

Marta Marchini, Campbell Rolian (U. of Calgary)

 bioRxiv link! 2 2.5 mm

Ctrl LS113.1% LS212.7%

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Longshanks selection experiment for long tibiae

Three lines of CD-1 outbred mice, 16 pairs per generation

  • M. Marchini, C. Rolian (U. of Calgary) & QG estimates N. Barton (IST Austria)

Ctrl

N=1331

LS1

N=3060

LS2

N=3098

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ℎ2 = 0.51 𝑇 = 0.02* Ne = 46

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All breeders whole-genome sequenced N = 1,550

Founders (F0) and F17 at 100x coverage (~5x / individual) All other generations 30x coverage (~0.5x / individual)

F0F17: João Castro, Mish Yancoskie et al., eLIFE, in revision

Ctrl LS1 LS2

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Ctrl

N=1331 NWGS= 25 (F0) +33 (F17) + 316

LS1

N=3060 NWGS = 26 + 32+ 546

LS2

N=3098 NWGS = 25 + 32 + 514

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Change in allele frequencies in Ctrl line

Castro, Yancoskie et al., eLIFE, in revision

Genetic drift chr 5

Ctrl F0 vs. F17

∆z2/π2

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Broad polygenic response, parallel and line-specific

Castro, Yancoskie et al., eLIFE, in revision

chr 6

F0 vs. F17

∆z2/π2

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8 loci of major effect, top 2 are in parallel

Nick Barton, Stefanie Belohlavy (IST Austria)

Significant threshold from pedigree-calibrated infinitesimal model with LD

Castro, Yancoskie et al., eLIFE, in revision

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Hitchhiking filtered

LS1 LS2

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8 loci of major effect, top 2 are in parallel

Significant threshold from pedigree-calibrated infinitesimal model with LD

Castro, Yancoskie et al., eLIFE, in revision

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>5Mb region in chr10 Nkx3-2 in chr5 LS1 LS2

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8 loci of major effect, top 2 are in parallel

Significant threshold from pedigree-calibrated infinitesimal model with LD

Castro, Yancoskie et al., eLIFE, in revision

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>5Mb region in chr10 Nkx3-2 in chr5 No coding changes Functional test of enhancers F0 allele vs. F17 allele (3 SNPs) F0 F17

Loss of bone growth repression

LS1 LS2

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How did the Longshanks respond to selection?

  • Selection vs. genetic drift

Drift strong, selection stronger Near fixation by F17

  • How many genes

Very polygenic 8 major loci

  • Effect sizes

Nkx3-2 : 10%

  • Can we model the response

Yes! Linkage important

Quantitative genetics Population genetics DevBio

Nkx3-2 region No coding changes Cis-regulatory Loss of function

Castro, Yancoskie et al., eLIFE, in review

10  bioRxiv link!

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Reconstruction of selection response generation-to-generation

Ctrl LS1 LS2

generations 11

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Reconstruction of selection response generation-to-generation

Ctrl LS1 LS2 30x coverage (~0.5x / individual)

generations 12

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Reconstruction of selection response generation-to-generation

Allele trajectories

  • Allelic interactions (e.g., dominance)
  • Timing and relative importance of genes

Haplotype reconstruction with pedigree

  • Compare against models of linkage

Ctrl LS1 LS2

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Average each 100kb window across all chromosomes

Frequency of minor allele at each of 2133 SNPs

chr 1 || 2133 SNPs

Average frequency LS1

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Average each 100kb window across all chromosomes

Frequency of minor allele at each of 2133 SNPs Average frequency

chr 1 || 2133 SNPs * Reduces noise due to low coverage but haplotypes are likely larger than 100kb

LS1

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Trajectories of windows which started at 20-25% in founding population

LS1

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Trajectories of windows which started at 20-25% in founding population

LS1

Selected windows in chr 10

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Trajectories of windows which started at 20-25% in founding population

LS1

Selected windows in chr 10

LS2

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Side story. Late alleles: recessive or broke linkage with deleterious allele?

multi-locus adaptation

LS1

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Side story. Chr 6 region broke from deleterious allele at generation 11?

Or seeing many background haplotypes?

LS1

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“Drift zone” by simple Wright-Fisher simulation, 95% of 1000 simulations

LS1

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Estimate selection coefficient for a window

LS1

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Estimate selection coefficient for a window

LS1

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Change in allele frequency with selection

AA Aa aa p2 2pq q2 1+s 1+hs 1 p2(1+s) 2pq(1+hs) q2 Genotypes Frequency before selection Fitness Frequency after selection

iterate for 20 generations

dominance coefficient h = 0 : recessive A h = 0.5 : additive h = 1 : dominant A 24

pt+1 p2 (1 + s) + pq (1 + hs ) 1 + sp2 + 2hspq

=

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Change in allele frequency with selection

pt+1 p2 (1 + s) + pq (1 + hs ) 1 + sp2 + 2hspq

=

AA Aa aa p2 2pq q2 1+s 1+hs 1 p2(1+s) 2pq(1+hs) q2 Genotypes Frequency before selection Fitness Frequency after selection

iterate for 20 generations

Try many h and s combinations and calculate the likelihood that they would produce the observed trajectory

dominance coefficient h = 0 : recessive A h = 0.5 : additive h = 1 : dominant A 25

with help from Felicity Jones

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This allele in chr10 acts partially dominantly and selection is strong

LS1 Selection coefficient s Dominance coefficient h

best likelihood at s, h =

  • loglik

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LS1

pt+1 p2 (1 + s) + pq (1 + hs ) 1 + sp2 + 2hspq

=

Calculated coefficients fit the observed data well

s = 0.43 h = 0.73

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LS1

Estimate selection coefficient for Nkx3-2 selected alleles

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F0 F17

Loss of bone growth repression

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LS1

Overdominance in Nkx3-2 allele: reached an equilibrium

s = 0.35, h = 1.60, freqeq = 0.73

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LS1

Overdominance in Nkx3-2 allele: reached an equilibrium

s = 0.35, h = 1.60, freqeq = 0.73

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Check allelic interactions (e.g., dominance) with genotype frequencies

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LS1

Genome-wide: Most windows are not under selection Windows under selection tend to act in dominance (?)

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LS1

Genome-wide: Most windows are not under selection Windows under selection tend to act in dominance (?)

32 Windows outside “drift zone” for at least 5 generations 1.6%

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LS1

Genome-wide: Most windows are not under selection Windows under selection tend to act in dominance (?)

Windows outside “drift zone” for at least 5 generations 1.6% Selected windows in chr 10 Nkx3-2 33 Side story Recessive(?) alleles

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Genome-wide: Most windows are not under selection Windows under selection tend to act in dominance Similar pattern genome-wide for replicate lines

LS1 LS2

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Single-locus simulation with within-family selection

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Reconstruction of selection response generation-to-generation

Allele trajectories

  • Allelic interactions (i.e., dominance)
  • Timing and relative importance of genes

Haplotype reconstruction with pedigree

  • Compare against models of linkage

?

Can we fully map the timing and location of the selection response? How does strong selection distort the recombination landscape?

Founding haplotypes Selected haplotypes

time

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How did the Longshanks respond to selection?

  • Selection vs. genetic drift

Drift strong, selection stronger Near fixation by F17

  • How many genes

Very polygenic 8 major loci

  • Effect sizes

Nkx3-2 : 10%

  • Can we model the response

Yes, and linkage important

  • How do the alleles increase tibia length

cis - regulatory “breaking enhancers”

  • Allelic interactions

Most selected alleles act dominantly (?)

  • Haplotype segregation

Coming soon!

Castro, Yancoskie et al., eLIFE, in review

 bioRxiv link!

Quantitative genetics Population genetics DevBio

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Thank you!

 bioRxiv link!

Quantitative genetics Population genetics DevBio

Acknowledgements Frank Chan João Castro Mish Yancoskie Marek Kuçka Felicity Jones Bill Beluch Chan Lab Jones Lab Campbell Rolian Marta Marchini Isabella Skuplik John Cobb Nick Barton Stefanie Belohlavy Ronald Naumann

WE’RE HIRING!

  • Selection vs. genetic drift

Drift strong, selection stronger Near fixation by F17

  • How many genes

Very polygenic 8 major loci

  • Effect sizes

Nkx3-2 : 10%

  • Can we model the response

Yes, and linkage important

  • How do the alleles increase tibia length

cis - regulatory “breaking enhancers”

  • Allelic interactions

Most selected alleles act dominantly (?)

  • Haplotype segregation

Coming soon!

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