the genetic architecture of recombination rate variation in a natural population

The genetic architecture of recombination rate variation in a natural population.

Susan E. Johnston, Jon Slate, Josephine M. Pemberton

@SuseJohnston

Why recombine? An evolutionary perspective.

• Recombination can be beneficial.

– Can prevent accumulation of deleterious mutations.

– Can increase genetic variance for fitness.

• Recombination can be costly.

– May reduce genome integrity

– Can break up co-adapted gene complexes.

• Empirical studies have been limited by genetic resources.

Charlesworth & Barton (1996), Felsenstein (1974), Burt (2000), Inoue & Lupski (2002)

Understanding recombination rates in the genomics era

• Recombination rates vary from local to global level.

• Recombination rate may co-vary with fitness.

• Individual recombination rate can be heritable. – Genetic variants have associated with variation

– PRDM9, RNF212, etc.

• But little understanding on if, how and why RR varies at an individual level in natural populations.

h2 = 0.30

h2 = 0.46

h2 = 0.22

biologyfishman

David Illig

Aimeric Blaud

Kong et al (2004) Nat. Genet.

Baudat et al (2010) Science Kong et al (2008) Science

Kong et al (2010) Nature

St Kilda

• Wild population of Neolithic domestic sheep studied since 1985.

• Extensive life history, pedigree and phenotype information for ~ 7,000 individuals.

• 39,101 polymorphic SNPs typed in 5652 pedigreed sheep

Soay sheep (Ovis aries)

@SoaySheep

Pedigree and SNP information can be integrated to find meiotic crossovers.

Father Mother

Focal

ID

Offspring

Mate

gamete

CRIMAP v2.504 Green et al. (1990)


gamete karyotype

34 crossover events

Y

Father Mother

Focal

ID

Offspring

Mate

gamete

CRIMAP v2.504 Green et al. (1990)


3330 individual recombination counts in 813 unique focal individuals.

Is recombination rate heritable?

Is recombination rate driven by particular genetic variants?

Questions

Estimating heritability: an animal model approach.

Fixed effects Sex, Age, Condition

Genomic inbreeding coefficient

Random effects

Individual identity

Year of Birth

Year of Gamete Transfer

Mother identity

Modelled using ASReml-R (Butler et al. 2009) Genomic inbreeding/relatedness determined using GCTA (Yang et al. 2010)

Additive genetic effect

(heritability) Genomic relationship matrix using 39K SNP

markers

REML generalised linear mixed model:

*Only Sex and Additive genetic effect were significant.

Sex h2 VP

Female 0.16

(0.02)

31.7

(1.06)

Male 0.12

(0.03)

25.2

(1.16)

Males have 7.38 more crossovers per gamete.

Females have higher phenotypic variance

and heritability.

Is recombination rate heritable?

Is recombination rate driven by particular genetic variants?

Questions

1. Genome-wide association study

N = 1197 (227)

A region on chromosome 6 has a trans-acting, sex-limited effect on recombination rate.

N = 2134 (586)

RNF212

biologyfishman

David Illig

Aimeric Blaud

Candidate gene: ring finger protein 212 (RNF212)

• Locus associated with individual recombination rate variation in humans, cattle and mice.

• Sexually antagonistic effect on recombination in humans.

• Strong candidate for sex-limited effect on recombination rate.

Kong et al (2014) Nat. Genet.

Sandor et al (2012) PLoS Genetics Reynolds et al (2013) Nat. Genet.

Effect sizes at RNF212 in Soay sheep

Au

toso

mal

cro

sso

ver

cou

nt

The most significant SNP explains 35% of heritable variation in females.

SNP ID: oar3_OAR6_116402578

Au

toso

mal

cro

sso

ver

cou

nt

• Majority of heritable variation remains unexplained.

– Common phenomenon in GWAS studies.

• GWAS is a single locus approach

– Reduced power to detect rare variants…

– …and variants of small effect sizes.

• One solution: Regional heritability.

– Determine variance explained by defined regions.

– Incorporates the effects of multiple haplotypes.

Single vs. multimarker approaches

Wood et al. (2014) Nat. Genet.

Yang et al (2011) Nat. Genet Nagamine et al (2012) PLoS One

Santure et al (2013) Mol Ecol

Berenos et al (2015) Mol Ecol

2. Regional heritability analysis.

Regional additive genetic

variance

Genomic additive genetic

variance

Additive genetic effect

Yang et al (2011) Nat. Genet Nagamine et al (2012) PLoS One

Examined variance explained within sliding windows of 20 SNPs (~800kb windows)

N = 2134 (586)

N = 1197 (227)

N = 3330 (813)

RNF212 region explains 47% of heritable variation in females.

No regions identified in males.

Region with meiotic recombinant protein REC8

REC8 region explains 26% of heritable variation in both sexes.

N = 2134 (586)

N = 1197 (227)

N = 3330 (813)

RNF212 region explains 47% of heritable variation in females.

No regions identified in males.

REC8 region explains 26% of heritable variation in both sexes.

The approach may increase chances of finding new variants… …but power is likely to be limited in smaller sample sizes.

Region with meiotic recombinant protein REC8

Conclusions

• Recombination rate is heritable and has a sexually dimorphic genetic architecture in Soay sheep.

• Multi-locus approaches may improve variant detection

– But “missing heritability” issue indicates quantitative genetic framework still relevant.

• Is recombination rate under selection in the wild?

– Ongoing work!

ACKNOWLEDGEMENTS: St Kilda Photographs: Arpat Ozgul, Tom Black, Gina Prior, Owen Jones.

Josephine Pemberton Jon Slate Camillo Bérénos Jisca Huisman Jarrod Hadfield Craig Walling Bill Hill John Hickey Phil Ellis

Jill Pilkington Ian Stevenson Lynsey Bunnefeld Many Soay sheep project volunteers Wellcome Trust Genotyping Facility, Edinburgh.