Interactions between sequence POLYmorphisms and DNA MEthylation for the determination of PHEnotype in cattle – POLYPHEME
Over the past decades, bovine selection has led to considerable progress in the dairy cattle performances. Recently, epigenetic mechanisms have been regarded as a potential source of phenotypic variance unaccounted by genomic selection. POLYPHEME will explore whether epigenomics may provide opportunities for more efficient selection, focusing on interactions between sequence polymorphism and DNA methylation. We will address: (i) the genetic control of DNA methylation, with methylation quantitative trait loci (meQTLs) identification, (ii) the correlation of DNA methylation with performances (own and offspring); (iii) the role of DNA methylation in the dynamics and stability of cattle genome, through the identification of methylation-driven neo-mutations and recombination breakpoints. POLYPHEME involves 3 partners with complementary expertise and access to facilities and biological resources: INRAE BREED (DNA methylation analyses), INRAE GABI (genomics/quantitative genetics), ALLICE (fertility prediction, access to marketed bulls ‘samples).
POLYPHEME will mainly focus on bull sperm, since sperm methylome is crucial for male fertility and potentially affects subsequent embryo development as well as offspring phenotype. Furthermore, DNA methylation is relatively stable in the male germline during adulthood, suggesting that sperm methylome can be regarded as a proxy for DNA methylation during spermatogenesis, when meiotic recombination takes place and neo-mutations transmitted to next generations are more likely to occur. For (i), the sperm methylomes of 500 individuals will be analysed by reduced representation bisulfite sequencing, and meQTLs will be identified by genome-wide association studies at the whole sequence level. The concordance of meQTLs and performances measured on the bulls (fertility) and on large female progeny groups will next be examined. For (ii), we will focus on intra-individual epigenetic variation, and examine whether contrasted sperm methylomes can be associated with deviations in the performances of the daughters obtained from the same bull, in order to disentangle rare epigenetic inheritance phenomena from the wealth of genetically controlled traits in cattle. A quantitative genetics model extended to epigenetics will then be applied to explore the impact of sperm DNA methylation on phenotypes. For (iii), recent mutations and recombination events and breakpoints will be identified in 40 accurately selected cows deriving at 95% from 40 ancestors 4-6 generations ago. Next, we will investigate whether the mutation rate at CpGs and the probability of recombination events depends on the methylation status of the germline of ancestors.
Although this project involves basic research and molecular analyses at the individual level, it uses many resources generated by bovine selection and its outputs have the potential to help understanding the biological nature of the many identified QTLs and to modify selection methods in the future, with an expected positive impact on the resulting cattle population in terms of robustness. Knowledge about the genetic mechanisms underlying heritable variations of the methylome may allow selecting a cattle population with greater genome plasticity, which would certainly be an advantage in a context of global climate change and environmental instability. Irrespective of the volume of data, genome-wide association studies consistently fail to explain a majority of the expected heritable fraction of complex physiological traits and diseases. Molecular mechanisms underlying this so called “missing heritability” are not established, but epigenetic modifications may account for a fraction of this phenomenon. Taking epigenetic status into account should pave the way for a breakthrough innovation in genomic evaluation methods.
Madame Hélène KIEFER (Biologie de la Reproduction, Environnement, Epigénétique & Développement)
The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.
BREED Biologie de la Reproduction, Environnement, Epigénétique & Développement
GABI Génétique Animale et Biologie Intégrative
ALLICE ALLICE / Recherche et développement
Help of the ANR 365,555 euros
Beginning and duration of the scientific project: September 2021 - 36 Months