From sequence to phenotype: detecting deleterious variation by prediction of functionality

The past decade has seen a tremendous accumulation of genomic information for livestock species. For the major livestock species chicken, pigs, cattle and turkey, Wageningen University and the Breed4Food partners have access to genotypes and phenotypes for tens of thousands of individuals and complete genome sequences for hundreds to thousands of individuals.  

We have used this data for the identification of genetic variants (SNPs and structural variants) predicted to affect the phenotype with specific emphasis on the identification of lethal recessive variants. For pig and chicken we have applied a machine learning approach to predict the likelihood of a given variant to be deleterious or pathogenic, by integrating genome annotation, evolutionary conservation and functional genomics data, and transferring knowledge obtained from other species (human) as far as possible. The resulting Combined Annotation-Dependent Depletion (CADD) scores for pig (pCADD) and chicken (cCADD), provide impact scores of any nucleotide substitution in the genome. These CADD scores can now be used to prioritize functional, deleterious and disease causing variants over the entire genome or as priors in genomic selection.

The availability of tens of thousands of genotyped and phenotyped individuals from large pedigreed populations allows the identification of regions in the genome that carry recessive lethal variants. The approach is based on the identification of haplotypes for which homozygotes are missing from the population while, based on their allele frequency, one would expected to find in the population. In pigs this approach has enabled us to identify numerous lethal variants. Although the carrier frequencies of these lethal recessive variants generally is low, some nevertheless are found at relative high frequencies. We have shown that this likely is the result of drift, although also genetic hitchhiking and balancing selection have been shown to play a role for some of these variants.


Published results in this project are:


Derks MFL, Harlizius B, Lopes MS, Greijdanus-van der Putten SWM, Dibbits B, Laport K, Megens H-J,Groenen MAM (2019) Detection of a frameshift deletion in the SPTBN4 gene leads to prevention of severe myopathy and postnatal mortality in pigs. Front Genet. 10:1226.

Groß, C., M. Derks, H.-J. Megens, M. Bosse, M. A. M. Groenen, M. Reinders, and D. de Ridder. 2020. pCADD: SNV prioritisation in Sus scrofa. Genet. Sel. Evol. 52:4.

Derks, M. F. L., A. B. Gjuvsland, M. Bosse, M. S. Lopes, M. van Son, B. Harlizius, B. F. Tan, H. Hamland, E. Grindflek, M. A. M. Groenen, and H.-J. Megens. 2019. Loss of function mutations in essential genes cause embryonic lethality in pigs. PLOS Genetics. 15:e1008055.

Bosse, M., H.-J. Megens, M. F. L. Derks, Á. M. R. de Cara, and M. A. M. Groenen. 2019. Deleterious alleles in the context of domestication, inbreeding, and selection. Evol. Appl. 12:6-17.

Groß, C., D. de Ridder, and M. Reinders. 2018. Predicting variant deleteriousness in non-human species: applying the CADD approach in mouse. BMC Bioinform. 19:373.

Derks, M. F. L., H.-J. Megens, M. Bosse, J. Visscher, K. Peeters, M. C. A. M. Bink, A. Vereijken, C. Gross, D. de Ridder, M. J. T. Reinders, and M. A. M. Groenen. 2018. A survey of functional genomic variation in domesticated chickens. Genet. Sel. Evol. 50:17.

Derks, M. F. L., J. M. Herrero-Medrano, R. P. M. A. Crooijmans, A. Vereijken, J. A. Long, H.-J. Megens, and M. A. M. Groenen. 2018. Early and late feathering in turkey and chicken: same gene but different mutations. Genet. Sel. Evol. 50:7.

Derks, M. F. L., M. S. Lopes, M. Bosse, O. Madsen, B. Dibbits, B. Harlizius, M. A. M. Groenen, and H.-J. Megens. 2018. Balancing selection on a recessive lethal deletion with pleiotropic effects on two neighboring genes in the porcine genome. PLOS Genetics. 14:e1007661.

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Project supporters:

project partner Hendrix Genetics  project partner CRV  project partner Topigs Norsvin

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