title: Rare Variants in Transcript and Potential Regulatory Regions Explain a Small Percentage of the Missing Heritability of Complex Traits in Cattle.
abstract: The proportion of genetic variation in complex traits explained by rare variants is a key question for genomic prediction, and for identifying the basis of "missing heritability"--the proportion of additive genetic variation not captured by common variants on SNP arrays. Sequence variants in transcript and regulatory regions from 429 sequenced animals were used to impute high density SNP genotypes of 3311 Holstein sires to sequence. There were 675,062 common variants (MAF>0.05), 102,549 uncommon variants (0.01<MAF<0.05), and 83,856 rare variants (MAF<0.01). We describe a novel method for estimating the proportion of the rare variants that are sequencing errors using parent-progeny duos. We then used mixed model methodology to estimate the proportion of variance captured by these different classes of variants for fat, milk and protein yields, as well as for fertility. Common sequence variants captured 83%, 77%, 76% and 84% of the total genetic variance for fat, milk, and protein yields and fertility, respectively. This was between 2 and 5% more variance than that captured from 600k SNPs on a high density chip, although the difference was not significant. Rare variants captured 3%, 0%, 1% and 14% of the genetic variance for fat, milk and protein yields, and fertility respectively, whereas pedigree explained the remaining amount of genetic variance (none for fertility). The proportion of variation explained by rare variants is likely to be under-estimated due to reduced accuracies of imputation for this class of variants. Using common sequence variants slightly improved accuracy of genomic predictions for fat and milk yield, compared to high density SNP array genotypes. However, including rare variants from transcript regions did not increase the accuracy of genomic predictions. These results suggest that rare variants recover a small percentage of the missing heritability for complex traits, however very large reference sets will be required to exploit this to improve the accuracy of genomic predictions. Our results do suggest the contribution of rare variants to genetic variation may be greater for fitness traits.
authors.affiliation: Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, 3083, Australia.|Dairy Futures Cooperative Research Centre, Bundoora, Victoria, 3083, Australia.
authors.forename: Oscar
authors.initials: O
authors.lastname: Gonzalez-Recio
authors.affiliation: Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, 3083, Australia.|Dairy Futures Cooperative Research Centre, Bundoora, Victoria, 3083, Australia.|School of Applied Systems Biology, La Trobe University, Bundoora, Victoria, 3086, Australia.
authors.forename: Hans D
authors.initials: HD
authors.lastname: Daetwyler
authors.affiliation: Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, 3083, Australia.|Dairy Futures Cooperative Research Centre, Bundoora, Victoria, 3083, Australia.|Faculty of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Iona M
authors.initials: IM
authors.lastname: MacLeod
authors.affiliation: Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, 3083, Australia.|Dairy Futures Cooperative Research Centre, Bundoora, Victoria, 3083, Australia.|School of Applied Systems Biology, La Trobe University, Bundoora, Victoria, 3086, Australia.
authors.forename: Jennie E
authors.initials: JE
authors.lastname: Pryce
authors.affiliation: Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, 3083, Australia.|Dairy Futures Cooperative Research Centre, Bundoora, Victoria, 3083, Australia.
authors.forename: Phil J
authors.initials: PJ
authors.lastname: Bowman
authors.affiliation: Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, 3083, Australia.|Dairy Futures Cooperative Research Centre, Bundoora, Victoria, 3083, Australia.|School of Applied Systems Biology, La Trobe University, Bundoora, Victoria, 3086, Australia.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Hayes
authors.affiliation: Biosciences Research Division, Department of Economic Development, Jobs, Transport and Resources, Bundoora, Victoria, 3083, Australia.|Faculty of Veterinary and Agricultural Science, University of Melbourne, Parkville, Victoria, 3010, Australia.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Goddard
mesh_terms: D000818:Animals; D002417:Cattle / Q000235:genetics*; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000235:genetics*; D012045:Regulatory Sequences, Nucleic Acid
chemical_list: D012333:RNA, Messenger