Program Director/Principal Investigator (Da, Yang): Project Description MOTIVATION AND OBJECTIVES Complex genetic mechanism of quantitative traits may include gene interaction effects commonly referred to as epistasis and multiple genetic factors with small effects. This is among the most difficult genetic areas due to difficulties to discover and the need of large samples to detect many small effects. The U.S. Holstein cattle have the largest genomic evaluation program in the world with 3,852,580 genotyped cattle by March 2021, and the number of genotyped cattle increased at a pace of ~600,000 per year. Among the genotyped cows, phenotypic records were available for 43 traits covering production, reproduction, health, longevity, and body shape and structure. Majority of these traits have been collected and evaluated for decades. In addition, more new traits may become available continuously. The unprecedented sample sizes of the genomic selection data of U.S. Holstein cattle provide an unprecedented opportunity for understanding and utilizing complex genetic mechanisms of quantitative traits. Preliminary results using 294,076 Holstein cows for 8 traits already had interesting discovery that would have been unimaginable, including a single chromosome region interacting with all chromosomes, intra-chromosome epistasis covering an entire chromosome, and nearly exclusively inter-chromosome epistasis for one trait. With methods and computing tools to study complex genetics developed by PI’s group as well as encouraging preliminary results, this proposed research is an unprecedented large-scale study on genomic discovery and prediction for 43 traits mostly with one million cows using complex multigenic models that have never been attempted before, are expected to generate many new discoveries, and have potential to advance multigenic knowledge to a new level. The long-term goal of this project is to identify multigenetic factors underlying quantitative traits, to understand how multigenetic factors affect phenotypes, and to apply multigenetic mechanisms and factors to predict phenotypes. Specific aims are as follows. Aim 1: Large-scale discovery of global pairwise epistasis effects for 43 traits covering production, reproduction, health, and body shape and structure by testing four types of epistasis effects per SNP pair, additive × additive, additive × dominance, dominance × additive, and dominance × dominance using million cow genome-wide association study (GWAS) for most of the 43 traits. These tests will identify the most important epistasis type underlying each trait, and chromosome regions and genes with the most significant epistasis effects for epistasis network with unprecedented statistical confidence. All four types of epistasis effects will be further analyzed as intra- and inter-chromosome epistasis effects to investigate their potential association with the trait heritability and response to genetic selection. Selected chromosome regio...