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ARS Home Northeast Area Beltsville, Maryland (BARC) Beltsville Agricultural Research Center Animal Genomics and Improvement Laboratory Research





- Liu, Ge - George
- Rosen, Benjamin - Ben
- Schroeder, Steven - Steve
- Van Tassell, Curtis - Curt
- 2023
- Publications
- Food Animal Production (101)

Research Project: Accelerating Genetic Improvement of Ruminants Through Enhanced Genome Assembly, Annotation, and Selection **Location:
                            Animal Genomics and Improvement Laboratory** 2023 Annual Report **Objectives**
                                

Objective 1: Develop biological resources and computational tools to enhance the representation and annotation characterization of dairy breed-specific bovine and other genomes.
Sub-objective 1.A: Improve dairy breed-specific bovine and other genome assemblies for pangenome representation.
Sub-objective 1.B: SNP and CNV mapping in cattle and other ruminants.
Sub-objective 1.C: Evaluate digestive tract function and identify gastrointestinal microorganism effects on nutrient digestibility, milk production capacity, nutrient use efficiency, and health in dairy cattle.

Objective 2: Apply novel tools to utilize genotypic and phenotypic data to enhance genetic improvement in ruminant production systems.
Sub-objective 2.A: Continue work on community-based breeding programs and develop imputation pipeline and data in goats.
Sub-objective 2.B: Characterize and localize within and across breed measures of dominance as observed in inbreeding depression and heterosis.

Objective 3: Characterize functional genetic and epigenetic variations for improved fertility, growth, health, production, reproduction, and environmental sustainability of ruminants.
Sub-objective 3.A: Epigenome-wide Association Study based on DNA methylation.
Sub-objective 3.B: FarmGTEx for goats. **Approach**
                                

Completion of our objectives is expected, in the short term, to improve genome-wide selection in the U.S. dairy industry as well as facilitate new genome-enhanced breeding strategies to bring economic and genetic stability to various ruminant value chains. Ultimately, longer term objectives to identify and understand how causative genetic variation affects livestock biology will require a combination of genome sequencing and comparative genomics, quantitative genetics, epigenomics and metagenomics, all of which are components of this project plan and areas of expertise in our group. Efforts to characterize genome activity and structural conservation/variation are an extension of our current research program in applied genomics. This project plan completely leverages the resources derived from the Bovine Genomes, HapMap, 1000 Bull Genomes, FAANG, Bovien Pangenome, and FarmGTEx projects, and genotypic data derived from the Council on Dairy Cattle Breeding (CDCB) genome-enhanced genetic evaluations for North American dairy cattle. **Progress Report**
                                

This is the first report for the new NP101 Project 8042-31000-112-000D which started July 24, 2022, entitled “Accelerating Genetic Improvement of Ruminants Through Enhanced Genome Assembly, Annotation, and Selection”.

For Objective 1.A, the T2T/Bovine Pangenome Consortium was launched to describe the full extent of genetic variation in cattle through the creation of genome assemblies for bovine species of economic and biodiversity importance. Using the trio-binning method, the Consortium has released 15 breed-specific reference assemblies. The genome assemblies were generated from trios of Angus and Brahman, Nelore and Brown Swiss, and Original Braunvieh breeds. Additionally, Highland cattle and yak, Piedmontese cattle and gaur, Simmental cattle and bison, as well as for Holsteins and Jerseys to improve earlier efforts, and tropically adapted indicine breeds (Sahiwal, and Tharparkar). AGIL has generated assemblies for additional 17 breeds for the Consortium: 1960’s Holstein, Ayrshire, Charolais, Chianina, Gelbvieh, Guzerat, Gyr, Maine-Anjou, Red Wagyu, Retinta, Rubia Gallega, Sarda, Tuli, Wagyu, Welsh Black, White Fulani, Whitebred Shorthorn. 

For Objective 1.B, a new cattle pangenome and an enhanced structural variation catalog for global breeds are generated, revealing missing sequences, novel structural variations, their diversity, and their evolutionary history. This cattle pangenome was created based on the genome sequences of 898 cattle representing 57 breeds. The pangenome identified 83 Mb of sequence not found in the cattle reference genome, representing 3.1% novel sequence. A catalog of structural variants included 3.3 million deletions, 0.12 million inversions, and 0.18 million duplications. Estimates of breed ancestry and hybridization between cattle breeds using insertion/deletions as markers were similar to those produced by single nucleotide polymorphism–based analysis. Hundreds of deletions were observed to have stratification based on subspecies and breed. The results indicate that pangenomes are a valuable resource for studying diversity and evolutionary history, and help to delineate how domestication, trait-based breeding, and adaptive introgression have shaped the cattle genome.

Objective 1C is pending revision due to critical vacancy.

For Objective 2.A, use of genome-wide SNP information will increase the accuracy of predictions of genetic merit. A total of 1,372 whole genome sequenced goats from diverse breeds and geographical backgrounds were used as a reference population to develop an imputation pipeline that aims to facilitate fine mapping, meta-analysis, and genomic prediction. The Beagle 5.3 software1 was used for the phasing and imputation process of 74 million variants across 29 autosomal chromosomes, utilizing the high-performance computing cluster at the USDA (https://scinet.usda.gov). To evaluate the imputation pipeline, a dataset2 comprising 3,197 diverse goat genotypes with 46,654 markers was used. The accuracy estimation involved leave-one-out cross-validation of 30 randomly selected whole genome sequenced samples, assessing correlation coefficients as a measure of accuracy. To further validate the pipeline, an additional dataset3 from a different geographical background is currently being evaluated. 

The final pipeline and associated scripts will be made publicly available soon through a GitHub repository (https://github.com/goatimpuation/GoatWGSimputation), enabling the scientific community to benefit from this valuable resource.

For Objective 2.B, the global application of genomic selection in dairy cattle has raised interest in characterizing dominance effects for a better understanding of inbreeding depression. We believe that a richer understanding of additive (ADD), dominance (DOM), and runs of homozygosity (ROH) effects in purebred and crossbred dairy cattle will help to understand the impact of these factors on inbreeding depression and heterosis. To identify and localize genomic regions associated with ADD, DOM, and ROH effects we performed a large-scale single-SNP GWAS analysis, where SNPs were fitted as fixed effects for the ADD, DOM, and ROH one locus at a time. To this end, we developed quantitative methods, programs and scripts and made needed software packages available. These have been first tested on small datasets. 

We then applied our methods, programs, and scripts to more than 1 million U.S. Holstein cows genotyped on 79,294 SNP markers. To date, we have analyzed 3 production traits, 3 fertility traits, and somatic cell score (SCS). For the production traits, SNPs on BTA14 had the largest ADD effects. For fertility traits, SNPs on BTA1 had the most significant ADD effects. SCS had no significant DOM effects. Few DOM effects were detected for production traits and these effects had lower significance than ADD effects. Estimates of fertility traits DOM were detected with similar statistical significance as the ADD effects. The ROH revealed fewer significance peaks than the ADD effects for all traits. We also found confounding between DOM and ROH components – that is DOM and ROH capture the same variance. We will continue to work to extend this study to genomic data for Jersey cows and all available crossbreds.

For Objective 3.A, DNAm microarray data were collected for a better understanding of functional genetic variations. Using over 200 Holstein cattle and a newly designed DNAm microarray, 432 DNAm microarray data were generated, covering various production and reproduction traits, such as feed efficiency and parasite resistance. For Objective 3.B, the FarmGTEx (genotype-tissue expression) Consortium Sheep/Goat project was launched to provide a comprehensive atlas of tissue-specific gene expression and genetic regulation in sheep and goats. Thousands of transcript sequencing data in over 100 tissues/cell types among dozens of breeds were collected for both species. They will provide the transcriptome landscape across tissues and define thousands of variants associated with gene expression and alternative splicing for dozens of major tissues. **Accomplishments**
                                

1. Construction of improved genome assemblies through the Ruminant Telomere-to-Telomere (T2T) and Bovine Pangenome Consortiums. Breeding better cattle using genomics requires informative reference genomes. Previously, an incomplete genome based on a single Hereford cow provided the sole reference. This deprived researchers and breeders of important information about variation in many complex genomic regions as well as among individuals and breeds. Led by ARS scientists in Beltsville, Maryland, and Clay Center, Nebraska, the Ruminant T2T and Bovine Pangenome Consortia are developing new and improved genome assemblies. The Ruminant T2T team has generated a nearly complete reference assembly for cattle without the numerous gaps present in current assemblies. This new reference includes a complete cattle Y chromosome for the very first time, now available through NCBI. The Bovine Pangenome Consortium has prioritized cattle breeds having important economic impacts and sought to capture appreciable genetic variation. This cutting-edge group grew to over 90 members at 58 institutions in 27 countries. The Consortium plans to integrate the nearT2T assembly with over 50 breed-specific assemblies into a single, graph-based reference genome. **Review Publications**
                            *Zhang, Y., Liu, A., Huang, S., Evans, J.D., Cook, S.C., Palmer-Young, E., Corona, M.V., Alburaki, M., Liu, G., Han, R., Li, W., Hao, Y., Li, J., Gilligan, T., Smith-Pardo, A.H., Banmeke, O., Posada-Florez, F.J., Gao, Y.H., Hoffman, G.D., Xie, H., Chen, Y. 2022. Mediating a host cell signaling pathway linked to the overwinter mortality offers a promising therapeutic approach for improving bee health. Journal of Advanced Research. https://doi.org/10.1016/j.jare.2022.12.011.*
                                *Boschiero, C., Gao, Y., Baldwin, R.L., Ma, L., Liu, G.E., Li, C.-J. 2022. Characterization of accessible chromatin regions in cattle rumen epithelial tissue during weaning. Genes. 13:535. https://doi.org/10.3390/genes13030535.*
                                *Guo, J., Sun, X., Mao, A., Liu, H., Zhan, S., Li, L., Zhong, T., Wang, L., Cao, J., Liu, G., Zheng, H. 2022. A 13.42-kb tandem duplication at the ASIP locus is strongly associated with the pigmentation phenotype of Swiss markings in goats. BMC Genomics. 23:437. https://doi.org/10.1186/s12864-022-08672-9.*
                                *Boschiero, C., Gao, Y., Baldwin, R.L., Ma, L., Li, C., Liu, G. 2022. Differentially CTCF-binding sites in cattle rumen tissue during weaning. International Journal of Molecular Sciences. 23(16):9070. https://doi.org/10.3390/ijms23169070.*
                                *Sun, X., Guo, J., Li, L., Zhong, T., Wang, L., Zhan, S., Dai, D., Lu, J., Wang, D., Liu, G., Zheng, H. 2022. Genetic diversity and selection signatures in Jianchang Black goats revealed by whole-genome sequencing data. Animals. 12(18):2365. https://doi.org/10.3390/ani12182365.*
                                *Boschiero, C., Gao, Y., Baldwin, R.L., Ma, L., Li, C., Liu, G. 2022. Butyrate induces modifications of the CTCF-binding landscape in cattle cells. Biomolecules. 12(9):1177.  https://doi.org/10.3390/biom12091177.*
                                *Zhao, R., Talenti, A., Fang, L., Liu, S., Liu, G., Chue Hong, N.P., Tenesa, A., Hassan, M., Prendergast, J.G. 2022. The conservation of human functional variants and their effects across livestock species. Communications Biology. 5:1003. https://doi.org/10.1038/s42003-022-03961-1.*
                                *Wang, X., Li, W., Feng, X., Li, J., Liu, G., Fang, L., Yu, Y. 2023. Harnessing male germline epigenomics for the genetic improvement in cattle. Journal of Animal Science and Biotechnology. 14:76. https://doi.org/10.1186/s40104-023-00874-9.*
                                *Naji, M.M., Jiang, Y., Utsunomiya, Y.T., Rosen, B.D., Solkner, J., Wang, C., Jiang, L., Zhang, Q., Zhang, Y., Ding, X., Meszaros, G. 2022. Favored single nucleotide variants identified using whole genome re-sequencing of Austrian and Chinese cattle breeds. Frontiers in Genetics. https://doi.org/10.3389/fgene.2022.974787.*
                                *Akounda, B., Ouedraogo, D., Soudre, A., Burger, P.A., Rosen, B.D., Van Tassell, C.P., Solkner, J. 2023. Morphometric characterization of local goat breeds in two agroecological zones of Burkina Faso, West Africa. Animals. 13(12):1931. https://doi.org/10.3390/ani13121931.*


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