Animal & Avian Sciences Research Works
Permanent URI for this collectionhttp://hdl.handle.net/1903/1600
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Item Characterization of Copy Number Variation’s Potential Role in Marek’s Disease(MDPI, 2017-05-09) Xu, Lingyang; He, Yanghua; Ding, Yi; Sun, Guirong; Carrillo, Jose Adrian; Li, Yaokun; Ghaly, Mona M.; Ma, Li; Zhang, Huanmin; Liu, George E.; Song, JiuzhouMarek’s Disease (MD) is a highly contagious pathogenic and oncogenic disease primarily affecting chickens. Chicken Lines 63 and 72, as well as their recombinant congenic strains (RCS) with varied susceptibility to MD, are ideal models to study the complex mechanisms of genetic resistance to MD. In this study, we investigated copy number variation (CNV) in these inbred chicken lines using the Affymetrix Axiom HD 600 K SNP genotyping array. We detected 393 CNV segments across all ten chicken lines, of which 12 CNVs were specifically identified in Line 72. We then assessed genetic structure based on CNV and observed markedly different patterns. Finally, we validated two deletion events in Line 72 and correlated them with genes expression using qPCR and RNA-seq, respectively. Our combined results indicated that these two CNV deletions were likely to contribute to MD susceptibility.Item X-inactivation informs variance-based testing for X-linked association of a quantitative trait(Springer Nature, 2015) Ma, Li; Hoffman, Gabriel; Keinan, AlonThe X chromosome plays an important role in human diseases and traits. However, few X-linked associations have been reported in genome-wide association studies, partly due to analytical complications and low statistical power. In this study, we propose tests of X-linked association that capitalize on variance heterogeneity caused by various factors, predominantly the process of X-inactivation. In the presence of X-inactivation, the expression of one copy of the chromosome is randomly silenced. Due to the consequent elevated randomness of expressed variants, females that are heterozygotes for a quantitative trait locus might exhibit higher phenotypic variance for that trait. We propose three tests that build on this phenomenon: 1) A test for inflated variance in heterozygous females; 2) A weighted association test; and 3) A combined test. Test 1 captures the novel signal proposed herein by directly testing for higher phenotypic variance of heterozygous than homozygous females. As a test of variance it is generally less powerful than standard tests of association that consider means, which is supported by extensive simulations. Test 2 is similar to a standard association test in considering the phenotypic mean, but differs by accounting for (rather than testing) the variance heterogeneity. As expected in light of X-inactivation, this test is slightly more powerful than a standard association test. Finally, test 3 further improves power by combining the results of the first two tests. We applied the these tests to the ARIC cohort data and identified a novel X-linked association near gene AFF2 with blood pressure, which was not significant based on standard association testing of mean blood pressure. Variance-based tests examine overdispersion, thereby providing a complementary type of signal to a standard association test. Our results point to the potential to improve power of detecting X-linked associations in the presence of variance heterogeneity.Item Ruminant-specific multiple duplication events of PRDM9 before speciation(Springer Nature, 2017-03-14) Padhi, Abinash; Shen, Botong; Jiang, Jicai; Zhou, Yang; Liu, George E.; Ma, LiUnderstanding the genetic and evolutionary mechanisms of speciation genes in sexually reproducing organisms would provide important insights into mammalian reproduction and fitness. PRDM9, a widely known speciation gene, has recently gained attention for its important role in meiotic recombination and hybrid incompatibility. Despite the fact that PRDM9 is a key regulator of recombination and plays a dominant role in hybrid incompatibility, little is known about the underlying genetic and evolutionary mechanisms that generated multiple copies of PRDM9 in many metazoan lineages. The present study reports (1) evidence of ruminant-specific multiple gene duplication events, which likely have had occurred after the ancestral ruminant population diverged from its most recent common ancestor and before the ruminant speciation events, (2) presence of three copies of PRDM9, one copy (lineages I) in chromosome 1 (chr1) and two copies (lineages II & III) in chromosome X (chrX), thus indicating the possibility of ancient inter- and intra-chromosomal unequal crossing over and gene conversion events, (3) while lineages I and II are characterized by the presence of variable tandemly repeated C2H2 zinc finger (ZF) arrays, lineage III lost these arrays, and (4) C2H2 ZFs of lineages I and II, particularly the amino acid residues located at positions −1, 3, and 6 have evolved under strong positive selection. Our results demonstrated two gene duplication events of PRDM9 in ruminants: an inter-chromosomal duplication that occurred between chr1 and chrX, and an intra-chromosomal X-linked duplication, which resulted in two additional copies of PRDM9 in ruminants. The observation of such duplication between chrX and chr1 is rare and may possibly have happened due to unequal crossing-over millions of years ago when sex chromosomes were independently derived from a pair of ancestral autosomes. Two copies (lineages I & II) are characterized by the presence of variable sized tandem-repeated C2H2 ZFs and evolved under strong positive selection and concerted evolution, supporting the notion of well-established Red Queen hypothesis. Collectively, gene duplication, concerted evolution, and positive selection are the likely driving forces for the expansion of ruminant PRDM9 sub-family.Item Dissection of additive, dominance, and imprinting effects for production and reproduction traits in Holstein cattle(Springer Nature, 2017-05-30) Jiang, Jicai; Shen, Botong; O’Connell, Jeffrey R.; VanRaden, Paul M.; Cole, John B.; Ma, LiAlthough genome-wide association and genomic selection studies have primarily focused on additive effects, dominance and imprinting effects play an important role in mammalian biology and development. The degree to which these non-additive genetic effects contribute to phenotypic variation and whether QTL acting in a non-additive manner can be detected in genetic association studies remain controversial. To empirically answer these questions, we analyzed a large cattle dataset that consisted of 42,701 genotyped Holstein cows with genotyped parents and phenotypic records for eight production and reproduction traits. SNP genotypes were phased in pedigree to determine the parent-of-origin of alleles, and a three-component GREML was applied to obtain variance decomposition for additive, dominance, and imprinting effects. The results showed a significant non-zero contribution from dominance to production traits but not to reproduction traits. Imprinting effects significantly contributed to both production and reproduction traits. Interestingly, imprinting effects contributed more to reproduction traits than to production traits. Using GWAS and imputation-based fine-mapping analyses, we identified and validated a dominance association signal with milk yield near RUNX2, a candidate gene that has been associated with milk production in mice. When adding non-additive effects into the prediction models, however, we observed little or no increase in prediction accuracy for the eight traits analyzed. Collectively, our results suggested that non-additive effects contributed a non-negligible amount (more for reproduction traits) to the total genetic variance of complex traits in cattle, and detection of QTLs with non-additive effect is possible in GWAS using a large dataset.Item Characterization of recombination features and the genetic basis in multiple cattle breeds(Springer Nature, 2018-04-27) Shen, Botong; Jiang, Jicai; Seroussi, Eyal; Liu, George E.; Ma, LiCrossover generated by meiotic recombination is a fundamental event that facilitates meiosis and sexual reproduction. Comparative studies have shown wide variation in recombination rate among species, but the characterization of recombination features between cattle breeds has not yet been performed. Cattle populations in North America count millions, and the dairy industry has genotyped millions of individuals with pedigree information that provide a unique opportunity to study breed-level variations in recombination. Based on large pedigrees of Jersey, Ayrshire and Brown Swiss cattle with genotype data, we identified over 3.4 million maternal and paternal crossover events from 161,309 three-generation families. We constructed six breed- and sex-specific genome-wide recombination maps using 58,982 autosomal SNPs for two sexes in the three dairy cattle breeds. A comparative analysis of the six recombination maps revealed similar global recombination patterns between cattle breeds but with significant differences between sexes. We confirmed that male recombination map is 10% longer than the female map in all three cattle breeds, consistent with previously reported results in Holstein cattle. When comparing recombination hotspot regions between cattle breeds, we found that 30% and 10% of the hotspots were shared between breeds in males and females, respectively, with each breed exhibiting some breed-specific hotspots. Finally, our multiple-breed GWAS found that SNPs in eight loci affected recombination rate and that the PRDM9 gene associated with hotspot usage in multiple cattle breeds, indicating a shared genetic basis for recombination across dairy cattle breeds. Collectively, our results generated breed- and sex-specific recombination maps for multiple cattle breeds, provided a comprehensive characterization and comparison of recombination patterns between breeds, and expanded our understanding of the breed-level variations in recombination features within an important livestock species.Item Genomic predictions combining SNP markers and copy number variations in Nellore cattle(Springer Nature, 2018-06-05) Hay, El Hamidi A.; Utsunomiya, Yuri T.; Xu, Lingyang; Zhou, Yang; Neves, Haroldo H. R.; Carvalheiro, Roberto; Bickhart, Derek M.; Ma, Li; Garcia, Jose Fernando; Liu, George E.Due to the advancement in high throughput technology, single nucleotide polymorphism (SNP) is routinely being incorporated along with phenotypic information into genetic evaluation. However, this approach often cannot achieve high accuracy for some complex traits. It is possible that SNP markers are not sufficient to predict these traits due to the missing heritability caused by other genetic variations such as microsatellite and copy number variation (CNV), which have been shown to affect disease and complex traits in humans and other species. In this study, CNVs were included in a SNP based genomic selection framework. A Nellore cattle dataset consisting of 2230 animals genotyped on BovineHD SNP array was used, and 9 weight and carcass traits were analyzed. A total of six models were implemented and compared based on their prediction accuracy. For comparison, three models including only SNPs were implemented: 1) BayesA model, 2) Bayesian mixture model (BayesB), and 3) a GBLUP model without polygenic effects. The other three models incorporating both SNP and CNV included 4) a Bayesian model similar to BayesA (BayesA+CNV), 5) a Bayesian mixture model (BayesB+CNV), and 6) GBLUP with CNVs modeled as a covariable (GBLUP+CNV). Prediction accuracies were assessed based on Pearson’s correlation between de-regressed EBVs (dEBVs) and direct genomic values (DGVs) in the validation dataset. For BayesA, BayesB and GBLUP, accuracy ranged from 0.12 to 0.62 across the nine traits. A minimal increase in prediction accuracy for some traits was noticed when including CNVs in the model (BayesA+CNV, BayesB+CNV, GBLUP+CNV). This study presents the first genomic prediction study integrating CNVs and SNPs in livestock. Combining CNV and SNP marker information proved to be beneficial for genomic prediction of some traits in Nellore cattle.Item Genome changes due to artificial selection in U.S. Holstein cattle(Springer Nature, 2019-02-11) Ma, Li; Sonstegard, Tad S.; Cole, John B.; VanTassell, Curtis P.; Wiggans, George R.; Crooker, Brian A.; Tan, Cheng; Prakapenka, Dzianis; Liu, George E.; Da, YangThe availability of a unique unselected Holstein line since 1964 provided a direct comparison between selected and unselected Holstein genomes whereas large Holstein samples provided unprecedented statistical power for identifying high-confidence SNP effects. Utilizing these unique resources, we aimed to identify genome changes affected by selection since 1964.Item Array CGH-based detection of CNV regions and their potential association with reproduction and other economic traits in Holsteins(Springer Nature, 2019-03-07) Liu, Mei; Fang, Lingzhao; Liu, Shuli; Pan, Michael G.; Seroussi, Eyal; Cole, John B.; Ma, Li; Chen, Hong; Liu, George E.Copy number variations (CNVs) are structural variants consisting of large-scale insertions and deletions of genomic fragments. Exploring CNVs and estimating their effects on phenotypes are useful for genome selection but remain challenging in the livestock.Item Functional annotation of the cattle genome through systematic discovery and characterization of chromatin states and butyrate-induced variations(Springer Nature, 2019-08-16) Fang, Lingzhao; Liu, Shuli; Liu, Mei; Kang, Xiaolong; Lin, Shudai; Li, Bingjie; Connor, Erin E.; Baldwin, Ransom L. VI; Tenesa, Albert; Ma, Li; Liu, George E.; Li, Cong-junThe functional annotation of genomes, including chromatin accessibility and modifications, is important for understanding and effectively utilizing the increased amount of genome sequences reported. However, while such annotation has been well explored in a diverse set of tissues and cell types in human and model organisms, relatively little data are available for livestock genomes, hindering our understanding of complex trait variation, domestication, and adaptive evolution. Here, we present the first complete global landscape of regulatory elements in cattle and explore the dynamics of chromatin states in rumen epithelial cells induced by the rumen developmental regulator—butyrate.Item Bos taurus–indicus hybridization correlates with intralocus sexual-conflict effects of PRDM9 on male and female fertility in Holstein cattle(Springer Nature, 2019-08-28) Seroussi, Eyal; Shirak, Andrey; Gershoni, Moran; Ezra, Ephraim; Santos, Daniel Jordan de Abreu; Ma, Li; Liu, George E.Crossover localization during meiotic recombination is mediated by the fast-evolving zinc-finger (ZnF) domain of gene PRDM9. To study its impact on dairy cattle performance, we compared its genetic variation between the relatively small Israeli (IL) Holsteins and the North American (US) Holsteins that count millions.