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 Insights from Initial Variant Detection by Sequencing Single Sperm in Cattle(MDPI, 2021-11-15) Yang, Liu; Gao, Yahui; Boschiero, Clarissa; Li, Li; Zhang, Hongping; Ma, Li; Liu, George E.Meiotic de novo mutation (DNM) is one of the important phenomena contributing to gamete genome diversity. However, except for humans and a few model organisms, they are not well studied in livestock, including cattle. Moreover, bulk sperm samples have been routinely utilized in experiments, which include millions of single sperm cells and only report high-frequency variants. In this study, we isolated and sequenced 143 single sperms from two Holstein bulls and identified hundreds of candidate DNM events in ten sperms with deep sequencing coverage. We estimated DNM rates ranging from 1.08 × 10−8 to 3.78 × 10−8 per nucleotide per generation. We further validated 12 out of 14 selected DNM events using Sanger sequencing. To our knowledge, this is the first single sperm whole-genome sequencing effort in livestock, which provided useful information for future studies of point mutations and male fertility. Our preliminary results pointed out future research directions and highlighted the importance of uniform whole genome amplification, deep sequence coverage, and dedicated software pipelines for genetic variant detection using single-cell sequencing data.Item Comparative transcriptome in large-scale human and cattle populations(Springer Nature, 2022-08-22) Yao, Yuelin; Liu, Shuli; Xia, Charley; Gao, Yahui; Pan, Zhangyuan; Canela-Xandri, Oriol; Khamseh, Ava; Rawlik, Konrad; Wang, Sheng; Li, Bingjie; Zhang, Yi; Pairo-Castineira, Erola; D’Mellow, Kenton; Li, Xiujin; Yan, Ze; Li, Cong-jun; Yu, Ying; Zhang, Shengli; Ma, Li; Cole, John B.; Ross, Pablo J.; Zhou, Huaijun; Haley, Chris; Liu, George E.; Fang, Lingzhao; Tenesa, AlbertCross-species comparison of transcriptomes is important for elucidating evolutionary molecular mechanisms underpinning phenotypic variation between and within species, yet to date it has been essentially limited to model organisms with relatively small sample sizes. Here, we systematically analyze and compare 10,830 and 4866 publicly available RNA-seq samples in humans and cattle, respectively, representing 20 common tissues. Focusing on 17,315 orthologous genes, we demonstrate that mean/median gene expression, inter-individual variation of expression, expression quantitative trait loci, and gene co-expression networks are generally conserved between humans and cattle. By examining large-scale genome-wide association studies for 46 human traits (average n = 327,973) and 45 cattle traits (average n = 24,635), we reveal that the heritability of complex traits in both species is significantly more enriched in transcriptionally conserved than diverged genes across tissues. In summary, our study provides a comprehensive comparison of transcriptomes between humans and cattle, which might help decipher the genetic and evolutionary basis of complex traits in both species.Item Investigation of rumen long noncoding RNA before and after weaning in cattle(Springer Nature, 2022-07-20) Marceau, Alexis; Gao, Yahui; Baldwin VI, Ransom L.; Li, Cong-jun; Jiang, Jicai; Liu, George E.; Ma, LiThis study aimed to identify long non-coding RNA (lncRNA) from the rumen tissue in dairy cattle, explore their features including expression and conservation levels, and reveal potential links between lncRNA and complex traits that may indicate important functional impacts of rumen lncRNA during the transition to the weaning period. A total of six cattle rumen samples were taken with three replicates from before and after weaning periods, respectively. Total RNAs were extracted and sequenced with lncRNA discovered based on size, coding potential, sequence homology, and known protein domains. As a result, 404 and 234 rumen lncRNAs were identified before and after weaning, respectively. However, only nine of them were shared under two conditions, with 395 lncRNAs found only in pre-weaning tissues and 225 only in post-weaning samples. Interestingly, none of the nine common lncRNAs were differentially expressed between the two weaning conditions. LncRNA averaged shorter length, lower expression, and lower conservation scores than the genome overall, which is consistent with general lncRNA characteristics. By integrating rumen lncRNA before and after weaning with large-scale GWAS results in cattle, we reported significant enrichment of both pre- and after-weaning lncRNA with traits of economic importance including production, reproduction, health, and body conformation phenotypes. The majority of rumen lncRNAs are uniquely expressed in one of the two weaning conditions, indicating a functional role of lncRNA in rumen development and transition of weaning. Notably, both pre- and post-weaning lncRNA showed significant enrichment with a variety of complex traits in dairy cattle, suggesting the importance of rumen lncRNA for cattle performance in the adult stage. These relationships should be further investigated to better understand the specific roles lncRNAs are playing in rumen development and cow performance.Item Genome-wide recombination map construction from single sperm sequencing in cattle(Springer Nature, 2022-03-05) Yang, Liu; Gao, Yahui; Li, Mingxun; Park, Ki-Eun; Liu, Shuli; Kang, Xiaolong; Liu, Mei; Oswalt, Adam; Fang, Lingzhao; Telugu, Bhanu P.; Sattler, Charles G.; Li, Cong-jun; Cole, John B.; Seroussi, Eyal; Xu, Lingyang; Yang, Lv; Zhou, Yang; Li, Li; Zhang, Hongping; Rosen, Benjamin D.; Van Tassell, Curtis P.; Ma, Li; Liu, George E.Meiotic recombination is one of the important phenomena contributing to gamete genome diversity. However, except for human and a few model organisms, it is not well studied in livestock, including cattle. To investigate their distributions in the cattle sperm genome, we sequenced 143 single sperms from two Holstein bulls. We mapped meiotic recombination events at high resolution based on phased heterozygous single nucleotide polymorphism (SNP). In the absence of evolutionary selection pressure in fertilization and survival, recombination events in sperm are enriched near distal chromosomal ends, revealing that such a pattern is intrinsic to the molecular mechanism of meiosis. Furthermore, we further validated these findings in single sperms with results derived from sequencing its family trio of diploid genomes and our previous studies of recombination in cattle. To our knowledge, this is the first large-scale single sperm whole-genome sequencing effort in livestock, which provided useful information for future studies of recombination, genome instability, and male infertility.Item Towards the detection of copy number variation from single sperm sequencing in cattle(Springer Nature, 2022-03-17) Yang, Liu; Gao, Yahui; Oswalt, Adam; Fang, Lingzhao; Boschiero, Clarissa; Neupane, Mahesh; Sattler, Charles G.; Li, Cong-jun; Seroussi, Eyal; Xu, Lingyang; Yang, Lv; Li, Li; Zhang, Hongping; Rosen, Benjamin D.; Van Tassell, Curtis P.; Zhou, Yang; Ma, Li; Liu, George E.Copy number variation (CNV) has been routinely studied using bulk-cell sequencing. However, CNV is not well studied on the single-cell level except for humans and a few model organisms. We sequenced 143 single sperms of two Holstein bulls, from which we predicted CNV events using 14 single sperms with deep sequencing. We then compared the CNV results derived from single sperms with the bulk-cell sequencing of one bull’s family trio of diploid genomes. As a known CNV hotspot, segmental duplications were also predicted using the bovine ARS-UCD1.2 genome. Although the trio CNVs validated only some single sperm CNVs, they still showed a distal chromosomal distribution pattern and significant associations with segmental duplications and satellite repeats. Our preliminary results pointed out future research directions and highlighted the importance of uniform whole genome amplification, deep sequence coverage, and dedicated software pipelines for CNV detection using single cell sequencing data.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.