College of Agriculture & Natural Resources

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Author: search.filters.author.Shen, Botong

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    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, Li
    Understanding 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.
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    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, Li
    Although 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.
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    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, Li
    Crossover 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.
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    CHARACTERIZATION OF GENETIC RECOMBINATION AND ITS INFLUENCING FACTORS IN CATTLE
    (2018) Shen, Botong; Ma, Li; Animal Sciences; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)
    Meiotic recombination is a fundamental biological process in which parental genetic materials are exchanged during egg or sperm development. Recombination is necessary for proper chromosomal disjunction during meiosis. Aberrations in this process have been confirmed as the cause of aneuploidy, leading to a potentially deleterious outcome. Along with mutation, recombination is a major force to promote genetic diversity and drive the evolution of genomes. Despite the importance of recombination, the frequency and location of recombination vary wildly within and between individuals, populations, and species. In this thesis, I characterized patterns of recombination in the cattle genome and conducted a comprehensive study of the effect of genetics, sex and age on recombination and its evolution using a uniquely large cattle database hosted at the USDA, where over a million animals with full pedigree information have been genotyped and new data are being generated at an increasing speed. First, we characterized five PRDM9 alleles and generated allele-specific recombination maps using data derived from over 239,000 meioses in Holstein. We found one allele of PRDM9 to be very different from others in both protein composition and recombination landscape. By comparing recombination maps from sperm and pedigree data, we validated the quality of pedigree-based results. Second, we extended our analysis in recombination patterns to four major U.S. dairy cattle breeds, Holstein, Jersey, Ayrshire, and Brown Swiss. We identified over 8.9 million crossover events and constructed eight genome-wide recombination maps for the two sexes in four cattle breeds. We confirmed a longer male genetic map in bovine and found breed-specific recombination hotspots. Our GWAS analyses confirmed seven loci associated with genome-wide recombination rate and the association of the PRDM9 gene with hotspot usage in two sexes and multiple cattle breeds. Third, we explored the plastic nature of recombination in cattle by examining the effect of maternal age and temperature using data derived from 36,999 three-generation families in Holstein for which temperature data were available. We presented a quadratic relationship between recombination frequency and maternal age and a positive correlation between temperature and recombination rate. By analyzing large genomic datasets with pedigree information in cattle, these studies advanced our understanding of meiotic recombination in a domestic livestock species.