The world demand for animal-based food products is anticipated to increase by 70% by 2050. Meeting this demand in a way that has a minimal impact on the environment will require the implementation of ...advanced technologies, and methods to improve the genetic quality of livestock are expected to play a large part. Over the past 10 years, genomic selection has been introduced in several major livestock species and has more than doubled genetic progress in some. However, additional improvements are required. Genomic information of increasing complexity (including genomic, epigenomic, transcriptomic and microbiome data), combined with technological advances for its cost-effective collection and use, will make a major contribution.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Faithful reconstruction of haplotypes from diploid marker data (phasing) is important for many kinds of genetic analyses, including mapping of trait loci, prediction of genomic breeding values, and ...identification of signatures of selection. In human genetics, phasing most often exploits population information (linkage disequilibrium), while in animal genetics the primary source of information is familial (Mendelian segregation and linkage). We herein develop and evaluate a method that simultaneously exploits both sources of information. It builds on hidden Markov models that were initially developed to exploit population information only. We demonstrate that the approach improves the accuracy of allele phasing as well as imputation of missing genotypes. Reconstructed haplotypes are assigned to hidden states that are shown to correspond to clusters of genealogically related chromosomes. We show that these cluster states can directly be used to fine map QTL. The method is computationally effective at handling large data sets based on high-density SNP panels.
Artificial selection has created myriad breeds of domestic animals, each characterized by unique phenotypes pertaining to behavior, morphology, physiology, and disease. Most domestic animal ...populations share features with isolated founder populations, making them well suited for positional cloning. Genome sequences are now available for most domestic species, and with them a panoply of tools including high-density single-nucleotide polymorphism panels. As a result, domestic animal populations are becoming invaluable resources for studying the molecular architecture of complex traits and of adaptation. Here we review recent progress and issues in the positional identification of genes underlying complex traits in domestic animals. As many phenotypes studied in animals are quantitative, we focus on mapping, fine mapping, and cloning of quantitative trait loci.
Herpes simplex virus type 1 (HSV-1) is a prevalent human pathogen. HSV-1 genomes persist in trigeminal ganglia neuronal nuclei as chromatinized episomes, while epithelial cells are typically killed ...by lytic infection. Fluctuations in anti-viral responses, broadly defined, may underlay periodic reactivations. The ganglionic immune response to HSV-1 infection includes cell-intrinsic responses in neurons, innate sensing by several cell types, and the infiltration and persistence of antigen-specific T-cells. The mechanisms specifying the contrasting fates of HSV-1 in neurons and epithelial cells may include differential genome silencing and chromatinization, dictated by variation in access of immune modulating viral tegument proteins to the cell body, and protection of neurons by autophagy. Innate responses have the capacity of recruiting additional immune cells and paracrine activity on parenchymal cells, for example
chemokines and type I interferons. In both mice and humans, HSV-1-specific CD8 and CD4 T-cells are recruited to ganglia, with mechanistic studies suggesting active roles in immune surveillance and control of reactivation. In this review we focus mainly on HSV-1 and the TG, comparing and contrasting where possible observational, interventional, and
studies between humans and animal hosts.
Texel sheep are renowned for their exceptional meatiness. To identify the genes underlying this economically important feature, we performed a whole-genome scan in a Romanov × Texel F2 population. We ...mapped a quantitative trait locus with a major effect on muscle mass to chromosome 2 and subsequently fine-mapped it to a chromosome interval encompassing the myostatin (GDF8) gene. We herein demonstrate that the GDF8 allele of Texel sheep is characterized by a G to A transition in the 3′ UTR that creates a target site for mir1 and mir206, microRNAs (miRNAs) that are highly expressed in skeletal muscle. This causes translational inhibition of the myostatin gene and hence contributes to the muscular hypertrophy of Texel sheep. Analysis of SNP databases for humans and mice demonstrates that mutations creating or destroying putative miRNA target sites are abundant and might be important effectors of phenotypic variation.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
One of the 'grand challenges' in modern biology is to understand the genetic basis of phenotypic diversity within and among species. Thousands of years of selective breeding of domestic animals has ...created a diversity of phenotypes among breeds that is only matched by that observed among species in nature. Domestic animals therefore constitute a unique resource for understanding the genetic basis of phenotypic variation. When the genome sequences of domestic animals become available the identification of the mutations that underlie the transformation from a wild to a domestic species will be a realistic and important target.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Reprogramming of mRNA translation has a key role in cancer development and drug resistance
. However, the molecular mechanisms that are involved in this process remain poorly understood. Wobble tRNA ...modifications are required for specific codon decoding during translation
. Here we show, in humans, that the enzymes that catalyse modifications of wobble uridine 34 (U
) tRNA (U
enzymes) are key players of the protein synthesis rewiring that is induced by the transformation driven by the BRAF
oncogene and by resistance to targeted therapy in melanoma. We show that BRAF
-expressing melanoma cells are dependent on U
enzymes for survival, and that concurrent inhibition of MAPK signalling and ELP3 or CTU1 and/or CTU2 synergizes to kill melanoma cells. Activation of the PI3K signalling pathway, one of the most common mechanisms of acquired resistance to MAPK therapeutic agents, markedly increases the expression of U
enzymes. Mechanistically, U
enzymes promote glycolysis in melanoma cells through the direct, codon-dependent, regulation of the translation of HIF1A mRNA and the maintenance of high levels of HIF1α protein. Therefore, the acquired resistance to anti-BRAF therapy is associated with high levels of U
enzymes and HIF1α. Together, these results demonstrate that U
enzymes promote the survival and resistance to therapy of melanoma cells by regulating specific mRNA translation.
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KISLJ, NUK, SBMB, UL, UM, UPUK
We use >250,000 cross-over events identified in >10,000 bovine sperm cells to perform an extensive characterization of meiotic recombination in male cattle. We map Quantitative Trait Loci (QTL) ...influencing genome-wide recombination rate, genome-wide hotspot usage, and locus-specific recombination rate. We fine-map three QTL and present strong evidence that genetic variants in REC8 and RNF212 influence genome-wide recombination rate, while genetic variants in PRDM9 influence genome-wide hotspot usage.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Human T-cell leukaemia virus type-1 (HTLV-1) and bovine leukaemia virus (BLV) infect T- and B-lymphocytes, respectively, provoking a polyclonal expansion that will evolve into an aggressive ...monoclonal leukaemia in ∼5% of individuals following a protracted latency period. It is generally assumed that early oncogenic changes are largely dependent on virus-encoded products, especially TAX and HBZ, while progression to acute leukaemia/lymphoma involves somatic mutations, yet that both are independent of proviral integration site that has been found to be very variable between tumours. Here, we show that HTLV-1/BLV proviruses are integrated near cancer drivers which they affect either by provirus-dependent transcription termination or as a result of viral antisense RNA-dependent cis-perturbation. The same pattern is observed at polyclonal non-malignant stages, indicating that provirus-dependent host gene perturbation contributes to the initial selection of the multiple clones characterizing the asymptomatic stage, requiring additional alterations in the clone that will evolve into full-blown leukaemia/lymphoma.
Five to ten percent of mammalian genomes is occupied by multiple clades of endogenous retroviruses (ERVs), that may count thousands of members. New ERV clades arise by retroviral infection of the ...germline followed by expansion by reinfection and/or retrotransposition. ERV mobilization is a source of deleterious variation, driving the emergence of ERV silencing mechanisms, leaving "DNA fossils". Here we show that the ERVK2-1-LTR clade is still active in the bovine and a source of disease-causing alleles. We develop a method to measure the rate of ERVK2-1-LTR mobilization, finding an average of 1 per ~150 sperm cells, with >10-fold difference between animals. We perform a genome-wide association study and identify eight loci affecting ERVK2-1-LTR mobilization. We provide evidence that polymorphic ERVK2-1-LTR elements in four of these loci cause the association. We generate a catalogue of full length ERVK2-1-LTR elements, and show that it comprises 15% of C-type autonomous elements, and 85% of D-type non-autonomous elements lacking functional genes. We show that >25% of the variance of mobilization rate is determined by the number of C-type elements, yet that de novo insertions are dominated by D-type elements. We propose that D-type elements act as parasite-of-parasite gene drives that may contribute to the observed demise of ERV elements.
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