Biology subjects

Taylor, J.

Publications and source records attributed to Taylor, J..

24 records · Page 2Linked to original sources

bioRxiv2017

Lethal Haplotypes And Candidate Casual Mutations In Angus Cattle

BackgroundIf unmanaged, high rates of inbreeding in livestock populations adversely impact their reproductive fitness. In beef cattle, historical selection strategies have increased the frequency of several segregating fatal autosomal recessive polymorphisms. Selective breeding has also decreased the extent of haplotypic diversity genome-wide. By identifying haplotypes for which homozygotes are not observed but would be expected based on their frequency, developmentally lethal recessive loci can be localized. This analysis comes without the need for observation of the loss-associated phenotype (e.g., failure to implant, first trimester abortion, deformity at birth). In this study, haplotypes were estimated for 3,961 registered Angus individuals using 52,545 SNP loci using findhap v2, which exploited the complex pedigree among the individuals in this population.\n\nResultsSeven loci were detected to possess haplotypes that were not observed in homozygous form despite a sufficiently high frequency and pedigree-based expectation of homozygote occurrence. These haplotypes were identified as candidates for harboring autosomal recessive lethal alleles. Of the genotyped individuals, 109 were resequenced to an average 27X depth of coverage to identify putative loss-of-function alleles genome-wide and had variants called using a custom in-house developed pipeline. For the candidate lethal-harboring haplotypes present in these bulls, sequence-called genotypes were used to identify concordant variants. In addition, whole-genome sequence imputation of variants was performed into the set of 3,961 genotyped animals using the 109 resequenced animals to identify candidate lethal recessive variants at the seven loci.\n\nConclusionsSelective breeding programs could utilize the predicted lethal haplotypes associated with SNP genotypes. Sequencing and other methods for identifying the causal variants underlying these haplotypes can allow for more efficient methods of management such as gene editing. These two methods in total will reduce the negative impacts of inbreeding on fertility and maximize overall genetic gains.

genomics↗

bioRxiv2017

Chromosome Conformation Paints Reveal The Role Of Lamina Association In Genome Organization And Regulation

Non-random, dynamic three-dimensional organization of the nucleus is important for regulation of gene expression. Numerous studies using chromosome conformation capture strategies have uncovered ensemble organizational principles of individual chromosomes, including organization into active (A) and inactive (B) compartments. In addition, large inactive regions of the genome appear to be associated with the nuclear lamina, the so-called Lamina Associated Domains (LADs). However, the interrelationship between overall chromosome conformation and association of domains with the nuclear lamina remains unclear. In particular, the 3D organization of LADs within the context of the entire chromosome has not been investigated. In this study, we describe \"chromosome conformation paints\" to determine the relationship in situ between LAD and non-LAD regions of the genome in single cells. We find that LADs organize into constrained and compact regions at the nuclear lamina, and these findings are supported by an integrated analysis of both DamID and Hi-C data. Using a refined algorithm to identify active (A) and inactive (B) compartments from Hi-C data, we demonstrate that the LADs correspond to the B compartment. We demonstrate that in situ single cell chromosome organization is strikingly predicted by integrating both Hi-C and DamID data into a chromosome conformation model. In addition, using the chromosome conformation paints, we demonstrate that LAD (and B-compartment) organization is dependent upon both chromatin state and Lamin A/C. Finally, we demonstrate that small regions within LADs escape the repressive regime at the peripheral zone to interact with the A-compartment and are enriched for both transcription start sites (TSSs) and active enhancers.

cell biology↗

bioRxiv2016

LOCALIZER: subcellular localization prediction of plant and effector proteins in the plant cell

Pathogens are able to deliver effector proteins into plant cells to enable infection. Some effectors have been found to enter subcellular compartments by mimicking host targeting sequences. Although many computational methods exist to predict plant protein subcellular localization, they perform poorly for effectors. We introduce LOCALIZER for predicting plant and effector protein localization to chloroplasts, mitochondria, and nuclei. LOCALIZER shows greater prediction accuracy for chloroplast and mitochondrial targeting compared to other methods for 652 plant proteins. For 108 eukaryotic effectors, LOCALIZER outperforms other methods and predicts a previously unrecognized chloroplast transit peptide for the ToxA effector, which we show translocates into tobacco chloroplasts. Secretome-wide predictions and confocal microscopy reveal that rust fungi might have evolved multiple effectors that target chloroplasts or nuclei. LOCALIZER is the first method for predicting effector localisation in plants and is a valuable tool for prioritizing effector candidates for functional investigations. LOCALIZER is available at http://localizer.csiro.au/.

bioinformatics↗

bioRxiv2016

A Novel DNA-binding Protein Coordinates Asymmetric Chromosome Replication and Chromosome Partitioning

Bacterial chromosome replication is regulated from a single replication origin (ori) that receives cell cycle signals. Following replication, bacteria often use the parABS partition system with a centromere-like parS locus to place the chromosomes into the daughter cells. Our knowledge of cell cycle regulation is incomplete and we searched for novel regulators of chromosome replication. Here we show that in the cell cycle model Caulobacter crescentus a novel DNA-binding protein promotes both the initiation of chromosome replication and the earliest step of chromosome partitioning. We used biochemical fractionation to identify a protein (OpaA) that preferentially binds to mutated ori DNA that also increases ori-plasmid replication in vivo. OpaA represents a previously unknown class of DNA-binding proteins. opaA gene expression is essential and sufficient OpaA levels are required for the correct timing of chromosome replication. Whole genome ChIP-seq identified the genomic binding sites for OpaA, with the strongest associations at the parABS locus near ori. Using molecular-genetic and fluorescence microscopy experiments, we showed that OpaA also promotes the first step of chromosome partitioning, the initial separation of the duplicated parS loci following ori replication. This separation occurs before the parABS mechanism and it coincides with the regulatory step that splits the symmetry of the chromosomes so that they are placed at distinct cell-poles which develop into replicating and non-replicating cell-types. We propose that OpaA coordinates replication with the poorly understood mechanism of early chromosome separation. opaA lethal suppressor and antibiotic experiments argue that future studies be focused on the mechanistic roles for transcription and translation at this critical step of the cell cycle.\n\nAuthor SummaryLike all organisms, bacteria must replicate their chromosomes and move them into the newly dividing cells. Eukaryotes use non-overlapping phases, first for chromosome replication (S-phase) followed by mitosis (M-phase) when the completely duplicated chromosomes are separated. However, bacteria combine both phases so chromosome replication and chromosome separation (termed chromosome \"partitioning\") overlap. In many bacteria, including Caulobacter crescentus, chromosome replication initiates from a single replication origin (ori) and the first duplicated regions of the chromosome immediately begin \"partitioning\" towards the cell poles long before the whole chromosome has finished replication. This partitioning movement uses the centromere-like DNA called \"parS\" that is located near the ori. Here we identify a completely novel type of DNA-binding protein called OpaA and we show that it acts at both ori and parS. The timing and coordination of overlapping chromosome replication and partitioning phases is a special regulatory problem for bacteria. We further demonstrate that OpaA is selectively required for the initiation of chromosome replication at ori and likewise that OpaA is selectively required for the initial partitioning of parS. Therefore, we propose that OpaA is a novel regulator that coordinates chromosome replication with the poorly understood mechanism of early chromosome separation.

microbiology↗

bioRxiv2016

Polygenic transmission disequilibrium confirms that common and rare variation act additively to create risk for autism spectrum disorders

Autism spectrum disorder (ASD) risk is influenced by both common polygenic and de novo variation. The purpose of this analysis was to clarify the influence of common polygenic risk for ASDs and to identify subgroups of cases, including those with strong acting de novo variants, in which different types of polygenic risk are relevant. To do so, we extend the transmission disequilibrium approach to encompass polygenic risk scores, and introduce the polygenic transmission disequilibrium test. Using data from more than 6,400 children with ASDs and 15,000 of their family members, we show that polygenic risk for ASDs, schizophrenia, and greater educational attainment is over transmitted to children with ASDs in two independent samples, but not to their unaffected siblings. These findings hold independent of proband IQ. We find that common polygenic variation contributes additively to risk in ASD cases that carry a very strong acting de novo variant. Lastly, we find evide ...

genetics↗

bioRxiv2016

Selection Corrected Statistical Inference for Region Detection with High-throughput Assays

Scientists use high-dimensional measurement assays to detect and prioritize regions of strong signal in a spatially organized domain. Examples include finding methylation enriched genomic regions using microarrays and identifying active cortical areas using brain-imaging. The most common procedure for detecting potential regions is to group together neighboring sites where the signal passed a threshold. However, one needs to account for the selection bias induced by this opportunistic procedure to avoid diminishing effects when generalizing to a population. In this paper, we present a model and a method that permit population inference for these detected regions. In particular, we provide non-asymptotic point and confidence interval estimates for mean effect in the region, which account for the local selection bias and the non-stationary covariance that is typical of these data. Such summaries allow researchers to better compare regions of different sizes and different correlation structures. Inference is provided within a conditional one-parameter exponential family for each region, with truncations that match the constraints of selection. A secondary screening-and-adjustment step allows pruning the set of detected regions, while controlling the false-coverage rate for the set of regions that are reported. We illustrate the benefits of the method by applying it to detected genomic regions with differing DNA-methylation rates across tissue types. Our method is shown to provide superior power compared to non-parametric approaches.

bioinformatics↗