16 research outputs found
Transmission-Blocking Vaccines: Focus on Anti-Vector Vaccines against Tick-Borne Diseases
Tick-borne diseases are a potential threat that account for significant morbidity and mortality in human population worldwide. Vaccines are not available to treat several of the tick-borne diseases. With the emergence and resurgence of several tick-borne diseases, emphasis on the development of transmission-blocking vaccines remains increasing. In this review, we provide a snap shot on some of the potential candidates for the development of anti-vector vaccines (a form of transmission-blocking vaccines) against wide range of hard and soft ticks that include Ixodes, Haemaphysalis, Dermacentor, Amblyomma, Rhipicephalus and Ornithodoros species
Unravelling higher order chromatin organisation through statistical analysis
Recent technological advances underpinned by high throughput sequencing have
given new insights into the three-dimensional structure of mammalian genomes.
Chromatin conformation assays have been the critical development in this area,
particularly the Hi-C method which ascertains genome-wide patterns of intra and
inter-chromosomal contacts. However many open questions remain concerning the
functional relevance of such higher order structure, the extent to which it varies, and
how it relates to other features of the genomic and epigenomic landscape.
Current knowledge of nuclear architecture describes a hierarchical organisation
ranging from small loops between individual loci, to megabase-sized self-interacting
topological domains (TADs), encompassed within large multimegabase chromosome
compartments. In parallel with the discovery of these strata, the ENCODE project has
generated vast amounts of data through ChIP-seq, RNA-seq and other assays applied
to a wide variety of cell types, forming a comprehensive bioinformatics resource.
In this work we combine Hi-C datasets describing physical genomic contacts with
a large and diverse array of chromatin features derived at a much finer scale in the
same mammalian cell types. These features include levels of bound transcription
factors, histone modifications and expression data. These data are then integrated
in a statistically rigorous way, through a predictive modelling framework from the
machine learning field. These studies were extended, within a collaborative project, to
encompass a dataset of matched Hi-C and expression data collected over a murine
neural differentiation timecourse.
We compare higher order chromatin organisation across a variety of human cell
types and find pervasive conservation of chromatin organisation at multiple scales.
We also identify structurally variable regions between cell types, that are rich in active
enhancers and contain loci of known cell-type specific function. We show that broad
aspects of higher order chromatin organisation, such as nuclear compartment domains,
can be accurately predicted in a variety of human cell types, using models based upon
underlying chromatin features. We dissect these quantitative models and find them
to be generalisable to novel cell types, presumably reflecting fundamental biological
rules linking compartments with key activating and repressive signals. These models
describe the strong interconnectedness between locus-level patterns of local histone
modifications and bound factors, on the order of hundreds or thousands of basepairs,
with much broader compartmentalisation of large, multi-megabase chromosomal
regions.
Finally, boundary regions are investigated in terms of chromatin features and
co-localisation with other known nuclear structures, such as association with the
nuclear lamina. We find boundary complexity to vary between cell types and link
TAD aggregations to previously described lamina-associated domains, as well as
exploring the concept of meta-boundaries that span multiple levels of organisation.
Together these analyses lend quantitative evidence to a model of higher order genome
organisation that is largely stable between cell types, but can selectively vary locally,
based on the activation or repression of key loci
Cohesin regulates tissue-specific expression by stabilizing highly occupied cis-regulatory modules
The cohesin protein complex contributes to transcriptional regulation in a CTCF-independent manner by colocalizing with master regulators at tissue-specific loci. The regulation of transcription involves the concerted action of multiple transcription factors (TFs) and cohesin's role in this context of combinatorial TF binding remains unexplored. To investigate cohesin-non-CTCF (CNC) binding events in vivo we mapped cohesin and CTCF, as well as a collection of tissue-specific and ubiquitous transcriptional regulators using ChIP-seq in primary mouse liver. We observe a positive correlation between the number of distinct TFs bound and the presence of CNC sites. In contrast to regions of the genome where cohesin and CTCF colocalize, CNC sites coincide with the binding of master regulators and enhancer-markers and are significantly associated with liver-specific expressed genes. We also show that cohesin presence partially explains the commonly observed discrepancy between TF motif score and ChIP signal. Evidence from these statistical analyses in wild-type cells, and comparisons to maps of TF binding in Rad21-cohesin haploinsufficient mouse liver, suggests that cohesin helps to stabilize large protein-DNA complexes. Finally, we observe that the presence of mirrored CTCF binding events at promoters and their nearby cohesin-bound enhancers is associated with elevated expression levels
Insights into hominid evolution from the gorilla genome sequence
Gorillas are humans' closest living relatives after chimpanzees, and are of comparable importance for the study of human origins and evolution. Here we present the assembly and analysis of a genome sequence for the western lowland gorilla, and compare the whole genomes of all extant great ape genera. We propose a synthesis of genetic and fossil evidence consistent with placing the human-chimpanzee and human-chimpanzee-gorilla speciation events at approximately 6 and 10 million years ago. In 30% of the genome, gorilla is closer to human or chimpanzee than the latter are to each other; this is rarer around coding genes, indicating pervasive selection throughout great ape evolution, and has functional consequences in gene expression. A comparison of protein coding genes reveals approximately 500 genes showing accelerated evolution on each of the gorilla, human and chimpanzee lineages, and evidence for parallel acceleration, particularly of genes involved in hearing. We also compare the western and eastern gorilla species, estimating an average sequence divergence time 1.75 million years ago, but with evidence for more recent genetic exchange and a population bottleneck in the eastern species. The use of the genome sequence in these and future analyses will promote a deeper understanding of great ape biology and evolution. © 2012 Macmillan Publishers Limited. All rights reserved