Publications by authors named "James G D Prendergast"

23 Publications

  • Page 1 of 1

Whole-Genome Sequence Data Suggest Environmental Adaptation of Ethiopian Sheep Populations.

Genome Biol Evol 2021 Mar;13(3)

Roslin Institute, University of Edinburgh, Midlothian, United Kingdom.

Great progress has been made over recent years in the identification of selection signatures in the genomes of livestock species. This work has primarily been carried out in commercial breeds for which the dominant selection pressures are associated with artificial selection. As agriculture and food security are likely to be strongly affected by climate change, a better understanding of environment-imposed selection on agricultural species is warranted. Ethiopia is an ideal setting to investigate environmental adaptation in livestock due to its wide variation in geo-climatic characteristics and the extensive genetic and phenotypic variation of its livestock. Here, we identified over three million single nucleotide variants across 12 Ethiopian sheep populations and applied landscape genomics approaches to investigate the association between these variants and environmental variables. Our results suggest that environmental adaptation for precipitation-related variables is stronger than that related to altitude or temperature, consistent with large-scale meta-analyses of selection pressure across species. The set of genes showing association with environmental variables was enriched for genes highly expressed in human blood and nerve tissues. There was also evidence of enrichment for genes associated with high-altitude adaptation although no strong association was identified with hypoxia-inducible-factor (HIF) genes. One of the strongest altitude-related signals was for a collagen gene, consistent with previous studies of high-altitude adaptation. Several altitude-associated genes also showed evidence of adaptation with temperature, suggesting a relationship between responses to these environmental factors. These results provide a foundation to investigate further the effects of climatic variables on small ruminant populations.
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http://dx.doi.org/10.1093/gbe/evab014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7955157PMC
March 2021

Investigating the origin and authenticity of Victoria Cross medals using X-ray fluorescence spectrometry.

Sci Rep 2020 11 19;10(1):19953. Epub 2020 Nov 19.

The Roslin Institute, University of Edinburgh, Easter Bush Campus, Midlothian, EH25 9RG, UK.

The Victoria Cross is the United Kingdom's premier military award for bravery, presented for gallantry during active operations. Since its inception in 1856 just 1358 have been awarded, and, due to their rarity and historic interest, have become highly prized amongst private and public collections. Unresolved, however, is a debate about the source material of the medals. Some authorities adhere to a traditional belief that all medals have been cast from the bronze of guns captured from the Russians at Sebastopol. Furthermore, controversy is attached to the authenticity of some VCs. In this study we used X-ray fluorescence spectrometry data to compare the metal compositions of 100 Victoria Crosses, covering 7% of those ever issued. Using Gaussian mixture modelling we identify that Victoria Crosses fall into four distinct clusters, confirming that the primary split occurred between medals issued prior to and after 1914. Using these data we investigate the potential of X-ray fluorescence to inform the study of medals whose authenticity have been queried, showing some have unusually similar compositions to other VCs. This paper highlights how X-ray fluorescence data in conjunction with clustering approaches can be used to effectively and non-destructively investigate the authenticity and history of Victoria Crosses.
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http://dx.doi.org/10.1038/s41598-020-76783-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7678865PMC
November 2020

Whole genome analysis of water buffalo and global cattle breeds highlights convergent signatures of domestication.

Nat Commun 2020 09 21;11(1):4739. Epub 2020 Sep 21.

The Roslin Institute, University of Edinburgh, Easter Bush, Midlothian, EH25 9RG, UK.

More people globally depend on the water buffalo than any other domesticated species, and as the most closely related domesticated species to cattle they can provide important insights into the shared evolutionary basis of domestication. Here, we sequence the genomes of 79 water buffalo across seven breeds and compare patterns of between breed selective sweeps with those seen for 294 cattle genomes representing 13 global breeds. The genomic regions under selection between cattle breeds significantly overlap regions linked to stature in human genetic studies, with a disproportionate number of these loci also shown to be under selection between water buffalo breeds. Investigation of potential functional variants in the water buffalo genome identifies a rare example of convergent domestication down to the same mutation having independently occurred and been selected for across domesticated species. Cross-species comparisons of recent selective sweeps can consequently help identify and refine important loci linked to domestication.
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http://dx.doi.org/10.1038/s41467-020-18550-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505982PMC
September 2020

Species-Specificity of Transcriptional Regulation and the Response to Lipopolysaccharide in Mammalian Macrophages.

Front Cell Dev Biol 2020 21;8:661. Epub 2020 Jul 21.

Mater Research Institute-University of Queensland, Translational Research Institute, Woolloongabba, QLD, Australia.

Mammalian macrophages differ in their basal gene expression profiles and response to the toll-like receptor 4 (TLR4) agonist, lipopolysaccharide (LPS). In human macrophages, LPS elicits a temporal cascade of transient gene expression including feed forward activators and feedback regulators that limit the response. Here we present a transcriptional network analysis of the response of sheep bone marrow-derived macrophages (BMDM) to LPS based upon RNA-seq at 0, 2, 4, 7, and 24 h post-stimulation. The analysis reveals a conserved transcription factor network with humans, and rapid induction of feedback regulators that constrain the response at every level. The gene expression profiles of sheep BMDM at 0 and 7 h post LPS addition were compared to similar data obtained from goat, cow, water buffalo, horse, pig, mouse and rat BMDM. This comparison was based upon identification of 8,200 genes annotated in all species and detected at >10TPM in at least one sample. Analysis of expression of transcription factors revealed a conserved transcriptional millieu associated with macrophage differentiation and LPS response. The largest co-expression clusters, including genes encoding cell surface receptors, endosome-lysosome components and secretory activity, were also expressed in all species and the combined dataset defines a macrophage functional transcriptome. All of the large animals differed from rodents in lacking inducible expression of genes involved in arginine metabolism and nitric oxide production. Instead, they expressed inducible transporters and enzymes of tryptophan and kynurenine metabolism. BMDM from all species expressed high levels of transcripts encoding transporters and enzymes involved in glutamine metabolism suggesting that glutamine is a major metabolic fuel. We identify and discuss transcripts that were uniquely expressed or regulated in rodents compared to large animals including , CXC and CC chemokines, , , , , , , , , , , and . Conversely, the data confirm the conserved regulation of multiple transcripts for which there is limited functional data from mouse models and knockouts. The data provide a resource for functional annotation and interpretation of loci involved in susceptibility to infectious and inflammatory disease in humans and large animal species.
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http://dx.doi.org/10.3389/fcell.2020.00661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386301PMC
July 2020

Examining the Impact of Imputation Errors on Fine-Mapping Using DNA Methylation QTL as a Model Trait.

Genetics 2019 07 30;212(3):577-586. Epub 2019 Apr 30.

Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4072, Australia.

Genetic variants disrupting DNA methylation at CpG dinucleotides (CpG-SNP) provide a set of known causal variants to serve as models to test fine-mapping methodology. We use 1716 CpG-SNPs to test three fine-mapping approaches (Bayesian imputation-based association mapping, Bayesian sparse linear mixed model, and the J-test), assessing the impact of imputation errors and the choice of reference panel by using both whole-genome sequence (WGS), and genotype array data on the same individuals ( = 1166). The choice of imputation reference panel had a strong effect on imputation accuracy, with the 1000 Genomes Project Phase 3 (1000G) reference panel ( = 2504 from 26 populations) giving a mean nonreference discordance rate between imputed and sequenced genotypes of 3.2% compared to 1.6% when using the Haplotype Reference Consortium (HRC) reference panel ( = 32,470 Europeans). These imputation errors had an impact on whether the CpG-SNP was included in the 95% credible set, with a difference of ∼23% and ∼7% between the WGS and the 1000G and HRC imputed datasets, respectively. All of the fine-mapping methods failed to reach the expected 95% coverage of the CpG-SNP. This is attributed to secondary genetic effects that are unable to be statistically separated from the CpG-SNP, and through a masking mechanism where the effect of the methylation disrupting allele at the CpG-SNP is hidden by the effect of a nearby SNP that has strong linkage disequilibrium with the CpG-SNP. The reduced accuracy in fine-mapping a known causal variant in a low-level biological trait with imputed genetic data has implications for the study of higher-order complex traits and disease.
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http://dx.doi.org/10.1534/genetics.118.301861DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6614908PMC
July 2019

Arginine to Glutamine Variant in Olfactomedin Like 3 () Is a Candidate for Severe Goniodysgenesis and Glaucoma in the Border Collie Dog Breed.

G3 (Bethesda) 2019 03 7;9(3):943-954. Epub 2019 Mar 7.

The Roslin Institute and Royal (Dick) School of Veterinary Studies, Easter Bush, EH25 9RG, United Kingdom

Goniodysgenesis is a developmental abnormality of the anterior chamber of the eye. It is generally considered to be congenital in dogs (), and has been associated with glaucoma and blindness. Goniodysgenesis and early-onset glaucoma initially emerged in Border Collies in Australia in the late 1990s and have subsequently been found in this breed in Europe and the USA. The objective of the present study was to determine the genetic basis of goniodysgenesis in Border Collies. Clinical diagnosis was based on results of examinations by veterinary ophthalmologists of affected and unaffected dogs from eleven different countries. Genotyping using the Illumina high density canine single nucleotide variant genotyping chip was used to identify a candidate genetic region. There was a highly significant peak of association over chromosome 17, with a -value of 2 × 10 Expression profiles and evolutionary conservation of candidate genes were assessed using public databases. Whole genome sequences of three dogs with glaucoma, three severely affected by goniodysgenesis and three unaffected dogs identified a missense variant in the olfactomedin like 3 () gene in all six affected animals. This was homozygous for the risk allele in all nine cases with glaucoma and 12 of 14 other severely affected animals. Of 67 reportedly unaffected animals, only one was homozygous for this variant (offspring of parents both with goniodysgenesis who were also homozygous for the variant). Analysis of pedigree information was consistent with an autosomal recessive mode of inheritance for severe goniodysgenesis (potentially leading to glaucoma) in this breed. The identification of a candidate genetic region and putative causative variant will aid breeders to reduce the frequency of goniodysgenesis and the risk of glaucoma in the Border Collie population.
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http://dx.doi.org/10.1534/g3.118.200944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6404605PMC
March 2019

Linked Mutations at Adjacent Nucleotides Have Shaped Human Population Differentiation and Protein Evolution.

Genome Biol Evol 2019 03;11(3):759-775

Glasgow Polyomics, College of Medical, Veterinary and Life Science, University of Glasgow, United Kingdom.

Despite the fundamental importance of single nucleotide polymorphisms (SNPs) to human evolution, there are still large gaps in our understanding of the forces that shape their distribution across the genome. SNPs have been shown to not be distributed evenly, with directly adjacent SNPs found unusually frequently. Why this is the case is unclear. We illustrate how neighboring SNPs that cannot be explained by a single mutation event (that we term here sequential dinucleotide mutations [SDMs]) are driven by distinct processes to SNPs and multinucleotide polymorphisms (MNPs). By studying variation across populations, including a novel cohort of 1,358 Scottish genomes, we show that, SDMs are over twice as common as MNPs and like SNPs display distinct mutational spectra across populations. These biases are not only different to those observed among SNPs and MNPs but are also more divergent between human population groups. We show that the changes that make up SDMs are not independent and identify a distinct mutational profile, CA → CG → TG, that is observed an order of magnitude more often than expected from background SNP rates and the numbers of other SDMs involving the gain and deamination of CpG sites. Intriguingly particular pathways through the amino acid code appear to have been favored relative to that expected from intergenic SDM rates and the occurrences of coding SNPs, and in particular those that lead to the creation of single codon amino acids. We finally present evidence that epistatic selection has potentially disfavored sequential nonsynonymous changes in the human genome.
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http://dx.doi.org/10.1093/gbe/evz014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424222PMC
March 2019

Shared regulatory sites are abundant in the human genome and shed light on genome evolution and disease pleiotropy.

PLoS Genet 2017 03 10;13(3):e1006673. Epub 2017 Mar 10.

The Roslin Institute, The University of Edinburgh, Easter Bush, Midlothian, Scotland, United Kingdom.

Large-scale gene expression datasets are providing an increasing understanding of the location of cis-eQTLs in the human genome and their role in disease. However, little is currently known regarding the extent of regulatory site-sharing between genes. This is despite it having potentially wide-ranging implications, from the determination of the way in which genetic variants may shape multiple phenotypes to the understanding of the evolution of human gene order. By first identifying the location of non-redundant cis-eQTLs, we show that regulatory site-sharing is a relatively common phenomenon in the human genome, with over 10% of non-redundant regulatory variants linked to the expression of multiple nearby genes. We show that these shared, local regulatory sites are linked to high levels of chromatin looping between the regulatory sites and their associated genes. In addition, these co-regulated gene modules are found to be strongly conserved across mammalian species, suggesting that shared regulatory sites have played an important role in shaping human gene order. The association of these shared cis-eQTLs with multiple genes means they also appear to be unusually important in understanding the genetics of human phenotypes and pleiotropy, with shared regulatory sites more often linked to multiple human phenotypes than other regulatory variants. This study shows that regulatory site-sharing is likely an underappreciated aspect of gene regulation and has important implications for the understanding of various biological phenomena, including how the two and three dimensional structures of the genome have been shaped and the potential causes of disease pleiotropy outside coding regions.
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http://dx.doi.org/10.1371/journal.pgen.1006673DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5365138PMC
March 2017

hapbin: An Efficient Program for Performing Haplotype-Based Scans for Positive Selection in Large Genomic Datasets.

Mol Biol Evol 2015 Nov 6;32(11):3027-9. Epub 2015 Aug 6.

Roslin Institute, University of Edinburgh, Scotland, United Kingdom

Understanding how the genome is shaped by selective processes forms an integral part of modern biology. However, as genomic datasets continue to grow larger it is becoming increasingly difficult to apply traditional statistics for detecting signatures of selection to these cohorts. There is therefore a pressing need for the development of the next generation of computational and analytical tools for detecting signatures of selection in large genomic datasets. Here, we present hapbin, an efficient multithreaded implementation of extended haplotype homzygosity-based statistics for detecting selection, which is up to 3,400 times faster than the current fastest implementations of these algorithms.
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http://dx.doi.org/10.1093/molbev/msv172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4651233PMC
November 2015

Exome sequencing to detect rare variants associated with general cognitive ability: a pilot study.

Twin Res Hum Genet 2015 Apr 6;18(2):117-25. Epub 2015 Mar 6.

Centre for Cognitive Ageing and Cognitive Epidemiology,The University of Edinburgh,Edinburgh,UK.

Variation in human cognitive ability is of consequence to a large number of health and social outcomes and is substantially heritable. Genetic linkage, genome-wide association, and copy number variant studies have investigated the contribution of genetic variation to individual differences in normal cognitive ability, but little research has considered the role of rare genetic variants. Exome sequencing studies have already met with success in discovering novel trait-gene associations for other complex traits. Here, we use exome sequencing to investigate the effects of rare variants on general cognitive ability. Unrelated Scottish individuals were selected for high scores on a general component of intelligence (g). The frequency of rare genetic variants (in n = 146) was compared with those from Scottish controls (total n = 486) who scored in the lower to middle range of the g distribution or on a proxy measure of g. Biological pathway analysis highlighted enrichment of the mitochondrial inner membrane component and apical part of cell gene ontology terms. Global burden analysis showed a greater total number of rare variants carried by high g cases versus controls, which is inconsistent with a mutation load hypothesis whereby mutations negatively affect g. The general finding of greater non-synonymous (vs. synonymous) variant effects is in line with evolutionary hypotheses for g. Given that this first sequencing study of high g was small, promising results were found, suggesting that the study of rare variants in larger samples would be worthwhile.
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http://dx.doi.org/10.1017/thg.2015.10DOI Listing
April 2015

Sequence-level mechanisms of human epigenome evolution.

Genome Biol Evol 2014 Jun 24;6(7):1758-71. Epub 2014 Jun 24.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, United Kingdom.

DNA methylation and chromatin states play key roles in development and disease. However, the extent of recent evolutionary divergence in the human epigenome and the influential factors that have shaped it are poorly understood. To determine the links between genome sequence and human epigenome evolution, we examined the divergence of DNA methylation and chromatin states following segmental duplication events in the human lineage. Chromatin and DNA methylation states were found to have been generally well conserved following a duplication event, with the evolution of the epigenome largely uncoupled from the total number of genetic changes in the surrounding DNA sequence. However, the epigenome at tissue-specific, distal regulatory regions was observed to be unusually prone to diverge following duplication, with particular sequence differences, altering known sequence motifs, found to be associated with divergence in patterns of DNA methylation and chromatin. Alu elements were found to have played a particularly prominent role in shaping human epigenome evolution, and we show that human-specific AluY insertion events are strongly linked to the evolution of the DNA methylation landscape and gene expression levels, including at key neurological genes in the human brain. Studying paralogous regions within the same sample enables the study of the links between genome and epigenome evolution while controlling for biological and technical variation. We show DNA methylation and chromatin divergence between duplicated regions are linked to the divergence of particular genetic motifs, with Alu elements having played a disproportionate role in the evolution of the epigenome in the human lineage.
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http://dx.doi.org/10.1093/gbe/evu142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4122940PMC
June 2014

A promoter-level mammalian expression atlas.

Nature 2014 Mar;507(7493):462-70

Regulated transcription controls the diversity, developmental pathways and spatial organization of the hundreds of cell types that make up a mammal. Using single-molecule cDNA sequencing, we mapped transcription start sites (TSSs) and their usage in human and mouse primary cells, cell lines and tissues to produce a comprehensive overview of mammalian gene expression across the human body. We find that few genes are truly 'housekeeping', whereas many mammalian promoters are composite entities composed of several closely separated TSSs, with independent cell-type-specific expression profiles. TSSs specific to different cell types evolve at different rates, whereas promoters of broadly expressed genes are the most conserved. Promoter-based expression analysis reveals key transcription factors defining cell states and links them to binding-site motifs. The functions of identified novel transcripts can be predicted by coexpression and sample ontology enrichment analyses. The functional annotation of the mammalian genome 5 (FANTOM5) project provides comprehensive expression profiles and functional annotation of mammalian cell-type-specific transcriptomes with wide applications in biomedical research.
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http://dx.doi.org/10.1038/nature13182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4529748PMC
March 2014

Side effects: substantial non-neutral evolution flanking regulatory sites.

PLoS Genet 2013 May 30;9(5):e1003528. Epub 2013 May 30.

MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.

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http://dx.doi.org/10.1371/journal.pgen.1003528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667769PMC
May 2013

A genome-wide screen in human embryonic stem cells reveals novel sites of allele-specific histone modification associated with known disease loci.

Epigenetics Chromatin 2012 May 19;5(1). Epub 2012 May 19.

MRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Crewe Road, , Edinburgh, EH4 2XU, UK.

Background: Chromatin structure at a given site can differ between chromosome copies in a cell, and such imbalances in chromatin structure have been shown to be important in understanding the molecular mechanisms controlling several disease loci. Human genetic variation, DNA methylation, and disease have been intensely studied, uncovering many sites of allele-specific DNA methylation (ASM). However, little is known about the genome-wide occurrence of sites of allele-specific histone modification (ASHM) and their relationship to human disease. The aim of this study was to investigate the extent and characteristics of sites of ASHM in human embryonic stem cells (hESCs).

Results: Using a statistically rigorous protocol, we investigated the genomic distribution of ASHM in hESCs, and their relationship to sites of allele-specific expression (ASE) and DNA methylation. We found that, although they were rare, sites of ASHM were substantially enriched at loci displaying ASE. Many were also found at known imprinted regions, hence sites of ASHM are likely to be better markers of imprinted regions than sites of ASM. We also found that sites of ASHM and ASE in hESCs colocalize at risk loci for developmental syndromes mediated by deletions, providing insights into the etiology of these disorders.

Conclusion: These results demonstrate the potential importance of ASHM patterns in the interpretation of disease loci, and the protocol described provides a basis for similar studies of ASHM in other cell types to further our understanding of human disease susceptibility.
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http://dx.doi.org/10.1186/1756-8935-5-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3438052PMC
May 2012

Widespread signatures of recent selection linked to nucleosome positioning in the human lineage.

Genome Res 2011 Nov 8;21(11):1777-87. Epub 2011 Sep 8.

MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XU, United Kingdom.

In this study we investigated the strengths and modes of selection associated with nucleosome positioning in the human lineage through the comparison of interspecies and intraspecies rates of divergence. We identify significant evidence for both positive and negative selection linked to human nucleosome positioning for the first time, implicating a widespread and important role for DNA sequence in the location of well-positioned nucleosomes. Selection appears to be acting on particular base substitutions to maintain optimum GC compositions in core and linker regions, with, e.g., unexpectedly elevated rates of C→T substitutions during recent human evolution at linker regions 60-90 bp from the nucleosome dyad but significant depletion of the same substitutions within nucleosome core regions. These patterns are strikingly consistent with the known relationships between genomic sequence composition and nucleosome assembly. By stratifying nucleosomes according to the GC content of their genomic neighborhood, we also show that the strength and direction of selection detected is dictated by local GC content. Intriguingly these signatures of selection are not restricted to nucleosomes in close proximity to exons, suggesting the correct positioning of nucleosomes is not only important in and around coding regions. This analysis provides strong evidence that the genomic sequences associated with nucleosomes are not evolving neutrally, and suggests that underlying DNA sequence is an important factor in nucleosome positioning. Recent signatures of selection linked to genomic features as ubiquitous as the nucleosome have important implications for human genome evolution and disease.
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http://dx.doi.org/10.1101/gr.122275.111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3205563PMC
November 2011

Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer.

PLoS Genet 2011 Jun 2;7(6):e1002105. Epub 2011 Jun 2.

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.

Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.
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http://dx.doi.org/10.1371/journal.pgen.1002105DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3107194PMC
June 2011

Sequencing illustrates the transcriptional response of Legionella pneumophila during infection and identifies seventy novel small non-coding RNAs.

PLoS One 2011 Mar 3;6(3):e17570. Epub 2011 Mar 3.

UCD Conway Institute for Biomolecular and Biomedical Research, Dublin, Ireland.

Second generation sequencing has prompted a number of groups to re-interrogate the transcriptomes of several bacterial and archaeal species. One of the central findings has been the identification of complex networks of small non-coding RNAs that play central roles in transcriptional regulation in all growth conditions and for the pathogen's interaction with and survival within host cells. Legionella pneumophila is a gram-negative facultative intracellular human pathogen with a distinct biphasic lifestyle. One of its primary environmental hosts in the free-living amoeba Acanthamoeba castellanii and its infection by L. pneumophila mimics that seen in human macrophages. Here we present analysis of strand specific sequencing of the transcriptional response of L. pneumophila during exponential and post-exponential broth growth and during the replicative and transmissive phase of infection inside A. castellanii. We extend previous microarray based studies as well as uncovering evidence of a complex regulatory architecture underpinned by numerous non-coding RNAs. Over seventy new non-coding RNAs could be identified; many of them appear to be strain specific and in configurations not previously reported. We discover a family of non-coding RNAs preferentially expressed during infection conditions and identify a second copy of 6S RNA in L. pneumophila. We show that the newly discovered putative 6S RNA as well as a number of other non-coding RNAs show evidence for antisense transcription. The nature and extent of the non-coding RNAs and their expression patterns suggests that these may well play central roles in the regulation of Legionella spp. specific traits and offer clues as to how L. pneumophila adapts to its intracellular niche. The expression profiles outlined in the study have been deposited into Genbank's Gene Expression Omnibus (GEO) database under the series accession GSE27232.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0017570PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3048289PMC
March 2011

Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33.

Nat Genet 2010 Nov 24;42(11):973-7. Epub 2010 Oct 24.

Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.

Genome-wide association studies (GWAS) have identified ten loci harboring common variants that influence risk of developing colorectal cancer (CRC). To enhance the power to identify additional CRC risk loci, we conducted a meta-analysis of three GWAS from the UK which included a total of 3,334 affected individuals (cases) and 4,628 controls followed by multiple validation analyses including a total of 18,095 cases and 20,197 controls. We identified associations at four new CRC risk loci: 1q41 (rs6691170, odds ratio (OR) = 1.06, P = 9.55 × 10⁻¹⁰ and rs6687758, OR = 1.09, P = 2.27 × 10⁻⁹, 3q26.2 (rs10936599, OR = 0.93, P = 3.39 × 10⁻⁸), 12q13.13 (rs11169552, OR = 0.92, P = 1.89 × 10⁻¹⁰ and rs7136702, OR = 1.06, P = 4.02 × 10⁻⁸) and 20q13.33 (rs4925386, OR = 0.93, P = 1.89 × 10⁻¹⁰). In addition to identifying new CRC risk loci, this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.
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http://dx.doi.org/10.1038/ng.670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5098601PMC
November 2010

Sequencing and analysis of an Irish human genome.

Genome Biol 2010 7;11(9):R91. Epub 2010 Sep 7.

Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.

Background: Recent studies generating complete human sequences from Asian, African and European subgroups have revealed population-specific variation and disease susceptibility loci. Here, choosing a DNA sample from a population of interest due to its relative geographical isolation and genetic impact on further populations, we extend the above studies through the generation of 11-fold coverage of the first Irish human genome sequence.

Results: Using sequence data from a branch of the European ancestral tree as yet unsequenced, we identify variants that may be specific to this population. Through comparisons with HapMap and previous genetic association studies, we identified novel disease-associated variants, including a novel nonsense variant putatively associated with inflammatory bowel disease. We describe a novel method for improving SNP calling accuracy at low genome coverage using haplotype information. This analysis has implications for future re-sequencing studies and validates the imputation of Irish haplotypes using data from the current Human Genome Diversity Cell Line Panel (HGDP-CEPH). Finally, we identify gene duplication events as constituting significant targets of recent positive selection in the human lineage.

Conclusions: Our findings show that there remains utility in generating whole genome sequences to illustrate both general principles and reveal specific instances of human biology. With increasing access to low cost sequencing we would predict that even armed with the resources of a small research group a number of similar initiatives geared towards answering specific biological questions will emerge.
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http://dx.doi.org/10.1186/gb-2010-11-9-r91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2965383PMC
February 2011

Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer.

Nat Genet 2008 Dec 16;40(12):1426-35. Epub 2008 Nov 16.

Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK.

Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci with similar effect sizes, we conducted a meta-analysis of two GWA studies, comprising 13,315 individuals genotyped for 38,710 common tagging SNPs. We undertook replication testing in up to eight independent case-control series comprising 27,418 subjects. We identified four previously unreported CRC risk loci at 14q22.2 (rs4444235, BMP4; P = 8.1 x 10(-10)), 16q22.1 (rs9929218, CDH1; P = 1.2 x 10(-8)), 19q13.1 (rs10411210, RHPN2; P = 4.6 x 10(-9)) and 20p12.3 (rs961253; P = 2.0 x 10(-10)). These findings underscore the value of large sample series for discovery and follow-up of genetic variants contributing to the etiology of CRC.
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http://dx.doi.org/10.1038/ng.262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2836775PMC
December 2008

A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3.

Nat Genet 2008 May 30;40(5):623-30. Epub 2008 Mar 30.

Molecular and Population Genetics Laboratory, London Research Institute, Cancer Research UK, London WC2A 3PX, UK.

To identify colorectal cancer (CRC) susceptibility alleles, we conducted a genome-wide association study. In phase 1, we genotyped 550,163 tagSNPs in 940 familial colorectal tumor cases (627 CRC, 313 high-risk adenoma) and 965 controls. In phase 2, we genotyped 42,708 selected SNPs in 2,873 CRC cases and 2,871 controls. In phase 3, we evaluated 11 SNPs showing association at P < 10(-4) in a joint analysis of phases 1 and 2 in 4,287 CRC cases and 3,743 controls. Two SNPs were taken forward to phase 4 genotyping (10,731 CRC cases and 10,961 controls from eight centers). In addition to the previously reported 8q24, 15q13 and 18q21 CRC risk loci, we identified two previously unreported associations: rs10795668, located at 10p14 (P = 2.5 x 10(-13) overall; P = 6.9 x 10(-12) replication), and rs16892766, at 8q23.3 (P = 3.3 x 10(-18) overall; P = 9.6 x 10(-17) replication), which tags a plausible causative gene, EIF3H. These data provide further evidence for the 'common-disease common-variant' model of CRC predisposition.
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http://dx.doi.org/10.1038/ng.111DOI Listing
May 2008

Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.

Nat Genet 2008 May 30;40(5):631-7. Epub 2008 Mar 30.

Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Edinburgh EH4 2XU, UK.

In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.
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http://dx.doi.org/10.1038/ng.133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2778004PMC
May 2008

Chromatin structure and evolution in the human genome.

BMC Evol Biol 2007 May 9;7:72. Epub 2007 May 9.

Colon Cancer Genetics Group, Division of Oncology, University of Edinburgh, Western General Hospital, Edinburgh, UK.

Background: Evolutionary rates are not constant across the human genome but genes in close proximity have been shown to experience similar levels of divergence and selection. The higher-order organisation of chromosomes has often been invoked to explain such phenomena but previously there has been insufficient data on chromosome structure to investigate this rigorously. Using the results of a recent genome-wide analysis of open and closed human chromatin structures we have investigated the global association between divergence, selection and chromatin structure for the first time.

Results: In this study we have shown that, paradoxically, synonymous site divergence (dS) at non-CpG sites is highest in regions of open chromatin, primarily as a result of an increased number of transitions, while the rates of other traditional measures of mutation (intergenic, intronic and ancient repeat divergence as well as SNP density) are highest in closed regions of the genome. Analysis of human-chimpanzee divergence across intron-exon boundaries indicates that although genes in relatively open chromatin generally display little selection at their synonymous sites, those in closed regions show markedly lower divergence at their fourfold degenerate sites than in neighbouring introns and intergenic regions. Exclusion of known Exonic Splice Enhancer hexamers has little affect on the divergence observed at fourfold degenerate sites across chromatin categories; however, we show that closed chromatin is enriched with certain classes of ncRNA genes whose RNA secondary structure may be particularly important.

Conclusion: We conclude that, overall, non-CpG mutation rates are lowest in open regions of the genome and that regions of the genome with a closed chromatin structure have the highest background mutation rate. This might reflect lower rates of DNA damage or enhanced DNA repair processes in regions of open chromatin. Our results also indicate that dS is a poor measure of mutation rates, particularly when used in closed regions of the genome, as genes in closed regions generally display relatively strong levels of selection at their synonymous sites.
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http://dx.doi.org/10.1186/1471-2148-7-72DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1876461PMC
May 2007