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Background The maturing field of genomics is rapidly increasing the number of sequenced genomes and producing more information from those previously sequenced. Much of this additional information is variation data derived from sampling multiple individuals of a given species with the goal of discovering new variants and characterising the population frequencies of the variants that are already known. These data have immense value for many studies, including those designed to understand evolution and connect genotype to phenotype. Maximising the utility of the data requires that it be stored in an accessible manner that facilitates the integration of variation data with other genome resources such as gene annotation and comparative genomics. Description The Ensembl project provides comprehensive and integrated variation resources for a wide variety of chordate genomes. This paper provides a detailed description of the sources of data and the methods for creating the Ensembl variation databases. It also explores the utility of the information by explaining the range of query options available, from using interactive web displays, to online data mining tools and connecting directly to the data servers programmatically. It gives a good overview of the variation resources and future plans for expanding the variation data within Ensembl. Conclusions Variation data is an important key to understanding the functional and phenotypic differences between individuals. The development of new sequencing and genotyping technologies is greatly increasing the amount of variation data known for almost all genomes. The Ensembl variation resources are integrated into the Ensembl genome browser and provide a comprehensive way to access this data in the context of a widely used genome bioinformatics system. All Ensembl data is freely available at http://www.ensembl.org and from the public MySQL database server at ensembldb.ensembl.org.

As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control. Stretches of DNA called cis-regulatory modules (or CRMs for short) could help researchers to identify the regions of DNA that are most important for controlling genes. CRMs are regions where multiple transcription factors—proteins that control when and how genes are expressed—bind to DNA. As important biological pathways are often regulated by more than one transcription factor, CRMs are therefore a good target when looking for DNA regions that, if mutated, are likely to cause disease. If a stretch of DNA performs an important role, it is often conserved throughout evolution. This is often observed for genes that make proteins. Indeed, DNA regions that specify critical amino acids that make up proteins are often conserved across distantly related species. However, unlike the changes made to the amino acid encoding parts of genes, it is currently a challenge to predict which changes in the rest of the genome will affect gene expression. One reason for this challenge is that transcription factor binding sites are rapidly evolving. This rapid evolution means that strictly comparing DNA sequences between species may fail to identify where transcription factors like to bind in the genome. Numerous experimental efforts have therefore been made to map these sites. These have revealed that there are a huge number of regions in the human genome that can bind transcription factors: hundreds of thousands of sites, far more than there are genes. For this reason, there is a great interest in revealing which of these regulatory regions are critical for maintaining normal levels and timings of gene expression. Ballester et al. compared the binding sites of four transcription factors responsible for regulating liver function in humans, macaques, mice, rats, and dogs. About two-thirds of these binding sites were found in CRMs. Less than half of the CRMs in humans were also CRMs in another species—but Ballester et al. found that these shared CRMs are predominantly in charge of regulating the essential biological pathways that allow the liver to function correctly. In addition, Ballester et al. identified several examples of disease-causing DNA mutations in shared CRMs that affected the expression of genes that make up pathways such as the blood clotting cascade. Genome-wide association studies also uncovered common variants for liver-related traits that were enriched for the CRMs found in more than one species, further supporting their importance. As transcription factors work in different ways in different tissues, further studies are now required to expand these observations to organs other than the liver. Future work is also needed to investigate the function of thousands of conserved CRMs whose role in liver gene regulation remains unknown.

Background Advances in sequencing and genotyping technologies are leading to the widespread availability of multi-species variation data, dense genotype data and large-scale resequencing projects. The 1000 Genomes Project and similar efforts in other species are challenging the methods previously used for storage and manipulation of such data necessitating the redesign of existing genome-wide bioinformatics resources. Results Ensembl has created a database and software library to support data storage, analysis and access to the existing and emerging variation data from large mammalian and vertebrate genomes. These tools scale to thousands of individual genome sequences and are integrated into the Ensembl infrastructure for genome annotation and visualisation. The database and software system is easily expanded to integrate both public and non-public data sources in the context of an Ensembl software installation and is already being used outside of the Ensembl project in a number of database and application environments. Conclusions Ensembl's powerful, flexible and open source infrastructure for the management of variation, genotyping and resequencing data is freely available at http://www.ensembl.org .

We tested 310,605 SNPs for association in 778 individuals with celiac disease and 1,422 controls. Outside the HLA region, the most significant finding (rs13119723; P = 2.0 × 10 −7 ) was in the KIAA1109 - TENR - IL2 - IL21 linkage disequilibrium block. We independently confirmed association in two further collections (strongest association at rs6822844, 24 kb 5′ of IL21 ; meta-analysis P = 1.3 × 10 −14 , odds ratio = 0.63), suggesting that genetic variation in this region predisposes to celiac disease.

Who exactly can be held responsible for \"taking\" a member of a species protected by the Endangered Species Act (ESA)? Since the ESA's enactment, this simple question, when brought before courts, invariably yields complex answers. Can a reckless boater be held liable for taking an endangered Hawaiian monk seal, assuming the boater knows that species is endemic to the area? Perhaps, yes. Does this conclusion differ regarding the entity responsible for providing that person with a boating license in the first place? As the degree of causation and connection to the \"take\" becomes more remote, the lines of liability become blurred. This concept is solidifìed by a series of cases exploring issues similar to the questions posed above. The theory of ESA vicarious liability has expanded and contracted over time. Recently, its use has dwindled and its efficacy has come into question. To determine whether this fringe source of liability will have any place in the future of ESA jurisprudence, lessons must be learned from the past. This Comment will attempt to draw out distinct themes from the small litany of cases on ESA vicarious liability. Further, those themes will be applied to other statutory regimes that operate to protect valued species, namely the Migratory Bird Treaty Act and the Bald and Golden Eagle Protection Act. In the end, some clarity will be shed on whether ESA vicarious liability has retained its viability or whether, all told, it is nearingits own extinction.

The zebra finch is an important model organism in several fields with unique relevance to human neuroscience. Like other songbirds, the zebra finch communicates through learned vocalizations, an ability otherwise documented only in humans and a few other animals and lacking in the chicken-the only bird with a sequenced genome until now. Here we present a structural, functional and comparative analysis of the genome sequence of the zebra finch (Taeniopygia guttata), which is a songbird belonging to the large avian order Passeriformes. We find that the overall structures of the genomes are similar in zebra finch and chicken, but they differ in many intrachromosomal rearrangements, lineage-specific gene family expansions, the number of long-terminal-repeat-based retrotransposons, and mechanisms of sex chromosome dosage compensation. We show that song behaviour engages gene regulatory networks in the zebra finch brain, altering the expression of long non-coding RNAs, microRNAs, transcription factors and their targets. We also show evidence for rapid molecular evolution in the songbird lineage of genes that are regulated during song experience. These results indicate an active involvement of the genome in neural processes underlying vocal communication and identify potential genetic substrates for the evolution and regulation of this behaviour.

Our genome-wide association study of celiac disease previously identified risk variants in the IL2 – IL21 region. To identify additional risk variants, we genotyped 1,020 of the most strongly associated non- HLA markers in an additional 1,643 cases and 3,406 controls. Through joint analysis including the genome-wide association study data (767 cases, 1,422 controls), we identified seven previously unknown risk regions ( P < 5 × 10 −7 ). Six regions harbor genes controlling immune responses, including CCR3 , IL12A , IL18RAP , RGS1 , SH2B3 (nsSNP rs3184504) and TAGAP . Whole-blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ , IL2 – IL21 , CCR3 and SH2B3 risk regions. Thus, this extensive genome-wide association follow-up study has identified additional celiac disease risk variants in relevant biological pathways.

As exome sequencing gives way to genome sequencing, the need to interpret the function of regulatory DNA becomes increasingly important. To test whether evolutionary conservation of cis-regulatory modules (CRMs) gives insight into human gene regulation, we determined transcription factor (TF) binding locations of four liver-essential TFs in liver tissue from human, macaque, mouse, rat, and dog. Approximately, two thirds of the TF-bound regions fell into CRMs. Less than half of the human CRMs were found as a CRM in the orthologous region of a second species. Shared CRMs were associated with liver pathways and disease loci identified by genome-wide association studies. Recurrent rare human disease causing mutations at the promoters of several blood coagulation and lipid metabolism genes were also identified within CRMs shared in multiple species. This suggests that multi-species analyses of experimentally determined combinatorial TF binding will help identify genomic regions critical for tissue-specific gene control.

Our celiac disease genome-wide association study identified IL2/IL21 region risk variants. We genotyped 1,020 of the most associated non-HLA markers in a further 1,643 cases and 3,406 controls. Joint analysis including the genome-wide association study data (767 cases, 1422 controls) identified seven new risk regions (P <5×10-7). Six regions harbor genes controlling immune responses, including: CCR3, IL12A, IL18RAP, RGS1, SH2B3 (nsSNP rs3184504), TAGAP. Whole blood IL18RAP mRNA expression correlated with IL18RAP genotype. Type 1 diabetes and celiac disease share HLA-DQ, IL2/IL21, CCR3 and SH2B3 risk regions. Extensive genome-wide association study follow-up has identified additional celiac disease risk variants in relevant biological pathways.