The Zoonomia Project is investigating the genomics of shared and specialized traits in eutherian mammals. Here we provide genome assemblies for 131 species, of which all but 9 are previously uncharacterized, and describe a whole-genome alignment of 240 species of considerable phylogenetic diversity, comprising representatives from more than 80% of mammalian families. We find that regions of reduced genetic diversity are more abundant in species at a high risk of extinction, discern signals of evolutionary selection at high resolution and provide insights from individual reference genomes. By prioritizing phylogenetic diversity and making data available quickly and without restriction, the Zoonomia Project aims to support biological discovery, medical research and the conservation of biodiversity.

Background: Expression of a large number of yeast genes is repressed by glucose. The zinc finger protein Mig1 is the main effector in glucose repression, but yeast also has two related proteins: Mig2 and Mig3. We have used microarrays to study global gene expression in all possible combinations of mig1, mig2 and mig3 deletion mutants.

We have screened the Eurofan deletion strain collection for mutants that are either sensitive or resistant to three drugs known to affect intracellular transport: brefeldin A, monensin and C2‐ceramide. Drug‐sensitive mutants were analysed by complementation with cognate clones and tetrad analysis to confirm that the phenotypes are linked to the deletions. Out of 620 deletion strains, we found 18 mutants that were sensitive to either brefeldin A, monensin or both. Several of these mutants are deleted for genes that are known to be involved in intracellular transport, membrane biogenesis and/or cell wall biosynthesis. Among such previously known genes were VAM6, VAC7, SYS1, TLG2, RCY1, ERG4, ALG9 and ALG12. Some other genes recovered in our screen were not previously implicated in intracellular transport, but are related to other yeast genes with such a function. Still other genes encode proteins with no obvious link to intracellular transport. Several of these are putative transcription factors or RNA‐binding proteins, which suggests that they may affect drug sensitivity by modulating the expression of other genes or proteins. Copyright © 2000 John Wiley & Sons, Ltd.

Background Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. Methods To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. Results We identified BACH2 (rs62408233‐A, OR = 2.01 (1.71–2.37), P = 1.66 × 10−15, MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. Conclusion Whilst BACH2 has been previously reported to associate with organ‐specific autoimmune diseases co‐inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

Gliomas are the most common form of malignant primary brain tumors in humans and second most common in dogs, occurring with similar frequencies in both species. Dogs are valuable spontaneous models of human complex diseases including cancers and may provide insight into disease susceptibility and oncogenesis. Several brachycephalic breeds such as Boxer, Bulldog and Boston Terrier have an elevated risk of developing glioma, but others, including Pug and Pekingese, are not at higher risk. To identify glioma-associated genetic susceptibility factors, an across-breed genome-wide association study (GWAS) was performed on 39 dog glioma cases and 141 controls from 25 dog breeds, identifying a genome-wide significant locus on canine chromosome (CFA) 26 (p = 2.8 x 10−8). Targeted re-sequencing of the 3.4 Mb candidate region was performed, followed by genotyping of the 56 SNVs that best fit the association pattern between the re-sequenced cases and controls. We identified three candidate genes that were highly associated with glioma susceptibility: CAMKK2, P2RX7 and DENR. CAMKK2 showed reduced expression in both canine and human brain tumors, and a non-synonymous variant in P2RX7, previously demonstrated to have a 50% decrease in receptor function, was also associated with disease. Thus, one or more of these genes appear to affect glioma susceptibility.

Canine degenerative myelopathy (DM) is a naturally occurring neurodegenerative disease with similarities to some forms of amyotrophic lateral sclerosis (ALS). Most dogs that develop DM are homozygous for a common superoxide dismutase 1 gene (SOD1) mutation. However, not all dogs homozygous for this mutation develop disease. We performed a genome-wide association analysis in the Pembroke Welsh Corgi (PWC) breed comparing DM-affected and -unaffected dogs homozygous for the SOD1 mutation. The analysis revealed a modifier locus on canine chromosome 25. A haplotype within the SP110 nuclear body protein (SP110) was present in 40% of affected compared with 4% of unaffected dogs (P = 1.5 × 10 −5), and was associated with increased probability of developing DM (P = 4.8 × 10 −6 ) and earlier onset of disease (P = 1.7 × 10 −5 ). SP110 is a nuclear body protein involved in the regulation of gene transcription. Our findings suggest that variations in SP110-mediated gene transcription may underlie, at least in part, the variability in risk for developing DM among PWCs that are homozygous for the disease-related SOD1 mutation. Further studies are warranted to clarify the effect of this modifier across dog breeds.degenerative myelopathy | amyotrophic lateral sclerosis | ALS | SOD1 | SP110

Canine mammary tumours (CMT) are the most common neoplasia in unspayed female dogs. CMTs are suitable naturally occurring models for human breast cancer and share many characteristics, indicating that the genetic causes could also be shared. We have performed a genome-wide association study (GWAS) in English Springer Spaniel dogs and identified a genome-wide significant locus on chromosome 11 (praw = 5.6x10-7, pperm = 0.019). The most associated haplotype spans a 446 kb region overlapping the CDK5RAP2 gene. The CDK5RAP2 protein has a function in cell cycle regulation and could potentially have an impact on response to chemotherapy treatment. Two additional loci, both on chromosome 27, were nominally associated (praw = 1.97x10-5 and praw = 8.30x10-6). The three loci explain 28.1±10.0% of the phenotypic variation seen in the cohort, whereas the top ten associated regions account for 38.2±10.8% of the risk. Furthermore, the ten GWAS loci and regions with reduced genetic variability are significantly enriched for snoRNAs and tumour-associated antigen genes, suggesting a role for these genes in CMT development. We have identified several candidate genes associated with canine mammary tumours, including CDK5RAP2. Our findings enable further comparative studies to investigate the genes and pathways in human breast cancer patients.

Napin is a seed storage protein from Brassica napus (rape) that is encoded by a gene family. We have isolated and characterized a novel napin gene, napB. Comparisons of the 5'-upstream region of napB to the promoter regions of previously published napin genes reveal that certain sequence motives are evolutionary conserved and may be implicated in gene regulation. These consensus motives, that overlap with purine/pyrimidine stretches, are TACACAT and CATGCA both of which frequently occur as overlapping, direct repeats. Related or identical sequences are also found in the upstream regions of the homologous genes of Arabidopsis thaliana. One copy of the CATGCA motif occurs in close proximity to the TATA box in all the above genes. In this case it overlaps with an octamer sequence (ATGCAAAT) which is a sequence element common in many eukaryotic promoters and enhancers. The TACACAT sequence, as part of a longer purine/pyrimidine stretch, was found to interact with a protein present in crude nuclear extracts from developing B. napus seeds. Napin genes appear to be methylated to almost equal extents whether present in expressing or non-expressing tissue.Seed storage proteins serve as a nitrogen and sulfur source for the developing plant seedling during the period of early germination. Storage proteins from cultivated plant species also constitute a major animal and human protein source. Since storage proteins are only expressed in embryonic and/ or endosperm tissues during seed development, they are presently in the focus for studies on developmentally regulated gene expression in plants. Napin is one of the dominating storage proteins of Brassica napus (rape) and variant forms are found among the Brassicaceae, e. g. Raphanus sativus (radish) [l], Sinapis alba (white mustard) [2], and Arabidopsis thaliana [3]. In addition, homologous storage proteins have been characterised in Bertholletia exelsa (brazil nut) [4], Hellianthus annus (sun flower) [5], Triticum aestivum (wheat) [6], and Ricinus communis (castor bean) [7]. The presence of a related protein in the spores of a fern (Matteucia struthiopteris) has also been reported [8, 91. Napin is encoded by a gene family [lo, 111 and several isoforms of napin exist [12]. The sequences of three napin genes, napA [lo], pGNA [ll], and BngNAPl [13], have so far been published. Radke et al. [14] have shown that 300 bp of the 5' flanking sequence in front of the translation initiation codon are sufficient to give a developmentally faithful expression of a chimeric gene construct in transgenic B. napus plants. However, it has not been ascertained whether all sequence motives regulating the napin gene expression are included in this segment of the upstream region.With the underlying assumption that regulatory promoter elements will prove to be conserved between the different Correspondence to