Here we describe the SweGen data set, a comprehensive map of genetic variation in the Swedish population. These data represent a basic resource for clinical genetics laboratories as well as for sequencing-based association studies by providing information on genetic variant frequencies in a cohort that is well matched to national patient cohorts. To select samples for this study, we first examined the genetic structure of the Swedish population using high-density SNP-array data from a nation-wide cohort of over 10 000 Swedish-born individuals included in the Swedish Twin Registry. A total of 1000 individuals, reflecting a cross-section of the population and capturing the main genetic structure, were selected for whole-genome sequencing. Analysis pipelines were developed for automated alignment, variant calling and quality control of the sequencing data. This resulted in a genome-wide collection of aggregated variant frequencies in the Swedish population that we have made available to the scientific community through the website https://swefreq.nbis.se. A total of 29.2 million single-nucleotide variants and 3.8 million indels were detected in the 1000 samples, with 9.9 million of these variants not present in current databases. Each sample contributed with an average of 7199 individual-specific variants. In addition, an average of 8645 larger structural variants (SVs) were detected per individual, and we demonstrate that the population frequencies of these SVs can be used for efficient filtering analyses. Finally, our results show that the genetic diversity within Sweden is substantial compared with the diversity among continental European populations, underscoring the relevance of establishing a local reference data set.

The quaking viable mouse mutation (qk v ) is a deletion including the 5 regulatory region of the quaking gene (Qki), which causes body tremor and severe dysmyelination in mouse. The function of the human quaking gene, called quaking homolog KH domain RNAbinding (mouse) (QKI), is not well known. We have previously shown that QKI is a new candidate gene for schizophrenia. Here we show that human QKI mRNA levels can account for a high proportion (47%) of normal interindividual mRNA expression variation (and covariation) of six oligodendrocyte-related genes (PLP1, MAG, MBP, TF, SOX10, and CDKN1B) in 55 human brain autopsy samples from individuals without psychiatric diagnoses. In addition, the tightly coexpressed myelin-related genes (PLP1, MAG, and TF) have decreased mRNA levels in 55 schizophrenic patients, as compared with 55 control individuals, and most of this difference (68 -96%) can be explained by variation in the relative mRNA levels of QKI-7kb, the same QKI splice variant previously shown to be down-regulated in patients with schizophrenia. Taken together, our results suggest that QKI levels may regulate oligodendrocyte differentiation and maturation in human brain, in a similar way as in mouse. Moreover, we hypothesize that previously observed decreased activity of myelin-related genes in schizophrenia might be caused by disturbed QKI splicing.myelin ͉ quaking ͉ splice variant

A data set of 77 genomic mouse/human gene pairs has been compiled from the EMBL nucleotide database, and their corresponding features determined. This set was used to analyze the degree of conservation of noncoding sequences between mouse and human. A new alignment algorithm was developed to cope with the fact that large parts of noncoding sequences are not alignable in a meaningful way because of genetic drift. This new algorithm, DNA Block Aligner (DBA), finds colinear-conserved blocks that are flanked by nonconserved sequences of varying lengths. The noncoding regions of the data set were aligned with DBA. The proportion of the noncoding regions covered by blocks >60% identical was 36% for upstream regions, 50% for 5Ј UTRs, 23% for introns, and 56% for 3Ј UTRs. These blocks of high identity were more or less evenly distributed across the length of the features, except for upstream regions in which the first 100 bp upstream of the transcription start site was covered in up to 70% of the gene pairs. This data set complements earlier sets on the basis of cDNA sequences and will be useful for further comparative studies.[This paper contains supplementary data that can be found at http://www.genome.com.]Comparative analysis of genomic sequences is becoming increasingly important as a tool to elucidate coding and regulatory regions in genomic DNA. Several comparative studies have been done on large sequence regions of human and various species (summarized in Hardison et al. 1997). It is evident from these studies that coding regions are generally well conserved. Most protein sequences are easily alignable at least as far back in evolution as the split between fish and higher vertebrates (450 Myr), and at that distance splicing patterns are largely conserved (Elgar 1996). Noncoding regions, on the other hand, show a much more varying degree of conservation. Some regions appear to be drifting randomly, whereas others are conserved by selective pressure. Evolutionary distances on the order of 50-100 Myr such as mouse to human (80 Myr; Li and Graur 1991) can reveal functionally conserved regions among nonconserved sequences. The use of phylogenetic comparisons to reveal conserved functional elements has been termed phylogenetic footprinting (Tagle et al. 1988). Reasons for conservation of noncoding regions include that these regions are important for regulating gene expression, maintaining the structural organization of the genome, and contributing to other hitherto-unknown functions of the chromosomes (Koop and Hood 1994).Because of the value of genome sequence comparisons in identifying such functional regions and the importance of the mouse as a genetic model system in its own right, plans are under way for large-scale sequencing of the mouse genome (Collins et al. 1998). To make maximal use of the sequence comparisons that will result, we need tools and a background base line from existing data. Although comparative studies of noncoding regions of genomic DNA have been done among mammals and birds, amphibians, and ...

We examined expression ofthe ES tranform- The significance of these disparate findings to the in vivo activity of BPV-1 is unclear in the absence of data on the site of expression of the E5 protein in virus-induced fibropapilloma tissue. We now present evidence for two physically and temporally remote sites of BPV-1 E5 gene expression within the epithelial layers of naturally infected fibropapilloma tissue, suggesting that the E5 protein may be involved in the early (transforming) phase and in the late (maturation) phase of the BPV-1 replication cycle in keratinocytes.MATERIALS AND METHODS Antirm. Polyclonal E5 antisera were raised in two rabbits against the synthetic peptide Leu-Val-Tyr-Trp-Asp-His-PheGlu-Cys-Ser-Cys-Thr-Gly-Leu-Pro-Phe corresponding to the C-terminal 16-amino acid segment of the BPV-1 E5 protein.Cell Culture and Immunoprecipitation. Transformation of bovine conjunctival fibroblasts and murine C127 cells by infection with purified BPV-1 virions has been described (10). (volume, 1.5 ml). The cultures were washed twice with phosphate-buffered saline (PBS) and cells were collected by scraping into 1 ml of PBS. The cells were pelleted by centrifugation at 5000 x g, 40C for 2 min, and were then lysed for 5 min on ice in 1 ml of RIPA buffer [50 mM Tris'HCl (pH 7.9), 150 mM NaCl, 1% (vol/vol) Nonidet P40,0.5% (wt/vol) Abbreviations: BPV-1, bovine papillomavirus type 1; HPV, human papillomavirus; PDGF-R, platelet-derived growth factor receptor. tTo whom reprint requests should be addressed. 5665The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.