Our data suggest caution when formulating strategies where delivery of type VII collagen is likely to exceed levels seen under normal physiological conditions in a patient group with a higher inherent risk of developing skin cancer.
32Adult height was one of the earliest putative examples of polygenic adaptation in human. By 33 constructing polygenic height scores using effect sizes and frequencies from hundreds of genomic loci 34 robustly associated with height, it was reported that Northern Europeans were genetically taller than 35Southern Europeans beyond neutral expectation. However, this inference was recently challenged. 36Sohail et al. and Berg et al. showed that the polygenic signature disappeared if summary statistics from 37 UK Biobank (UKB) were used in the analysis, suggesting that residual uncorrected stratification from 38 large-scale consortium studies was responsible for the previously noted genetic difference . It thus 39 remains an open question whether height loci exhibit signals of polygenic adaptation in any human 40population. In the present study, we re-examined this question, focusing on one of the shortest 41European populations, the Sardinians, as well as on the mainland European populations in general. We 42found that summary statistics from UKB significantly correlate with population structure in Europe. To 43 further alleviate concerns of biased ascertainment of GWAS loci, we examined height-associated loci 44 from the Biobank of Japan (BBJ). Applying frequency-based inference over these height-associated loci, 45we showed that the Sardinians remain significantly shorter than expected (~ 0.35 standard deviation 46shorter than CEU based on polygenic height scores, P = 1.95e-6). We also found the trajectory of 47 polygenic height scores decreased over at least the last 10,000 years when compared to the British 48 population (P = 0.0123), consistent with a signature of polygenic adaptation at height-associated loci. 49Although the same approach showed a much subtler signature in mainland European populations, we 50 found a clear and robust adaptive signature in UK population using a haplotype-based statistic, tSDS, 51 driven by the height-increasing alleles (P = 4.8e-4). In summary, by examining frequencies at height loci 52 ascertained in a distant East Asian population, we further supported the evidence of polygenic 53 adaptation at height-associated loci among the Sardinians. In mainland Europeans, we also found an 54 adaptive signature, although becoming more pronounced only in haplotype-based analysis. 55
The core promoter of hepatitis B virus shows hepatocyte specificity, which is largely dependent on an upstream regulatory sequence that overlaps with viral enhancer II. Footprint analyses by numerous groups have shown binding by cellular proteins over a large stretch of DNA in this region, but the identity of these proteins and their role in core promoter function remain largely unknown. We present data showing that the transcription factor HNF-4 is one such factor, as it activates the core promoter approximately 20-fold via a binding site within the upstream regulatory sequence. Since HNF-4 is enriched in hepatocytes, its involvement at least partially explains the hepatocyte specificity of this promoter. In addition, however, we have found a region upstream of the HNF-4 site that suppresses activation by HNF-4 in HeLa cells but not in hepatoma cells. Therefore, the cell type specificity of the core promoter appears to result from a combination of activation by one or more factors specifically enriched in hepatocytes and repression by some other factor(s) present in nonhepatocytes, and it may provide a convenient model system for studying this type of tissue-specific transcriptional regulation in mammalian cells.
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