Hsiang‐Yu Yuan

Single nucleotide polymorphism (SNP) prioritization based on the phenotypic risk is essential for association studies. Assessment of the risk requires access to a variety of heterogeneous biological databases and analytical tools. FASTSNP (function analysis and selection tool for single nucleotide polymorphisms) is a web server that allows users to efficiently identify and prioritize high-risk SNPs according to their phenotypic risks and putative functional effects. A unique feature of FASTSNP is that the functional effect information used for SNP prioritization is always up-to-date, because FASTSNP extracts the information from 11 external web servers at query time using a team of web wrapper agents. Moreover, FASTSNP is extendable by simply deploying more Web wrapper agents. To validate the results of our prioritization, we analyzed 1569 SNPs from the SNP500Cancer database. The results show that SNPs with a high predicted risk exhibit low allele frequencies for the minor alleles, consistent with a well-known finding that a strong selective pressure exists for functional polymorphisms. We have been using FASTSNP for 2 years and FASTSNP enables us to discover a novel promoter polymorphism. FASTSNP is available at http://fastsnp.ibms.sinica.edu.tw.

Warfarin, a commonly prescribed anticoagulant, exhibited large inter-individual and inter-ethnic differences in the dose required for its anticoagulation effect. Asian populations, including Chinese, require a much lower maintenance dose than Caucasians, for which the mechanisms still remain unknown. We determined DNA sequence variants in CYP2C9 and VKORC1 in 16 Chinese patients having warfarin sensitivity (≤1.5 mg/day, n=11) or resistance (≥6.0 mg/day, n=5), 104 randomly selected Chinese patients receiving warfarin, 95 normal Chinese controls and 92 normal Caucasians. We identified three CYP2C9 variants, CYP2C9*3, T299A and P382L, in four warfarin-sensitive patients. A novel VKORC1 promoter polymorphism (−1639 G>A) presented in the homozygous form (genotype AA) was found in all warfarin-sensitive patients. The resistant patients were either AG or GG. Among the 104 randomly selected Chinese patients receiving warfarin, AA genotype also had lower dose than the AG/GG genotype (P<0.0001). Frequencies of AA, AG and GG genotypes were comparable in Chinese patients receiving warfarin (79.7, 17.6 and 2.7%) and normal Chinese controls (82, 18 and 0%), but differed significantly from Caucasians (14, 47 and 39%) (P<0.0001). The promoter polymorphism abolished the E-box consensus sequences and dual luciferase assay revealed that VOKRC1 promoter with the G allele had a 44% increase of activity when compared with the A allele. The differences in allele frequencies of A/G allele and its levels of VKORC1 promoter activity may underscore the inter-individual differences in warfarin dosage as well as inter-ethnic differences between Chinese and Caucasians.

Despite broad agreement on the negative consequences of vaccine inequity, the distribution of COVID-19 vaccines is imbalanced. Access to vaccines in high-income countries (HICs) is far greater than in low- and middle-income countries (LMICs). As a result, there continue to be high rates of COVID-19 infections and deaths in LMICs. In addition, recent mutant COVID-19 outbreaks may counteract advances in epidemic control and economic recovery in HICs. To explore the consequences of vaccine (in)equity in the face of evolving COVID-19 strains, we examine vaccine allocation strategies using a multistrain metapopulation model. Our results show that vaccine inequity provides only limited and short-term benefits to HICs. Sharper disparities in vaccine allocation between HICs and LMICs lead to earlier and larger outbreaks of new waves. Equitable vaccine allocation strategies, in contrast, substantially curb the spread of new strains. For HICs, making immediate and generous vaccine donations to LMICs is a practical pathway to protect everyone.

BACKGROUND: Transcription initiation is a key component in the regulation of gene expression. mRNA 5' full-length sequencing techniques have enhanced our understanding of mammalian transcription start sites (TSSs), revealing different initiation patterns on a genomic scale. RESULTS: To identify TSSs in Drosophila melanogaster, we applied a hierarchical clustering strategy on available 5' expressed sequence tags (ESTs) and identified a high quality set of 5,665 TSSs for approximately 4,000 genes. We distinguished two initiation patterns: 'peaked' TSSs, and 'broad' TSS cluster groups. Peaked promoters were found to contain location-specific sequence elements; conversely, broad promoters were associated with non-location-specific elements. In alignments across other Drosophila genomes, conservation levels of sequence elements exceeded 90% within the melanogaster subgroup, but dropped considerably for distal species. Elements in broad promoters had lower levels of conservation than those in peaked promoters. When characterizing the distributions of ESTs, 64% of TSSs showed distinct associations to one out of eight different spatiotemporal conditions. Available whole-genome tiling array time series data revealed different temporal patterns of embryonic activity across the majority of genes with distinct alternative promoters. Many genes with maternally inherited transcripts were found to have alternative promoters utilized later in development. Core promoters of maternally inherited transcripts showed differences in motif composition compared to zygotically active promoters. CONCLUSIONS: Our study provides a comprehensive map of Drosophila TSSs and the conditions under which they are utilized. Distinct differences in motif associations with initiation pattern and spatiotemporal utilization illustrate the complex regulatory code of transcription initiation.

The rapid expansion of coronavirus disease 2019 (COVID-19) has been observed in many parts of the world. Many newly reported cases of COVID-19 during early outbreak phases have been associated with travel history from an epidemic region (identified as imported cases). For those cases without travel history, the risk of wider spreads through community contact is even higher. However, most population models assume a homogeneous infected population without considering that the imported and secondary cases contracted by the imported cases can pose different risks to community spread. We have developed an “easy-to-use” mathematical framework extending from a meta-population model embedding city-to-city connections to stratify the dynamics of transmission waves caused by imported, secondary, and others from an outbreak source region when control measures are considered. Using the cumulative number of the secondary cases, we are able to determine the probability of community spread. Using the top 10 visiting cities from Wuhan in China as an example, we first demonstrated that the arrival time and the dynamics of the outbreaks at these cities can be successfully predicted under the reproduction number R0 = 2.92 and incubation period τ = 5.2 days. Next, we showed that although control measures can gain extra 32.5 and 44.0 days in arrival time through an intensive border control measure and a shorter time to quarantine under a low R0 (1.4), if the R0 is higher (2.92), only 10 extra days can be gained for each of the same measures. This suggests the importance of lowering the incidence at source regions together with infectious disease control measures in susceptible regions. The study allows us to assess the effects of border control and quarantine measures on the emergence and global spread of COVID-19 in a fully connected world using the dynamics of the secondary cases.