Mammalian promoters can be separated into two classes, conserved TATA box-enriched promoters, which initiate at a well-defined site, and more plastic, broad and evolvable CpG-rich promoters. We have sequenced tags corresponding to several hundred thousand transcription start sites (TSSs) in the mouse and human genomes, allowing precise analysis of the sequence architecture and evolution of distinct promoter classes. Different tissues and families of genes differentially use distinct types of promoters. Our tagging methods allow quantitative analysis of promoter usage in different tissues and show that differentially regulated alternative TSSs are a common feature in protein-coding genes and commonly generate alternative N termini. Among the TSSs, we identified new start sites associated with the majority of exons and with 3' UTRs. These data permit genome-scale identification of tissue-specific promoters and analysis of the cis-acting elements associated with them.

This study describes comprehensive polling of transcription start and termination sites and analysis of previously unidentified full-length complementary DNAs derived from the mouse genome. We identify the 5' and 3' boundaries of 181,047 transcripts with extensive variation in transcripts arising from alternative promoter usage, splicing, and polyadenylation. There are 16,247 new mouse protein-coding transcripts, including 5154 encoding previously unidentified proteins. Genomic mapping of the transcriptome reveals transcriptional forests, with overlapping transcription on both strands, separated by deserts in which few transcripts are observed. The data provide a comprehensive platform for the comparative analysis of mammalian transcriptional regulation in differentiation and development.

The Pacific plate converges with northeastern Eurasia at a rate of 8-9 m per century along the Kamchatka, Kuril and Japan trenches. Along the southern Kuril trench, which faces the Japanese island of Hokkaido, this fast subduction has recurrently generated earthquakes with magnitudes of up to approximately 8 over the past two centuries. These historical events, on rupture segments 100-200 km long, have been considered characteristic of Hokkaido's plate-boundary earthquakes. But here we use deposits of prehistoric tsunamis to infer the infrequent occurrence of larger earthquakes generated from longer ruptures. Many of these tsunami deposits form sheets of sand that extend kilometres inland from the deposits of historical tsunamis. Stratigraphic series of extensive sand sheets, intercalated with dated volcanic-ash layers, show that such unusually large tsunamis occurred about every 500 years on average over the past 2,000-7,000 years, most recently approximately 350 years ago. Numerical simulations of these tsunamis are best explained by earthquakes that individually rupture multiple segments along the southern Kuril trench. We infer that such multi-segment earthquakes persistently recur among a larger number of single-segment events.

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10−11 to 5.0 × 10−21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10−6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.