Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.

We report the generation and analysis of functional data from multiple, diverse experiments performed on a targeted 1% of the human genome as part of the pilot phase of the ENCODE Project. These data have been further integrated and augmented by a number of evolutionary and computational analyses. Together, our results advance the collective knowledge about human genome function in several major areas. First, our studies provide convincing evidence that the genome is pervasively transcribed, such that the majority of its bases can be found in primary transcripts, including non-protein-coding transcripts, and those that extensively overlap one another. Second, systematic examination of transcriptional regulation has yielded new understanding about transcription start sites, including their relationship to specific regulatory sequences and features of chromatin accessibility and histone modification. Third, a more sophisticated view of chromatin structure has emerged, including its inter-relationship with DNA replication and transcriptional regulation. Finally, integration of these new sources of information, in particular with respect to mammalian evolution based on inter- and intra-species sequence comparisons, has yielded new mechanistic and evolutionary insights concerning the functional landscape of the human genome. Together, these studies are defining a path for pursuit of a more comprehensive characterization of human genome function.

Human skin is a large, heterogeneous organ that protects the body from pathogens while sustaining microorganisms that influence human health and disease. Our analysis of 16S ribosomal RNA gene sequences obtained from 20 distinct skin sites of healthy humans revealed that physiologically comparable sites harbor similar bacterial communities. The complexity and stability of the microbial community are dependent on the specific characteristics of the skin site. This topographical and temporal survey provides a baseline for studies that examine the role of bacterial communities in disease states and the microbial interdependencies required to maintain healthy skin.The skin is a critical interface between the human body and its external environment, preventing loss of moisture and barring entry of pathogenic organisms (1). The skin is also an ecosystem, harboring microbial communities that live in a range of physiologically and topographically distinct niches (2). For example, hairy, moist underarms lie a short distance from smooth dry forearms, but these two niches are likely as ecologically dissimilar as rainforests are to deserts. Traditional culture-based characterizations of the skin microbiota are biased toward species that readily grow under standard laboratory conditions, such as Staphylococci spp. However, †To whom correspondence should be addressed. jsegre@nhgri.nih.gov. * See supporting online material for names of group members. Characterizing the microbiota that inhabit specific sites may provide insight into the delicate balance between skin health and disease. Certain dermatological disorders manifest at stereotypical skin sites [e.g., psoriasis on the outer elbow and atopic dermatitis (eczema) on the inner bend of the elbow]. Moreover, antibiotic exposure, modified hygienic practices, and lifestyle changes have the potential to alter the skin microbiome selectively and may underlie the increased incidence of human disorders such as atopic dermatitis. Understanding naturally occurring symbiotic microbial communities will provide insight into the conditions that favor the emergence of antibiotic-resistant organisms [e.g., the highly pathogenic strain of methicillin-resistant S. aureus, which acquired genes that promote growth on skin from the symbiont S. epidermidis (6)].We characterized the topographical and temporal diversity of the human skin microbiome with the use of 16S rRNA gene phylotyping, and generated 112,283 near-full-length bacterial 16S gene sequences from samples of 20 diverse skin sites on each of 10 healthy humans (7) (fig. S1 and table S1). Nineteen bacterial phyla were detected, but most sequences were assigned to four phyla: Actinobacteria (51.8%), Firmicutes (24.4%), Proteobacteria (16.5%), and Bacteroidetes (6.3%). Of the 205 identified genera represented by at least five sequences, three were associated with more than 62% of the sequences: Corynebacteria (22.8%; Actinobacteria), Propionibacteria (23.0%; Actinobacteria), and Staphylococci (16.8%; Firmicutes). At the species...

Since its initial release in 2000, the human reference genome has covered only the euchromatic fraction of the genome, leaving important heterochromatic regions unfinished. Addressing the remaining 8% of the genome, the Telomere-to-Telomere (T2T) Consortium presents a complete 3.055 billion–base pair sequence of a human genome, T2T-CHM13, that includes gapless assemblies for all chromosomes except Y, corrects errors in the prior references, and introduces nearly 200 million base pairs of sequence containing 1956 gene predictions, 99 of which are predicted to be protein coding. The completed regions include all centromeric satellite arrays, recent segmental duplications, and the short arms of all five acrocentric chromosomes, unlocking these complex regions of the genome to variational and functional studies.