Strategic vision for improving human health at The Forefront of Genomics.

Starting with the launch of the Human Genome Project three decades ago, and continuing after its completion in 2003, genomics has progressively come to have a central and catalytic role in basic and translational research. In addition, studies increasingly demonstrate how genomic information can be effectively used in clinical care. In the future, the anticipated advances in technology development, biological insights, and clinical applications (among others) will lead to more widespread integration of genomics into almost all areas of biomedical research, the adoption of genomics into mainstream medical and public-health practices, and an increasing relevance of genomics for everyday life. On behalf of the research community, the National Human Genome Research Institute recently completed a multi-year process of strategic engagement to identify future research priorities and opportunities in human genomics, with an emphasis on health applications. Here we describe the highest-priority elements envisioned for the cutting-edge of human genomics going forward-that is, at 'The Forefront of Genomics'.

Centers for Mendelian Genomics: A decade of facilitating gene discovery.

PURPOSE: Mendelian disease genomic research has undergone a massive transformation over the past decade. With increasing availability of exome and genome sequencing, the role of Mendelian research has expanded beyond data collection, sequencing, and analysis to worldwide data sharing and collaboration. METHODS: Over the past 10 years, the National Institutes of Health-supported Centers for Mendelian Genomics (CMGs) have played a major role in this research and clinical evolution. RESULTS: We highlight the cumulative gene discoveries facilitated by the program, biomedical research leveraged by the approach, and the larger impact on the research community. Beyond generating a list of gene-phenotype relationships and participating in widespread data sharing, the CMGs have created resources, tools, and training for the larger community to foster understanding of genes and genome variation. The CMGs have participated in a wide range of data sharing activities, including deposition of all eligible CMG data into the Analysis, Visualization, and Informatics Lab-space (AnVIL), sharing candidate genes through the Matchmaker Exchange and the CMG website, and sharing variants in Genotypes to Mendelian Phenotypes (Geno2MP) and VariantMatcher. CONCLUSION: The work is far from complete; strengthening communication between research and clinical realms, continued development and sharing of knowledge and tools, and improving access to richly characterized data sets are all required to diagnose the remaining molecularly undiagnosed patients.

The NIH Human Microbiome Project.

The Human Microbiome Project (HMP), funded as an initiative of the NIH Roadmap for Biomedical Research (http://nihroadmap.nih.gov), is a multi-component community resource. The goals of the HMP are: (1) to take advantage of new, high-throughput technologies to characterize the human microbiome more fully by studying samples from multiple body sites from each of at least 250 "normal" volunteers; (2) to determine whether there are associations between changes in the microbiome and health/disease by studying several different medical conditions; and (3) to provide both a standardized data resource and new technological approaches to enable such studies to be undertaken broadly in the scientific community. The ethical, legal, and social implications of such research are being systematically studied as well. The ultimate objective of the HMP is to demonstrate that there are opportunities to improve human health through monitoring or manipulation of the human microbiome. The history and implementation of this new program are described here.

Genetic Variation in Flowering Traits of Tasmanian Leptospermum scoparium and Association with Provenance Home Site Climatic Factors.

Leptospermum scoparium is emerging as an economically important plant for the commercial production of manuka honey and essential oils, both exhibiting unique antibacterial attributes. To support its domestication this is the first quantitative genetic study of variation for L. scoparium traits. It utilised plants from 200 open-pollinated families derived from 40 native populations, from across the species range in Tasmania, grown in a common garden field trial. The traits studied were survival, growth, and the flowering traits precocity, the timing of seasonal peak flowering, flowering duration, and flowering intensity. Significant genetic variation was evident at the population level for all traits studied and at the family level for three traits-growth, flowering precocity, and time to peak flowering. These three traits had moderate to high narrow-sense heritability estimates ranging from 0.27 to 0.69. For six of the traits studied, population differences were associated with climate attributes at the locations where seed was collected, suggesting adaptation to the local climate may have contributed to the observed population differentiation. Population level geographical trends suggest that genotypes to focus on for domestication originate from the eastern half of Tasmania for precociousness and the western half of Tasmania for earlier time to peak flowering and extended flowering duration.

Role and regulation of iron-sulfur cluster biosynthesis genes in Shigella flexneri virulence.

Shigella flexneri, a causative agent of bacterial dysentery, possesses two predicted iron-sulfur cluster biosynthesis systems called Suf and Isc. S. flexneri strains containing deletion mutations in the entire suf operon (UR011) or the iscSUA genes (UR022) were constructed. Both mutants were defective in surviving exposure to oxidative stress. The suf mutant showed growth that was comparable to that of the parental strain in both iron-replete and iron-limiting media; however, the isc mutant showed reduced growth, relative to the parental strain, in both media. Although the suf mutant formed wild-type plaques on Henle cell monolayers, the isc mutant was unable to form plaques on Henle cell monolayers because the strain was noninvasive. Expression from both the suf and isc promoters increased in iron-limiting media and in the presence of hydrogen peroxide. Iron repression of the suf promoter was mediated by Fur, and increased suf expression in iron-limiting media was enhanced by the presence of IscR. Iron repression of the isc promoter was mediated by IscR. Hydrogen peroxide-dependent induction of suf expression, but not isc expression, was mediated by OxyR. Furthermore, IscR was a positive regulator of suf expression in the presence of hydrogen peroxide and a negative regulator of isc expression in the absence of hydrogen peroxide. Expression from the S. flexneri suf and isc promoters increased when Shigella was within Henle cells, and our data suggest that the intracellular signal mediating this increased expression is reduced iron levels.