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23 January 2008A new project has been launched to fully sequence the genomes of 1,000 anonymous individuals. The project is being run by an international research consortium involving the Wellcome Trust Sanger Institute in Hinxton, UK, the Beijing Genomics Institute, Shenzhen (BGI Shenzhen) in China and the National Human Genome Research Institute (NHGRI), part of the National Institutes of Health (NIH).

The so-called “1000 Genomes Project” project will use samples from anonymous volunteers who have previously given their informed consent for their DNA to be analyzed and placed in public databases such as the International HapMap Project.

The project is expected to cost around $30-50 million and will be divided into several phases. Phase 1, which is expected to last around a year to complete, will be divided into three pilot studies in order to decide how best to cost efficiently and cost effectively produce a map of human genetic variation. This will be followed by a 2 year production phase, during which sequence data will be delivered at a staggering average rate of about 8.2 billion bases per day – the equivalent of more than two human genomes every 24 hours!

The overall intention of the project is to create a publically available map of the human genome and its variations that will provide important biomedical information, although it is currently unclear exactly how genomic information of this sort will be translated into tangible health benefits. According to the official website, the primary goals of the project are threefold: to discover single nucleotide variants at frequencies of 1% or higher in diverse populations; to uncover variants down to frequencies of 0.1 – 0.5% in functional gene regions; and to reveal structural variants, such as copy number variants, insertions and deletions.

“This project will increase the sensitivity of disease discovery efforts across the genome five-fold and within gene regions at least 10-fold,” said NHGRI Director Francis Collins MD PhD, adding “…this will change the way we carry out studies of genetic disease.”

18 January 2008The US Agency for Healthcare Research and Quality (AHRQ) has released a new report sponsored by the Center for Disease Control (CDC) on the use of gene expression profiling of breast tumour samples as a guide to prognosis and treatment. The report, Impact of Gene Expression Profiling Tests on Breast Cancer Outcomes, looked at three commercially available gene expression assays in order to determine whether there was sufficient evidence to support their claims of improved prognostic accuracy, treatment choice and health outcomes in women with early-stage breast cancer.

The assays examined were Genomics Health’s Oncotype DX™, Agendia’s MammaPrint® and AviaraDX’s H/I™ test, and they were assessed for their analytic and clinical validity, clinical utility and impact on healthcare (including costs), and any associated harms. Relatively little evidence was identified for any of the assays, but the authors of the report found that the Oncotype DX did enhance standard prognostic indices “in a clinically meaningful manner” but evidence of clinical utility was not found for the other two tests. Assessments of the cost-effectiveness of the assays were inconclusive.

Overall, the conclusion was that further study was required to provide reliable evidence on the use of all three forms of test, although the Oncotype DX was “furthest along the validation pathway”. Of note, Food and Drugs Agency (FDA) guidance on applications for In Vitro Diagnostic Multivariate Index Asseys (IVDMIAs) such as the gene expression profiling kits requires evidence of analytical and clinical validity for the test (see previous news), but not of clinical utility.

18 January 2008The UK Human Fertilisation and Embryology Authority (HFEA) has issued one-year licences permitting the creation of chimeric human-animal embryos for research purposes to two centres at King's College London and Newcastle University (see press release). Both centres wish to create embryonic stem cells for medical research purposes; creating hybrids by using enucleated animal egg cells fused with a human cell nucleus provides a better source of (near) human embryos than using surplus embryos from in vitro fertilization treatment.

The HFEA postponed a decision on these applications in order to carry out a public consultation exercise on the issue (see previous news), but in September 2007 they concluded that there was there was no fundamental barrier to such cytoplasmic hybrid research as it was ‘in principle, necessary and desirable in both scientific and ethical terms’ (see previous news) and the public were ‘at ease’ with the concept. However, opponents of such research contend that it is both ethically unacceptable, and also unnecessary in the light of alternative approaches to the creation of human stem cells.

3 January 2008The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group has released the first in a planned series of recommendation statements (see press release) on the use of genetic tests in clinical practice. EGAPP aims “to establish and test a systematic, evidence-based process for evaluating genetic tests and other applications of genomic technology in transition from research to practice” (see previous news).

The statement addresses the use of cytochrome P450 (CYP450) genetic testing in adults with non-psychotic depression beginning treatment with selective serotonin reuptake inhibitors (SSRIs), a common class of antidepressants. The EGAPP Working Group concluded that there was insufficient evidence linking CYP450 testing in adults treated with SSRIs with clinical outcomes to support a recommendation for or against use of the pharmacogenetic test, and therefore decided to discourage its use “until further clinical trials are completed”. This conclusion is in line with an earlier report by the US Agency for Healthcare Research and Quality (AHRA), which also found a lack of data on the utility of testing for CYP450 genotypes (see previous news).

EGAPP Chair Alfred Berg commented: "This first release from EGAPP has helped us understand some of the challenges we face in evaluating genomic innovations, such as the quality of research designs, dealing with data that are proprietary, scant evidence on benefits and harms, and the lack of comparisons with current practice, of testing in typical populations, and of information about cost and cost-effectiveness" (see press release).

2 January 2008As part of its Roadmap Initiative (see previous news), the US National Institutes of Health (NIH) has launched the Human Microbiome Project. The ‘human microbiome’ refers to the collective genomes of all microorganisms present in or on the human body, of which there are actually more than there are human cells, although they comprise only 1-2% of total body mass.

The aim of the project is to explore the role of these microorganisms in human health and disease, and it will commence by awarding funding for the sequencing of 600 microbial genomes, bringing the total number available for further research up to around 1000. Researchers will also characterize the different forms of microbes present in samples from the digestive tract, mouth, skin, nose, and female urogenital tract of healthy human volunteers, and later from individuals with specific diseases, in the hope of linking specific changes in the microbiome with these diseases. The project will employ a relatively new approach called metagenomic sequencing, which sequences all DNA in samples, as opposed to that of isolated samples of individual species of microbe.

National Human Genome Research Institute Director, Francis S. Collins, who co-chairs the Human Microbiome Project Implementation Group, commented: "Our goal is to discover what microbial communities exist in different parts of the human body and to explore how these communities change in the presence of health or disease… In addition, we will likely identify novel genes and functional elements in microbial genomes that will reshape the way we think about and approach human biology” (see press release).

The Human Microbiome Project will also monitor and support research on the ethical, legal and social implications of the research., focusing on areas including the clinical and health implications of using probiotics, potential forensic uses of microbiome profiles, bioterrorism and biodefence applications, the application of new technologies from the project, and patenting and privacy issues.

3 January 2008Human variome microattribution reviews. (2008)Nat Genet. 40(1):1. Editorial setting out policy for commissioning reviews on variation at selected genomic loci, as an incentive to stimulate ‘high-quality community annotation of the human genome’ (PubMed).

Copy-number analysis goes more than skin deep. McCarroll SA (2008) Nat Genet. 40(1):5-6. News and views article looking at new research into copy-number polymorphisms in psoriasis and how it may influence future attempts to measure such variants (PubMed).

Genomic rearrangements in the spotlight. Osborne LR (2008) Nat Genet. 40(1):6-7. News and views article on new evidence that suggests genomic rearrangements such as microdeletions are currently significantly underdiagnosed (PubMed).

BRCA1- sowing the seeds crooked in the furrow. Foulkes WD (2008) Nat Genet. 40(1):8-9. News and views article on a study showing that microdeletions in the PTEN gene are a common signature of DNA repair deficiency in breast tumours, especially in BRCA1 mutation carriers (PubMed).

The emerging landscape of breast cancer susceptibility. Stratton MR, Rahman N (2008) Nat Genet. 40(1):17-22. Perspectives piece on current understanding of genetic susceptibility to breast cancer and how this may provide insight into other common diseases (PubMed).

Identifying genetic risk factors for serious adverse drug reactions: current progress and challenges. Wilke RA et al. (2007) Nat Rev Drug Discov. 6(11):904-16. Review looking at three specific types of adverse drug reaction: liver damage, myotoxicity and the cardiac conditions long QT and torsades de pointes (PubMed).

Human Genetics: The Hidden Text of Genome-wide Associations. Gibson G, Goldstein DB (2007) Curr Biol. 17(21):R929-32. Review looking at the challenges in translating emerging evidence of genetic associations with complex diseases into public health outcomes, and integrating this information with broader biological understanding of disease processes (PubMed).

Rules of engagement. Taylor PL (2007) Nature 450(7167):163-4. Commentary arguing that more public engagement over scientific issues is necessary to maintain public confidence (PubMed).

A timely harvest. Joly PB, Rip A (2007) Nature 450(7167):174. Essay proposing that public opinion should be sought earlier in the process of science and policy development, when there is still room for their opinions to influence strategy (PubMed).

Public health. Biobanks in developing countries: needs and feasibility. Sgaier SK et al. (2007) Science 318(5853):1074-5. Policy forum piece looking at the scope for developing biobanks in developing countries and prospects for international collaboration between biobank projects (PubMed).

New links to the pathogenesis of Crohn disease provided by genome-wide association scans. Mathew CG (2008)Nat Rev Genet. 9(1):9-14. Summary of recent findings, also exploring the possibility that GWAs may provide new insight into causal genetic variants and disease (PubMed).

Nucleosome destabilization in the epigenetic regulation of gene expression. Henikoff S (2008) Nat Rev Genet. 9(1):15-26. Review (PubMed).

Coupling and coordination in gene expression processes: a systems biology view. Komili S, Silver PA (2008)Nat Rev Genet. 9(1):38-48. Review of functional interactions involved in the regulation of gene expression (PubMed).

Steady progress and recent breakthroughs in the accuracy of automated genome annotation. Brent MR (2008) Nat Rev Genet. 9(1):62-73. Review of progress in genome annotation (PubMed).

Accommodating dissent. Leach M (2007) Nature 450(7169):483. Science and politics essay arguing that scientists and policy-makers must take public opinion more seriously in the development of health programmes; failure to properly engage with issues (even those that are cultural or emotional in origin) risks wasted investment in public health through public mistrust (PubMed).

The two faces of miRNA. Buchan JR, Parker R (2007) Science 318(5858):1877-8. Perspectives piece on the capacity of miRNAs to stimulate or block translation of target mRNAs, accompanying new research (PubMed).

Is therapeutic cloning dead? Cibelli J (2007) Science 318(5858):1879-80. Perspectives piece looking at whether human therapeutic cloning to produce sources of stem cells will be necessary in the light of recent developments in inducing pluripotency in non-embryonic stem cells (PubMed).

Implementation science. Madon T, Hofman KJ, Kupfer L, Glass RI (2007) Science 318(5857):1728-9. Policy forum article looking at the difficulties in translating scientific advances into health benefits, especially in poorer countries, and proposing a framework for implementation research (PubMed).

Cancer diagnostics: One-stop shop. Uhr JW (2007) Nature 450(7173):1168-9. News and views piece on a new ‘lab-on-a-chip’ device that can separate and quantify circulating tumour cells (PubMed)

Molecular biology: genome under surveillance. Arndt KM (2007) Nature 450(7172):959-60. News and Views piece on how a yeast protein regulates gene expression across the genome via a chromatin-based mechanism (PubMed).

Proteins to proteomes. Chouard T, Finkelstein J (2007) Nature 450(7172):963. Editorial introducing special Insight feature section onproteomics and systems biology (PubMed).

Cystic fibrosis. Davies JC, Alton EW, Bush A (2007) BMJ 335(7632):1255-9. Clinical review (PubMed).

The ethical regulation of science. Warnock M (2007) Nature 450(7170):615. Science and policy essay on the inherent problems in effective regulation of controversial research (such as that involving human embryos) which is subject to public rather than private morality (PubMed).

The influence of genetic variation on gene expression. Williams RB, Chan EK, Cowley MJ, Little PF (2007) Genome Res.17(12):1707-16. Review concluding that, although the influence of genetic variation on gene-expression levels is increasingly understood, there is a long way to go in understanding how this translates into phenotypic and evolutionary outcomes (PubMed).

Genetics of late-onset Alzheimer's disease: progress and prospect. Li Y, Grupe A (2007) Pharmacogenomics 8(12):1747-55. Review suggesting that since genetic susceptibility factors (with the exception of APOE4) for late-onset Alzheimer's disease are likely to have only weak effects, greater research collaboration will be needed to identify and exploit them for diagnosis, prognosis and therapy (PubMed).

Hereditary colorectal cancer syndromes: molecular genetics, genetic counseling, diagnosis and management. Lynch HT, Lynch JF, Lynch PM, Attard T (2007) Fam Cancer. Nov 13; [Epub ahead of print]. Review, including the recommendation that where there is a significant family history but no mutation is identified, surveillance and management strategies should be implemented anyway (PubMed).

Genetic profiling and tailored therapy in asthma: Are we there yet? Lugogo NL, Ginsburg GS, Que LG (2007)Curr Opin Mol Ther. 9(6):528-37. Reviewon the pharmacogenomics of asthma therapeutics and prospects for genotyping as a tool to guide treatment (PubMed).

The impact of pharmacogenetics on the development and use of antipsychotic drugs. Reynolds GP (2007)Drug Discov Today. 212(21-22):953-9. Review on the prospects for pharmacogenetic testing to guide antipsychotic drug use (PubMed)

Constitutional polymorphisms of prostate cancer: prognostic and diagnostic implications. Hahn NM, Kelley MR, Klaunig JE, Koch MO, Li L, Sweeney CJ (2007) Future Oncol. 3(6):665-682. Review on the potential of microarray SNP analysis to identify patients at high risk of developing aggressive lethal forms of prostate cancer (PubMed).

Can genomics help heal the schism between medicine and public health? Muin J. Khoury (presentation) and Genomic medicine and health disparities. Charles Rotimi (presentation). Online seminars provided by the US CDC National Office of Public Health Genomics and National Center for Chronic Disease Prevention and Health Promotion

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