Whole-genome association studies for multigenic diseases: ethical dilemmas arising from commercialization--the case of genetic testing for autism.

This paper examines some ethical issues arising from whole-genome association studies for multigenic diseases, focusing on the case of autism. Events occurring following the announcement of a genetic test for autism in France (2005-2009) are described to exemplify the ethical controversies that can arise when genetic testing for autism is applied prematurely and inappropriately promoted by biotech companies. The authors argue that genetic tests assessing one or a few genes involved in highly multigenic disorders can only be useful if: (1) the genetic linkage found in the scientific study must be statistically convincing, reproducible and also applicable to the population to which the individual considered belongs (scientific validity); (2) the relative risk conferred by the 'high-risk' allele should be high enough to be significant to the patient (significant impact); (3) use of the test should lead to some improvement of outcome for the patient, resulting from adapted treatment if available, or at least from adjustment of lifestyle (or life goals) prompted by the new knowledge generated (clinical utility). Decisions concerning genetic testing for autism involve scientific judgement, value judgement and good knowledge of a constantly evolving therapeutic environment. The implementation of genetic tests for highly multigenic diseases thus requires strong mechanisms to ensure that they are used in a fashion that can benefit patients, and these mechanisms must be able to cope with rapid progress in scientific knowledge and therapeutic intervention.

The Hiroshima/Nagasaki Survivor Studies: Discrepancies Between Results and General Perception.

The explosion of atom bombs over the cities of Hiroshima and Nagasaki in August 1945 resulted in very high casualties, both immediate and delayed but also left a large number of survivors who had been exposed to radiation, at levels that could be fairly precisely ascertained. Extensive follow-up of a large cohort of survivors (120,000) and of their offspring (77,000) was initiated in 1947 and continues to this day. In essence, survivors having received 1 Gy irradiation (∼1000 mSV) have a significantly elevated rate of cancer (42% increase) but a limited decrease of longevity (∼1 year), while their offspring show no increased frequency of abnormalities and, so far, no detectable elevation of the mutation rate. Current acceptable exposure levels for the general population and for workers in the nuclear industry have largely been derived from these studies, which have been reported in more than 100 publications. Yet the general public, and indeed most scientists, are unaware of these data: it is widely believed that irradiated survivors suffered a very high cancer burden and dramatically shortened life span, and that their progeny were affected by elevated mutation rates and frequent abnormalities. In this article, I summarize the results and discuss possible reasons for this very striking discrepancy between the facts and general beliefs about this situation.

Cloning and sequencing the first HLA gene.

This Perspectives article recounts the isolation and sequencing of the first human histocompatibility gene (HLA) in 1980-1981. At the time, general knowledge of the molecules of the immune system was already fairly extensive, and gene rearrangements in the immunoglobulin complex (discovered in 1976) had generated much excitement: HLA was quite obviously the next frontier. The author was able to use a homologous murine H-2 cDNA to identify putative human HLA genomic clones in a lambda-phage library and thus to isolate and sequence the first human histocompatibility gene. This personal account relates the steps that led to this result, describes the highly competitive international environment, and highlights the role of location, connections, and sheer luck in such an achievement. It also puts this work in perspective with a short description of the current knowledge of histocompatibility genes and, finally, presents some reflections on the meaning of "discovery."

Is there a niche for DNA microarrays in molecular diagnostics?

DNA microarrays, 15 years after their appearance, have achieved presence in a number of medical settings. Several tests have been introduced and have obtained regulatory approval, mostly in the fields of bacterial identification, mutation detection and the global assessment of genome alterations, a particularly successful case being the whole-genome assay of copy-number variations. Gene-expression applications have been less successful because of technical issues (e.g., reproducibility, platform-to-platform consistency and statistical issues in data analysis) and difficulties in demonstrating the clinical utility of expression signatures. In their different applications, DNA arrays have faced competition from PCR-based assays for low and intermediate multiplicity. Now they have a new competitor, new-generation sequencing, that can provide a wealth of direct sequence information, or digital gene-expression data, at a constantly decreasing cost. In this article we evaluate the strengths and weaknesses of the DNA microarray approach to diagnostics, and highlight the fields in which it is most likely to achieve a durable presence.

Ipsogen.

Ipsogen is a molecular diagnostics company focused on the development and commercialization of innovative tests used to guide and personalize treatment options in cancer. Ipsogen has built a comprehensive portfolio of unique blood cancer diagnostic products available worldwide to leading cancer care institutions in more than 50 countries. Ipsogen's core expertise is focused on large-scale gene expression profiling of tumors in a clinical context, and includes proven know-how for the translation of discoveries into industry standard diagnostic tools. This is achieved, for blood cancers, by an array of individual DNA or RNA tests targeting known anomalies, and for breast cancer by expression profiling and interpretation of the results on the basis of extensive retrospective and prospective studies performed by the company. These products and services make personalized cancer treatment both possible and effective.

DNA microarrays in the clinic: how soon, how extensively?

Although DNA microarrays are now widely used in research settings, they have been slow to penetrate clinical practice in spite of their apparent advantages. This is due to the very different requirements for a clinical test in contrast to a research tool, and to a strict necessity for demonstrated clinical utility. There is a clear differentiation between two types of DNA array tests: "genomic" diagnostics, developed to ascertain the presence or absence of mutations, deletions or duplications, and for which clinical evidence is already established, and tests using expression profiling for prognosis or predictive purposes, in which case the clinical correlate must be proven. Most array diagnostics currently used belong, understandably, to the "genomic" variety. It is to be expected that future improvements in tailored technology, as well as a logical trend towards measuring an ever-increasing number of parameters, will ensure an important diagnostic role for DNA arrays in the coming decade.

How consistent are expression chip platforms?

DNA arrays are now widely used in academia and industry, and expression profiling is recognised as a major tool for basic research as well as for drug development. It is also likely, in the near future, that DNA arrays will be used in clinical laboratories for diagnostic and prognostic purposes. Since several types of arrays are being used, the coherence of results obtained using these diverse platforms becomes an important issue: to what extent can data obtained in different laboratories and with different equipment be combined? Several recent papers address this issue and demonstrate that the expected agreement is not necessarily found. Consistent results can be obtained, but this requires careful identification of the genes assessed by the arrays, and scrupulous adherence to strict experimental procedures.

Wdr12, a mouse gene encoding a novel WD-Repeat Protein with a notchless-like amino-terminal domain.

The WD-repeat protein family consists of a large group of structurally related yet functionally diverse proteins found predominantly in eukaryotic cells. These factors contain several (4-16) copies of a recognizable amino-acid sequence motif (the WD unit) thought to be organized into a "propeller-like" structure involved in protein-protein regulatory interactions. Here, we report the cloning of a mouse cDNA, referred to as Wdr12, which encodes a novel WD-repeat protein of 423 amino acids. The WDR12 protein was predicted to contain seven WD units and a nuclear localization signal located within a protruding peptide between the third and fourth WD domains. The amino-terminal region shows similarity to that of the Notchless WD repeat protein. Sequence comparisons revealed WDR12 orthologs in various eukaryotic species. Wdr12 seems to correspond to a single-copy gene in the mouse genome, located within the C1-C2 bands of chromosome 1. These data, together with the results of Wdr12 gene expression studies and evidence of in vitro binding of WDR12 to the cytoplasmic domain of Notch1, led us to postulate a function for the WDR12 protein in the modulation of Notch signaling activity.

Expression profiling in mouse fetal thymus reveals clusters of coordinately expressed genes that mark individual stages of T-cell ontogeny.

To search for genes that participate in regulatory networks sustaining mouse embryonic T-cell development, we have performed expression profiling using nylon macroarrays. Labeled samples representative of individual developmental stages were utilized, taking advantage of cell homogeneity during early thymus ontogeny. cDNAs revealing differential expression were further selected using labeled samples derived from lymphoid versus non-lymphoid tissues, and from mutant thymi exhibiting T-cell developmental defects. We thus identified clusters of coexpressed genes during T-cell embryogenesis and characterized their sequences through bioinformatics. We compare our results with those from other profiling analyses in the immune system, and discuss their implications for the definition of genes whose products are involved in T-cell development.