[Desperately seeking targets]. / Recherche cibles, désespérément - Chroniques génomiques.

In clinical oncology, obtaining sequence data from tumour samples has become practical in terms of logistics, turnover time and costs. The major issue now is the interpretation of this sequence to define actionable targets, i.e. genome changes that are involved in tumorogenesis and that predict the efficacy of existing and available targeted treatments. This is the focus of major efforts from public clinical centres and from companies that see it as a promising commercial activity.

[Genes for extreme violent behaviour?]. / Encore le « gène du crime ¼ ? - Chroniques génomiques.

A new genetic study focussing on the degree of violence in criminals and using both candidate gene and GWAS approaches finds statistically significant associations of extreme violent behaviour with low activity alleles of monoamine oxydase A (MAOA) and with the CD13 gene. However, the alleles implicated are common in the general population, thus they cannot be causal, and only represent potential indicators of increased risk.

[Utterly unanticipated findings]. / Chroniques génomiques - Des résultats tout à fait inattendus.

There are now a number of cases in which non-invasive prenatal testing (NIPT) has detected signs of cancer in pregnant women. These unexpected findings raise a number of difficult questions regarding their communication to the patient as well as the wording of informed consent forms.

[23 and Me: how to make (a lot of) money out of your customers]. / 23andMe ou comment (très bien) valoriser ses clients - Chroniques génomiques.

The announcement of several deals between the DTC genetics firm 23 and Me and Genentech, Pfizer and other corporations reveals the real business model of the company: selling access to sets of characterized patients for targeted drug development. This may be a useful strategy, but it raises a number of questions concerning the privacy of the company's customers and also of adequate compensation when they become valuable currency.

[The return of germline gene therapy]. / Chroniques génomiques--Thérapie génique germinale, le retour ?

The recent development of a powerful and flexible genome editing technique (the CRISP-cas9 method) accelerates tremendously the production of animal models and will significantly enhance the perspectives of (somatic) gene therapy. However, it also raises a real possibility of germline modifications in humans, with therapeutic aims or for "improvement": this raises thorny ethical questions that are no longer theoretical (as in the 1990s) but will have to be faced in the very near future.

Genes and non-mendelian diseases: dealing with complexity.

The first decades of the new medical genetics (1980 to 2000) were marked by resounding successes, with the identification of the genes responsible (when defective) for muscular dystrophy, cystic fibrosis, or Huntington's disease, to name justa few of the several thousand Mendelian genetic conditions whose causes are now known. In contrast, the search for genes involved in common disorders such as diabetes,hypertension, schizophrenia, or autism failed miserably in the 1990s, with inconsistent and conflicting results--although the strong genetic component of these diseases (that also involve environmental factors) was (and still is) beyond doubt. From 2000 on,thanks to huge progress in genomic knowledge, technology, and analytical methods, it became possible to reliably identify genes influencing the risk of complex conditions,using the so-called GWAS (Genome-Wide Association Study) approach. Yet many problems remain, such as the vexing question of the "missing heritability," or the difficulty of translating these scientific results into genetic tests with real clinical validity and utility. Autism is one of the cases in which a strong genetic component has been demonstrated, but where the search for causative genes remains difficult and attempts at developing valid genetic tests have failed, because of the many genes involved and possibly of the heterogeneity of the condition.

[Rare variants and demographic explosion]. / Variants rares et explosion démographique - chroniques génomiques.

The abundance of rare variants in human DNA is the consequence of tremendous recent expansion of our population. Careful measurement of neutral variants in a European population points to more recent and more rapid expansion than previously believed.

[Single-cell sequencing and tumour heterogeneity]. / Hétérogénéité des tumeurs : l'apport du séquençage sur cellules individuelles - Chroniques génomiques.

The heterogeneity of tumours is now beginning to be documented precisely by single-cell new-generation sequencing. Recently published results on breast tumours show that each of the cells analysed displays a unique pattern of point mutations. This extensive genetic diversity is present before any treatment, and is likely to cause resistance to initially successful targeted therapies.

[Genes « for ¼ schizophrenia]. / Les « gènes ¼ de la schizophrénie - Chroniques génomiques.

Very large-scale GWAS analyses confirm the genetic complexity of schizophrenia and provide some new leads to understand the etiology of the condition.

[Surprising results from Hiroshima studies]. / Les leçons inattendues d'Hiroshima - Chroniques génomiques.

One of the initial motivations for the Genome project was to improve the detection of possible mutations in children of atomic bomb survivors. In fact it has proved very difficult to find any genetic effect in these descendants in spite of the strong irradiation suffered by their parents: this factual evidence is largely ignored in the current debates about the effects of radiation and the future of nuclear energy. Sequencing studies on this population would be very desirable.

[From exome sequencing to avatar creation: towards « precision oncology ¼?]. / De l'exome à l'avatar: vers une « oncologie de précision ¼ ? - Chroniques génomiques.

According to recent reports, the success rate of targeted therapy directed by "actionable mutations" found in tumour DNA is rather low (10 to 20%). Interesting attempts have been made to improve this by establishing mouse "avatars" and testing drugs on them. The first results are promising, but the clinical utility of this expensive and cumbersome approach needs to be ascertained by more extensive testing.

[Monshot projects in biology]. / Course à la lune en biologie - chroniques génomiques.

Three recent and very large projects aim to integrate several "omics" approaches in order to promote pro-active medicine and to create a "Wellness industry".

[An invasion of non-invasive diagnostic tests]. / L'invasion des tests non invasifs - chroniques génomiques.

Non-invasive prenatal testing is becoming commonplace, but, in addition, other tests using only a blood sample are being developed and will have a significant impact, notably in oncology.

[What "look-alike" individuals tell us]. / Sous le capot des sosies.

Rare unrelated individuals show striking resemblance, almost as high as monozygotic twins. Extensive genetic analysis of a set of such individuals shows that every couple shares a given allele at a large set of loci, enriched for "face genes". The similarity is limited to this set of loci, and the rest of the genome is quite diverse in these "look alike" individuals.

[The foetal exome revealed]. / L'ADN fœtal révélé.

New developments in the analysis of maternal cell-free DNA now allow complete analysis of the foetal exome. This makes possible an important extension of the breadth of prenatal diagnostics but raises significant ethical questions.

[Why did I get cancer?] / D'où vient mon cancer ?

Two interesting papers explore the beliefs of individuals (general population, or cancer survivors) on the causes of cancer. They reveal a huge discrepancy between scientifically proven factors and spontaneous opinions, that consider "stress" as the major cause of cancer. This is understandable in terms of psychological needs, and must be taken into account in cancer information campaigns.

[Ancient DNA speaks]. / L'ADN ancien parle de plus en plus.

Many human DNA sequences have been obtained from ancient remains dating back from several millennia. However, these have low coverage and may contain many errors; this has limited their usefulness for many analyses, in particular the search for Identical By Descent (IBD) segments that is very powerful for detection of kinship. A new method, using imputation from database data and sophisticated statistical analysis, proves able to detect IBD segments (and thus parenthood) in low-quality DNA sequences from individuals linked only by sixth degree parenthood, opening a whole new field of investigation using ancient DNA.

[A surprising commercial success]. / Chroniques génomiques - Un triomphe commercial surprenant.

Direct-to-consumer (DTC) genetic tests have become quite popular in the USA. This article explores the uses to which they are put and the motivations of the customers.

[Lessons from the HeLa story]. / Henrietta Lacks et les cellules HeLa - Les leçons d'une histoire.

An exceptional arrangement concluded for access to the HeLa cell line sequence highlights the problems involved in studies on « old ¼ samples obtained before ethical and privacy safeguards were in place.

[Eating my hat?]. / Un chapeau pour mon repas ?

After clearing many hurdles, gene therapy is now reaching the commercialization stage and can be expected to make a modest but real contribution to treatment in the near future.