**About the Editors**

**John Engelhardt** please add John Engelhardt Biographical Notes.

**Claude Ferec** MD-PhD, Pharm, Prof of Genetics. I have 35 years of experience in genetics research, with an emphasis on applying molecular analytical technologies to achieve a better understanding of complex genetic disorders. My team in Brest for a long time has been involved in the study of two genetic disorders particularly present in our isolated Celtic population: cystic fibrosis and haemochromatosis. We also study other disorders, such as hereditary pancreatitis and polycystic kidney disease. Focusing on cystic fibrosis (CF), we propose to illustrate what has been the road map of our research projects during the last thirty years and to show how the impact of gene discovery and genetic and genomic progresses has dramatically modified our view on predictive medicine; personalized medicine; and, not the least, patient care. 1) Mapping and cloning the gene responsible for the disorder: After the CFTR gene was cloned in the late 1990s, we immediately embarked on the CF genetic analysis consortium with the aim of identifying the molecular defects of the gene. We were the first to identify nearly all the mutants in a large population of 3 million inhabitants (Ferec et al. ´ Nat Genet 1992) and—to make a long story short—our lab has identified more than 400 mutations and set up new methods to scan the 27 exons of the gene in only one week (Audrezet et al. Hum Mol ´ Genet 1993; Le Marechal et al. Hum Genet 2001; Audr ´ ezet et al. J Mol Diagn 2008). We were also ´ the first to perform a systematic screen of genomic rearrangements in the CFTR gene, leading to the identification of a large number of gross deletions (Audrezet et al. Hum Mutat 2004) and, through ´ a worldwide collaborative study, to describe the distribution of these rearrangements in different populations of the world (Ferec et al. Eur J Hum Genet 2006). We finally set up a custom CGH ´ array assay to precisely narrow down these deletions/duplications (Quemener et al. Hum Mutat ´ 2010).2) Study of genotype/phenotype correlations: The genotype/phenotype correlations among CF patients sharing the same mutation is complex, suggesting that the phenotype is influenced, beyond environmental factors, by factors such as modifier genes or the long-distance regulation of the gene itself (Ferec et al. Hum Mol Genet 1993; Braun et al. J Cyst Fibros 2006). Knowledge of mutations ´ in the gene has completely modified the spectrum of phenotypes associated with CFTR dysfunction. As, for example, CFTR-related disorders such as sterility in men with absence of vas deferens are associated with specific mutated alleles (Chillon et al. N Engl J Med 1995). 3) Development of genetic epidemiology: The high incidence of CF in our geographic area (Brittany) combined with our long experience in newborn screening for this disease have led us to develop, in the last twenty years, a research program devoted to the genetic epidemiology of CF. This program aims to measure the changes observed in the incidence, survival, and clinical outcomes of CF. The pilot newborn screening project implemented in our area thirty years ago was an excellent example of a successful program combining a biochemical marker test with, for the first time, a mutation screening test (Scotet et al. Lancet 2000). 4) The development of regulation and functional study of the CFTR protein: In this field, our aim is to identify new proteins interacting with the wild-type CFTR protein. We have shown for the first time that AnxA5 interacts directly with CFTR and regulates its normal function (Trouve et al. Biochim Biophys Acta 2007). Indeed, we have shown that AnxA5 is involved in the ´ cell surface localization of the F508del CFTR and that the Cl channel function of the mutated CFTR is increased, indicating that the mechanisms regulating AnxA5 are potential therapeutic targets in CF (Le Drevo et al. Biochim Biophys Acta 2008). We also showed, for the first time, that the altered apoptosis observed in CF under stress conditions (inflammation, infection) is due to altered Cal-1, Csp12, and mostly Csp-3 activation (Kerbiriou et al. PLoS One 2009). 5) Impact of gene discovery on health policies: The discovery of the CFTR gene, the identification of its mutations, and the development of newborn screening and the prenatal molecular diagnosis test have dramatically changed the epidemiology of CF. As a model in Brittany, a region of 3 million inhabitants where all the mutated alleles are identified, we set up a newborn screening pilot program as early as 1989, proposed a prenatal test to accurately identify at-risk families, and systematically proposed in affected families a cascade screening for mutation carrier detection. We were able to assess the impact of those public health policies (Scotet et al. Lancet 2000; Scotet et al. Prenat Diagn 2008, Duguep´ eroux et al. ´ J Cyst Fibros 2016). In our area, around 37,000 births occur each year and a mean of 11 newborns are screened positive for CF. This leads to a CF incidence of 1/3300, which is decreasing (Scotet et al. Orphanet J Rare Dis. 2012). The results of those different policies have decreased the incidence of CF by one third (Scotet et al. Hum Genet 2003). I am well prepared to serve as Principal Investigator on this project, entitled "Origin of F508del-CF and Heterozygote Selective Advantage: Role of Arsenic". In fact, our INSERM team is uniquely well prepared for this project because of expertise in genetic analysis of both the genes responsible for CF (CFTR) and haemochromatosis (HFE) as well as our large number of stored DNA specimens. During 20 years of collaboration with Prof Farrell, we have explored explanations for the relatively high frequency of the F508del allele with studies of ancient DNA and modern DNA from trios to identify when and where F508del arose and its pattern of dissemination (Farrell et al. Nature Precedings 2007; Farrell et al. Eur J Hum Genet 2018). Now, we are ready to determine its origin more specifically and why there must have been a selective advantage for the F508del/wt carrier.
