Drug Metabol Pers Ther 2016; 31(1): 3–8 Mini Review Maria Apellaniz-Ruiza, Cristina Gallegoa, Sara Ruiz-Pintoa, Angel Carracedo and Cristina Rodríguez-Antona* Human genetics: international projects and personalized medicine DOI 10.1515/dmpt-2015-0032 Received August 31, 2015; accepted October 19, 2015; previously Introduction published online November 18, 2015 Genetic variation databases describe naturally occur- Abstract: In this article, we present the progress driven ring genetic differences among individuals of the same by the recent technological advances and new revolu- species. This variation, accounting for 0.1% of our DNA tionary massive sequencing technologies in the field of [1], permits the flexibility and survival of a population human genetics. We discuss this knowledge in relation in the face of changing environmental circumstances, with drug response prediction, from the germline genetic but it also influences how people differ in their risk of variation compiled in the 1000 Genomes Project or in the disease or their response to drugs. It is well known that Genotype-Tissue Expression project, to the phenome- variability in response to drug therapy is the rule rather genome archives, the international cancer projects, such than the exception for most drugs, and these differences as The Cancer Genome Atlas or the International Cancer are among the major challenges in current clinical prac- Genome Consortium, and the epigenetic variation and its tice, drug development, and drug regulation [2, 3]. Thus, influence in gene expression, including the regulation of rather than accepting the “one drug fits all” approach, drug metabolism. This review is based on the lectures pre- researchers envision that drugs need to be tailored to fit sented by the speakers of the Symposium “Human Genet- the profile of each individual patient. Therefore, discover- ics: International Projects & New Technologies” from the ing the DNA sequence variants that contribute to common VII Conference of the Spanish Pharmacogenetics and disease risk and drug toxicity offers one of the best oppor- Pharmacogenomics Society, held on the 20th and 21st of tunities for understanding the complex causes of disease April 2015. in humans and learning how to better treat them. Over the last decade, many efforts have been put to accomplish Keywords: epigenetics; genetic variation; human genome; this goal and to provide a detailed picture of human differ- pharmacogenomics. ences and similarities at the genetic level. The first human genome sequence was completed in 2003 using first-generation sequencing technolo- aMaria Apellaniz-Ruiz, Cristina Gallego and Sara Ruiz-Pinto contributed equally to this work. gies (i.e. Sanger sequencing) [4, 5]. Many previous steps *Corresponding author: Cristina Rodríguez-Antona, Hereditary were crucial to this success, such as the discovery of the Endocrine Cancer Group, Spanish National Cancer Research Center double helical structure of the DNA molecule in 1953 by (CNIO), Madrid, Spain, Phone: +34 917328000, Francis Crick and James Watson [6], the development of Fax: +34 912246972, E-mail: [email protected]; and ISCIII Center DNA sequencing performed by Edward Sanger in the mid- for Biomedical Research on Rare Diseases (CIBERER), Madrid, Spain 1970s [7], and finally the automation of DNA sequencing Maria Apellaniz-Ruiz: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain in the 1980s. Since then, the demand for cheaper and Cristina Gallego: Stroke pharmacogenomics and genetics, Fundació faster sequencing methods has driven the development Docència i Recerca Mutua Terrassa, Hospital Universitari Mútua de of second-generation sequencing methods, also called Terrassa, Terrassa (Barcelona), Spain next-generation sequencing (NGS). This massively par- Sara Ruiz-Pinto: Human Genotyping-CEGEN Unit, Spanish National allel sequencing technology facilitates high-throughput Cancer Research Centre (CNIO), Madrid, Spain Angel Carracedo: Fundación Pública de Medicina Xenómica- sequencing, allowing an entire genome to be sequenced SERGAS. Grupo de Medicina Xenómica, CIBERER, IDIS, Santiago de in < 1 day. This new availability of large number of complete Compostela, Spain human genome sequences is boosting the identification of 4 Apellaniz-Ruiz et al.: Human genetics: international projects and personalized medicine genetic variants responsible for the pathogenesis of dis- drug metabolism, drug transport, and drug targets, which eases and drug therapy response. could affect either efficacy or drug toxicity, and (ii) the After the publication of the human genome, it became disease heterogeneity that mainly affects drug efficacy. In clear that the DNA sequence changes were not the only recent years, many international efforts are being put into factor shaping gene expression and phenotypes. This unveiling the genetic variability among the population opened the door to epigenetics, a new field still in its early that could explain these differences. Therefore, there has development. Epigenetics refers to nongenetic factors that been a proliferation of both public and private projects have a key role in gene expression and regulation. This that make genomic information widely and rapidly avail- new field explains why different cell types, which have able for the scientific community. the same genome, have different phenotypes [8]. Epige- Known genome browsers for the retrieval of genomic netics also provides an explanation for differences in information exist. Among them, Ensembl (http://www. traits, such as disease discordance, observed in monozy- ensembl.org) is a joint scientific project between the gotic twins [9, 10]. NGS technologies had contributed to European Bioinformatics Institute and the Wellcome the rapid increase of epigenetic studies, adding one more Trust Sanger Institute, which includes genomes of several layer to the genetic information. Therefore, identifying species and different genomic and epigenomic informa- epigenetic patterns associated with complex diseases and tion. Similar databases and browsers are found at the drug response is another step toward the personalization National Center for Biotechnology Information (http:// of medicine. www.ncbi.nlm.nih.gov/), a branch of the National Insti- Many national and international projects focus on tutes of Health, which houses a series of databases rele- unveiling human genetic and epigenetic variation and vant to biotechnology and biomedicine (GenBank, dbSNP, their contribution to the heterogeneity of diseases. This PubMed, or OMIM). The University of California Santa information will be critical to individualize medicine, Cruz browser (https://genome.ucsc.edu/) allows to have making it the norm rather than the exception, maximizing a rapid display of any requested portion of the genome drug efficacy and minimizing drug toxicity. In this review, at any scale, together with dozens of aligned annotation we will describe major international projects studying tracks (known genes, predicted genes, ESTs, mRNAs, CpG genetic variation (e.g. HapMap, the 1000 Genomes islands, mouse homologies, etc.). Project, The Cancer Genome Atlas [TCGA], and the Inter- Concerning germline genetic variation, the Inter- national Cancer Genome Consortium [ICGC]), gene national HapMap Project (http://hapmap.ncbi.nlm.nih. expression and regulation across multiple human tissues gov/) was created to determine the common patterns of (the Genotype-Tissue Expression [GTEx] project) and pro- DNA sequence variation in the human genome by deter- viding phenotype-genotype associations (the European mining the genotypes of more than one million sequence Genome-Phenome Archive [EGA], a repository for all types variants, their frequencies, and the degree of association of genotype experiments, including case control, popula- between them in DNA samples from populations with tion, and family studies, and phenotypic data). Going a ancestry from parts of Africa, Asia, and Europe. step further, we will also discuss gene regulation through Not only projects compiling interindividual genetic epigenetics and how it can modify disease risks and drug variability have been developed, but also databases to responses. This new genetic and epigenetic knowledge unveil disease heterogeneity. This is the case of cancer, will constitute the basis for a more efficient personal- in which the identification of genes mutated and driving ized medicine. In this contribution, we review the latest oncogenesis has been a central aim. Some of the major developments in this field presented in the Symposium cancer databases are the ICGC (https://icgc.org/) and “Human Genetics: International Projects & New Technolo- TCGA (http://cancergenome.nih.gov/). They are compre- gies” from the VII Conference of the Spanish Pharmacoge- hensive catalogues of genomic and molecular abnormali- netics and Pharmacogenomics Society (SEFF), on the 20th ties (somatic mutations, abnormal expression of genes, and 21st of April 2015. and epigenetic modifications) in tumors from different cancer types and/or subtypes and are of clinical and societal importance across the globe. In addition, the Wellcome Trust Sanger Institute’s Cancer Genome Project Advances in human genetics (https://www.sanger.ac.uk/research/projects/cancerge- nome/) is using high-throughput techniques to identify Two major factors have to be taken into account to per- tumor-acquired sequence variants/mutations and hence sonalize medicine: (i) the