* To produce deep sequence information from eight European population-based biobanks including minority populations, to establish a catalogue of the genetic diversity of the complete human exome+ (all functional regions). The sequence information obtained will be 10-fold deeper than the goal of the 1000 Genomes project (www.1000genomes.org) on European samples, and will sample more regions of Europe.

* To produce a catalogue of known and new exonic CNVs in European populations, using a combination of array-Comparative Genomic Hybridisation (aCGH) in a subset of samples and sequence data in all samples. CNVs mined from sequence data will be extensively validated with aCGH data.

* To produce corresponding CNV and exome+ sequence variation catalogues from samples of European minority populations.

* To use these data to produce a much more detailed characterisation of genetic variation in Europe than available to date. This should result in an informatics platform for the future analysis of both rare and common disorders in European samples, including imputing low frequency coding and other functional sequence variants onto genotyped samples in a population specific manner.

* To provide candidate loci for follow-up association studies for disease end points through large international collaborations

* To produce information on functional variants that influence quantitative traits in different European populations. We aim to contribute to this goal by including the expression data from white cells or lymphocytes from 3300 individuals for which the exome+ sequence is produced (the remaining already have the transcriptomic data of lymphocytes on the same platform). Combining 1) the deep sequence information, revealing SNPs, small indels and CNVs and 2) the aCGH data from 320 individuals to cover more complex genome variation, with 3) the transcriptomics data, we should be able to determine the functional role of the majority of identified exome+ variations in expression and relate these to traits assessed in the cohorts.

* To make the collected anonymised sequencing data accessible to all investigators via the European Genotype Archive (EGA), as openly as possible subject to full ethical protection of the rights and privacy of the participants.

* To spearhead the technology needed to perform large scale sequencing and make methodological details and knowhow accessible to investigators via our website.

* To develop data analysis methods and tools to support accurate and reliable inference of population properties and functional quantitative trait variants from joint sequence, transcriptome and microarray datasets. These will include methodology for joint analysis, correlating our measurements with phenotypic and transcriptomic data.

* To characterize the distribution of rare and common functional sequence and copy number variants across European populations and its implications for the design of next-generation genome-wide genotyping and medical resequecing studies

* To quantify the strength of natural selection operating on different categories of genetic variants in the exome+ (i.e., non-synonymous changes, short indels, regulatory elements) and to predict the functional (i.e., benign, possibly damaging, probably damaging) and evolutionary importance (i.e., neutral, negatively selected, positively selected) of all genetic variants found by the project.