NIAID genomics programs and global health

12(Suppl 1):I18 Deep exome resequencing is a powerful approach for delineating patterns of protein-coding variation among genes, pathways, individuals and populations.We analyzed exome data from 2,440 individuals of European and African ancestry as part of the National Heart, Lung, and Blood Institute's Exome Project, the aim of which is to discover novel genes and mechanisms that contribute to heart, lung and blood disorders.Each exome was sequenced to a mean coverage of 116×, allowing detailed inferences about the population genomic patterns of both common variation and rare coding variation.We identifi ed more than 500,000 single nucleotide variations, the majority of which were novel and rare (76% of variants had a minor allele frequency of less than 0.1%), refl ecting the recent dramatic increase in the size of the human population.The unprecedented magnitude of this dataset allowed us to rigorously characterize the large variation in nucleotide diversity among genes (ranging from 0 to 1.32%), as well as the role of positive and purifying selection in shaping patterns of proteincoding variation and the diff erential signatures of population structure from rare and common variation.This dataset provides a framework for personal genomics and is an important resource that will allow inferences of broad importance to human evolution and health. I2 Characterizing triple-negative breast cancer tumorsSam Aparicio BC Cancer Agency, Vancouver, BC, Canada Genome Biology 2011, 12(Suppl 1):I9 Primary triple-negative breast cancers represent approximately 16% of all breast cancers and, based on expression profi ling, are a heterogeneous tumor type.We present an integrated analysis of somatic aberrations (nonsynonymous coding mutations, copy number aberrations, fusions and translocations) in 104 of these cancers, using multiple views of the genome and transcriptome.We show that the basal subtype of triple-negative breast cancer contains more somatic aberrations of all types than the nonbasal subtype, as well as enrichment for mutations in certain pathways; some pathways exhibit an unprecedented somatic mutation enrichment pattern for low-frequency, single gene mutations, but in many related gene family members.We found that triple-negative breast cancers of both subtypes are heterogeneous at the time of diagnosis, with a wide variation in the content and type of somatic aberration among tumors.However, individual tumors can be grouped by the degree and extent of somatic aberration in ten distinct pathways, suggesting a future route for genomic phenotyping of these cancers. I3Are clinical genomes already becoming semi-routine for patient care?