title: Transcriptome genetics using second generation sequencing in a Caucasian population.
abstract: Gene expression is an important phenotype that informs about genetic and environmental effects on cellular state. Many studies have previously identified genetic variants for gene expression phenotypes using custom and commercially available microarrays. Second generation sequencing technologies are now providing unprecedented access to the fine structure of the transcriptome. We have sequenced the mRNA fraction of the transcriptome in 60 extended HapMap individuals of European descent and have combined these data with genetic variants from the HapMap3 project. We have quantified exon abundance based on read depth and have also developed methods to quantify whole transcript abundance. We have found that approximately 10 million reads of sequencing can provide access to the same dynamic range as arrays with better quantification of alternative and highly abundant transcripts. Correlation with SNPs (small nucleotide polymorphisms) leads to a larger discovery of eQTLs (expression quantitative trait loci) than with arrays. We also detect a substantial number of variants that influence the structure of mature transcripts indicating variants responsible for alternative splicing. Finally, measures of allele-specific expression allowed the identification of rare eQTLs and allelic differences in transcript structure. This analysis shows that high throughput sequencing technologies reveal new properties of genetic effects on the transcriptome and allow the exploration of genetic effects in cellular processes.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, 1211 Switzerland. stephen.montgomery@unige.ch
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.forename: Micha
authors.initials: M
authors.lastname: Sammeth
authors.forename: Maria
authors.initials: M
authors.lastname: Gutierrez-Arcelus
authors.forename: Radoslaw P
authors.initials: RP
authors.lastname: Lach
authors.forename: Catherine
authors.initials: C
authors.lastname: Ingle
authors.forename: James
authors.initials: J
authors.lastname: Nisbett
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigo
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
mesh_terms: D000483:Alleles; D017398:Alternative Splicing / Q000235:genetics; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods*; D006239:Haplotypes / Q000235:genetics; D006720:Homozygote; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis* / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D044465:White People / Q000235:genetics*
chemical_list: D012333:RNA, Messenger