title: Transcriptome and genome sequencing uncovers functional variation in humans.
abstract: Genome sequencing projects are discovering millions of genetic variants in humans, and interpretation of their functional effects is essential for understanding the genetic basis of variation in human traits. Here we report sequencing and deep analysis of messenger RNA and microRNA from lymphoblastoid cell lines of 462 individuals from the 1000 Genomes Project--the first uniformly processed high-throughput RNA-sequencing data from multiple human populations with high-quality genome sequences. We discover extremely widespread genetic variation affecting the regulation of most genes, with transcript structure and expression level variation being equally common but genetically largely independent. Our characterization of causal regulatory variation sheds light on the cellular mechanisms of regulatory and loss-of-function variation, and allows us to infer putative causal variants for dozens of disease-associated loci. Altogether, this study provides a deep understanding of the cellular mechanisms of transcriptome variation and of the landscape of functional variants in the human genome.
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva Medical School, 1211 Geneva, Switzerland. tuuli.e.lappalainen@gmail.com
authors.forename: Tuuli
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authors.lastname: Lappalainen
authors.forename: Michael
authors.initials: M
authors.lastname: Sammeth
authors.forename: Marc R
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authors.lastname: Friedländer
authors.forename: Peter A C
authors.initials: PA
authors.lastname: 't Hoen
authors.forename: Jean
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authors.lastname: Monlong
authors.forename: Manuel A
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authors.lastname: Rivas
authors.forename: Mar
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authors.forename: Natalja
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authors.lastname: Kurbatova
authors.forename: Thasso
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authors.forename: Matthias
authors.initials: M
authors.lastname: Barann
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authors.forename: Liliana
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authors.forename: Maarten
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authors.lastname: van Iterson
authors.forename: Jonas
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authors.lastname: Almlöf
authors.forename: Paolo
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authors.lastname: Ribeca
authors.forename: Irina
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authors.lastname: Pulyakhina
authors.forename: Daniela
authors.initials: D
authors.lastname: Esser
authors.forename: Thomas
authors.initials: T
authors.lastname: Giger
authors.forename: Andrew
authors.initials: A
authors.lastname: Tikhonov
authors.forename: Marc
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authors.lastname: Sultan
authors.forename: Gabrielle
authors.initials: G
authors.lastname: Bertier
authors.forename: Daniel G
authors.initials: DG
authors.lastname: MacArthur
authors.forename: Monkol
authors.initials: M
authors.lastname: Lek
authors.forename: Esther
authors.initials: E
authors.lastname: Lizano
authors.forename: Henk P J
authors.initials: HP
authors.lastname: Buermans
authors.forename: Ismael
authors.initials: I
authors.lastname: Padioleau
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzmayr
authors.forename: Olof
authors.initials: O
authors.lastname: Karlberg
authors.forename: Halit
authors.initials: H
authors.lastname: Ongen
authors.forename: Helena
authors.initials: H
authors.lastname: Kilpinen
authors.forename: Sergi
authors.initials: S
authors.lastname: Beltran
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.forename: Katja
authors.initials: K
authors.lastname: Kahlem
authors.forename: Vyacheslav
authors.initials: V
authors.lastname: Amstislavskiy
authors.forename: Oliver
authors.initials: O
authors.lastname: Stegle
authors.forename: Matti
authors.initials: M
authors.lastname: Pirinen
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.forename: Peter
authors.initials: P
authors.lastname: Donnelly
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Paul
authors.initials: P
authors.lastname: Flicek
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.forename: Hans
authors.initials: H
authors.lastname: Lehrach
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Ralf
authors.initials: R
authors.lastname: Sudbrak
authors.forename: Angel
authors.initials: A
authors.lastname: Carracedo
authors.forename: Stylianos E
authors.initials: SE
authors.lastname: Antonarakis
authors.forename: Robert
authors.initials: R
authors.lastname: Häsler
authors.forename: Ann-Christine
authors.initials: AC
authors.lastname: Syvänen
authors.forename: Gert-Jan
authors.initials: GJ
authors.lastname: van Ommen
authors.forename: Alvis
authors.initials: A
authors.lastname: Brazma
authors.forename: Thomas
authors.initials: T
authors.lastname: Meitinger
authors.forename: Philip
authors.initials: P
authors.lastname: Rosenstiel
authors.forename: Roderic
authors.initials: R
authors.lastname: Guigó
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.forename: Xavier
authors.initials: X
authors.lastname: Estivill
authors.forename: Emmanouil T
authors.initials: ET
authors.lastname: Dermitzakis
mesh_terms: D000483:Alleles; D002461:Cell Line, Transformed; D005091:Exons / Q000235:genetics; D020869:Gene Expression Profiling; D014644:Genetic Variation / Q000235:genetics*; D015894:Genome, Human / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D040641:Quantitative Trait Loci / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D017423:Sequence Analysis, RNA; D059467:Transcriptome / Q000235:genetics*
chemical_list: D012333:RNA, Messenger
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