title: Transcriptome sequencing from diverse human populations reveals differentiated regulatory architecture.
abstract: Large-scale sequencing efforts have documented extensive genetic variation within the human genome. However, our understanding of the origins, global distribution, and functional consequences of this variation is far from complete. While regulatory variation influencing gene expression has been studied within a handful of populations, the breadth of transcriptome differences across diverse human populations has not been systematically analyzed. To better understand the spectrum of gene expression variation, alternative splicing, and the population genetics of regulatory variation in humans, we have sequenced the genomes, exomes, and transcriptomes of EBV transformed lymphoblastoid cell lines derived from 45 individuals in the Human Genome Diversity Panel (HGDP). The populations sampled span the geographic breadth of human migration history and include Namibian San, Mbuti Pygmies of the Democratic Republic of Congo, Algerian Mozabites, Pathan of Pakistan, Cambodians of East Asia, Yakut of Siberia, and Mayans of Mexico. We discover that approximately 25.0% of the variation in gene expression found amongst individuals can be attributed to population differences. However, we find few genes that are systematically differentially expressed among populations. Of this population-specific variation, 75.5% is due to expression rather than splicing variability, and we find few genes with strong evidence for differential splicing across populations. Allelic expression analyses indicate that previously mapped common regulatory variants identified in eight populations from the International Haplotype Map Phase 3 project have similar effects in our seven sampled HGDP populations, suggesting that the cellular effects of common variants are shared across diverse populations. Together, these results provide a resource for studies analyzing functional differences across populations by estimating the degree of shared gene expression, alternative splicing, and regulatory genetics across populations from the broadest points of human migration history yet sampled.
authors.affiliation: Stanford University School of Medicine, Department of Genetics, Stanford, California, United States of America.
authors.forename: Alicia R
authors.initials: AR
authors.lastname: Martin
authors.affiliation: Stanford University School of Medicine, Department of Genetics, Stanford, California, United States of America.
authors.forename: Helio A
authors.initials: HA
authors.lastname: Costa
authors.affiliation: Stanford University School of Medicine, Department of Genetics, Stanford, California, United States of America.
authors.forename: Tuuli
authors.initials: T
authors.lastname: Lappalainen
authors.affiliation: Stony Brook University, SUNY, Department of Ecology and Evolution, Stony Brook, New York, United States of America.
authors.forename: Brenna M
authors.initials: BM
authors.lastname: Henn
authors.affiliation: University of Michigan School of Medicine, Department of Human Genetics, Ann Arbor, Michigan, United States of America.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Kidd
authors.affiliation: Stanford University School of Medicine, Department of Genetics, Stanford, California, United States of America.
authors.forename: Muh-Ching
authors.initials: MC
authors.lastname: Yee
authors.affiliation: Stanford University School of Medicine, Department of Genetics, Stanford, California, United States of America.
authors.forename: Fabian
authors.initials: F
authors.lastname: Grubert
authors.affiliation: Foundation Jean Dausset, Centre d'Etude du Polymorphisme Humain, Paris, France.
authors.forename: Howard M
authors.initials: HM
authors.lastname: Cann
authors.affiliation: Stanford University School of Medicine, Department of Genetics, Stanford, California, United States of America.
authors.forename: Michael
authors.initials: M
authors.lastname: Snyder
authors.affiliation: Stanford University School of Medicine, Department of Genetics, Stanford, California, United States of America; Stanford University School of Medicine, Department of Pathology, Stanford, California, United States of America.
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Montgomery
authors.affiliation: Stanford University School of Medicine, Department of Genetics, Stanford, California, United States of America.
authors.forename: Carlos D
authors.initials: CD
authors.lastname: Bustamante
mesh_terms: D020869:Gene Expression Profiling; D053263:Gene Regulatory Networks; D005828:Genetics, Population; D015894:Genome, Human; D060148:HapMap Project; D006239:Haplotypes / Q000235:genetics*; D016045:Human Genome Project; D063426:Human Migration; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci / Q000235:genetics