Modifier Effects between Regulatory and Protein-Coding Variation

Genome-wide associations have shown a lot of promise in dissecting the genetics of complex traits in humans with single variants, yet a large fraction of the genetic effects is still unaccounted for. Analyzing genetic interactions between variants (epistasis) is one of the potential ways forward. We investigated the abundance and functional impact of a specific type of epistasis, namely the interaction between regulatory and protein-coding variants. Using genotype and gene expression data from the 210 unrelated individuals of the original four HapMap populations, we have explored the combined effects of regulatory and protein-coding single nucleotide polymorphisms (SNPs). We predict that about 18% (1,502 out of 8,233 nsSNPs) of protein-coding variants are differentially expressed among individuals and demonstrate that regulatory variants can modify the functional effect of a coding variant in cis. Furthermore, we show that such interactions in cis can affect the expression of downstream targets of the gene containing the protein-coding SNP. In this way, a cis interaction between regulatory and protein-coding variants has a trans impact on gene expression. Given the abundance of both types of variants in human populations, we propose that joint consideration of regulatory and protein-coding variants may reveal additional genetic effects underlying complex traits and disease and may shed light on causes of differential penetrance of known disease variants.

[1]  K. Broman,et al.  High-Resolution Quantitative Trait Locus Mapping Reveals Sign Epistasis Controlling Ovariole Number Between Two Drosophila Species , 2006, Genetics.

[2]  L. Liang,et al.  A genome-wide association study of global gene expression , 2007, Nature Genetics.

[3]  R. Redon,et al.  Relative Impact of Nucleotide and Copy Number Variation on Gene Expression Phenotypes , 2007, Science.

[4]  P. Donnelly,et al.  Genome-wide strategies for detecting multiple loci that influence complex diseases , 2005, Nature Genetics.

[5]  John D. Storey,et al.  Genetic interactions between polymorphisms that affect gene expression in yeast , 2005, Nature.

[6]  David M. Evans,et al.  Two-Stage Two-Locus Models in Genome-Wide Association , 2006, PLoS genetics.

[7]  Lon R. Cardon,et al.  Functional epistasis on a common MHC haplotype associated with multiple sclerosis , 2006, Nature.

[8]  Joshua T. Burdick,et al.  Common genetic variants account for differences in gene expression among ethnic groups , 2007, Nature Genetics.

[9]  R. Nagel,et al.  Epistasis and the genetics of human diseases. , 2005, Comptes rendus biologies.

[10]  C. Laurie,et al.  Associations between DNA sequence variation and variation in expression of the Adh gene in natural populations of Drosophila melanogaster. , 1991, Genetics.

[11]  Trudy F C Mackay,et al.  Dynamic Genetic Interactions Determine Odor-Guided Behavior in Drosophila melanogaster , 2006, Genetics.

[12]  William Stafford Noble,et al.  Identification and analysis of functional elements in 1% of the human genome by the ENCODE pilot project , 2007, Nature.

[13]  S. Hunt,et al.  Genome-Wide Associations of Gene Expression Variation in Humans , 2005, PLoS genetics.

[14]  L. Almasy,et al.  Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes , 2007, Nature Genetics.

[15]  Gil McVean,et al.  Perspectives on Human Genetic Variation from the HapMap Project , 2005, PLoS genetics.

[16]  M. Olivier A haplotype map of the human genome , 2003, Nature.

[17]  L. Kruglyak,et al.  Genetic Dissection of Transcriptional Regulation in Budding Yeast , 2002, Science.

[18]  Zhaohui S. Qin,et al.  A second generation human haplotype map of over 3.1 million SNPs , 2007, Nature.

[19]  Terence P. Speed,et al.  A comparison of normalization methods for high density oligonucleotide array data based on variance and bias , 2003, Bioinform..

[20]  Philippe Rigault,et al.  A novel, high-performance random array platform for quantitative gene expression profiling. , 2004, Genome research.

[21]  C. Laurie,et al.  Molecular dissection of a major gene effect on a quantitative trait: the level of alcohol dehydrogenase expression in Drosophila melanogaster. , 1996, Genetics.

[22]  Albert-László Barabási,et al.  Genetic Dissection of Transcriptional Regulation in Budding Yeast , 2002 .

[23]  R. Doolittle,et al.  A simple method for displaying the hydropathic character of a protein. , 1982, Journal of molecular biology.

[24]  E. Birney,et al.  Pfam: the protein families database , 2013, Nucleic Acids Res..

[25]  D. Allison,et al.  Detection of gene x gene interactions in genome-wide association studies of human population data. , 2007, Human heredity.

[26]  C. Molony,et al.  Genetic analysis of genome-wide variation in human gene expression , 2004, Nature.

[27]  L. Holm,et al.  The Pfam protein families database , 2005, Nucleic Acids Res..

[28]  Thomas J. Hudson,et al.  Cis-Acting Regulatory Variation in the Human Genome , 2004, Science.

[29]  Simon Tavaré,et al.  beadarray: R classes and methods for Illumina bead-based data , 2007, Bioinform..

[30]  V. McKusick Mendelian inheritance in man , 1971 .

[31]  B. Wirth,et al.  Plastin 3 Is a Protective Modifier of Autosomal Recessive Spinal Muscular Atrophy , 2008, Science.

[32]  M. Olivier A haplotype map of the human genome. , 2003, Nature.

[33]  Stephen L. Hauser,et al.  The genetics of multiple sclerosis: SNPs to pathways to pathogenesis , 2008, Nature Reviews Genetics.

[34]  G. Gibson,et al.  Genetic Variation for Cardiac Dysfunction in Drosophila , 2007, PloS one.

[35]  F. Ayala,et al.  Evolution of cis-regulatory regions versus codifying regions. , 2003, The International journal of developmental biology.

[36]  T. Hudson,et al.  Influence of human genome polymorphism on gene expression. , 2006, Human molecular genetics.

[37]  D. Kwiatkowski,et al.  Localization of a long-range cis-regulatory element of IL13 by allelic transcript ratio mapping. , 2006, Genome research.