A survey of allelic imbalance in F1 mice

Campbell, Catarina D.; Kirby, Andrew; Nemesh, James; Daly, Mark J.; Hirschhorn, Joel N.

doi:10.1101/gr.068692.107

Cited by 28 publications

(40 citation statements)

References 32 publications

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“…Tissue specificity of allelic expression was recently highlighted in mice (Campbell et al 2008). Our AE screening data in LCLs and primary osteoblasts also implies that even for genes expressed in both tissues the same haplotypes (the osteoblast cohort is of Northern European origin similar to the origin of CEU LCLs) may exert different effects in ∼50% of cases.…”

Section: Genome Research 123supporting

confidence: 51%

Targeted screening of cis-regulatory variation in human haplotypes

Verlaan¹,

Ge²,

Grundberg³

et al. 2008

Genome Res.

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Regulatory cis-acting variants account for a large proportion of gene expression variability in populations. Cis-acting differences can be specifically measured by comparing relative levels of allelic transcripts within a sample. Allelic expression (AE) mapping for cis-regulatory variant discovery has been hindered by the requirements of having informative or heterozygous single nucleotide polymorphisms (SNPs) within genes in order to assign the allelic origin of each transcript. In this study we have developed an approach to systematically screen for heritable cis-variants in common human haplotypes across >1000 genes. In order to achieve the highest level of information per haplotype studied, we carried out allelic expression measurements by using both intronic and exonic SNPs in primary transcripts. We used a novel RNA pooling strategy in immortalized lymphoblastoid cell lines (LCLs) and primary human osteoblast cell lines (HObs) to allow for high-throughput AE. Screening hits from RNA pools were further validated by performing allelic expression mapping in individual samples. Our results indicate that >10% of expressed genes in human LCLs show genotype-linked AE. In addition, we have validated cis-acting variants in over 20 genes linked with common disease susceptibility in recent genome-wide studies. More generally, our results indicate that RNA pooling coupled with AE read-out by second generation sequencing or by other methods provides a high-throughput tool for cataloging the impact of common noncoding variants in the human genome.

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Section: Genome Research 123supporting

confidence: 51%

Targeted screening of cis-regulatory variation in human haplotypes

Verlaan¹,

Ge²,

Grundberg³

et al. 2008

Genome Res.

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“…The influence of genetic variation on phenotype is condition-dependent and is influenced both by external (18) and internal factors such as tissue type. For example, alleles of IRGM, that confer risk and protection for Crohn's disease, show different patterns of tissue-specific expression (19) and allelic imbalances that confer tissue specificity are likely to be common (20). Moreover, there are a number of ''hotspot'' genes associated to a broad range of diseases including MHC and ApoE.…”

Section: Discussionmentioning

confidence: 99%

Modularity and interactions in the genetics of gene expression

Litvin

Causton

Chen

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Understanding the effect of genetic sequence variation on phenotype is a major challenge that lies at the heart of genetics. We developed GOLPH (GenOmic Linkage to PHenotype), a statistical method to identify genetic interactions, and used it to characterize the landscape of genetic interactions between gene expression quantitative trait loci. Our results reveal that allele-specific interactions, in which a gene only exerts an influence on the phenotype in the presence of a particular allele at the primary locus, are widespread and that genetic interactions are predominantly nonadditive. The data portray a complex picture in which interacting loci influence the expression of modules of coexpressed genes involved in coherent biological processes and pathways. We show that genetic variation at a single gene can have a major impact on the global transcriptional response, altering interactions between genes through shutdown or activation of pathways. Thus, different cellular states occur not only in response to the external environment but also result from intrinsic genetic variation.computational biology ͉ gene regulation ͉ molecular networks ͉ systems biology U nderstanding the effect of genetic sequence variation on phenotype is a major challenge that lies at the heart of genetics. Recent technological advances in genotyping have now made it possible to obtain a comprehensive view of genomewide variation in a large number of individuals. However, association studies involving tens of thousands of individuals (1) have, for the most part, only been able to detect loci that collectively account for 3% of the heritable phenotype. This finding suggests that the connection between genotype and phenotype is more complex than previously assumed and that more sophisticated approaches are needed to interpret the data.Quantitative trait mapping of gene expression abundances [expression quantitative trait locus (eQTL)] has proved a powerful model system for studying genetic traits in a number of organisms (2-5). To study gene-gene interactions between QTL, we use gene expression and genotype data on segregants generated in a cross between a laboratory strain (BY) and a wild strain (RM) of Saccharomyces cerevisiae (6, 7). We developed GOLPH (GenOmic Linkage to PHenotype), a statistical algorithm to identify multiple genetic factors influencing gene expression abundance. Our premise is that the modular organization of gene regulation can be used to enhance the statistical power of linkage to eQTLs.GOLPH identifies an unprecedented number of linked regions for each gene. We used GENATOMY, our custom-built analysis tool, to visualize and analyze the resulting genetic interactions between QTL. Our results portray a complex picture in which multiple interacting loci influence the expression of modules of coexpressed genes that define coherent biological processes. The data show that genetic polymorphism can give rise to distinct cellular states in which entire metabolic pathways and biological processes are activated to different ...

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“…While cis-regulatory variation is substantial in natural populations (Osada et al 2006;Campbell et al 2008;Genissel et al 2008;Gruber and Long 2009;Lemmon et al 2014), trans-acting variation contributes more to polymorphic expression variation within species (Lemos et al 2008;Wittkopp et al 2008;Coolon et al 2014). M. m. domesticus and M. m. musculus diverged roughly 350,000 years ago and still share some ancestral variation.…”

Section: Discussionmentioning

confidence: 99%

Gene regulation and speciation in house mice

2016

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One approach to understanding the process of speciation is to characterize the genetic architecture of post-zygotic isolation. As gene regulation requires interactions between loci, negative epistatic interactions between divergent regulatory elements might underlie hybrid incompatibilities and contribute to reproductive isolation. Here, we take advantage of a cross between house mouse subspecies, where hybrid dysfunction is largely unidirectional, to test several key predictions about regulatory divergence and reproductive isolation. Regulatory divergence between Mus musculus musculus and M. m. domesticus was characterized by studying allele-specific expression in fertile hybrid males using mRNA-sequencing of whole testes. We found extensive regulatory divergence between M. m. musculus and M. m. domesticus, largely attributable to cis-regulatory changes. When both cis and trans changes occurred, they were observed in opposition much more often than expected under a neutral model, providing strong evidence of widespread compensatory evolution. We also found evidence for lineage-specific positive selection on a subset of genes related to transcriptional regulation. Comparisons of fertile and sterile hybrid males identified a set of genes that were uniquely misexpressed in sterile individuals. Lastly, we discovered a nonrandom association between these genes and genes showing evidence of compensatory evolution, consistent with the idea that regulatory interactions might contribute to Dobzhansky-Muller incompatibilities and be important in speciation.

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A survey of allelic imbalance in F1 mice

Cited by 28 publications

References 32 publications

Targeted screening of cis-regulatory variation in human haplotypes

Targeted screening of cis-regulatory variation in human haplotypes

Modularity and interactions in the genetics of gene expression

Gene regulation and speciation in house mice

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