Genetics of gene expression surveyed in maize, mouse and man

Schadt, Eric E.; Monks, Stephanie A.; Drake, Thomas A.; Lusis, Aldons J.; Che, Nam; Colinayo, Veronica; Ruff, Thomas G.; Milligan, Stephen B.; Lamb, John; Cavet, Guy; Linsley, Peter S.; Mao, Mao; Stoughton, Roland; Friend, Stephen H.

doi:10.1038/nature01434

Cited by 1,372 publications

(1,307 citation statements)

References 23 publications

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“…If the expression of Kras2 was solely under the control of trans-acting factors (trans-QTL) 26,27 at different genomic locations, this would not be compatible with the model proposed. To examine these alternative possibilities, we generated an additional independent population of untreated, wild-type (FVBSPRETF1)FVB backcross mice, and measured the expression levels of Kras2 in the normal lungs of a total of 47 animals.…”

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confidence: 88%

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

Pérez-Losada

Mao

et al. 2006

Nat Genet

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Pulmonary adenoma susceptibility 1 (Pas1) is the major mouse lung cancer susceptibility locus on chromosome 6 (ref. 1), spanning a region containing six genes 2 , one of which is Kras2. Kras2 is a common target of somatic mutation in chemically induced mouse lung tumors 3,4 , and is a candidate Pas1 gene 5 . M. spretus mice (SPRET) carry a Pas1 resistance haplotype for chemically induced lung tumors 6 . We demonstrate here that the SPRET/Ei Pas1 allele is switched from resistance to susceptibility by fixation of the parental origin of the mutant Kras2 allele in Kras2 LA2 mice. This switch correlates with low expression of endogenous Kras2 in SPRET/Ei. We propose that the Pas1 modifier effect is due to Kras2, and that a sensitive balance between the expression levels of wild-type and mutant alleles determines lung tumor susceptibility. These data demonstrate that cancer predisposition should also be considered in the context of somatic events, and could have major implications for the design of human association studies to identify cancer susceptibility genes. KeywordsLung Cancer; Pas-1; Susceptibility; Kras2The critical Pas1 interval encompasses Bcat1, Lrmp, Las1, Ghiso, Kras2,. Of these, only Kras2 is a known target of mutation in lung tumors 3,4 , and mice expressing oncogenic Kras2 have a high incidence of early onset lung cancer 7,8 . Lung tumors from F1-hybrid mice showed a strong bias for Kras2 mutation involving the allele inherited from the more susceptible parent 9 , rendering Kras2 a candidate for Pas1. However, no coding sequence differences in Kras2 have been detected among all mouse strains studied, and the possible mechanisms by which Kras2 may contribute to the effect of Pas1 remain unclear, causing some investigators to focus on other genes in the Pas1 region COMPETING INTERESTS STATEMENTThe authors declare that they have no competing financial interests. hybrids generated between Kras2 LA2 FVB/N and SPRET/Ei had relatively low tumor incidence and number at 6 months ( Fig. 1a), and some animals survived well over one year without becoming moribund. HHS Public AccessWe mated female FVBSPRETF1 hybrids with male Kras2 LA2 FVB/N mice to generate a large population of interspecific backcross mice. A total of 224 (FVBSPRETF1)FVBKras2 LA2 backcross mice were aged to 6 months, and sacrificed for assessment of tumor number. The distribution of tumor number was very wide (Fig. 1a), in agreement with the observation that there are many lung tumor susceptibility/resistance loci 15,16 . These animals were genotyped using markers on chromosome 6 to test for linkage to Pas1. We initially envisaged two possible outcomes: (i) If Kras2 is the Pas1 gene, there should be no linkage to the region, as every mouse carries the same parental mutant allele. This would be compatible with a mechanism in which selection for a more highly active or highly expressed Kras2 mutant allele in chemical carcinogenesis studies accounts completely for the effect of Pas1 (ref. 9). (ii) IfPas1 is a different gene(s) in the regi...

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confidence: 88%

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

Pérez-Losada

Mao

et al. 2006

Nat Genet

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“…Gene expression profiling can be combined with QTL mapping (genetical genomics) and the usefulness of the approach has been demonstrated in mice (Schadt et al, 2003).…”

Section: Functional Genomics: Transcriptomicsmentioning

confidence: 99%

Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities

Beerda

Wyszyńska-Koko

Pas

et al. 2008

Animal

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Subfertility has negative effects for dairy farm profitability, animal welfare and sustainability of animal production. Increasing herd sizes and economic pressures restrict the amount of time that farmers can spend on counteractive management. Genetic improvement will become increasingly important to restore reproductive performance. Complementary to traditional breeding value estimation procedures, genomic selection based on genome-wide information will become more widely applied. Functional genomics, including transcriptomics (gene expression profiling), produces the information to understand the consequences of selection as it helps to unravel physiological mechanisms underlying female fertility traits. Insight into the latter is needed to develop new effective management strategies to combat subfertility. Here, the importance of functional genomics for dairy cow reproduction so far and in the near future is evaluated. Recent gene profiling studies in the field of dairy cow fertility are reviewed and new data are presented on genes that are expressed in the brains of dairy cows and that are involved in dairy cow oestrus (behaviour). Fast-developing new research areas in the field of functional genomics, such as epigenetics, RNA interference, variable copy numbers and nutrigenomics, are discussed including their promising future value for dairy cow fertility.

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“…11 Gene expression levels are known to be heritable. [12][13][14] Genetic variants correlated with nearby transcript levels are defined as cis-expression quantitative trait loci (cis-eQTL). Indeed, GWASascertained phenotype-associated single-nucleotide polymorphisms (SNPs) are enriched in cis-eQTLs.…”

Section: Introductionmentioning

confidence: 99%

Variants at IRX4 as prostate cancer expression quantitative trait loci

Hussain

Vijai

et al. 2013

Eur J Hum Genet

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Genome-wide association studies (GWAS) have identified numerous prostate cancer-associated risk loci. Some variants at these loci may be regulatory and influence expression of nearby genes. Such loci are known as cis-expression quantitative trait loci (cis-eQTL). As cis-eQTLs are highly tissue-specific, we asked if GWAS-identified prostate cancer risk loci are cis-eQTLs in human prostate tumor tissues. We investigated 50 prostate cancer samples for their genotype at 59 prostate cancer riskassociated single-nucleotide polymorphisms (SNPs) and performed cis-eQTL analysis of transcripts from paired primary tumors within two megabase windows. We tested 586 transcript-genotype associations, of which 27 were significant (false discovery rate r10%). An equivalent eQTL analysis of the same prostate cancer risk loci in lymphoblastoid cell lines did not result in any significant associations. The top-ranked cis-eQTL involved the IRX4 (Iroquois homeobox protein 4) transcript and rs12653946, tagged by rs10866528 in our study (P ¼ 4.91 Â 10 À5 ). Replication studies, linkage disequilibrium, and imputation analyses highlight population specificity at this locus. We independently validated IRX4 as a potential prostate cancer risk gene through cis-eQTL analysis of prostate cancer risk variants. Cis-eQTL analysis in relevant tissues, even with a small sample size, can be a powerful method to expedite functional follow-up of GWAS.

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Genetics of gene expression surveyed in maize, mouse and man

Cited by 1,372 publications

References 23 publications

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

A functional switch from lung cancer resistance to susceptibility at the Pas1 locus in Kras2LA2 mice

Expression profiles of genes regulating dairy cow fertility: recent findings, ongoing activities and future possibilities

Variants at IRX4 as prostate cancer expression quantitative trait loci

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