复杂性状遗传CC小鼠——肿瘤研究新平台
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摘要
癌症是由于机体细胞失去正常调控过度增殖而引发的一系列复杂性状疾病的统称,其本质上是一种基因疾病。用于传统肿瘤小鼠模型的重组近交(RI)品系由于只起源于两个近交祖系,因此规模小且等位基因多样性较少,在统计功效上存在局限性。复杂性状遗传(Collaborative Cross mice,CC)小鼠是由来自八个原始种系近交产生的数百种基因型不同的小鼠品系,能够体现不同小鼠亚种的遗传学变异,具有高遗传多样性,大种群规模等重要特征。它可以模拟人类复杂性状疾病中不同人群对病因或治疗方法个体易感性的差异,为促进复杂性状疾病易感基因筛查、基因功能发现等方面的研究提供了一个更好的研究工具与信息平台。本文就CC小鼠在医学应用中的研究现状、挑战性与局限性、以及其在肿瘤研究中的应用前景进行综述。
Cancer is a general term of a series of complex traits of the disease triggered by the body cells losing their normal regulation of excessive proliferation,which essentially is a genetic disease. Recombinant inbred strain( RI)mouse generated from one pair of founders has been widely used in traditional tumor model. However,RI has many limitations on the statistic efficiency because of the small scale and lacking of allele diversity. The Collaborative Cross( CC) was designed to generate hundreds of recombinant inbred lines by 8 divergent strains of mice. CC mice embody a tremendous amount of natural genetic variation in different sub-strains of mouse and the single nucleotide polymorphism is four times of the traditional experimental mice. The high-genetic diversity and large scale population enables CC mice simulates the differences of individual susceptibility to the pathogeny or the therapies,thus provides a better research tool and information platform for expediting discovery of genes and genes function in human complex traits diseases. This review summarizes our current knowledge of this field,including methodologic aspects,applications,challenges and limitations,and utilization for cancer research.
Cancer is a general term of a series of complex traits of the disease triggered by the body cells losing their normal regulation of excessive proliferation,which essentially is a genetic disease. Recombinant inbred strain( RI)mouse generated from one pair of founders has been widely used in traditional tumor model. However,RI has many limitations on the statistic efficiency because of the small scale and lacking of allele diversity. The Collaborative Cross( CC) was designed to generate hundreds of recombinant inbred lines by 8 divergent strains of mice. CC mice embody a tremendous amount of natural genetic variation in different sub-strains of mouse and the single nucleotide polymorphism is four times of the traditional experimental mice. The high-genetic diversity and large scale population enables CC mice simulates the differences of individual susceptibility to the pathogeny or the therapies,thus provides a better research tool and information platform for expediting discovery of genes and genes function in human complex traits diseases. This review summarizes our current knowledge of this field,including methodologic aspects,applications,challenges and limitations,and utilization for cancer research.
引文
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[22]Rogala AR,Morgan AP,Christensen AM,et al.The collaborative Cross as a resource for modeling human disease:CC011/Unc,a new mouse model for spontaneous colitis[J].Mamm Genome,2014,25(3-4):95-108.
[23]Weerasekera LY,Balmer LA,Ram R,et al.Characterization of retinal vascular and neural damage in a novel model of diabetic retinopathy[J].Invest Ophthalmol Vis Sci,2015,56(6):3721-3730.
[24]Rasmussen AL,Okumura A,Ferris MT,et al.Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance[J].Science,2014,346(6212):987-991.
[25]Ferris MT,Aylor DL,Bottomly D,et al.Modeling host genetic regulation of influenza pathogenesis in the collaborative cross[J].PLo S Pathog,2013,9(2):e1003196.
[26]Leist SR,Pilzner C,van den Brand JM,et al.Influenza H3N2infection of the collaborative cross founder strains reveals highly divergent host responses and identifies unique phenotype in CAST/Ei J mice[J].BMC Genomics,2016,17(1):143.
[27]Xiong H,Morrison J,Ferris MT,et al.Genomic profiling of collaborative cross founder mice infected with respiratory viruses reveals novel transcripts and infection-specific gene and isoform expression[J].G3(Bethesda).2014,4(8):1429-1444.
[28]Durrant C,Tayem H,Yalcin B,et al.Collaborative Cross mice and their power to map host susceptibility to Aspergillus fumigatus infection[J].Genome Res,2011,21(8):1239-1248.
[29]Vered K,Durrant C,Mott R,et al.Susceptibility to Klebsiella Pneumonaie infection in collaborative cross mice is a complex trait controlled by at least three loci acting at different time points[J].BMC Genomics,2014,15:865.
[30]Ferguson B,Ram R,Handoko HY,et al.Melanoma susceptibility as a complex trait:genetic variation controls all stages of tumor progression[J].Oncogene,2015,34(22):2879–2886.
[31]Schmidt CW.Diversity outbred:a new generation of mouse model[J].Environ Health Perspect,2015,123(3):A64-67.
[32]Flint J,Mott R.Applying mouse complex-trait resources to behavioural genetics[J].Nature,2008,456(7223):724-727.
[2]World Health Organization(WHO).World Cancer Report 2014.Chapter 1.1[M].ISBN 9283204298.
[3]Siegel R,Miller KD,Jemal A.Cancer statistics,2015[J].CA Cancer J Clin,2015,65,5-29.
[4]Manton KG,Akushevich I,Kravchenko J.Cancer mortality and morbidity patterns in the US population:An interdisciplinary approach[M].Springer Science&Business Media.2008.89-140.
[5]Anand P,Kunnumakara AB,Sundaram C,et al.Cancer is a preventable disease that requires major lifestyle changes[J].Pharm Res,2008,25(9):2097-2116.
[6]Threadgill D,Churchill G.Ten Years of the Collaborative Cross[J].Genetics,2012,2(2):153-156.
[7]Chesler EJ,Miller DR,Branstetter LR,et al.The Collaborative Cross at Oak Ridge National Laboratory:developing a powerful resource for systems genetics[J].Mamm Genome,2008,19(6):382-389.
[8]Churchill G,Airey D,Allayee H,et al.The Collaborative Cross,a community resource for the genetic analysis of complex traits[J].Nat Genet,2004,36(11):1133-1137.
[9]Broman KW.The genomes of recombinant inbred lines[J].Genetics,2005,169(2):1133-1146.
[10]Roberts A,Pardo-Manul de-Villena F,Wang W,et al.The polymorphism architecture of mouse genetic resources elucidated using genome-wide resequencing data:implications for QTL discovery and systems genetics[J].Mamm Genome,2007,18(6-7):473-481.
[11]Yang H,Wang JR,Didion JP,et al.Subspecific origin and haplotype diversity in the laboratory mouse[J].Nat Genet,2011,43(7):648-655.
[12]Morahan G,Balmer L,Monley D.Establishment of‘‘The Gene Mine‘’:a resource for rapid identification of complex trait genes[J].Mamm Genome,2008,19(6):390–393.
[13]Threadgill DW,Hunter KW,Williams RW.Genetic dissection of complex and quantitative traits:from fantasy to reality via a community effort[J].Mamm Genome,2002,13(4):175-178.
[14]Lander ES,Schork NJ.Genetic dissection of complex traits[J].Science 1994,265:2037-2048.
[15]Paterson AH.Molecular dissection of quantitative traits:progress and prospects[J].Genome Res,1995,5(4):321-333.
[16]Iraqi FA,Churchill G,Mott R.The Collaborative Cross,developing a resource for mammalian systems genetics:a status report of the Wellcome Trust cohort[J].Mamm Genome,2008,19:379–381.
[17]Morgan AP,Welsh CE.Informatics resources for the Collaborative Cross and related mouse population[J].Mamm Genome,2015,26(9-10):521-539.
[18]Soller M,Iraqi FA.The Collaborative Cross–A next generation mouse genetic resource population for high resolution genomic analysis of complex traits[J].Livestock Science,2014,166(4):19-25.
[19]Aylor DL,Valdae W,Foulds-Mathes W,et al.Genetic analysis of complex traits in the emerging collaborative Cross[J].Genome Res,2011,21(8):1213-1222.
[20]Philip VM,Sokoloff G,Ackert-Bicknell CL,et al.Genetic analysis in the Collaborative Cross breeding population[J].Genome Res,2011,21(8):1223-1238.
[21]Ram R,Mehta M.Balmer L,et al.Rapid identification of major-effect genes using the collaborative cross[J].Genetics,2014,198(1):75-86.
[22]Rogala AR,Morgan AP,Christensen AM,et al.The collaborative Cross as a resource for modeling human disease:CC011/Unc,a new mouse model for spontaneous colitis[J].Mamm Genome,2014,25(3-4):95-108.
[23]Weerasekera LY,Balmer LA,Ram R,et al.Characterization of retinal vascular and neural damage in a novel model of diabetic retinopathy[J].Invest Ophthalmol Vis Sci,2015,56(6):3721-3730.
[24]Rasmussen AL,Okumura A,Ferris MT,et al.Host genetic diversity enables Ebola hemorrhagic fever pathogenesis and resistance[J].Science,2014,346(6212):987-991.
[25]Ferris MT,Aylor DL,Bottomly D,et al.Modeling host genetic regulation of influenza pathogenesis in the collaborative cross[J].PLo S Pathog,2013,9(2):e1003196.
[26]Leist SR,Pilzner C,van den Brand JM,et al.Influenza H3N2infection of the collaborative cross founder strains reveals highly divergent host responses and identifies unique phenotype in CAST/Ei J mice[J].BMC Genomics,2016,17(1):143.
[27]Xiong H,Morrison J,Ferris MT,et al.Genomic profiling of collaborative cross founder mice infected with respiratory viruses reveals novel transcripts and infection-specific gene and isoform expression[J].G3(Bethesda).2014,4(8):1429-1444.
[28]Durrant C,Tayem H,Yalcin B,et al.Collaborative Cross mice and their power to map host susceptibility to Aspergillus fumigatus infection[J].Genome Res,2011,21(8):1239-1248.
[29]Vered K,Durrant C,Mott R,et al.Susceptibility to Klebsiella Pneumonaie infection in collaborative cross mice is a complex trait controlled by at least three loci acting at different time points[J].BMC Genomics,2014,15:865.
[30]Ferguson B,Ram R,Handoko HY,et al.Melanoma susceptibility as a complex trait:genetic variation controls all stages of tumor progression[J].Oncogene,2015,34(22):2879–2886.
[31]Schmidt CW.Diversity outbred:a new generation of mouse model[J].Environ Health Perspect,2015,123(3):A64-67.
[32]Flint J,Mott R.Applying mouse complex-trait resources to behavioural genetics[J].Nature,2008,456(7223):724-727.