Epistatic Relationships in the BRCA1-BRCA2 Pathway 英文参考文献.docVIP

Perspective EpistaticRelationshipsintheBRCA1-BRCA2Pathway RalphScully* DepartmentofMedicine,HarvardMedicalSchoolandBethIsraelDeaconessMedicalCenter,Boston,Massachusetts,UnitedStatesofAmerica Inmodernmoleculargenetics, epistasis analysisisatoolforprobing therelation- ship between two genes and, hence, between the two genes’ products. In its broadest sense, an epistatic relationship existswhencombinationsofspecificalleles of two or more genes generate a quanti- tative phenotype that differs from the simple addition of phenotypes associated witheachindividualallele.Manydifferent types of gene–gene interaction could be characterized as epistatic. In its purest form, an allele a of gene A is said to be epistatic to (literally, ‘‘standing over’’) allele b of gene B if both a and b individually confer a quantitative defect in a particular phenotype, the defect caused by a is more severe than b , and thephenotypeofabresemblesthatofa .In this case, the presence of allele b is irrelevant if allele a is present. Clear-cut genetic interactions of this type might indicate that there is an equally clear-cut biochemical interaction between thegene products, A and B. In the example outlined above, A might act on the same biochemical pathway as B and effectively controlitsactivities. thelethalphenotypeofBRCA1nullmiceis largely suppressed by deletion of 53BP1 [2,3]. importantlightonthefunctionalrelation- ships between BRCA1, BRCA2, Rad51, andotherHRmediators.First, bygener- ating a (probable) null allele of BRCA2, theyshowthatcompleteornear-complete lossofBRCA2functioniscompatiblewith cell viability, in dramatic contrast to the Rad51nullphenotype,whichiscelllethal in DT40 [5]. Thus, although BRCA2 loadsRad51protein,Rad51musthavecell viabilityfunctionsthatareindependentof BRCA2.CombineddeletionofBRCA1and BRCA2 produced no additive impairment ofcellgrowth.However,whentheauthors studied the impact of combined BRCA1 and BRCA2 mutations on sensitivity to DNA damaging