RESUMO
OBJECTIVE: The LEW/OlaHsd and BC/CpbU rat inbred strains differ markedly in blood and hepatic cholesterol levels before and after a cholesterol-rich diet. To define loci controlling these traits and related phenotypes, an F2 population derived from these strains was genetically analyzed. METHODS AND RESULTS: For each of the 192 F2 animals, phenotypes were determined, and genomic DNA was screened for polymorphic microsatellite markers. Significant quantitative trait loci (QTLs) were detected for basal serum cholesterol level on chromosome 1 (D1Rat335-D1Rat27: total population, lod score 9.6; females, lod score 10.3) and chromosome 7 (D7Rat69: males, lod score 4.1), for postdietary serum cholesterol level on chromosome 2 (D2Rat69: total population, lod score 4.4) and chromosome 16 (D16Rat6-D16Rat44: total population, lod score 3.3), for postdietary serum phospholipid level on chromosome 11 (D11Rat10: total population, lod score 4.1; females, lod score 3.6), and for postdietary serum aldosterone level on chromosome 1 (D1Rat14: females, lod score 3.7) and chromosome 18 (D18Rat55-D18Rat8: females, lod score 2.9). In addition, QTLs with borderline significance were found on chromosomes 3, 5 to 11, 15, and 18. CONCLUSIONS: QTLs involved in blood and/or hepatic cholesterol concentrations (or related phenotypes) in the rat were identified. This contributes to the value of the rat as an animal model in studies researching the role of cholesterol in the pathogenesis of atherosclerosis and other cholesterol-related diseases.
Assuntos
Colesterol/sangue , Colesterol/genética , Fígado/química , Locos de Características Quantitativas/genética , Animais , Colesterol/metabolismo , Colesterol/fisiologia , Colesterol na Dieta/metabolismo , Mapeamento Cromossômico/métodos , Dieta , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/genética , Genes/genética , Masculino , Repetições de Microssatélites/genética , Fenótipo , Fosfolipídeos/sangue , Polimorfismo Genético/genética , Ratos , Ratos Endogâmicos Lew , Ratos EndogâmicosRESUMO
Renal cell carcinomas (RCCs) occur in both sporadic and familial forms. In a subset of families the occurrence of RCCs co-segregates with the presence of constitutional chromosome 3 translocations. Previously, such co-segregation phenomena have been widely employed to identify candidate genes in various hereditary (cancer) syndromes. Here we survey the translocation 3-positive RCC families that have been reported to date and the subsequent identification of its respective candidate genes using positional cloning strategies. Based on allele segregation, loss of heterozygosity and mutation analyses of the tumors, a multi-step model for familial RCC development has been generated. This model is relevant for (i) understanding familial tumorigenesis and (ii) rational patient management. In addition, a high throughput microarray-based strategy is presented that will enable the rapid identification of novel positional candidate genes via a single step procedure. The functional consequences of the (fusion) genes that have been identified so far, the multi-step model and its consequences for clinical diagnosis, the identification of persons at risk and genetic counseling in RCC families are discussed.
Assuntos
Carcinoma de Células Renais/genética , Cromossomos Humanos Par 3 , Neoplasias Renais/genética , Translocação Genética , Adulto , Idoso , Cromossomos Humanos Par 1 , Cromossomos Humanos Par 2 , Família , Aconselhamento Genético , Humanos , Pessoa de Meia-Idade , Análise de Sequência com Séries de OligonucleotídeosRESUMO
The amplified fragment length polymorphism (AFLP) technique has been used to enhance marker density in a large set of recombinant inbred strains (H x B and B x H) derived from a spontaneously hypertensive rat (SHR/OlaIpcv) and a Brown-Norway (BN.lx/Cub) inbred strain. Thirteen different primer combinations were tested and a total of 191 polymorphic bands were detected. From these polymorphic bands 89 AFLP markers could be assigned to specific chromosomes. Several of these AFLP markers were mapped to regions with low marker density, thus filling up gaps in the existing genetic map of these recombinant inbred strains. These results substantiate the value of the AFLP technology in increasing marker density in genetic maps.