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UNC-Chapel Hill ENVR 132 - Role of Genetic Polymorphisms in Responses to Toxic Agents

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Role of Genetic Polymorphisms in Responses to Toxic Agents Definitions Forward genetics and toxicology Reverse genetics and toxicology Genetic markers SNPs and their use in toxicology Ethical Legal and Social Issues ELSI Toxicology is concerned with the interaction between xenobiotics and biological molecules directly or indirectly coded in the DNA and can be regarded as a branch of GENETICS Michael F W Festing 2001 Gregor Mendel 1822 1884 TERMINOLOGY Gene A sequence of DNA bases that encodes a protein Allele A sequence of DNA bases Locus Physical location of an allele on a chromosome Linkage Proximity of two alleles on a chromosome Marker An allele of known position on a chromosome Distance Number of base pairs between two alleles centiMorgan Probabilistic distance of two alleles Phenotype An outward observable character trait Genotype The internally coded inheritable information Penetrance No with phenotype No with allele Modified from M F Ramoni Harvard Medical School The 80s Revolution and the Human Genome Project Genetic Polymorphisms naturally occurring DNA markers that identify regions of the genome and vary among individuals The intuition that polymorphisms could be used as markers sparkled the revolution On February 12 2001 the Human Genome Project announced the completion of a first draft of the human genome and declared A SNP map promises to revolutionize both mapping diseases and tracing human history SNP are Single Nucleotide Polymorphisms subtle variations of the human genome across individuals Modified from M F Ramoni Harvard Medical School DISTANCES ON A GENETIC MAP Physical distances between alleles are base pairs But the recombination frequency is not constant A useful measure of distance is based on the probability of recombination the Morgan A distance of 1 centiMorgan cM between two alleles means that they have 1 chance of being separated by recombination A genetic distance of 1 cM is roughly equal to a physical distance of 1 million base pairs 1Mb Modified from M F Ramoni Harvard Medical School MORE TERMINOLOGY Physical Maps maps in base pairs Human physical map 3000Mb Mega bases Genetic Maps maps in centiMorgan Human Male Map Length 2851cM Human Female Map Length 4296cM Correspondence between maps Male cM 1 05 Mb Female cM 0 88Mb Modified from M F Ramoni Harvard Medical School Simple and Complex Traits Single Gene Mendelian diseases Autosomal dominant Huntington Autosomal recessive Cystic Fibrosis X linked dominant Rett X linked recessive Lesch Nyhan Today over 400 single gene diseases have been identified Problem traits don t always follow single gene models Complex Trait phenotype genotype interaction Multiple cause multiple genes in several loci determine a phenotype in conjunction with non genetic factors accidents of development social factors environment infections other factors Multiple effect gene causes more than one phenotype Modified from M F Ramoni Harvard Medical School Toxicology Genetics There is substantial polymorphism in genes that determine the response to xenobiotics both in humans and animals This has important implications for toxicology and pharmacology adverse reactions to drugs cause thousands of deaths each year and many of those are associated with susceptible phenotypes are we protecting the most sensitive in human population when occupational environmental limits of exposure are established how to account for strain differences in susceptibility in animal studies 1000 fold differences have been reported for TCDD LD50 in rats genotyping of individuals from a sample of blood DNA is becoming increasingly easy so it is possible to genotype people for loci that are thought to control susceptibility to certain drugs xenobiotics Adapted in part from M F W Festing Tox Lett 120 293 300 2001 loci that are thought to control susceptibility to certain drugs xenobiotics Before we can correctly interpret genotyping results we need to gain a much better understanding of the genetics of susceptibility know the mode of action of xenobiotics Problem relatively little research is done on the genetics of susceptibility and toxicologists in general seem to be unaware of the extent of genetic variation in response among the experimental animals that are being used Problem modes of action of an overwhelming majority of established toxic substances are still largely unknown not even worth mentioning scores of compounds that are being newly developed Adapted in part from M F W Festing Tox Lett 120 293 300 2001 Genotype Phenotype Interactions in Complex Biological Systems Age Environment Adapted from Huang 2002 Reverse Genetics Forward Genetics Forward and Reverse Genetics and Toxicology Phenotype e g toxic symptoms cancer Studying the mechanisms of action Genes that control susceptibility resistance Genotype e g gene knockout certain polymorphism Studying the mechanisms of action Phenotype Adapted in part from M F W Festing Tox Lett 120 293 300 2001 Forward Genetics and Toxicology Different animal strains nearly always respond differently to the same agent dose unless the toxic insult is so dramatic that all the animals die very quickly Examples of strain differences rats in response to xenobiotics 3 2 dimethyl 4 aminobiphenyl prostate tumors 48 F344 41 ACI 13 LEW 7 CD 0 Wistar N methyl N nitro N nitrosoguanidine MNNG stomach adenocarcinomas 67 WKY 60 S D 53 LEW 23 Wistar 6 F344 There is no such thing as an animal strain that is particularly susceptible resistant to carcinogenesis Adapted in part from M F W Festing Tox Lett 120 293 300 2001 Forward Genetics and Toxicology Designing an IDEAL forward genetics animal study for investigating genetic variability in response to a toxic agent Survey the known facts about susceptibility in different strains of rodents Small numbers of animals 4 6 per strain of several strains should be used to characterize the response to the toxic agent X At least 5 strains should be studied Dose levels should be selected to elicit a suitable response Endpoints should be quantitative e g number of tumors Adapted in part from M F W Festing Tox Lett 120 293 300 2001 Response to aceteminophen in a genetically diverse population Once a susceptible resistant strains have been identified loci can be mapped In mice Recombinant Inbread strains susceptible x resistant can be generated A set of RI strains can be tested for the susceptibility to agent X Once the phenotype have been established mice can be genotyped to determine which


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UNC-Chapel Hill ENVR 132 - Role of Genetic Polymorphisms in Responses to Toxic Agents

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