Linkage and Genetic Mapping

1. Linkage and Genetic Mapping Lecture 1 Human Molecular Genetics (Strachan and Read) Chapters 4, 13, 14

2. What are genetic diseases? There are two basic types 1. Simple Mendelian (easy to analyse) e.g. Huntington's disease, cystic fibrosis, Duchenne muscular dystrophy follow a simple pattern of inheritance (e.g. autosomal dominant, autosomal recessive, X-linked recessive). There is a complete correlation between genotype and phenotype. If you've got the mutant gene, you'll get the disease. 2. Complex or multifactorial (hard to analyse) e.g. many common diseases, such as cancer, asthma, schizophrenia, hypertension, heart disease.The risk of getting the disease is modified by individual's genotype. Evidence for "genetic-ness" of a disease is expressed as l = (risk to 1st degree relatives of patient)/(population risk). For type I diabetes, l = 15 (6%/0.4%). Other factors, especially other genes and environment, also influence risk of getting disease.

3. Strategies for cloning a disease gene If you know the biochemical basis of the disease, e.g. there is an enzyme missing from a biochemical pathway, you can go straight to the gene that codes for the enzyme/protein. This called functional cloning If you have some idea of the pathological basis of the disease, or if there is a similar animal or human disease for whose basis is known, you might be able to guess what the gene might be and test that gene directly in patients: the candidate gene approach If the only thing you know about the disease gene is its location in the genome from linkage studies, the approach used is called positional cloning Positional cloning can be based on translocations or deletions that disrupt the gene and cause the phenotype (rare), or on linkage mapping in families

4. The main questions that have to be answered when planning the strategy What type of inheritance? Simple (which mode?) or complex? How to search? Can you guess at a candidate gene? If so, test it directly in patients and controls to see if a mutation is associated with disease state Are families available? If so can use the genetic linkage approach - study the inheritance of polymorphic DNA sequences, see if any segregate with the disease. This identifies candidate region of genome.