LECTURE 12-Human disease genes risky science and the new infinity

LECTURE 12-Human disease genes risky science and the new infinity

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Human disease genes summary 1. Goals: discover the basis for disease, understand key processes, and develop diagnostics and cures. 2. Finding human disease genes -- OMIM 3. Sickle Cell Anemia 4. Inheritance and linkage 5. RFLPs and chromosome “walking” 6. Huntington’s disease -- Scientific suicide 7. Future
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Some examples of single-gene diseases Common?
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Find disease genes At OMIM ( O nline M endelian I nheritance in M an) http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM This database catalogs human genes and genetic disorders. The database contains textual information and references. It also contains links to MEDLINE and sequence records in the Entrez system, and links to additional related resources.
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Sequencing Hb S proteins revealed a single change: Glu6Val in the β chain. Fiber formation (R) at low [O 2 ] causes sickling of RBCs (center). Gene finding 1. Sequence candidate genes or proteins
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Autosome: not a sex chromosome X, Y: sex chromosomes = Male (XY) = Female (XX) Inheritance
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Markers separated by 1 centimorgan have a 1% chance of being separated in meiosis. 1 centimorgan corresponds to ~ 750,000 bp in humans! Linkage--Recombination during meiosis separates genes 1. Genes on different chromosomes assort independently 2. Genes on the same chromosome are linked 3. This linkage is not absolute
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Gene finding 2. RFLP analysis Look for restriction fragment length polymorphism (RFLP) that correlates with the inheritance pattern of the disease. Fig. 9-46. Three alleles of a RFLP on chromosome 5 in 14 individuals in 3 generations. Each lane corresponds to the individual above it.
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Can a gene be located by RFLP linkage? A “crazy” approach: 1. Collect DNA from 100s of related individuals with and without the disease. 1. Establish their pedigrees without errors. 1. Digest their DNA with various restriction enzymes. 1. Probe Southern blots with RANDOM probes. 1. Look for an RFLP that is inherited with the same pattern as the disease.
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Markers separated by 1 centimorgan have a 1% chance of being separated in meiosis. 1 centimorgan corresponds to ~ 750,000 bp in humans! For a “fully penetrant”, single-gene disease: Linkage of a RFLP to a disease in 99/100 patients implies the RFLP may be within 750 kbp of the disease mutation. In practice, many more patients are needed to get reliable linkage statistics. Linkage mapping requires large patient populations
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Jim Gusella commits “scientific suicide” 1980: Gusella starts his first faculty job at Massachusetts General Hospital with the aim of finding an RFLP marker for Huntington’s disease. No one had ever found an RFLP marker for an unmapped disease gene.
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This note was uploaded on 01/12/2010 for the course MCB 110 taught by Professor Alber,zhou,nogales during the Fall '07 term at Berkeley.

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LECTURE 12-Human disease genes risky science and the new infinity

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