1 / 13

Key words

Discuss key features of polygenic and multifactorial diseases. How would you go about isolating a gene involved in polygenic inheritance? Helen Stuart Cardiff. Complex disorders Continuous traits Quantitative trait loci Linkage analysis Linkage disequilibrium Genetic heterogeneity

barth
Télécharger la présentation

Key words

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Discuss key features of polygenic and multifactorial diseases. How would you go about isolating a gene involved in polygenic inheritance?Helen StuartCardiff

  2. Complex disorders Continuous traits Quantitative trait loci Linkage analysis Linkage disequilibrium Genetic heterogeneity Allele-sharing methods Identical-by-descent Association studies Admixture Array chips Experimental crosses Quantitative trait loci Candidate genes Key words

  3. Definitions • Polygenic disease = A genetic disease caused by the combined actions of two or more genes. E.g. coronary heart disease, hypertension • Multifactorial disease = A disease caused by the complex interaction of many environmental and genetic susceptibility factors. E.g. diabetes mellitus, Alzheimer's disease. Aka complex disorders Note: some of the genetic factors can even be protective for the occurrence of the disease

  4. Key features • High population incidence • The disease can occur in isolation • Non-Mendelian inheritance • Low heritability • Higher recurrence risk with increased number of siblings/relatives affected • Higher recurrence risk if relative is more severely affected • Consanguinity increases probability of being affected • Sexes have different probabilities of being affected • Environmental influences can increase or decrease the risk of multifactorial diseases

  5. Medical Definition of Polygenic inheritance Inheritance in which a measurable phenotype is generated by many loci, the contributions of which are statistically independent, additive, and of about equal value.

  6. Isolation of a gene involved in polygenic inheritance • Linkage analysis • Allele-sharing methods • Association studies • Experimental crosses

  7. Isolation of a gene I:Linkage analysis • If two loci are usually inherited together, they are said to be linked (linkage disequilibrium) • Transmission within a pedigree • Quantitative trait loci (QTL) • Linkage only within some pedigrees – genetic heterogeneity

  8. Genetic (locus) heterogeneity • Genetic heterogeneity complicates the analysis of complex disorders • Different genotype > same phenotype

  9. Isolation of a gene II:Allele-sharing methods • Affected individuals inherit identical copies of a region more often than by chance • Highly polymorphic markers • Multiple families • Identical-by-descent…use lots of markers

  10. Isolation of gene III:Association studies • Compare unrelated affected and unaffected individuals within a population • Genome-wide association studies (GWAS) • Array chip (high-density SNPs) • Identify SNPs associated with a disease (QTL) • Associations because: • SNP is cause of disease • SNP is in linkage disequilibrium with the causal gene • Artefact (admixture)

  11. Isolation of gene IV:Experimental crosses • Large number of progeny • Genetic homogeneity • Only identifies QTLs that differ in parents • Effects of QTLs may change - epistasis

  12. Candidate genes • Gene expression - in the right tissues at the right time • Animal models - lack of specific gene sequence (or gene product) + phenotype of interest • Identification of human chromosomal rearrangements or mutations in these candidate genes that cause the phenotype of interest • Previous human linkage and/or linkage disequilibrium/association studies – supporting findings • Determine function of WT and mutant gene products

  13. References • Chial, H (2008) Polygenic inheritance and gene mapping. Nature Education 1(1) • Lander, E.S. and Schork, N.J. (1994) Genetic dissection of complex traits. Science 265 • Hitzemann, R. et al (2008) Quantitative trait locus analysis: multiple cross and heterogeneous stock mapping. Alcohol Research and Health 31(3) • Jorde, L.B. (2000) Linkage disequlibrium and the search for complex genes. Genome Res 10(10):1435-44

More Related