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L27 - Linkage Recombination and Mapping (53-76) Understand that mapping…

- - - - Evidence to suggest a genetic origin for disease/trait
        
        Twin Studies
        
        Compare Monozygotic and Dizygotic Twins
        
        Monozygotic Twins : Genetically identical
        
        Dizygotic Twins : Like siblings (1/2 genome shared)
        
        Compare concordance rates of disease across MZ and DZ twins
        
        Families Segregation
        
        Increased risk for disease among family members of an affected individual
        
        Compare frequency of disease among first degree relatives of affected individuals with the frequency of the disease in the general population.*
    - - 1. Monogenic (Mendelian) Disorders
        
        Genetic Cause is more obvious
        
        Observable genetic segregatio within the pedigrees/families
      - 2. Genetically Complex Disorders
        
        There may be no recognizable pattern of inheritance
        
        Likely due to the action of multiple genes
        
        Genes may be interacting with each other to result in disease phenotypes
        
        Environmental factors or gene environmental interactions may affect disease.*
        
        Risk Factors for Complex Diseases = Multfactorial
        
        Interplay between Environmental influences and often multiple genes
        
        Expressivity of the disease/severity of presentation will therefore be case dependant and not universal aross all families
        
        Identifying Causative Genetic Variation
        
        1. Functional Cloning
        Sickle Cell Anaemia
        
        Disease
        Phenotype observed
        
        Function
        Function which disease impedes is determined
        
        Gene
        Likely gene candidates causing loss of function nominated
        
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        2. Positional Cloning
        Huttington Gene, Cystic Fibrosis
        Identifying a gene based solely on its position in the genome
        
        Strengths
        
        No Knowlede of gene product required
        
        Effective for MONOGENIC DISORDERS
        
        Weaknesses
        
        Understainding of gene function is uncertain
        
        Ineffective for Complex Disorders
        
        Disease
        
        Linkage Map
        Scan whole genome without prior info.
        
        Gene
        Once Linkage mapping has focused search to a few "candidate"genes => use segments of DNA (clones) isolated by Chr. "walking"and "jumping" to discover which genes may be causing disease
        
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        Statistical Approaches to Gene Mapping
        
        Linkage analysis
        
        Association studies (Linkage disequilibrium)
        
        Principle
        A comaprison of individuals who express the same disease phenotype, should reveal high degrees of similarity - at least higher than expected levels - in the genetic material proximal to those genes causing the disease
        
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- - - - Advantages of DNA Marking
        
        DNA markers can be applied rapidly (PCR sequecing)
        
        Microsatellite markers can identify regions across multiple alleles. SNVs are biallelic markers
        
        Do not reuqire a calculation of recombination frequency => no need to wait fro progeny to develop phenotype either.
        
        Detecting Phenotypes incurs human error
        
        Markers allow distinction between homo/hetero-zygotes
    - - More Markers = Greater precision of Genetic Mapping
        Reduces the amount of genetic material between markers, thereby reducing the likelihood of missing recombination events between markers
        =>
        E.g. Recombination between 2 and 1 is undetetcted