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Week 5: Linkage, Recombination, & Mapping (Linked genes (Examples…

- - - - Cells contain two copies (alleles) of each gene, which separate during meiosis (gamete formation). Each of these gametes carry only one copy of each gene (random).
    - - Gene pairs on different chromosome pairs assort independently at meiosis, i.e. alleles at different loci separate independently of one another.
  - - - A heterozygote for a single gene, e.g. A/a
    - - Genes on same chromosome: AB/ab
      - Location of genes unknown: A/a * B/b
      - Genes on different chromosomes: A/a ; B/b
    - - Green round X wrinkled yellow
        
        3:1 ratio for seed shape
        
        3:1 ratio for seed colour
        
        9:3:3:1 ratio
- - - - Genes located close together on the same chromosome; belonging to the same linkage group
      - Travel together in meiosis and arrive at the same destination (i.e. gamete), and are not expected to assort independently
    - - Need to know genotypes AND the arrangement of genes on chromosome
        
        AB/ab indicates A and B are on same homologous chromosome
        
        Two alleles at a locus are always located on different homologous chromosomes, i.e. never Aa/Bb
        
        Configuration
        
        Repulsion/trans
        
        Wild type (dominant) and mutant (recessive) alleles on same chromosome
        
        Coupling/cis
        
        Wild type and mutant alleles on different chr.
  - - - 95% = pattern baldness
        
        2005: Pattern baldness and SNPs are linked on X chromosomes
      - Castrated rarely bald (androgen-receptor)
    - - Bateson's experiment
        
        Flower colour
        
        Pollen shape
        
        Non 9:3:3:1 ratios indicating linkage
    - - Colour of thorax/puarium
        
        Differences due to configuration
    - - Nail-patella syndrome: abnormal fingernails, absent kneecaps
        
        Generation II
        
        NP syndrome children had blood group B or O
        
        Blood group A children did not have NP syndrome
      - ABO blood groups: autosomal locus with multiple alleles
  - - - No crossover
        
        Complete linkage
        
        No recombination
        
        Non-Mendelian ratios: >50% non-recombinant, <50% recombinant genotypes
        
        Intrachromosomal recombination
        
        Crossover less common for linked genes (not independently assorted)
      - Crossover
        
        Genes switch from one homologous chromosome to another, breaking up association of linked genes
        
        25% of each of four genotypes: 50% total recombinant, 50% total non-recombinant
        
        Frequency of recombinant gametes is half the frequency of crossover
        
        Interchromosomal recombination
      - Crossover: exchange of genetic material between non-sister chromatids that takes place during Prophase I of meiosis
  - - - Chance alone accounts for deviations between number of observed and number expected
      - Assumptions
        
        Probability of each single-locus genotype is 50%
        
        Genotypes at two loci are inherited independently
      - df = (# expected phenotypes) - 1
      - NB: use numbers of individuals, not proportions /percentages, to calculate
- - - - Note: crossover events occur randomly up and down the chromosome
    - - Physical distance along chromosome
        
        Physical map
      - Genetic recombination
        
        Genetic map
        
        1 m.u. (map unit) = 1% recombination = 1 cM (centiMorgan)
        
        Distances approx. additive
        
        Limitations
        
        Cannot distinguish between genes on different chromosomes and genes located far apart on the same chromosome
        
        Testcross for genes that are far apart underestimate true physical distance, as it will not reveal double crossovers
        
        Multiple crossovers
        
        Two-strand crossover
        
        Two out of 4 chromatids undergo crossover
        
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        Three-strand crossover
        
        Three of 4 chromatids undergo crossover
        
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        Four-strand crossover
        
        Four of 4 chromatids undergo crossover
        
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  - - - Steps
        
        2) Identify the double-crossover progeny: two least-numerous phenotypes
        
        3) Compare phenotype of double-crossover progeny with that of non-recombinant progeny; should be alike in two characteristics and differ in one
        
        1) Identify non-recombinant progeny: two most numerous phenotypes
        
        4) Differentiating characteristic is encoded by the middle gene
  - - - Data combined from multiple families
  - - - No requirement to wait for phenotype expression (which is sometimes difficult to distinguish) to get genotype information
      - Rapid (PCR, sequencing)
      - SNVs are biallelic
      - Allow distinction between homozygous and heterozygous (testcross)
      - Microsatellite markers are multiallelic
    - - Inherited within chromosomes
        
        Genetic markers are polymorphic loci whose locations are known (AFLP, RFLP), most often SNPs or microsatellites
- - - - Families segregation
        
        Compare frequency of disease among first-degree relatives with that of general population
      - Twin studies
        
        Compare monozygotic and dizygotic twins for concordance rates
    - - Not simple Mendelian
        
        No recognisable pattern of inheritance
        
        Likely due to action of multiple genes
        
        Genes may be interacting with each other to result in disease phenotypes
        
        Environmental factors/gene-environmental interactions
  - - - Disease
        
        Function
        
        Gene
        
        Map
        
        E.g. Sickle-cell anaemia
    - - Disease
        
        Map
        
        Gene
        
        Function
        
        E.g. Huntington gene
        
        E.g. Cystic fibrosis
        
        First gene responsible for human genetic disease that was identified by this method
        
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      - Identification of a gene based solely on its position in the genome
        
        Most widespread strategy in human genetics in last 15-25 years
        
        Strengths
        
        No knowledge of gene product required
        
        Very strong track record in single-gene disorders
        
        Weaknesses
        
        Understanding of function not a certain outcome
        
        Poor track record with multifactorial traits
  - - - Candidate Genes
        
        Candidate genes (those located in a chromosome region suspected of being involved in the expression of disease traits) can be identified by association and linkage with phenotypes
        
        Limited to the known biological functions for a particular disease
      - Whole Genome Screen
        
        Scan whole genome without prior information, can discover potential genes playing roles for diseases
        
        6-10k SNPs enough for linkage, 500k-1M SNPs recently available for association
  - - - Determine approximate location of disease-predisposing genes
      - Use genetic marker map to look for co-segregation with a marker; determine if marker allele at known locations travels with disease in a family
    - - Measures allele segregationand phenotype within a family
      - Use crossover occurring during meiosis II: genes that are physically close together are more likely to be co-inherited, while those far apart or less likely to be co-inherited
      - Detect over broad chromosomal regions on genome
    - - Evaluate the evidence of a direct correlation between a marker allele and a disease risk allele
      - Sharing of genetic material: actual sharing of the same allele