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A lot of this lecture comes from wikipedia:Genetic linkage.


  • We now have "the thousand genomes project" - the goal of which is to process 1000 genomes. This will allow us to appreciate diversity around the world. We're moving into an era where everyone will have a copy of their genome sequenced on a USB stick.
  • Many disorders are determined by complex inheritance (multiple genes, or disorders determined by a single gene, but that inheritance is complex)

Complex inheritance

Single gene vs complex

  • Traits may be single gene or complex
  • Most traits are complex (e.g. height, IQ, etc)
  • Single gene traits - there will be different discrete prevalences for different alleles available
  • Complex gene traits - there is a

Revision: modes of inheritance

  1. Does the trait skip a generation? (Yes-recessive; No-dominant)
  2. Are both males and females affected? (Yes-autosomal; No-sex chromosome-linked)
  3. Do affected males have affected sons? (No: X-linked)
  4. Remember: Y-linkage and X-linked dominant rare, disorders uncommon!

Incomplete penetrance

  • Penetrance: The proportion of individuals with the disease-causing allele that develop clinical symptoms
    • (We're looking at this in the case of a dominant disorder)
    • Example: Polydactyly
      • Not all the individuals with the disease causing allele have the disease
      • Because there are lots of other genes in individuals that can moderate the effect of the disease allele
      • This disease has incomplete penetrance

Variable expressivity

  • Expressivity: THe severity and type of symptoms shown in an individual with the disease-causing allele
  • In variable expressivity, people may have all the disease phenotypes, or just a mix of some of theme
    • This is because in these individuals there is a variable expression of this disease phenotype

Penetrance vs expressivity

  • Penetrance refers to proportion of individuals; expressivity refers to individual symptoms
    • Penetrance = do I have the disease or not?
    • Expressivity = how severe is my case of the disease?
  • Both of these suggest the trait is complex, and not single-gene

Complex traits

  • Determined by:
    • Genes
      • Additive (offspring have (A+B)/2)
      • Dominance (effect of recessive allele is masked by the dominant allele)
      • Interaction (genes of a metabolic pathway)
    • Environment
      • Diet/exercise
      • Smoking etc
  • G and E components vary according to the trait (expressed as contribution to phenotypic variance)
    • Diseases determined mostly by G will show a lot of heritability
    • Diseases determined mostly by E will show little heritability
  • The heritability of a trait depends on the size of G
  • Heritability can be either narrow-sense (h^2) or broad (H^2)

Narrow sense heritability (h^2)

  • Definition: The proportion of phenotypic variance that is due to additive genetic effects ((A+B)/2) - e.g. human height
  • Useful in selective breeding (animals/plants)
  • Estimated in humans using mid-parent values

Broad heritability (H^2)

  • Definition: THe proportion of phenotypic variance that is due to the sum of genetic effects
  • Most commonly quoted measure for humans
  • Estimated using twin studies
    • Identical or monozygotic (MZ) twins have the same genes, fraternal or dizygotic (DZ) twins share half their genes
  • Concordance in MZ twins provides an estimate of heritability

Estimates of H^2

  • Figures vary slightly from study to study

Gene mapping

  • Need to establish which DNA sequence is involved in disorder
  • Achieved using DNA markers - any sequence of DNA that can be used to trace a disease allele
  • These are used as a proxy to try to work out what sequences are involved in the disorder
  • If a marker is often inherited with a disease, then it may be close to the disease locus

DNA markers

  • Several requirements for markers to be useful:
    1. Clean Mendelian inheritance
    2. Sufficiently polymorphic (different between individuals)
    3. Easy to type
    4. High density (to get high specificity of results), spread across the genome (to identify many loci across the genome)

Types of DNA markers

  • SNPs are easy to type using high-throughput techniques

Modern DNA markers

  1. Microsatellites
    • Have an expanding repeat sequence (different individuals have different numbers of copies of the repeat sequence - due to a tendency of the polymerase to slip)
      • They are stable enough to trace through a pedigree but they aren't stable within individual
  2. Single nucleotide polymorphisms (SNPs)
    • E.g. A or C at a particular location.
    • Not very polymorphic
    • Can type very many of them (gives you a barcode of the genome)
    • Individually they're not very useful, but when you combine many it is very useful
  3. Restriction fragment length polymorphisms (RFLPs)
    • Sites where there is a recognition part for a restriction enzyme (like a SNP but influences whether we have an RF or not)

Marker locations are known from the Human Genome Project

Linkage analysis

  • If a marker is often inherited with a disease, then it may be close to the disease locus
  • In other words, marker and disease locus may be close together on the same chromosome (linked)
  • Assessed by observing how often disease and marker are linked (inherited together) in one or more pedigrees

Meiosis and linkage

  • During meiosis, there is a process of crossing over during prophase 1, involving the exchange of chromosome segments between homologous chromosomes
  • Marker and disease locus may be on the same or different chromosomes
    • Different chromosomes = independent assortment (50% chance of co-segregating)
    • Same chromosome = linked
  • Linked genes can be separated by recombination (crossing over), so

The closer two loci are, the more likely they are to be inherited together


  • If linked loci are separated by recombination, gametes will be recombinant; if not then gametes will show parental markers

Using linkage

  • Hence the frequency of recombination (ratio of recombinants to parentals) indicates how close together loci are on a chromosome.
  • This is used to determine the most likely position of a disease gene (i.e. the closest marker)
  • To understand this you need to know whether or not a person is a

LOD scores

  • Calculated using

Log of odds (LOD) = log (P(loci linked at theta)/P(no linkage))

  • Theta = recombination frequency
  • For no linkage, the probability is 0.5
  • Theta depends on the distance between the marker and disease locus
  • LOD scores ≥3 are significant at P≤0.05
    • It is 1000 times more likely that the disease locus and marker are linked than that they're unlinked

Summary: Linkage analysis

  • Examines co-segregation of markers and disorder phenotype to identify location of disease gene
  • Involves genotyping for microsatellites and/or SNPs, calculation of LOD scores and study of candidate genes
  • Limitations: may be limited by poor pedigree data, difficult for polygenic traits

Association studies

  • Use statistical association rather than direct observation of linkage
  • Involve looking for ancestral chromosome segments (haplotypes) that are shared between affecteds
    • Haplotype is all the markers that are present in order on a particular chromosome
  • Three major approaches
    1. Candidate gene approach - we think this gene may be involved, so we'll check it out
    2. Combined linkage and association
    3. Genome-wide association studies (GWAS) (common in the past few years because we have high throughput studies)
  • Rely on SNP data from HapMap project (

Example: GWAS

  • Sulem et al. (2007) examined genetic determinants of hair, eye and skin pigmentation in Europeans (Fig. 1)
  • GWAS: advantages and limitations
    • Bad news - the loci they've identified don't account for very much of the phenotypic variance we see
    • Has been a bit disappointing - trying to work out why we can't find the loci that have a big effect
    • Possible that some diseases are caused by many many loci, each with small effects (scary possibility for treatment)
    • Getting a lot more information, though