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Human Genetics

Human Genetics. Linkage. The observation that two genes are not transmitted independently. Why? Two genes physically near each other on a chromosome will not assort randomly in meiosis. Linkage. Linkage. Tightly linked: two types of gametes in this case - PL and pl. Unlinked:

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Human Genetics

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  1. Human Genetics Linkage

  2. The observation that two genes are not transmitted independently. Why? Two genes physically near each other on a chromosome will not assort randomly in meiosis. Linkage

  3. Linkage • Tightly linked: • two types of gametes • in this case - PL and pl Unlinked: - 4 type of gametes - PL, Pl, pL, pl NOTE: The alleles observed to be linked (PL and pl or Pl and pL) depends on which alleles are on the same chromosome in the parent!

  4. Recombination • When chromosomes recombine new combinations of alleles are created. • Parental chromosomes have the alleles present in the original configuration. • Recombinant chromosomes have new combinations of alleles.

  5. Recombination The frequency of recombination between two genes is proportional to the distance between the genes.

  6. 4 cM 6 cM 10 cM Linkage Map • A linkage map is a diagram indicating the relative distance between genes. • 1% recombination = 1 map unit = 1 centiMorgan (cM) • Map distances are additive. Z % recombination between genes X and Y 10 X and Z 4 Y and Z 6 X Y

  7. Inheritance of Linked Genes • Parent 2 (mother) produces 4% recombinant gametes, therefore the Rh factor gene and the anemia gene are 4 map units or 4 cM apart. • The genes for Rh factor (R) and anemia (E) are linked, but some recombination occurs between the two genes.

  8. Linkage Disequilibrium Two genes, A and B, exist in a population. • If the frequency of chromosomes with AB=Ab=aB=ab then the genes are in equilibrium. • If the frequency of one allele of gene A is seen more frequently with a particular allele of gene B, then the genes are in linkage disequilibrium. The non-random association between alleles at two locations on a chromosome is called linkage disequilibrium.

  9. LOD score • LOD is a statistical test for Linkage • It is the logarithm of the odds ratio • It is a statistical measure of likelihood that two genes are linked at a particular distance. • LOD scores of 3 or greater are considered significant and indicate the data would be observed by chance 1 in 1000 times.

  10. LOD Calculation • NR=number of non-recombinant offspring • R=number of recombinant offspring. • 0.5 is used in the denominator because any alleles that are completely unlinked (e.g. alleles on separate chromosomes) have a 50% chance of recombination, due to independent assortment.

  11. 11 11 11 11 11 22 22 22 22 22 Gene A Gene B Gene C Gene D Gene E Haplotype A haplotype is the set of alleles inherited on one chromosome. Each number indicates the allele present for one of 5 genes A-E. 1 1 1 1 1 2 2 2 2 2 Maternal haplotype Paternal haplotype

  12. 11 11 11 11 11 22 22 22 22 22 33 33 33 33 33 44 44 44 44 44 12 12 12 12 12 34 34 34 34 34 13 13 13 13 13 14 14 14 14 14 23 23 23 23 23 14 14 14 13 13 14 14 14 14 14 23 23 24 24 24 23 23 23 23 23 Mapping with haplotypes Gene A Gene B Gene C Gene D Gene E Segregation of a dominant trait is observed in this family (filled symbols). The trait segregates with thered haplotype.

  13. 11 11 11 11 11 22 22 22 22 22 33 33 33 33 33 44 44 44 44 44 12 12 12 12 12 34 34 34 34 34 III-3 and III-6 inherit recombinant chromosomes. The location of the recombination events indicate that the gene for this trait is located between genes B and D. 13 13 13 13 13 14 14 14 14 14 23 23 23 23 23 14 14 14 13 13 14 14 14 14 14 23 23 24 24 24 23 23 23 23 23 Mapping with haplotypes Gene A Gene B Gene C Gene D Gene E

  14. This diagram shows two ancestral chromosomes being scrambled through recombination over many generations to yield different descendant chromosomes. If a genetic variant marked by the A on the ancestral chromosome increases the risk of a particular disease, the two individuals in the current generation who inherit that part of the ancestral chromosome will be at increased risk. Adjacent to the variant marked by the A are many SNPs that can be used to identify the location of the variant. Origins of Haplotypes

  15. HapMap

  16. HapMap Construction • The construction of the HapMap occurs in three steps. • Single nucleotide polymorphisms(SNPs) are identified in DNA samples from multiple indivduals. • Adjacent SNPs that are inherited together are compiled into "haplotypes." • "Tag" SNPs within haplotypes are identified that uniquely identify those haplotypes. By genotyping the three tag SNPs shown in this figure, researchers can identify which of the four haplotypes shown here are present in each individual.

  17. HapMap Web Page • http://www.genome.gov/page.cfm?pageID=10001688

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