Tufts OpenCourseware
Author: Janet M. Cowan, Ph.D.
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Important key words or phrases.
Important concepts or main ideas.

The Human Genome And Gene Mapping


Jorde, Carey, Bamshad & White: Medical Genetics, 3rd edition, C.V. Mosby Publishing, 2005.

  • Structure of the Human Genome Chapter 2, 17-22
  • Detection of variation at the DNA level Chapter 3, 43-55
  • Gene Mapping and cloning Chapter 8, 160-189


The student will:

  • Understand the different types of genetic variation.
  • Be able to distinguish between genetic mapping and physical mapping.
  • Understand the basic concept of genetic linkage analysis
  • Understand different gene mapping techniques .

The Human Genome Project

  • Goal is/was determination of the complete sequence of the human genome
    • genes which define our phenotype
    • genes whose alteration leads to disease
  • Characterization of single gene disorders, multigene disorders
  • 3 x 109 bp (<5% encodes genes)
  • 24 different chromosomes
  • First draft of the sequence of human genome published in 2000


  • Genome maps are detailed constructs of the order and/or position of genetic markers and DNA sequence.
  • Maps are of two types:
    • Genetic maps - use recombination frequencies of markers at meiosis
    • Physical maps - identify exact location of DNA sequence in the genome

Human Genome Mapping

  • Individual chromosomes isolated, and used to prepare genomic DNA libraries in yeast artificial chromosomes
  • Unusual world-wide collaboration
  • New technology of robotic production lines (PCR tests)
  • Information shared on web (900 printed pages)

Genetic Markers

  • Freely recombine during meiosis unless they are physically close together
  • Linked markers usually inherited as a set

Genetic Maps

Genetic maps dependent on linkage analysis and recombination frequency:

  • Units of scale
    • Human = centimorgan (cM)
    • 1 cM = recombination fraction of 1/100 meioses
    • Equivalent to 0.7 - 1 Mb of DNA

Definitive genetic map

  • Assembled by Genethon laboratory (Paris)
  • Used microsatellite markers

Map Your Disease

  • Find a large family with a clearly defined disease
  • Using PCR check with 400 primers pairs, at about 11 cM intervals
  • Automation
  • Markers used in mapping
  • Restriction fragment polymorphisms (RFLP)
  • Minisatellites
  • Microsatellites


  • At least one marker should co-segregate with disease
  • Go to Human Genome Project to find linked loci
  • Fill in the gaps
  • Scan the human genome database for sequences associated with active genes in your marker

Proving You Have the Gene

  • Transgenic mouse - prove gene has biological function related to disease
  • Knockout mouse – inactivate gene and show disease develops
    Linkage, Prediction, Recombination

Linkage Calculation

  • LOD score = log of the odds score = statistical estimate of whether two loci are likely to lie near each other on a chromosome
  • If they are they are likely to be inherited together
  • LOD score > 3 generally taken to indicate that the two loci are close (1 to 1,000)
  • Determine recombination frequencies - can range from 0% (no recombination) to 50% (crossing over in half of meioses)
  • 50% recombination frequency would be observed from two markers on different chromosomes
  • Not calculated by hand...


  • Probability found by multiplying together the probabilities of each event happening independently
  • For instance: I need to be at work by 8 AM. For this to happen I have to set my alarm clock, I have to be lucky with traffic, and I have to find a parking space
  • Probability (work at 8) = Probability (set alarm) x Probability (no traffic) x Probability (parking space)

Physical Maps

  • Plot the actual location of DNA sequences on chromosomes
  • Units of scale = base pairs
  • Clone maps
  • Radiation hybrid maps - radiation breaks chromosomes
  • Fluorescent in situ hybridization (FISH)
  • Karyotype changes

Useful Terms

  • Genetic markers - provide the landmarks to plot positions within the genomic landscape
  • May be associated with phenotypic characteristics such as inherited diseases
  • Many not associated yet with observable phenotype = DNA sequence polymorphisms

Hapmap (Haplotype Map)

CEPH Donors

  • Reconsent from living donors
  • Local IRB gave permission to use samples from deceased donors
  • No names or other identifying information
  • No medical information
  • Only genotype information and sex released on Internet
  • More samples collected than used

Array Technology

  • Possible because of new technology
  • Allows better resolution than comparative genomic hybridization (CGH) on chromosomes

Array Analysis

  • Uses include gene expression, CGH, SNP analysis, protein analysis
  • Differences lie in material on array (DNA, cDNA, oligonucleotides, antibodies, proteins)
  • Choice of targets on array
  • Sensitivity - minimum region
  • Mosaics may not be detected
  • DNA - can do multiple tests in one experiment
  • Can compare multiple different individuals at multiple different targets


  • Human Genome Project resulted in explosion of new technology
  • Raised ethical questions (who owns the genome?)
  • Will enable faster identification of disease related genes
  • May enable personalized treatments