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The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
Figure 9.1: Deletion Mapping. The human gene for acid phosphatase exists in two alleles, A
and B. Karyotyping of a child of homozygous parents (A/A and B/B) revealed a chromosome
translocation, which mapped the gene’s locus to tip of the short arm of chromosome 2. After Sutton (1988)
Figure 9.2: Physical mapping by in situ hybridization Figure 9.3: Physical mapping of chromosomes by contigs.
The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
Figure 9.4: Linkage of the genes for nail-patella syndrome (NPS) and the A/
B/O blood types. In this human pedigree, the roman numerals represent three
successive generations. The blood type designations reflect the underlying
allele combinations. Members of this family who have NPS usually show the
BO blood type, except for individuals marked with an asterisk. Figure 9.5: Crossing over
between homologous
chromatids can generate new
combinations of genetic
alleles. Part (a) shows a pair of
human chromosomes 9 as
they would occur in
individual I/2 of Figure 9.4.
N = nail-patella mutant allele
n = nail-patella wild-type
allele IO, IB = blood antigen alleles
After Cummings (2006)
Figure S9.c:
Genetic Map
of human
chromosome 1
After Cummings
(2006)
The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
Figure 9.6: Single Nucleotide Polymorphism (SNP)
After Thieman & Palladino (2004)
Figure 9.7:
Variable Number
Tandem Repeats,
a.k.a.
Microsatellites
After Thieman & Palladino (2004)
Use of VNTRs in “DNA Fingerprinting”
From Thieman & Palladino (2004)
The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
Update 9.1: ENCyclopedia Of
DNA Elements (ENCODE) Project
Using hypersensitivity to DNaseI as a criterion, an
international consortium of 442 scientists from 32 institutions
has linked about 80% of the previously so-called “junk DNA”
to some biochemical function. Such non-translated but
functional DNA sequences include promoters, enhancers,
sequences encoding regulatory RNAs, and protein-binding
regions involved in DNA methylation as well as chromatin
organization. Some of these sequences have probably played
major roles in the evolution of complex traits. Six articles by
consortium members in the 6 September 2012 issue of Nature.
The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
Model organisms
The translated regions of a few thousand genes, many of them
involved in development, aging, and neural functions, have
been highly conserved in evolution. Thus, the protein
encoded by a human core gene is likely to be very similar in
C. elegans, Drosophila, and Danio rerio. These organisms,
because they are easy to maintain and breed in the laboratory,
can serve as model organisms for medically relevant research.
The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
Figure 9.8: Finding a human disease gene
Figure S9.d: Known genetic disorders of the human
From Peltonen and Kusick (2001))
The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
After Krogh (2005)
Figure 9.9: DNA
microarray. After Krogh (2005)
Update 9.2
For $ 99 and a saliva sample, personal genome testing
companies offer personal genome sequence data directly to
consumers. The Federal Drug Administration has posted on
their web site a warning letter to 23andMe charging that the
company has not provided adequate evidence about the
accuracy of their results. The concern is that false positives
may mislead concerned customers, such as women with a
family history of breast cancer, to take harmful but
unnecessary preventative measures.
Legal issue: Does 23andMe provide not only information but
also medical advice, which should be regulated?
New York Times, 26 November 2013
The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
Update 9.3
Concerns about civil liberties are raised by laws that allow
police to take blood or saliva samples from anyone who is
arrested. DNA information from such samples is stored in a
national data base and used to identify criminals. Such use
may include searches for imperfect matches, which could turn
up relatives of persons who left DNA at a crime scene. Such
relatives would then have to deal with unjust suspicion.
Officers of the federal government and more than half of the
U.S. states may take samples immediately, i.e. before a
prosecutor files charges. If charges are not filed or dropped
later, it is often left to the arrestee to ensure that his/her data
are expunged from the data base and that his/her samples are
removed from storage (Murphy, 2013). The Human Genome Project
•  Brief History of the Human Genome Project
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Physical Chromosome Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
What Have We learned from the HGP?
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications
Figure S9.a:
DNA cloning.
Preparation
and screening
of a mouse
DNA library
in
bacteriophage.
From Kalthoff
(2001)
Figure S9.b: DNA sequencing
The DNA segment to be sequenced is
replicated in vitro in a way that generates
labeled segments terminated randomly by
incorporation of a modified nucleotide.
This photograph shows the results of four
sequencing reactions, terminating with an
A, C, G, or T, and repeated four times
(brackets at bottom). The labeled
segments are separated by gel
electrophoresis and made visible by
autoradiography. From Kalthoff (2001)
The Human Genome Project
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Brief History of the Human Genome Project
Physical (or Molecular) Maps Genetic (or Linkage) Maps
DNA Markers
Sequencing and Annotating Genomic DNA
Identification of Disease Genes
Use of Genomics for Individualized Medicine
Ethical, Legal, and Social Implications