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Human Genome Project
Chapter 9
Central Points (1)
 Large, international project analyzing human
genome
 Gene mapping to locate human genes
 Number of surprises as human genome analyzed
Central Points (2)
 Scientists apply information from Human Genome
Project (HGP) to medical diagnosis and treatment
 Gene therapy is a future application of the HGP
 Ethical and legal aspects of the HGP discussed
Case A: The Future Tells All
 Natalie had fetal cells collected from her blood
 DNA of fetus analyzed
 Fetal sequencing helped them “know” their baby
before meeting it
9.1 Goals of HGP (1)
1. Create maps of the human and other creatures’
genomes
2. Find location of all genes
3. Compile lists of expressed genes and
nonexpressed sequences
4. Discover function of all genes
9.1 Goals of HGP (2)
5. ID proteins encoded by genes and their functions
6. Compare genes and proteins between species
7. Analyze DNA differences between genomes
8. Set up and manage databases based on
genomes discovered
HGP Timeline
Cracking
the
Code of life
Video
Human
genome
Project
Getting the
letters out
LQT1 Long
QT syndrome
Chromosome
Maps
Map shows
where all the
genes are
located on
each
chromosome
Diabetes type 2
Sickle cell anemia
Multiple tumors
of glands
Chromosome 11
Fig. 9-2, p. 156
Methods
 Began in 1990, human genome ~3.2 billion
nucleotides
 Required development of automated methods
 Bioinformatics created software, web-based
databases, and research tools to collect,
analyze, and store information
 Genomics: study of genomes
HGP Now
 Portion that carries genes was sequenced in 2003
 Function of remaining 15% unknown and currently
being sequenced
 Sequenced portion studied to ID genes and assign
functions
 Proteomics: study of protein structure and
function
9.2 Gene Mapping
 Genes close together on same chromosome
tend to be inherited together and show linkage
 In 1936, hemophilia and color blindness found to
be linked, both on X chromosome
 Difficult to map genes on autosomes, requires
very large families with two specific genetic traits
X-Linked Genes
Location of
hemophilia A gene
Location of color
blindness gene
X Chromosome
p. 147
Linked Genes Separate by Crossing Over
 Separation of the two alleles is result of crossing
over between two genes
 Occurs randomly in meiosis
 Frequency of crossing over related to distance
between two genes
 Linkage map of a chromosome can be
constructed
Autosomal Linkage
 ABO blood group and nail-patella syndrome
Crossing Over
Linkage or Genetic Map
 Order of genes on a chromosome and distance
between them
 Expressed as percentage of crossing-over events
 10% = 10 map units or centimorgans (cM) apart
 From this pedigree, frequency of crossing over:
2/16 = 12.5%. or 12.5 cM (actual value ~10cM)
Human Linkage Map
a
b
10.1 cM
c
6.2 cM
Fig. 9-3, p. 147
Positional Cloning
 Markers identified that show differences in:
• Restriction enzyme cutting sites
• Number of repeated DNA sequences (i.e., STRs)
 Markers assigned to chromosomes
 Used to follow genetic disorder in pedigrees
 Map one gene at a time, and by late 1980s,
more than 3,500 genes and markers
Genes Mapped by Positional Cloning
DNA Sequencing Today
 Can rapidly sequence DNA with computer
programs
 Sequence entire DNA sequence in genome
 Uses high-speed sequencers and computers
 Allowed HGP to succeed
9.3 Whole Genome Sequencing
 Construct a genomic library that contains all
sequences in a genome
 Fragments of DNA placed in a DNA sequencer
 Generates nucleotide sequence (As, Cs, Gs,
and Ts)
 Assemblers (specialized software) produce
sequence of genome
Finding Genes from Sequence
 Software programs scan sequences, searching
for promoter sequence
 Sequences that follow promoter are genes
 AA sequence determined by matching the
nucleotide triplets to corresponding AA
 ID protein encoded by this gene
9.4 What Have We Learned?
 > 3 billion nucleotides of DNA
 ~5% genes code for proteins
 Many remnants of genome’s evolutionary history
 > Half the genome is repetitive DNA
Types Repetitive DNA
 45%: transposons
• New copies can move (or transpose)
• Most not functional
• Do not replicate and move around
 17%: LINE 1 sequence
 10%: Alu sequences
 Others including short tandem repeats (STRs)
Other Surprises from HGP
 20,000–25,000 genes but > 500,000 known
proteins (possibly exceed 2 million)
 Possible mechanisms
• During processing mRNA, the coding segments
can be rearranged
• Proteins modified after synthesis
 Human Proteome Project (HUPO): ID proteins,
functions, and interactions
9.5 How Can Information Be Used?
1. ID location of gene
2. Function of the protein encoded by this gene
3. How the mutated gene or its protein product
results in a disorder
 Allow development of treatments and
medications
Cystic Fibrosis (CF) Gene
 Positional cloning ID gene, long arm of
chromosome 7
 Isolated nucleotide sequence, ID AA sequence
of CF protein
 Compared to databases of other organisms,
protein in plasma membrane
 Now developing medications
9.6 Future of Genome Sequencing
 New technologies to reduce cost and time
 Make sequencing routine in medical care
 Possible for doctors to monitor your health
 Provide:
• Information to reduce risks for certain diseases
• Early diagnosis of conditions
9.7 Gene Therapy
 Recombinant DNA technology to treat genetic
disorders
 Transfer copies of normal genes into cells (or
people) with defective copies of these genes
 Normal genes directs synthesis of the normal
protein
How Are Genes Transferred?
 Cells removed from the body
 Normal copies inserted using virus, or vector
 Cells grown in the laboratory
 Checked that normal gene actively making protein
 Cells transferred back into the body
First Gene Therapy Patient (1990)
 Ashanti DeSilva had severe combined
immunodeficiency disorder (SCID)
 No functional immune system, die from infection
 Inserted gene for adenosine deaminase (ADA)
into her white blood cells
 Treated cells injected into her, allowed her to
develop an immune system
Ongoing dilemma:
Parkinsons My father, my brother and me video
Problems with Gene Therapy
 In many cases, gene therapy has not worked
 Few patients developed leukemia
 At least two people died
 Scientists working to correct problems
 Need to develop new approaches to use genes
to treatment genetic diseases
 Gene patent video start 27:33- end 36:33
9.8 Legal and Ethical Issues