Variation in DNA sequence can be “silent” or lead to disease

DNA Genetic Code dictates amino acid identity in a protein

Variation in DNA sequence in gene can change the protein produced by the Genetic Code

Types of Inherited Human Diseases
• Single gene disorders – rare, familial (Eg.
Hemophilia)
• Chromosomal abnormalities – typically sporadic
(Eg. Down’s syndrome)
• Multifactorial disorders (Eg. Arthritis, diabetes)
-Several genes involved, complex inheritance
- Environmental factors

Human chromosomes

Genome
Chromosome
Gene
Atcgtacgtaggtcagttt accggtaccatgtatagg tacccgggtaccctaccc cggcacc
T
Agcatca tataggacacatactgat catgcattacggatcgta cgtaggtcagtttaccggt accatgtataggtacccg ggtaccctacccgggga
Normal atcgtacgtaggtcagttt accggtaccatgtatagg tacccgggtaccctaccc cggcacc
A agcatca tataggacacatactgat catgcattacggatcgta cgtaggtcagtttaccgg accatgtataggtacccg ggtaccctacccaggga
Patient

Goals of the Human Genome Project (1990)
• Identify all the genes in human DNA (now estimated at ~25,000)
•Determine the sequence of 3 billion chemical base pairs that make up human
DNA
•Determine the sequence of model organisms for comparison to human DNA sequence

Goals of the Human Genome Project (1990)
• Store the information in databases
•Improve tools for data analysis
•Transfer related technologies to the private sector
•Address the ethical, legal, and social issues (ELSI) that may arise from the project

The Human Genome Project: Why?
Sequence
Genome
Find Genes
Drug
Candidates
Establish
Function and
Disease Mechanism
Cure
Genetic Mapping,
Mutation Detection
Diagnostics/
Prognostics
Gene Therapy

Requisites for genetic mapping of a disease to a chromosome
1. F amilies with the disease
2. Accurate diagnosis
3. Defined pattern of inheritance
4. Polymorphic DNA markers

Tracking a disease mutation-bearing chromosome in a family
I.
A
N
1
A
N
Linkage
A
N
2 a
D b B B B
II.
1
A
N a
D
B B
A
N
2
A
N
3
A
N a
D
B b B b
A
N
4
A
N
5
A
N
A
N
6
A
N a
D
B B B b B B

FINE MAPPING AND MUTATION IDENTIFICATION
Post-genome era
1-5 Million base pairs
…..CGACCGGTATGCGATGACTGGTCATGTACTTACTATTC….
Human genome sequence
Gene content map
Gene
Normal
Patient
.......C C T A C.........
.......C T T A C.........
DNA sequence

Cumulative Pace of Monogenic Disease Gene
Discovery: 1981 - 2008
PCR HGP Draft sequence

Impact of Human Genome Project (HGP )
Disease Pre- HGP Post-HGP
Friedreich ataxia
Huntington disease
Spinocerebellar ataxia type 1
Molar hypodontia
Congenital tufting enteropathy
13 years
10 years
7 years
<2 months
<2 months

Directory of International Testing Laboratories www.genetests.org
575 Clinical and research laboratories
1115 Inherited diseases