1. The Human Genome Project: Impact on Human Health Pragna Patel, Ph.D. Institute for Genetic Medicine University of Southern California

3. Variation in DNA sequence can be silent or lead to disease

4. DNA Genetic Code dictates amino acid identity in a protein

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

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

7. Human chromosomes

8. Challenge of discovering a mutation in the genome 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

9. 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

10. 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

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

14. 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

15. Tracking a disease mutation-bearing chromosome in a family I. A N B A N B 12 A N b a D B 1324 56 A N B a D B A N B A N b A N B a D b A N B A N B A N B A N b A N B a D B Linkage II.

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

17. Cumulative Pace of Monogenic Disease Gene Discovery: 1981 - 2008 2008 Draft sequencePCR HGP

18. Impact of Human Genome Project (HGP ) DiseasePre- HGPPost-HGP Friedreich ataxia13 years Huntington disease10 years Spinocerebellar ataxia type 1 7 years Molar hypodontia<2 months Congenital tufting enteropathy <2 months

19. Current Status of DNA testing for single gene disorders Directory of International Testing Laboratories www.genetests.org 575 Clinical and research laboratories 1115 Inherited diseases