The Human Genome Project

Eric Lander PhDDirectorWhitehead Center for Genome ResearchCambridge, MA

Eric Topol MDProvost and Chief Academic Officer Chairman and ProfessorDepartment of CardiologyCleveland ClinicCleveland, OH

The Human Genome Project has been underway for 15 years.

1997-2001 were dedicated to sequencing with a final intensive push over the last 18 months.

February, 2001: dual publication of the genome maps, with some 94% of the human genome now freely available on the web.

Human Genome Project

History

Ahead of schedule

Every milestone in the project was met ahead of schedule.

The schedule was a shot in the dark; when the project started, no one knew how long it would take.

Human Genome Project

Incomplete

Human Genome Project

Despite the headlines, the sequence is still incomplete.

The project will be finished when:every last gap closed in the sequenceerrors are at a rate of <1 in 10,000

Expect most of the gaps to be filled by summer, 2001; another 18 months to tidy up the sequence

The target date to have everything pristine is April 23, 2003

Similarity of man and mouse

There is a difference of only a few hundred genes between man and mouse.

We shouldn’t be very surprised since man and mouse show great homology in physical systems.

While the large physiological systems are similar, the details in physiology and drug reaction are not; small variations in proteins have large consequences.

Human Genome Project

Two distinct effects are likely:

more sophisticated populationstudies to find causative genes will be possible

availability of the genome sequence will allow the detection of gene expression and proteomic analyses

New insights for coronary disease

Human Genome Project

A substantial fraction of cardiovascular disease is heritable, but finding the responsible genes has been difficult.

We already have identified 1.5 million (out of 4 million) sites of genetic variation in the genome.

When we have all major genetic variants, we can test each variant for correlation with CVD.

Finding causative genes

Human Genome Project

DNA arrays and proteomic analyses will become available.

Researchers will look at diseased and healthy tissue in different circumstances to examine the RNA and proteins expressed.

This will lead to an explosion of ideas and hypotheses on the pathophysiology and treatment of disease.

Pathophysiological insight

Human Genome Project

“I think it is going to change medicine the same way the periodic table changed chemistry.”

-Eric Lander

Systematic approach

Human Genome Project

The human population is 5000 generations removed from a small founding population.

Variants in the genome tend to group together in ancestral segments up and down the chromosome, making analysis easier.

The number of segments is probably between 30 and 40,000.

Studies will probably end up only involving some 100,000 genetic variants.

Too many variants?

Human Genome Project

Within the next 3 years, everything should be in place to begin large studies.

2 or 3 years after that should start netting us many of the important genes.

A decade out we will have a pretty solid understanding of etiology, pathophysiology and an explosion of treatment ideas, not unlike what has been happening in cancer already.

When will see a major impact?

Human Genome Project

A lot of progress has been made recently in understanding the genetics and treatment of certain types of cancers.

It may be more difficult to find therapies for CVD because in cancer, you just have to kill a diseased/aberrent cell while CVD requires more subtlety, since it deals with normal cells and normal responses.

Cancer treatment vs CV treatment

Human Genome Project

“I am extremely optimistic that the ground work is set now for a real molecular understanding that I think will then translate into the clinic.”

-Eric Lander

Optimism for the future

Human Genome Project