I was a sophomore in high school in 1987 when my science teacher told us how scientists were developing a plan to sequence the DNA of a whole human. The “Human Genome Project” began in 1990 and laid the foundation for having a deeper understanding of our genes, how they code for our traits, and how changes in those instructions can lead to genetic disorders.

Further, the story behind the researchers who worked on this project is filled with intrigue. There is Dr. Eric Lander who helped to lead the public version of the project and the effort to make DNA sequence information readily available to all. Then there is Dr. Craig Venter who started his own company, Celera, and used a new process called “shotgun sequencing” to accelerate the race to be the first to sequence the genome.

This race was beautifully described in NOVA’s video “Cracking the Code of Life”. Students love the intrigue of the history of the Human Genome Project as well as the issues it raises (should DNA sequences be patented?). What is difficult for students to understand is how sequencing works. In particular, the process of shotgun sequencing.

In order to help my students understand how shotgun sequencing works, I developed an activity which utilizes the children’s story “If You Give A Mouse A Cookie”. I typed the “If You Give A Mouse A Cookie” story into a document. I printed it once on white paper and cut it into segments (preferably, not always at the end of sentences).

I separate out the fragments into 4-5 parts of the story.  They work in groups to put together their portion of the story. I do not review the story with them beforehand. In fact, this works better if you do not.

I then encourage one group to begin reading their part out loud (hint: the story starts like the title). When they finish reading the story, I ask them how they knew to put together their section even if they did not remember the story. Importantly, there was context – periods, capitalized words to start a sentence, the story had to flow, etc. I also ask how confident they were that they had their section ordered correctly.

I print the story a second time on bright green paper. However, this time I print it twice. I cut both green copies in different locations in order to generate “staggered overlap.”

They then receive the second (green) version. I usually tell them this one has “staggered overlap.” When they finish putting this one together, I ask them how much context mattered (very little) and how confident they were that they were correct when they were done (only one way for the pieces to be put together).

After I collect all the bags of story pieces, we talk about how in DNA there isn’t any context in which all you are looking at are fragments of DNA letters – there is no way to know ahead of time which letter comes first, second, etc. Staggered overlap eliminates the need for overlap. In order to produce the staggered overlap, however, it requires multiple copies of the story, each version cut at a different location (otherwise, it isn’t staggered).

Shotgun sequencing requires multiple copies of a person’s DNA and each version is cut with a different restriction enzyme. Each fragment is sequenced and a computer can figure out how to overlap each of the fragments. This process works fairly well until you encounter regions of chromosomes which are highly repetitive: How would you know where the “staggered overlap” begins and ends? We tend to find these regions in the telomeres (ends) of chromosomes. The full genome complete was only recently completed because of these repetitive sequences.

The students enjoy the activity. They like the story (who doesn’t?), but more importantly, they understand the process of shotgun sequencing and how it was a valuable approach which greatly sped up the Human Genome Project.

Please let me know if you have any questions. Until next month…

PETER KRITSCH is an Oregon High School biology and biotechnology teacher who has been serving as an adjunct instructor and consultant for the BTC Institute for many years. He is primarily involved in our teacher training and support efforts. He also assists with the ongoing development of our Biotechnology Field Trips program and serves as an advisor for Camp Biotech I and Camp Biotech II for high school students.