DNA Sequencing and Personal Genomics Case Study for Intro Biology

The rapid advances in DNA sequencing technology are beginning to affect how human diseases are diagnosed, and will soon affect significant numbers of people in the developed world. Because this technology will fundamentally alter many fields of biological research, students even in freshman biology courses should become aware of the technology and its potential impact. I think stories of children with mystery diseases, who are diagnosed by genome sequencing and successfully treated as a result, will make a compelling learning experience and lead students to questions that address most aspects of genomics appropriate for a college-level introductory biology course.

Isn’t sequencing a human genome prohibitively expensive and time consuming?

The graph below from the National Human Genome Research Institute shows that the cost of DNA sequencing has plummeted in recent years. The $1,000 human genome sequence is within sight.

Advances in reducing the cost of sequencing a million bases of DNA, compared with Moore’s Law for advances in computing power

Declining cost of sequencing a human genome

The rapid decline in cost of sequencing resulted from the advent of next-generation sequencing platforms such as Roche 454 (a YouTube playlist for a number of different sequencing technologies: (http://www.youtube.com/view_play_list?p=1B2FEA81FFAD1748). The development of massively parallel high-throughput sequencing technologies, coupled with single-molecule sequencing (the so-called third generation), in a highly competitive marketplace, continues to lower the cost of obtaining a whole human genome sequence. Illumina announced in a June 8, 2011 press release a huge price drop for a human whole genome sequence, from $19,500 to $9,500 (Illumina 6/08/2011), along with release of a personal genome browser app for the iPad. In 2014, Illumina claimed that Hi-SeqX Ten lowers the cost to $1,000 per genome.

What does this mean for ordinary people? It means that the era of personalized genomic medicine has arrived. Instead of individual genetic tests, it will become cost-effective for each person to have his or her own genome sequence. Here is a series of excellent articles in the Milwaukee Journal Sentinel about the first published use of genome sequencing to diagnose and identify a cure for a boy, Nicholas Volker, suffering from a previously unknown disease:

Nicholas Volker, March 2010, age 5


In this case, rather than sequencing the entire genome, the researchers sequenced the boy’s exome, the 2% of the genome that encodes proteins. Their paper was published in March 2011 in Genetics in Medicine (http://dx.doi.org/10.1097/GIM.0b013e3182088158) – a proof is freely downloadable here with an accompanying commentary.

So what do you get when your DNA is sequenced?

Too much information? A bunch of As, Gs, Cs and Ts, in strings of 100-200 letters. Your DNA sample is shredded and random fragments are sequenced. To get 99% of the target DNA sequenced at least once, the researchers sequenced Nic’s exome to an average of 34-fold. Individual sequence strings are matched against the human reference genome and differences noted. For Nic Volker’s exome, Worthey et al. found more than 16,000 differences from the reference human sequence. Which of these, if any, is causing the boy’s disease? The paper by Worthey et al. describes the process of sifting through the chaff to identify candidate gene mutations.

Question #1 for student discussion: given this long list of differences from the reference sequence, how can we identify the most likely candidate mutations? What criteria should be used to eliminate or include mutations?

DNA sequencing gives you hypotheses, not necessarily answers.

Question #2 for student discussion: In what way, or under what circumstances, would exome sequencing fail to discover the cause of a rare disease?

See story by Ed Yong: “Under 3 layers of junk, the secret to a rare brain disease” (Update 7/17/12) and this excellent summary of how exome sequencing analyses can miss the cause of even a Mendelian disease: http://massgenomics.org/2012/07/6-causes-of-elusive-mendelian-disease-genes.html Really, the decision to sequence his exome was a gamble born of desperation.

Question #3 for student discussion: What are possible ethical, legal and social considerations for human genome sequencing?

Genome sequencing has collateral consequences, in the form of answers to questions not asked, and possibly not wanted. (Update 8/25/2012: NY Times piece on the ethical quandaries encountered when sequencing human gneomes: http://www.nytimes.com/2012/08/26/health/research/with-rise-of-gene-sequencing-ethical-puzzles.html)

Added April 2015: I’ve created a case with discussion/clicker questions on the Nic Volker story. Click the title below to download the ppt slides (updated July 2015):

Finding the Fault in Nick’s Genome – sp2015

Student Inquiry Activity: NCBI Tutorial/Practical on human genetic variation and disease using hemochromatosis and sickle cell ftp://ftp.ncbi.nlm.nih.gov/pub/FieldGuide/FGPlus/NLMDecember2007/DiseaseGenes/disease_fgplusnlm_HO_2007.pdf

A highly reduced subset of actual patient sequence data would be ideal, but this tutorial goes through all the steps, from BLAST, to identification of the gene, dbSNP, OMIM, and visualizing the altered amino acid on the 3-D structure of the protein in Cn3D. Update 11/16/2011: Although most individual human genome sequences on NCBI require authorization to access, human cell line DNA sequences are available. One example of 454 exome sequencing of human cell lines is this project on the NCBI trace archive: http://trace.ncbi.nlm.nih.gov/Traces/sra/sra.cgi?study=ERP000265 (end update 11/16/2011)

Additional stories about Nicholas Volker: http://blogs.forbes.com/matthewherper/2011/03/02/sequencing-a-childs-dna-and-convincing-an-insurance-company-to-pay/ http://www.technologyreview.com/biomedicine/35068/?a=f

A new story about pinpointing the cause of a rare genetic disorder in a Utah family by exome sequencing: http://www.nature.com/news/2011/110623/full/news.2011.382.html

Emory U. researchers use exome sequencing to identify cause of glycosylation defect: http://www.sciencedaily.com/releases/2012/02/120203182621.htm

Ed Yong’s blog post about discovering a mutation associated with a rare, fatal neural disorder; the mutation is located within a transposable element nested inside another transposable element located within an intron: http://blogs.discovermagazine.com/notrocketscience/2012/03/12/under-three-layers-of-junk-the-secret-to-a-fatal-brain-disease/

A news story about the impact of 23andMe SNP genotyping for consumers: http://roswell.patch.com/articles/at-home-dna-test-changes-roswell-womans-life

NIH launches a new genetic testing registry, with information about over 2,500 genetic tests: story on Genome Web: NIH launches genetic testing registry


Blog post by Daniel MacArthur on new NCBI browser for GWAS studies. http://www.wired.com/wiredscience/2011/02/the-disease-ridden-genome/

NCBI’s genome-wide association studies browser: http://www.ncbi.nlm.nih.gov/projects/gapplusprev/sgap_plus.htm

(Update 7/17/12) My blog post about my own exome sequence: https://jchoigt.wordpress.com/2012/07/02/a-first-look-at-my-exome-variants-from-23andme/

(Update 11/20/12) A new video about genome sequencing for lay audiences:

And of course, genetics is NOT fate: http://www.genomesunzipped.org/2012/04/identical-twins-usually-do-not-die-from-the-same-thing.php


About jchoigt

I'm an Associate Professor in the School of Biology at Georgia Tech, and Faculty Coordinator of the Professional MS Bioinformatics degree program.
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12 Responses to DNA Sequencing and Personal Genomics Case Study for Intro Biology

  1. jchoigt says:

    This July 2011 Tedx Boston talk (11 min) by Richard Resnick is accessible for lay audiences and intro biology students, and powerfully makes the point about how genome sequencing will be as disruptive as computing and the internet:

  2. jchoigt says:

    Daniel MacArthur et al. published a paper in Science about human loss-of-function variants; average person carries 100 loss-of-function variants, and has about 20 genes where no copy of the gene is functional! Read his blog about the research here: http://www.genomesunzipped.org/2012/02/all-genomes-are-dysfunctional-broken-genes-in-healthy-individuals.php and the Science paper itself: http://www.sciencemag.org/content/335/6070/823.full

  3. jchoigt says:

    Oxford Nanopore stunned attendees of the 2012 Advances in Genome Biology and Technology (AGBT) meeting with the announcement of their GridION scalable sequencer, that will be able to sequence the human genome in 15 minutes, with minimal sample preparation, and very long reads (>45,000 bases). Even more shocking was their announcement of the MinION, a disposable mini-sequencer that plugs into a laptop USB port and sequences nearly a billion base pairs in several hours! The cost of the MinION? $900. When can we expect it? Third quarter of this year, according to the company.
    Here’s a synopsis of the announcement:
    And an early rumination on what this means for human genetics:
    We live in interesting times!

  4. jchoigt says:

    PBS Nova produced a program featuring Nick Volker’s story and others that highlight the new era of genome sequencing as part of personal medicine: Cracking your genetic code – http://www.pbs.org/wgbh/nova/body/cracking-your-genetic-code.html

  5. jchoigt says:

    Nature News piece about human exome sequencing projects to discover genetic variants that can help cause mental disability – http://www.nature.com/news/gene-hunt-is-on-for-mental-disability-1.10463
    One great question is how geneticists and doctors will know that they have found the causal mutation, when even healthy people have around 100 mutations that knock out gene function.

  6. jchoigt says:

    A really good story about an 18-year old woman who decided to get tested for Huntington’s Disease after her mother died of the disease. http://www.usatoday.com/news/health/story/2012-04-09/genetic-testing-huntingtons-disease/54475708/1

  7. jchoigt says:

    An interesting story about how even “simple” Mendelian disorders can turn out to have complex effects. A boy diagnosed at 3 years old with arginine synthesis deficiency is treated successfully with arginine. But as a teenager, he develops complications because the same enzyme is required for nitric oxide (NO) biosynthesis. http://www.chron.com/news/houston-texas/article/In-saving-teen-docs-find-simple-genetic-3516987.php

  8. Duke Medical School did exome sequencing on 12 parent-child trios where the child had an undiagnosed congential disease. Exome sequencing found a causal mutation in half the cases.

  9. jchoigt says:

    Ed Yong wrote a nice piece on how genome sequencing helped Lilly Grossman: http://phenomena.nationalgeographic.com/2013/03/11/we-gained-hope-the-story-of-lilly-grossmans-genome/

  10. jchoigt says:

    A great story about DNA sequencing to diagnose an infant’s mystery rare disease, this time involving Georgia Tech alumni. They used social media to find others with the same genetic defect, and stimulated (and collectively funded) research. http://www.newyorker.com/magazine/2014/07/21/one-of-a-kind-2

  11. jchoigt says:

    Nature news story about rapid sequencing of newborns for diagnosis: http://www.nature.com/news/fast-genetic-sequencing-saves-newborn-lives-1.16027

  12. jchoigt says:

    A moving blog post about rare diseases, and the difficulties families have raising funds, compared to the ice bucket challenge or breast cancer.

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