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Genetic Linkage

23andMe's Exome Sequencing and the Tenth Edition of My Textbook

It’s been a strange week. The tenth edition of my human genetics textbook was published, just as 23andMe announced that they now offer whole exome sequencing, for $999. The exome is the part of the genome that encodes proteins, the 50 million or so of our 3.2 billion DNA bases that directly provide our inherited traits. It is the Cliffs Notes of the genome. The rest consists of repeats, controls, a viral sequence here and there, and stuff we don’t understand that was once called junk.


When I wrote the first edition of my textbook, in 1993, I couldn’t have imagined that the exome – a term not yet invented – could be sequenced in a spit sample sent in by anybody to a web-based company.

The timing of the two events got me thinking about what was going on in human genetics when I first scribbled my book's outline onto a napkin at a publisher's dinner. Turning back the clock, what was new in human genetics in 1993, and what hadn’t yet happened?

• The Huntington’s disease mutation had just, finally, been discovered, after a decade-long "chromosome walk" from a marker out on the tip of chromosome 4.

• Gene therapy basked in the afterglow following the first clinical trials to treat an immune deficiency; 18-year-old Jesse Gelsinger hadn’t yet died from his gene therapy for a urea cycle disorder, which derailed the field. (My new book about gene therapy chronicles the rebirth of the technology.)

• The Human Genome Project, public consortium version, was getting underway, but the Celera team that actually got to the finish line first didn’t exist, as such.

• Craig Venter had yet to sequence the first genome of a free-living organism – that would happen two years later.

• The film GATTACA was four years away from bringing the spectre of too much genetic information to the public.

To see how far we’ve come, I looked at Nature Genetics from September 1993. The lead editorial probed the infamous just-published paper by Dean Hamer from the National Cancer Institute suggesting what would become known as the gay gene on the X chromosome, ushering in the era of genetic determinism, the idea that we are our genes. Other articles mapped genes for infertility, migraine, and an assortment of rarities. A study about a baby with “leprechaunism” caught my eye – it’s been deemed non-PC since then and is now called Donohue syndrome.

The table of contents for the September 2011 issue of Nature Genetics is markedly different from its 1993 counterpart. 23andMe, apparently, is onto something, because exome sequencing dominates, beginning to replace the less meaningful genome-wide association studies. It’s powerful. Take a bunch of people with an illness whose parents don’t have it and compare their exomes to those of their parents. New mutants revealed! Such exome investigations show that schizophrenia, for example, is very often due to a new mutation.

Exome sequencing is a fantastic research tool, and of enormous benefit to families in desperate search of the mutations behind their illnesses. But how will exome sequencing affect the average person? At just twice the cost of an iPad, the test will surely find takers. But not me. Not yet.

If medical technology progresses in lock step so that physicians can pop exomes into a database, a la GATTACA, and get a fast diagnosis and treatment plan, that’s fine. But I don’t think we’re quite there yet. Until we are, I’ll keep my exome where it belongs, scattered across my genome, immersed in seas of meaningless DNA sequence, wound around its protein scaffolding and tucked neatly into my nuclei, shrouded in mystery.

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