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Musings of a Cancer Doctor
Wide-ranging views and perspective from George W. Sledge, Jr., MD
Monday, November 12, 2012
On Variability

There are, at most, two hundred thousand chimpanzees on the planet, and some seven billion humans, and yet any two chimps are less alike genetically than any two humans.  We simply don’t vary very much: a base pair per thousand between you and the person sitting next to you on the park bench.

 

Why this is the case is mysterious.  At some time in the past (the geneticists mutational clock would say 80,000 years ago) we went through a genetic bottleneck, Homo sapiens contracting to a few thousand (or perhaps a few hundred) breeding pairs.  We came very close to extinction.

 

That bottleneck past, we took off as a species, performing what the Harvard biologist E.O. Wilson calls “the social conquest of Earth,” and now our variability is on the upswing.  The anthropologist John Hawkes calculated several years ago that the human mutation rate is at its highest point ever, a function of increasing population size, increasing ecological niches occupied, and increasing exposure to environmental stressors.

 

Just how variable are we? The 1000 Genomes Project just published (in the November 1, 2012 issue of Nature) its deep dive into the human genome, examining the genomes of 1092 people from 14 populations around the globe. The article caps a spectacular year for genomic analysis that has included the ENCODE project and large-scale cancer genomic analysis for multiple cancers (from the TCGA and others).

 

It turns out that, if not quite as interesting as chimpanzees, we have somewhat more of the spice of life than we thought, and that our varieties matter. The investigators discovered some 38 million single nucleotide polymorphisms (twice the previous number of known SNPs), many of them quite rare, as well as 1.4 million short insertions and deletions, and some 14,000 larger deletions and rearrangements. The average person carries 76-190 rare deleterious variants expected to affect protein function, plus 20 more loss of function and disease-associated SNPs.

 

A decade or so ago, one used to hear concerns that insurance companies might use our growing genetic knowledge to discriminate against the genetically disadvantaged.  The 1000 Genomes Project is reassuring in this regard: once started down that path, there would be no one left to insure. We’re a genetic mess: imperfect creatures all. Mother Nature keeps piling up mutations.

 

How will we use this information, once we start performing deep sequencing in newborns? Will we all carry the memory stick around with us, ready to plug in to the health system’s computer when we are prescribed a new medicine? The bioinformatics challenge seems as large as the health maintenance promise.

 

Other layers of variation are superimposed on our genome.  Epigenetic studies are emphasizing how the environment can cause heritable changes in gene expression caused by mechanisms such as methylation and histone modification. For instance, the paternal grandsons of Swedish men exposed to famine at a young age in the 19th century are (a century later) less likely to die of cardiovascular disease.

 

This unexpected epigenetic source of variability plays a role in human cancer, with a thriving drug development effort now aimed at DNA demethylation and histone deacetylation.

 

A few years ago, based on an article attributing brain-enhancing qualities to Mozart, there was a fad for playing classical music to newborns. The then Governor of Georgia, among others, said it made the kids smarter, and tried to appropriate money for sending classical music CD’s home with mom and child.  This all seemed ineffably silly to me at the time, but who knows?  Maybe a Chopin etude methylates DNA differently than heavy metal. Claudio Brigati, in a recent issue of  Frontiers in Genetics, made the case for music inducing epigenetic changes with lasting neurophysiologic effects.

 

The greatest source of variability in humans is culture.  As E.O. Wilson notes, in his recent book The Social Conquest of Earth, we are by no means the only, or even the most successful, social species occupying the planet.  Ants have been around a lot longer.

 

But ant societies are locked in place, their cultures frozen in amber tens of millions of years ago, whereas human culture is in the process of hyper-evolution, with consequences yet unforeseen, both for our species and our planet. 

 

Serious social scientists once worried about the dangers of excessive conformity, with “The Man in the Gray Flannel Suit” representing a depressing terminus for modern society.  That danger, at least, has vanished, if it ever even really existed.  Does anyone wear gray flannel suits any more?

 

The social scientists now worry about the progressive atomization of society, the “Bowling Alone” phenomenon. Hypervariation, they warn us, may be a bad thing if it affects social cohesion to the point we no longer interact effectively.

 

I’m less concerned.  I like variation and individualization.  They’ve always smelled like freedom to me. I’ve never wanted to live in an ant colony.

About the Author

George W. Sledge, Jr., MD
GEORGE W. SLEDGE, JR., MD, is Chief of Oncology at Stanford University. His OT writing was recognized with an APEX Award for Publication Excellence in the category of “Regular Departments & Columns.”