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Musings of a Cancer Doctor
Wide-ranging views and perspective from George W. Sledge, Jr., MD
Monday, March 03, 2014
The Things We Pass On

I thought that there could not have been any better year for genomics than 2012, but the last year or so has matched it. The falling price of genomics, the development of new analytic techniques, and the inventiveness with which genomic technologies are applied have colluded in the creation of wonderful new insights. There is hardly an area of biology or medicine that hasn't benefited in some way.

Let's look at the study of human origins. We learned, just a few years ago, that most non-sub-Saharan moderns carry a touch of Neanderthal in their genome. This discovery is largely the work of a group led by Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Leipzig, Germany. Pääbo has also found evidence of other admixtures (the mysterious Denisovans who make up part of the modern genomic complement of Pacific islanders). 

 

It would have appalled our Victorian ancestors, as well as the many 20th century racial ideologues wedded to a belief in the purity of their particular ethnic group, to learn of this unwelcome ancestry. But I found it a charming thought.

 

If 1.5% or so of our genome come from Neanderthal ancestors, the interesting question is "which 1.5%?” Is it a random set of genes, or, as Darwinian theory might predict, a set that increased our biologic fitness? A first-pass look at our Neanderthal inheritance suggests the latter: definitely non-random, definitely selected for (or against). Two recent publications (in Science and Nature) suggest that there was positive selection for genes involved in skin and hair -- particularly the type II cluster of keratin genes on 12q13 -- suggesting that our “Out of Africa” Homo sapiens ancestors benefitted from Neanderthal cold climate genes. It turns out that when we say that someone is “thick-skinned” we are implying Neanderthal ancestry.

 

At the same time, there was significant negative selection for X chromosome (a five-fold reduction) and testes-specific genes, as well as reduction of Neanderthal DNA in a region of the genome containing a gene thought to play an important role in human speech and language. The authors suggest that human-Neanderthal hybrids had reduced fertility, resulting in elimination of the X chromosome genes causing the infertility.

 

Well, OK, but so what? Why should anyone really care, other than in the “gee whiz” way, which scientific curiosities of no particular current importance appeal to intelligent onlookers? Because, once again, William Faulkner was right: the past isn’t dead. It isn’t even past. The researchers identified nine variant genes associated with specific disease-linked traits, including (to quote the Nature paper) “alleles of Neanderthal origin that affect lupus, biliary cirrhosis, Crohn’s disease, optic-disk size, smoking behaviour, IL-18 levels and type 2 Diabetes.”

 

Many of my breast cancer patients dread the idea that they have passed on a mutation to their children that will doom them at some future point. The sense of guilt can be overwhelming, that fear of a dark cloud hanging over those they hold most dear aligned with the certainty that they were the cause of their children’s future grief. I tell them that it is certainly not their fault, any more than it was their parents or their parents’ parents. And the good things they have given their children -- life, love, home, and family -- certainly far outweigh the bad. But this view of the things they pass on rarely seems to assuage the guilt, nor the sadness that attends it.

 

BRCA mutations may date back a millennium or two. But to extend the disease-causing mutation story back several tens of thousands of years (the Neanderthals became extinct some 30,000-plus years ago, and the interbreeding is thought to have occurred 40-80,000 years ago) is just astonishing. 

 

Try explaining to a lung cancer patient that he couldn’t quit smoking because of a gene he inherited from an extinct species: doomed by your inner cave man, if you will. Or, perhaps, some weird cosmic revenge for wiping out the Neanderthals?

 

Human history is rife with examples of one population violating the space of another, but we rarely think of these interactions in genomic terms. A new analytic technique called Globetrotter changes that. Produced by researchers at Oxford University, and published recently in Science, Globetrotter uses modern human genomes to identify ancient population migration patterns. The authors call these “admixture events,” a polite term for what was often a very messy, very ugly history. You can take a look at these at the Globetrotter website at http://admixturemap.paintmychromosomes.com

 

The authors reasoned that if someone from population A hooked up with someone from population B, then their offspring would share the genetic history of both parents. And then, over time, genetic recombination would occur, allowing one to clock how long ago the genomic mash-up happened. A fairly simple idea, but an enormous amount of thought and work went into making Globetrotter a reality.

 

A decade ago studies of the Y chromosome suggested that a relatively large percentage of selected Asian populations descend from Genghis Khan. Globetrotter confirmed this analysis, looking, not at the Y chromosome, but at approximately a half-million SNPs throughout the genome in some 1500 individuals from around the world. The Mongol Horde was not some group of peace-loving picnickers camping out on the Silk Road: Genghis and his kids were very, very bad people, and we have the genetic evidence to prove it.

 

Globetrotter also defined several other admixture events. To quote the paper: “We identified events whose dates and participants suggest they describe genetic impacts of the Mongol empire, Arab slave trade, Bantu expansion, first millennium CE migrations in Eastern Europe, and European colonialism, as well as unrecorded events, revealing admixture to be an almost universal force shaping human populations.” Maybe those unrecorded events were peaceful ones, but the ones we know about were not. Universal force, indeed.

 

These are first revelations from Globetrotter, and no doubt others will emerge. It seems pretty clear that much of prehistory (and a fair amount of history) may need to be re-written in the next few years. Could anyone have predicted this synchronicity of history and biology a couple of decades ago? Will any legitimate historian, going forward, be able to ignore science? And, as the Neanderthal data suggests, will we MD’s be able to ignore the lessons of anthropology?

 

There were a few other recent genome-based history lessons worth mentioning. In 2012 one of the coolest stories involved the discovery of Richard III's bones under a parking lot. I wrote a blog post about it at the timeand the Shakespeare lover in me still finds this ineffably awesome. Now comes the suggestion that the bones of King Alfred the Great, or perhaps his son, have also been found. The evidence here is less compelling (unlike the Richard III story, there are no known modern descendants to compare genomes with) but still intriguing.

 

I note in passing that the Sledge family’s ancestral bones remain to be discovered. I’m not holding my breath. But the news from a 12,600 year-old burial site in Wilsall, Montana gives me some hope. Looking at the genome derived from the only human burial associated with the Clovis culture (makers of the beautiful Clovis point arrowheads), the investigators (a University of Copenhagen group publishing in a recent issue of Nature) demonstrated that some 80% of all present day Native Americans are direct descendants of the individual’s closest relatives. Though not, alas, of the boy buried in Wilsall: he died shortly after his first birthday.

 

There’s always something wonderful about these genome-based historical studies. You feel connected, knowing that men and women walking by you on the street today carry genes from the family of a child buried over 12,000 years ago in Montana, or from ancestors who met each other when Homo sapiens met Homo neanderthalensis somewhere in the Levant. And that someday we too will be links in the great chain, passing on (if we are lucky in the genetic game of chance) our own genes to some unimaginable future.

 

In my next post I’ll write about what we’ve learned about cancer genomics in the last year. It may not be quite as much fun as Neanderthals, Globetrotter, and Clovis culture genomics, but it is consequential and interesting. Our own cells pass on things as well: individual microevolution as opposed to global macroevolution.

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.”