One of the more amazing results of the genomic revolution has been the window it opened on our past. It is only a few years since the discovery of Neanderthal genes in the modern Eurasian genome, as well as the mysterious Denisovan genes present in modern Melanesian islanders. For most of my life, Neanderthals were hulking cave men, long extinct, their very name a term of abuse. Now, every morning when I shave, a Neanderthal face stares back at me from the mirror. My lack of photogenicity finally has a rational explanation.
But it turns out there is a great deal more. The last year has seen an explosion in genomic studies illuminating our past, all quite fascinating, and certainly unexpected.
Let's start with an obvious Charles Darwin sort of question. Neanderthals and our main line ancestors split apart half a million years or so ago. They met again on several occasions, and those happy reunions resulted in our current 2 percent or so of Neanderthalism. The 2 percent, by the way, appears to be down from 6 percent back in the day, if we look at ancient human genomes.
Are our legacy Neanderthal genes randomly distributed throughout our genome, or have they been selected for? No question, and no surprise: selected for.
A History of Genes
Let's start with the Y chromosome, that puny little thing, that living rebuke to Freud's concept of penis envy. It has an important tale to tell, for like the mitochondrial genome in women, it provides an easy gender-specific snapshot for men.
The modern human genome has no Neanderthal Y chromosome genes. None whatsoever, as far as we can observe. They were eliminated. This could represent random loss over time, but a recent deep dive into the Neanderthal Y chromosome suggests a probable culprit for this ethnic cleansing. The Neanderthal Y chromosome contains three minor histocompatibility antigens capable of triggering an immune response known to contribute to miscarriages.
This work adds to earlier data suggesting so-called "genomic deserts" for Neanderthal genes on the X chromosome and for genes governing testicular function, painting a picture of what is known as "hybrid infertility." Humans and Neanderthals lived right on the edge when it came to prospects for interbreeding.
What did we get from our Neanderthal ancestors? A nasty bunch of disease predispositions, for one thing. If one looks at single nucleotide polymorphisms (SNPs) derived from them, and then crosses those SNPs with the electronic health records of 28,000 adults of European descent, one sees sizeable increased risks for depression, actinic keratosis, hypercoagulable states, and tobacco addiction. I have this weird vision of a moody, cigar-smoking, warfarin-ingesting, bearskin-clad hulk with a bad complexion hunting wooly mammoths on the Eurasian steppes.
By the way, the paper that showed these things is quite wonderful, linking the electronic health records of 28,000 adults across numerous medical institutions to large SNP databases for those individuals to the Neanderthal genome. It is CancerLINQ for Neanderthals. The ready transportability of health data and its cross-linking with genome datasets for research purposes suggests they were not using the dominant electronic health record system found in the San Francisco Bay area.
On the plus side, Neanderthal genes appear to provide us protection against parasites. Our modern genome gets several members of the Toll-Like Receptor family (TLR1, TLR6 and TLR9) from our Neanderthal ancestors, and these immune receptors are valuable activators of our adaptive immune responses. There's a growing literature on Toll-Like Receptor's roles in antitumor immunity, so perhaps one day soon we'll enroll Neanderthal cell surface receptors in the fight against cancer. Neanderthal genes also affect our skin: if someone says you are "thick-skinned," your Neanderthal traits are being praised.
Speaking of the Y chromosome, one recent study looked at the modern Y chromosome in 1,200 men from 26 modern populations. All living men descend from a man living 190,000 years ago, the male equivalent of "mitochondrial Eve." This is unsurprising. What was of interest was evidence for male population explosions on five continents at different times over the past 100,000 years, with rapid expansion of specific male lineages in just a few generations.
Half of all men of Western European origin, for instance, descend from just one guy living 4,000 years ago. The authors of the Nature Genetics paper tried to imagine why this might have occurred: introduction of a new technology related to the agricultural revolution, perhaps. I'm doubtful that my ancestor proto-George (from the Greek [GAMMA][epsilon][omega][rho][gamma][iota][omicron][zeta] (Georgios) which was derived from [gamma][epsilon][omega][rho][gamma][omicron][zeta] (georgos) meaning "farmer, earthworker") was some peaceful, humble farm boy who invented the plow. Far more likely that he was some prolific thug with a gang, or whatever passed for a gang in 2,000 BC in France or Germany. Genghis Khan before Genghis Khan, lost to history but remembered in our genes.
Tracking Viral DNA
Neanderthals aren't the only interlopers in the modern human genome. Let's look at our viral genome. One of the great discoveries associated with the Human Genome Project was the large amount of viral DNA incorporated into human DNA, fully 8 percent or the whole.
For quite some time, this book was shelved under "Junk DNA" in the genome library. But no more. Work published in Science shows that the viral DNA (from so-called "endogenous viruses") is not randomly inserted in the human genome. Rather, it clusters, and clusters around those parts of the genome associated with immune function. Here's where the story gets really interesting. Our genomes appear to have co-opted the viral invaders for the purpose of-you guessed it-fighting off other viruses.
When the authors of the paper used CRISPR/Cas9 technology to snip out endogenous viruses close to the AIM2 immune gene, it no longer responded effectively to the interferon "alarm signal" released in response to a viral infection. Immune function suffered. Endogenous viruses are the family dog who protects villagers from marauding wolves, barking loudly whenever their genetic cousins come near.
I find this thought pleasant, and somehow comforting: we've been assimilating unwanted immigrants into our chromosomal society far longer than humans have existed. Not only are endogenous viruses not "junk DNA", they are valuable, well-behaved, even life-saving first responders.
What really amazes about all this is how much we learn about our history sitting in a laboratory. Our DNA is a time machine, traveling to places no historian can reach. Dig up some old bones from a cave in Spain or Siberia and wonderful mysteries are revealed. Those old bones still matter, eons after our ancestors shuffled off this mortal plane.
One last look at the Neanderthals before we go. Trying to get inside the heads of extinct ancestors is a dangerous enterprise, but enjoyable nevertheless. Recently, far inside Bruniquel Cave in southwestern France, investigators came across a fascinating human structure. The cave's occupants had broken off some 400 stalagmites and then rearranged them in a circle. These circles show signs of fire use, with soot-blackened, heat-fractured calcite and bone remnants. Using uranium-thorium dating techniques, the circles date out to 176,500 years, long before Homo sapiens entered Europe. Neanderthal spelunkers created the structures.
What were they doing there? Did the stalagmite circles have some ritual significance, some religious meaning? Or did the Neanderthals, like modern humans gathered around a flat screen TV, just like to have a family room where they could kick back and enjoy themselves after a long day hunting bison and woolly mammoths? We'll never know, but it makes me think we might have understood each other.