The Human Genome

Amongst evolutionary biologists, physicians, clinicians, medical researchers, psychologists, and all the other folks whose specialty involves the human animal, there is precious little agreement.  Humans are deterministic robots, disease-ridden test subjects, or perhaps merely Nature’s elaborate method of replicating genes.

There is, however, one area in which they all seem to agree: The Human Genome Project will make this the Century of the Genome.

I have no problem with this.  Identifying the 20,000-25,000 genes in human DNA and deciphering the 3 billion base pairs that make it up is a stunning achievement.  And while it is equally true that making all this information available to the world will provide an acid test of our wisdom (and potentially many wonderful demonstrations of the Law of Unintended Consequences), the potential for improving human understanding and perhaps human welfare outweighs all the fears we might have.

However, I must confess that my initial reaction to the news that they had decoded the “Human Genome” was, “Really?  Whose?”

Was it some fat, middle-aged white guy, with a hereditary disposition to clogged arteries and piles?  Was it yet another noble volunteer from our prison system with a sociopathic personality and incipient diabetes?  Or was it some nice housewife with two healthy kids and five relatives she doesn’t know about who all died of colon cancer before she was born?

The point, of course, is that the decoding of A human genome is practically and conceptually miles away from decoding The human genome.  In order to even begin to understand how the Genome really operates, we are going to have to decode those billions of base pairs from a statistically valid number of randomly selected individuals and do exhaustive studies on how the genes actually operate in those individuals.  Then, too, we would like to know what genes are essentially invariant across the species, what genes are shared by subgroups and what genes vary between individuals.  And above all else we are going to need a raft of brand new analytical tools (both hardware and software) to handle the mass of data and almost unimaginable number of correlations they will generate.

[If you happen to know some kid who is thinking about going into human biology, mathematics, or computer science and wants a future (and perhaps a Nobel Prize), I think this is the direction you should point.]

Analyzing human DNA across the populations is in its infancy, but some initial results are in and already the results are surprising.  According to a report in PLOS-Biology some fairly sophisticated mathematics have allowed a team of researchers to identify regions of single nucleotide polymorphism (SNP, variation in the genome) and to estimate their age, whether they are neutral, in the process of being eliminated, or are being preferentially selected.  To put that another way, they are able to tell how natural selection has been operating on SNP regions over the last 10,000 years or so. [Note that the term “SNP region” is used as we don’t know enough to identify the precise function of each SNP.  What we can say is that there is an SNP in a region that we already know has something to do with sperm motility, or lipid digestion, or whatnot.]

As a measure of how primitive our hardware, software, and available data still are, they were able to examine a grand total of 309 individual in three population groups: East Asian, Central European, and Yorubas from Africa.  Hardly seems an impressive number.  Until, that is, you realize that they were examining 800,000 SNPs for each member of their sample and then comparing the results across the sample.

That is one heck of a lot of data.

The math and methods are interesting only to nerds (mea culpa), and I’ll put the Web address of the paper at the bottom of this column for those crazy enough to want to read it.  For most of the rest, it is only the bottom line that really matters: what did they find out and what does it mean?

One of the assumptions that most of us have about evolution is the “Change or Die” hypothesis.  That is, we assume life normally goes on in a fairly stately rhythm, with all the biological niches filled and evolution, if it occurs at all, moving at a glacial pace.  Until, that is, some major environmental change like an asteroid hits or an ice age occurs.  Then everyone faces a brand new world, with a brand new set of rules, and has to either adapt or die.  Life after any really big change becomes a sort of cosmic game of musical chairs, complete with a fresh set of biological niches for everyone to fight over.

Since the last major shift that we know of was the last Ice Age, most of us would assume that evolution has been in Pause mode, mostly waiting for the next time God decides to reshuffle the deck.  Until, that is, we realize that nature is not the only driver for our species.

After the end of the last Ice Age, about 10,000 years ago, somewhere in the Middle East human beings began to settle down and practice agriculture.  Over the next few thousand years, this new idea seems to have spread throughout all of the regions where the human race had wandered.  Although many small groups stuck to the old, nomadic, hunter-gatherer way of life, the vast majority of humans settled down and took root.

This may seem a pretty trivial change from an evolutionary point of view, particularly when compared to an ice age or an asteroid collision, but its implications were profound.

Suddenly (more or less), man found himself living on a more dependable but much more restricted diet.  People grew smaller as they faced the dietary deficiencies of the few crops they had learned how to grow.  Domesticating their cows, pigs, birds, horses and whatnot, they found themselves sharing quarters with a whole new variety of animal-borne diseases, some of which showed a nasty talent for jumping species.  And by living in the same places year after year, they made some of those bugs endemic.  On the whole, people became smaller, dirtier, sicker, and much more prolific.  Man had reached a level of development that allowed him to radically alter his own environment and become his own evolutionary driver.

The result can be seen in this research.  For example, in the Central European sample, one of the SNPs with a highly favorable selectivity is in a region that controls the enzyme lactase.  One can easily see the connection with all those new farmers in Europe needing to be able get nourishment from those recently domesticated cows.  Many of the other favored regions to show up in the study relate to metabolism as well:  of lipids, carbohydrates, and phosphates, vitamin transport, etc.

Then, too, we have to remember those European settlers had moved out of Africa to the colder north.  Good for their animals, since the north had far fewer parasites and such, but the price was much less sunlight.  Ergo, no fewer than four of the favorably selected areas relate to skin color.  A lighter skin improved the production of vitamin D.

There are a fantastic number of other affected areas, spread right across all the populations, shared by some, specific in others.  Skeletal development, hair color and type, sperm motility,  egg fertilization, adipose tissue mass, response to malaria – the list goes on and on.  Interestingly, although one might imagine that the Yoruba, who stayed behind in Africa, would have been subject to fewer new pressures, the numbers don’t bear this out: of genomic regions under favorable selection, the Europeans had 188, the Asians 185, and the Yoruba 206.

What does all this mean?

A few year ago two scientists named Grant from Princeton examined how species of Galapagos finches reacted to a prolonged drought that radically altered their food supply.  In some really elegant work, the Grants were able to demonstrate (rather to everyone’s surprise) clear-cut operation of natural selection in the modern world.  It had been assumed that natural selection was an historical artifact.  The Grants proved that idea to be wrong.

The finches, though, in their tiny, isolated environments, were really no different from all those other species reacting to an ice age or some other cataclysm: adapting as best they could to the random actions of a fickle Mother Nature.  This study shows that we, on the other hand, have been and are continuing to go Mother Nature one better.  Operating first on himself, mankind has become a primary evolutionary driver, changing some species and eliminating others.

Given our problems with global warning, habitat destruction, and the rest, it remains to be seen whether our species will do such a splendid job of modifying the environment that we will become, all by ourselves, the next Big One:  our very own Extinction Level Event.

PLOS-Biology can be found at:  The paper is entitled “A Map of Recent Positive Selection in the Human Genome,” Pritchard et al.

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