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What Should We Be Worried About? Genetic Inequality

Edge posted its annual question: What Should We Be Worried About?  They received 150 responses from intellectuals and meritocrats, who are obviously blind to the main worry we non-meritocrats have: Genetic inequality.

Certainly Douglas T. Kenrick, Professor of Psychology, Arizona State University, touches on this inequality when he writes:

Just as countries differ in their distribution of wealth, they also differ in their distribution of IQ. ... Having a high IQ intellectual class—lots of people with accomplishments in science, math, technology and engineering—translated directly into more wealth for a country. To put it into purely economic terms, an increase of 1 IQ point among average citizens increases a country's average GDP by $229, whereas an increase of 1 IQ point in the intellectual elite is worth $468.

And Geoffrey Miller, Evolutionary psychologist, NYU Stern Business School and University of New Mexico, touches on another piece of the puzzle:

[China] is currently doing whole-genome sequencing of 1,000 very-high-IQ people around the world, hunting for sets of sets of IQ-predicting alleles. ... These IQ gene-sets will be found eventually. ... Potentially, the results would allow all Chinese couples to maximize the intelligence of their offspring by selecting among their own fertilized eggs for the one or two that include the highest likelihood of the highest intelligence. ... After a couple of generations, it would be game over for Western global competitiveness.

Yet meritocrats won't state the obvious conclusion: Genetic inequality is what we should be worried about.

The Cone of My Incompetence

Here's an excerpt from my new book, The Cone of My Incompetence: How My Genes Keep Me Down:

From an early age, I realized I was different.

Some people have natural gifts like energy, drive, charisma, motivation, calm under pressure, willpower, self-discipline and resilience. They’re lucky to be born with such rare and highly valued traits.

But I’m not so lucky. I lack natural potential and talent. And no amount of practice can change that.

I call it The Cone of My Incompetence.

My Cone determines my needs, wants, interests, fears, obsessions and desires. It resides deep in my subconscious brain, constructed by my DNA.

My Cone keeps me down. Managing people just makes me nervous. Power hierarchies leave me cold. Unless rallied by a natural leader, I’m a lazy sloth. I’m a natural born follower. A promotion is not in my DNA.

Those born with natural gifts are rewarded with lavish salaries, bonuses, perks, and promotions. But I’m not.

I never chose this Cone. It’s not something I have. It’s who I am.

And it’s not fair.

Here's another description from Amazon.com:

Frustrated by his own lack of talent and natural gifts, the author questions whether elite meritocrats--corporate executives, doctors, lawyers, lobbyists, bankers--who are lucky to be born with rare character traits like self-confidence, energy, resilience, and drive, truly deserve their enormous pay packages, bonuses and perks

You can order it here.

The Sports Gene

We each receive a copy of the ACTN3 gene from our parents.  It's one of the 21,500 genes we all share.  Yet the ACTN3 gene comes in different variants, or flavors.  You may get the R variant from your father, and the X variant from your mother (RX), or some other combination like RR and XX..

Yet according to the New York Times, having the R variant of the ACTN3 gene enhances your so-called "fast-twitch" muscles, to make them more "capable of the forceful, quick contractions necessary in speed and power sports".  If you inherit the X variant, you won't have that same capability.

A study "looked at 429 elite white athletes, including 50 Olympians, and found that 50 percent of the 107 sprint athletes had two copies of the R variant. Even more telling, no female elite sprinter had two copies of the X variant. All male Olympians in power sports had at least one copy of the R variant."

Of course, to make it to the Olympics, you must train and practice.  But if you don't have the R variant of the ACTN3 gene, all the training in the world won't get you there. 

In reality, you need two sets of genes to become an Olympic athlete.  First, you must possess the "ACTN3 variant R" gene for "fast-twitch" muscles.  Then you also need the "brain genes" for the drive and motivation to sustain you through the long, arduous, thankless years of training.  Drive and motivation are also innate.

Gene Expression vs. Genetic Variation

Gene Expression measures which of your 23,000 genes are currently active in your body. Genetic Variation describes the subtle differences between your 23,000 genes and your neighbor’s genes, which come in different flavors from your own. (Both gene expression and genetic variation can be measured using "gene chips").

Measuring gene expression can be misleading, becomes sometimes the effect of a gene comes long after it is switched off. Genes act as blueprints for miniature "protein factories" in our bodily cells. That’s what gene expression is. The resulting proteins ultimately build structures in the body, like organs and skin and muscles and brain tissue. But once the structures are built, the genes involved can then switch off (or go into occasional “maintenance mode”).

For example, the genes responsible for the eye’s development can mostly switch off after we're born, so many of the “eye development” genes are no longer expressed in adults, although the development of the eye is clearly genetic.

If you’re genetically pre-disposed to macular degeneration (an eye condition), you probably have different flavors of the eye development genes from your neighbor (who doesn’t suffer from the condition). That's gene variation. Whether the eye condition is caused by variants of your “development genes” which long ceased their activity or by “maintenance genes” is an open question. But if the former, you can treat the condition but never cure it.

So why aren’t all our genes dormant after we’ve reached adulthood? Aside from maintenance genes (if you cut your finger, you’d better hope these are still active, to repair the skin!), why do some of our genes still actively express their proteins?

First of all, genes don’t just act as blueprints for bodily structure. They build an elaborate signaling system in the body. For example, during pregnancy, hormones are used to signal the need for bodily changes. Hormones can also induce mood changes. So the genes that produce hormones must be able to switch on when needed, to produce more “signal”. (Neurotransmitters are another type of signaling mechanism in the brain.)

Hormones and neurotransmitters would have no effect unless “receptors” were placed strategically around the body and brain, to detect their signal and trigger a response. Hormone receptors are constructed and strategically positioned by the genes, although they are more permanent than the transient hormonal signal. Like soldiers on a battlefield awaiting the general’s order or command, the release of hormones into the bloodstream act as a signal, to activate the battle plans of the trained and ready army.

The brain has hormone receptors as well. So special modules in the brain remain ready, listening and vigilant. Once they detect the signal, they trigger a pre-established human behavior, e.g. maternal instinct. Pre-established human behaviors are really "brain modules" built by the genes (when we were young) to enact certain specific behaviors. Although those genes left behind brain modules that they constructed, are no longer active (i.e. no longer "expressed").

Much of your current gene expression is related to maintenance activities and fostering the body and brain’s elaborate signaling system. But neither your development (body and brain) nor your signaling system works the same as your neighbor’s, because you have gene variants. Your DNA differs from your neighbor’s by 1%, which doesn’t sound like a lot. But two keys that are 1% different still open different locks.

Genetic differences help explain variation in political participation

According to an article in the American Political Science Review:

...individual genetic differences make up a large and significant portion of the variation in political participation, even after taking socialization and other environmental factors into account.

The authors give no explanation of how differences in our DNA are responsible for such an effect. 

But the answer is not difficult, when you realize that variations in motivation are genetic.  Not everyone wants to be President.  Most of us seek a "just master".  We would rather be followers, not leaders. You just can't teach motivation.

Our genes are responsible for identifying what makes us happy.  Some people are happy being altruistic.  Some are happy being ambitious.  The differences in "wants" and "desires" are accounted for by our genes.  As Schopenhauer wrote, you can do what you want, but you can't want what you want.

I assume people are attracted to the Democratic party (and left-leaning Public Radio) because they feel good about what it stands for.  Others (with a different set of genetic variants) are attracted to the Republican party (and Fox News).

I think the more interesting question is: how do our genes affect the construction of our mind and brain, to account for these differences in desires, pleasures, motivators?  How did our DNA create the brain in such a way that we can differentially get motivated by different qualities of political parties?

Why can't a mouse be more like a man?

New drugs are usually tested and perfected in mice, before they are ever given to humans.  Mice make dependable subjects in a lab, and a drug that proves safe and effective in a mouse may very well be safe for humans.

But, alas, a mouse is not a man.  Too often, drugs show an effect in animals, but have little effect in humans. More importantly, drugs that prove safe for animals may have unwanted side-effects in humans.

For this reason, scientists are trying to make mice more "human-like", to make their drug response more predictive of human drug response.  Mice have different genes from humans (although there is at least a 95% DNA similarity), and this leads them to metabolize drugs differently.  So mice with more human-like genes are being genetically engineered for use in drug-testing.  A mouse can be more like a man, after all.

Yet any study (whether mouse or human) adds to the cost of developing new drugs.  So some scientists are also attempting to develop predictive computer models (in silico), to simulate (on a computer) the drug's effect on the body (such as "predicted liver toxicity"), without requiring as many animal studies.

But human studies will always be needed to test new drugs.  The human body is too complex and our genes are too unique from other animals to fully rely on other predictive models.

Out of Africa

In the beginning, there were no Whites and no Asians.  We were all Africans.

According to genetic studies, all humans evolved from a single female (named “Eve”) who lived in Africa 200,000 years ago.

How do we know?  Each generation, there are subtle changes in our DNA, which normally have little effect.  These DNA changes accumulate over time, as they are passed down from one generation to the next, and their frequency can be used for analysis of human migrations through history.  The further away from Africa you travel, the less genetic variability you see, implying that Africa was the ancient birthplace of modern man.

Sometimes these small DNA changes (or “genetic drifts”) are given specific names, to represent family branches, especially when new human migrations occur:

• After Eve, the L1 lineage branched off (some 125,500–165,500 years ago).  Today, the San and Mbuti peoples of Africa are Eve's direct descendants.  They set the stage for behavioral modernity between 100,000-50,000 years ago, when humans began to think more abstractly, engage in bartering and trade, and develop language and music
• Then, the L2 line branched off from the L1 line (around 70,000 years ago), and populated parts of western Africa.
• Another lineage, L3, also branched off from L1 (around 60,000 years ago), and populated parts of northeastern Africa

The L* lines are now largely confined to Africa (except those people who emigrated in the last 400 years, or, in that terrible chapter of human history, were captured and sold elsewhere as slaves).

• Around 60,000 years ago, a new branch, the M lineage, split from the L3 line and departed from Africa and crossed the Red Sea into the Middle East.
• From there, the M lineage migrated to Asia, and a new N lineage migrated to Europe. There are very few of the M lineage in Europe, but there are N's mixed with M's in Asia.
• Later (14,000 years ago, although some say it was 30,000 years ago), some Asians migrated across the Bering Straight to populate North and South America.  These are the American Indians, and other native peoples

In summary, if someone asks you where you're from originally, you'd never be wrong to say "Africa".

Al Gore's DNA

Former vice president Al Gore recently helped launch Navigenics, a new personal genomics service.  According to Gore, "on all these new genetic breakthroughs, there is always some resistance culturally, and then, where there's an evaluation of the inherent value, if the ethics are right, if the surrounding culture is right, then it just breaks through ... I think it's going to be a fantastic success."

Using Navigenics' service, you can determine your projected lifetime risk for certain conditions like heart disease, based on your personal genetic differences.

The Personal Genome Project

Harvard's George Church (with help from Google) plans to identify the genetic variations of 100,000 people (and perhaps eventually 1,000,000 people), and associate their gene variants with their health and family disease history.

According to a recent article in Bloomberg:

By matching genetic data from each person with his or her health history, Church would build a database that would link DNA variations and disease for scientists and drugmakers, the first step in deciding on treatments that can block the mutations or adjust how they work within the body. Church also said he'll explore other human traits under genetic control. Participants will give facial and body measurements, tell researchers what time they get up in the morning, and detail other behaviors, he said.

Previously, it's been difficult for scientists to determine which specific gene variants are responsible for disease, without having this much data to analyze.  There are 3 million "single letter" DNA differences between people (which account for 10% of the total genetic variation).  In order to make statistically valid associations between genetic variation and disease, you need to study the gene variants of hundreds of thousands (if not millions) of people.

Google is positioning itself to help consumers keep track of their complex genetic data, and self-manage their electronic healthcare records.  The U.S. Congress is lagging behind the rapid technology advances, and should immediately pass legislation that prohibits any genetic discrimination, especially by insurance providers.

What is a Chimera?

According to the New England Journal of Medicine, a woman named Lydia Fairchild gave birth to her own child in 2002, but genetic tests performed on her skin and hair did not match her child (except to the degree a grandmother might match).

However, DNA from other tissue in Fairchild's body did match her child. Lydia carried two distinct sets of DNA within her body, the defining characteristic of a chimera.

The most likely explanation is that Lydia Fairchild herself was a fusion of two sets of chromosomes from her parents, when she was born. Her mother simultaneously ovulated two eggs, which were both fertilized by different sperm from her father.  Then the two eggs fused into a single embryo, which grew up to be Lydia.

In other words, as Lydia Fairchild developed, both types of cells within her participated in constructing her various organs, but not all the DNA was represented in all her organs.  She had two distinct sets of DNA, as if she had twins inside her own body.

So when Lydia Fairchild had a child of her own, the child inherited one set of her DNA, but not the other set.

How many genes does it take to create life?

How many genes does it take to create life? Mycoplasma genitalium bacteria has 485 genes, and this is the fewest for any free-living organism. But 103 of its genes can be individually removed without killing it, so 382 genes seem to be essential for life.

At the J. Craig Venter Institute, scientists are assembling those 382 genes from scratch to synthesize new organisms. Their hope is to insert additional genes along the way, to generate useful bi-products.  Synthetic bacteria with added genes could become "trillion dollar organisms". For example, large vats of "enhanced" bacterium could produce bio-fuels (or any other organic product), and launch entirely new industries.

1000 Genomes Project

An international research consortium has announced it will sequence the complete DNA of 1,000 people.  The goal is to "catalog [DNA] variants that are present at 1 percent or greater frequency in the human population". The project will focus not only on mapping single-letter differences in DNA, but also "structural variants" such as DNA rearrangements, deletions or duplications of segments.

According to ScienceDaily: "It is important to understand the small fraction of genetic material that varies among people because it can help explain individual differences in susceptibility to disease, response to drugs or reaction to environmental factors."

Effects of variations in your DNA

If you like Wikipedia, you'll love the new SNPedia, which lists the effects of variations in your DNA (known as SNPs). Want to know what gene variants you have? Subscribe to 23andme.com. For the intrepid, you can also try the new Personal Genome Explorer.

Dusty old volumes from our Genetic Library

It seems that the process of evolution makes good use of old knowledge, stored away in our DNA library.  A new study shows how ancient DNA fragments (which are really just encapsulated knowledge from the pre-historic past) can be revived and applied, to design new forms of life, through changes to the genetic regulatory system.

Apologies for my lack of posts recently.  I'm writing a novel, based on this blog!  Should have something to show for it in the next month or two.

Genome-wide Association Studies (GWAS)

Genome-wide association studies are all the rage now.  With the availability of new gene chips that can cheaply and efficiently measure millions of genetic differences between individuals, it's now possible to associate observable traits (among a group of 5,000 or 30,000 or more human subjects) with their specific gene variants.

You need to study a lot of people (a large sample size) before you can confidently determine which gene variant does what.  These new cheaper gene chips allow for such large studies to be run, and the gene variants of thousands of people to be analyzed and compared.

For example, a recent study shows that having a variant of the HMGA2 gene can make you half a centimeter taller or shorter (depending on the HMGA2 variant you possess).

So what's the use of having this information?  Can you change the outcome?  Not really.  Since this is clearly a "development gene", you wouldn't be able to affect the outcome in height after you're fully grown.  You could intervene at an early age, by determining which gene variant you have, and bolstering your size with a regimen of human growth hormone (hGH) if you're not happy with the natural developmental outcome.  But you'd be too young to make that decision for yourself.

Consumer genetics

A number of companies now offer affordable genetic tests for consumers.  DNA Direct offers disease-related gene tests in the $200-$500 range.  And IBM’s popular Genographic Project kit allows individuals to trace their genealogical history for $99.

Now (according to a recent story) a Google-backed company (23andMe) has joined forces with Illumina - a maker of "gene chips" - to identify 550,000 genetic differences between individuals (for around $300-$600).

The function of all these genetic differences are not yet known, of course.  But the more people who get measured, the larger the sample size, and the more statistically relevant the results will be.

So what if you send a sample of your blood to 23andMe?  What happens next?  This is my guess.  I'm imagining they'll measure your unique set of 500,000 or 1 million genetic differences, and record them in a database.  Then they will send surveys to everyone in their network (who submitted a sample), to ask about their family history of disease, etc.  Once a million or more people join their network, the correlation between the responses to the survey ("my father had colon cancer") and the specific genetic differences for those response (e.g. "Gene X") will be much easier to accurately judge.

I'm not cynical about this.  I don't think 23andMe will try to sell your personal genetic information.  They are simply trying to learn about diseases correlated with genes (which they plan to share, and thus facilitate treatments).  They will need a lot of data to make the association (since there are so many possible genetic differences).  It's an exciting prospect, but we must ensure that our laws keep up with the science, and absolutely forbid any sort of genetic discrimination on a personal basis.  They data should be kept in an aggregate form.

RNA, it's the new DNA

The central dogma of genetics used to go something like this: Our genes (DNA) are transcribed into smaller pieces (RNA), which are then translated into the proteins that build our body.

Now it's looking like that old dogma just won't hunt. (Apologies for a bad pun at the expense of the scientific method, that great, messy, wonderful process -- just like democracy!)

Previously, scientists thought each of our genes acted as a blueprint for a single protein.  Then they discovered that single genes may be alternatively spliced into different RNA transcripts, resulting in different proteins from the same gene.  But they still claimed that only 5% of our genetic material was being used to encode for proteins, and the other 95% of the gene was snipped out in the transcription process, relegated to the cutting room floor as junk DNA.

Recently, however, a group of scientists comprising the ENCODE project decided to look more deeply into this puzzle, by examining 1% of our DNA in more detail.  And they found clues for what the other 95% of our DNA does.

According to Thomas D. Tullius, professor of chemistry at Boston University and one of the ENCODE researchers

"There were huge surprises; this research has upset a lot of thinking about how the genome works." ... "There now appear to be thousands of places in the genome that were long thought to be useless or meaningless [junk DNA], but which we now see to have a functional role. But we don't really understand what that role is."

Other interesting findings:

The new work suggests that the "control regions" in the DNA are far more extensive, perhaps embracing more than half of all DNA. Functions thought to be carried out by genes alone now appear to be managed by multiple, overlapping segments of DNA. In addition, other portions of the genome are believed to be on standby, as a toolbag to be utilized as humans evolve.

The ENCODE project found that much of our DNA doesn't code for proteins at all, but instead is transcribed into specialized microRNA molecules that may be just as interesting as DNA and proteins. These are scnRNAs, snRNAs, snoRNAs, rasiRNAs, tasiRNAs, natsiRNAs and piRNAs.

MicroRNAs seem to act as behind-the-scenes puppetmasters, helping to regulate protein activity. For example

Dave Bartel, of the Massachusetts Institute of Technology ... discovered microRNA genes interspersed among sets of protein-encoding genes called Hox clusters. Hox clusters contain basic instructions about body plans, and the genes within them are arranged in the order in which they influence their owner's shape during development. In short, a Hox gene at one end of a cluster contains the information: “Give this embryo a head”. The gene at the other end says: “And a tail, too”. The role of the interspersed microRNAs is to regulate these high-level commands.

Ronald Plasterk, of the University of Utrecht, in the Netherlands, suggests that microRNAs are important in the evolution of the human brain. In December's Nature Genetics, he compared the microRNAs encoded by chimpanzee and human genomes. About 8% of the microRNAs that are expressed in the human brain were unique to it, much more than chance and the evolutionary distance between chimps and people would predict.

RNA also opens up a mechanism for Intelligent Design because:

small RNAs are active in cells' nuclei as well as in their outer reaches. Greg Hannon, of the Cold Spring Harbor Laboratory in New York State, thinks that some of these RNA molecules are helping to direct subtle chemical modifications to DNA. ... They thus change the effective composition of the genome in a way similar to mutation of the DNA itself (it is such mutations that are the raw material of natural selection)....

RNA could itself provide an alternative evolutionary substrate. That is because RNA sometimes carries genetic information down the generations independently of DNA, by hitching a lift in the sex cells.

Everything old is new again

If you held on to that shirt you wore 30 years ago, it may just be back in style now.  You can’t always predict the future, but there’s a good chance that old times will become new again.  Things tend to run in cycles.

In the past, there were Ice Ages and times of Global Warming, and our ancestors evolved to adjust to each of these times.  There were epochs of plenty, and epochs of famine.  For each scenario, our ancestors evolved to fit their new environment, not just with bodily changes, but with instincts to fit the new times as well.  Monkeys evolved traits and body shapes to adapt to life in trees, and at other times, to life on the plains.  Before them, their ancestors evolved instincts for harsh times and flush times; times of war, and times of peace.  (Sorry, Jane Goodall, but even chimpanzees go to war!)

Every instinct is (obviously) an inborn behavior, maintained in our DNA, and expressed in the configuration of our brain.  Each time our ancestors evolved, they kept the DNA for those instincts filed away in our so-called “junk DNA” , the vast library of seemingly unused DNA we all have.  It's an immense burden to pass down this library of genetic knowledge, so it must be of some use for future generations.

And we don’t just get DNA from our ancestors.  Certain retroviruses can transmit DNA from other species to humans.  So we can learn their genetic lessons, even after our family trees split millions of years ago.

Good times and bad times always seem to return, in cycles.  Ten Ice Ages occur every million years or so.  Our DNA takes the long-term view, and retains its knowledge of useful instincts and body types for those previously experienced scenarios.

Over time, for example, there have existed long-necked animals – like giraffes – which evolved when the hunt for food was more competitive.  In other, less competitive times, when there was plenty of low-hanging fruit and leaves, the short-necked animals thrived.  But the evolved characteristic were stored in their collective DNA.  When those characteristics aren't needed, they lay dormant in the genetic code.  When needed again, they can be quickly brought back (or perhaps they were temporarily stored in a virus somewhere for safe-keeping!).

You have to wonder whether our DNA is self-aware enough to actually anticipate the return of bygone eras, since change itself is a constant characteristic of our environment.  And indeed, there is precedent for anticipation in our genes.  Genes also have the ability to modulate themselves, and even switch themselves off between generations.  So Lamarck may have been onto something after all.

Perhaps there are even shorter cycles built-in to our collective genome.  Times of peace and stability may induce children to become more hyperactive.  Who knows?

You can also look at any characteristic that exists today, and imagine it evolved millions of years ago.  For example, humans are intelligent designers, thus perhaps the ability to undergo intelligent design has existed in the DNA code for millions of years.

Diabetes, obesity and genetics

An article in Nature finds that variations in 4 specific genes (TCF7L2, SLC30A8, IDE–KIF11–HHEX and EXT2–ALX4) can explain 70% of who gets diabetes.  It makes you wonder why people have those gene variants to begin with.  What purpose do they serve?

Also, newly published research in Science shows that having a variant (or two copies) of the so-called FATSO gene can often lead to obesity.

I'm wondering if the susceptibility to diabetes is similar to that of hypertension (due to a salt imbalance).  An article a couple of years ago described how variants in the CYP3A gene are linked to salt retention in the body.  Africans who live near the equator have one form of the gene, and others (living farther from the equator) have another form of the gene!  According to a press release at that time:

In the sub-Saharan African regions where humans first appeared, available salt must have been limited and quickly lost through sweat. People who were better at retaining salt may have had a significant survival advantage.

The problem is (and anyone who's stopped by McDonalds for super-size fries well knows), salt is no longer scarce in the modern world.  So people with the stronger "salt retention" version of the gene are at greater risk for hypertension these days.

Evolution is about trade-offs.  Having the genes for better salt retention in warm climates can give you hypertension in the era of fast food.  Does diabetes work the same way?

“This could change the way we look for disease genes,” [said study author Anna Di Rienzo, Associate Professor in Human Genetics]. “Historically, we have searched for mutations, altered or damaged versions of genes that cause rare disorders, like cystic fibrosis or phenylketonuria. Now, we are starting to look for common genes that may have been beneficial in an environment of scarcity, but have become harmful in a world of plenty. In the modern setting, it may often be the genes that aren’t damaged that predispose to disease, such as the ‘thrifty genes’ associated with type 2 diabetes.”

Humans differ genetically by 1%

Scientists are now establishing a more accurate database of human genetic variation, after the shocking news late in 2006 that scientists underestimated the amount of genetic difference among humans by a factor of 10!  We humans are now understood to be 99% alike, not 99.9% alike as previously reported.

It turns out that 12% of our genome is involved in copy number variations (CNVs), with 1% of our genome actually different from other people.  CNVs include repeating and deleted sequences of DNA, implying that some people may have more DNA than other people!  These CNVs affect 2,900 genes (360 million genetic bases, or "letters"), including 15% of known disease gene variants.

The CNV variations are in addition to known single base ("letter") differences (SNPs), making a total of 30 million DNA differences among people (1% of the genome).  These include:

• 1.5 million single-letter differences (SNPs)
• 24 million letters of unmatched sequences among people (i.e. unique among human subgroups)
• 3.5 million multi-copy (repeating) sequences
• 1 million letters in inverted sequence

How much do we differ?

A recent article in Nature shows that we humans differ from each other by 1% of our DNA, due to "copy number variations", or CNVs, in our genes.  The previous theory (which relied on analysis of single nucleotide differences, or SNPs) erroneously stated that all humans are 99.9% alike. 

Both the old SNP-based and new CNV-based studies used human subjects from Europe, Africa and Asia:

1. SNP - The international HapMap project studied small genetic differences among people.  These SNPs, or single nucleotide polymorphisms, are differences in single DNA letters (A, T, G, or C) in the genome.  Scientists found at that time that 1 in 1000 DNA letters differ between people, erroneously implying we are all 99.9% alike.
2. CNV - The new international project studied larger pieces of DNA that repeat themselves as "copy number variations" (CNV) in our chromosomes.  Scientists found 1,447 CNVs in 2,900 different genes.  In other words, entire paragraphs of "DNA letters" repeat themselves in different ways in different people or ethnic groups.  Sometimes entire genes exist in multiple copies in the same person, or are deleted completely in another person.  Scientists found 1,447 of these repeating paragraphs which make up 12% of our DNA (1% of which is actually different).

So about 0.1% of the human genome differs across people due to SNPs, but much more may differ due to CNVs.  A CNV may be a piece of DNA that repeats once, twice, or many times in different individuals.  Or entire genes may repeat.  Some people may have several copies of the same gene, whereas other people may have none.

Genetic differences between people are sometimes related to diseases.  For example, studies show that 17 CNVs may be related to nervous system diseases like Parkinson's and Alzheimer's.  But more often genetic differences are a normal part of human variation.  They explain personality differences, and differences in appearance.

What separates us from monkeys?

Back in 1997, someone  wrote a letter to Time Magazine to say that “It's not the amount of difference [in DNA between organisms], it's where the difference lies.”  Small differences in genes can add up to dramatic differences in effects. 

A recent article in Time magazine describes research in DNA regions called HARs (human accelerated regions) – most of which lie in the junk DNA regions between genes – that have evolved the most rapidly from chimps to humans.  One such gene region (HAR1) is active “in fetal brain tissue only between the seventh and 19th weeks of gestation” when “a protein called reelin helps [the human brain] develop its characteristic six-layer structure”.

The Time article also mentions that humans possess an altered ("damaged") form of a gene for sialic acid (that acts as a docking site for many pathogens like malaria and influenza), which explains why humans are more susceptible than chimpanzees to those diseases.   I think it may be misleading to use the word "damaged".  Perhaps humans were able to evolve more quickly because we are more susceptible to disease.  Don't forget that human DNA is made up mostly of virus DNA!

One trap that the Time article (almost) steps into is assuming that a single gene (by itself) can account for complex behavior.  They describe the FOXP2 gene, that differs between chimps and humans in just 2 places, a “small change that may nevertheless explain the emergence of all aspects of human speech”.  By itself, one gene probably doesn’t explain much – genes operate in complex pathways.

Steven Pinker's "Dangerous Idea"

Steven Pinker's dangerous idea is that "Groups of people may differ genetically in their average talents and temperaments".

In a New York Times review of his book The Blank Slate, Pinker "reproaches those ... [who] have created a climate in which ''discoveries about human nature were greeted with fear and loathing because they were thought to threaten progressive ideals ... The politics and the science must be disentangled, Dr. Pinker argues. Equal rights and equal opportunities are moral principles, he says, not empirical hypotheses about human nature, and they do not require a biological justification, especially not a false one. "

According to Pinker:

Group differences, when they exist, pertain to the average or variance of a statistical distribution, rather than to individual men and women. Political equality is a commitment to universal human rights, and to policies that treat people as individuals rather than representatives of groups; it is not an empirical claim that all groups are indistinguishable. Yet many commentators seem unwilling to grasp these points, to say nothing of the wider world community.

Genes, they keep a-changin'

According to a New York Times article, scientists have recently discovered 700 examples where our gene variants appear to have been reshaped "within the last 5,000 to 15,000 years", and which "may underlie the present-day differences in racial appearance" and even "brain function".  Once again, the usual dupes are social scientists, who continue to write "scholarly articles based on the [false] assumption that "human evolution [ground] to a halt in the distant past".

Genes and brain size

Science magazine reports that "two genes involved in determining the size of the human brain have undergone substantial evolution" as recently as 5,800 years ago.  Those two genes are microcephalin and ASPM.  When those genes are completely switched off, they lead to "microcephaly", or small head.

Another gene, GPR56, appears to affect mainly the development of the frontal cortex.  According to Wikipedia, the "frontal lobes have been found to play a part in impulse control, judgment, language, memory, motor function, problem solving, sexual behavior, socialization and spontaneity. Frontal lobes assist in planning, coordinating, controlling and executing behavior."

With this knowledge, scientists investigated whether different variants of the genes were responsible for different brain sizes among people.  According to the New York Times:

About 70 percent of people in most European and East Asian populations carry [a specific variant of the microcephalin] gene, but it is much rarer in most sub-Saharan Africans.

With the other gene, ASPM, a new [variant of the gene] emerged 14,100 to 500 years ago, the researchers favoring a midway date of 5,800 years. The allele has attained a frequency of about 50 percent in populations of the Middle East and Europe, is less common in East Asia, and is found at low frequency in some sub-Saharan Africa peoples.

The Chicago team suggests that the new microcephalin [gene variant] may have arisen in Eurasia or as the first modern humans emigrated from Africa some 50,000 years ago. They note that the ASPM [variant] emerged about the same time as the spread of agriculture in the Middle East 10,000 years ago and the emergence of the civilizations of the Middle East some 5,000 years ago, but say that any connection is not yet clear.

How do our genes work?

How do our genes work?  How can a human trait be genetic?  To find the answer, we have to explore the activity of our genes at three levels:

1. Facilitation and construction
2. Simple receptors and signals
3. Recognition and ability

Facilitation and construction.  Individual genes usually act as blueprints for specific proteins.  Those proteins fold into a three-dimensional form, which can be used as building blocks throughout the body.  They can also be used as enzymes, or protein catalysts.  Some molecules (like estrogen) are synthesized by many cooperating proteins in a so-called pathway.

Biochemical pathways are fascinating in their complexity.  Genes are switched on by proteins (transcription factors), which themselves may need to be assisted (by so-called “co-factors”).  Have a look at the Boehringer Mannheim wallchart for a taste of the complexity in metabolic (catalytic) pathways and cellular processes.

Simple receptors and signals.  Some proteins are designed to be activated by other molecules, thus sending a cascade of signals throughout a cell to carry out a specific task.  For example, the estrogen receptor protein is designed to detect the presence of estrogen molecules.  If there is no estrogen in the bloodstream, those receptors sit by idle (yet still vigilant), like army captains waiting impatiently to relay a general’s order to highly trained soldiers.  As in a battlefield, the signal has no effect unless it exploits a capability that already exists.  The distribution and location of receptors are as important as the signal itself.

Recognition and ability.  At a higher level, social behavior genes (through their ability to create the basic structure of the brain) can set up the circumstances by which the brain is motivated to train itself.  For example, the brain can learn to recognize which potential mates are most desireable, an ability which can be later exploited by the genes (or other parts of the brain that were genetically constructed).  Genes can filter our experience and establish a “motivational center” in the brain, to guide us toward certain experiences and away from others.  Like soldiers in the field, these learned capabilities can be summoned by genetic signals later, for specific purposes.

Four Types of Genetic Variation

We all have variants of the same 20,000 genes.  A recent article lists four types of genetic variations:

1) Single "letter" variations (called SNPs -- these often get inherited together in blocks called haplotypes), 2) additions or deletions (InDels) of DNA units, 3) repetitions like those that underlie forensic DNA tests, and 4) flipping of large segments of DNA within a chromosome.

Some things to keep in mind, however.  At the level of philosophy, it's more important to express the gene variation in terms of how much information is being stored in the genes, and how many different branching points and scenarios can be represented.  The physical manifestation of variation in the DNA is somewhat irrelevant, as long as the information is there.

For example, we each have a number of repeating units (of 48 or 120 DNA letters, or bases) in our DRD4 gene, which may be responsible for novelty-seeking behavior.  The number of repeats (3, 5, 7... etc) seems to encode the amount of risk-taking you are comfortable with.

Gene Chips

Most people don't know it yet, but the year 2005 has been a turning point in affordability of measuring genetic variation between people.  The new Affymetrix gene chip can take a sample of your blood and discover 100,000 genetic differences between you and your neighbor for under $5,000.  That price keeps coming down every year, and pretty soon we're all going to be able to order a report on our genetic variations for the price of, well, a home computer.

We don't yet know what all the genetic differences mean.  But any day now, the ubiquity of genetic sequencing will change our world dramatically, the same way computers changed our lives when Bill Gates and Steve Jobs came on the scene in the 1970's, and especially, the early 1980's.  Perhaps gene chips will double in power every 24 months, as Gordon Moore predicted about computer chips. 

When that happens, it will be a whole new world.  Festering social debates will be re-opened, like cold cases re-opened by new DNA evidence.  Politicians will be forced to talk about genetic differences when they make policy (and the Democratic Party, which doesn't believe any of this, will probably cease to exist).  Biographers will have to consider alternative (genetic) theories about human behavior when they write their books.  We humans will opt to change ourselves, and adopt strange new genetic forms.  We will live in interesting times.

Everyone has the genes for every human trait, but an "on switch" for very few

We all have the same "genes", which are 99% similar to everyone else's.  Shy people and outgoing people have the same basic genes, but their personality traits are different.  How can that be?

It's important to understand that not all of our genes are put to use.  A shy person may have their "outgoing genes" permanently switched off by a few "master genes".  Most of the 1% difference among humans can be found in the genes that act as master keys.

This implies that everyone carries all the genes for all human traits, including the capacity to be a psychopath, which is simply a more rare innate trait. (The only exception is male/female traits, since women don't have a Y chromosome.) 

It's easy to see why this would be true.  If shy people had to inherit hundreds of unique (specialized) shyness genes as a package, that trait would quickly deteriorate when the genes were passed down from parent to child.  Having children tends to remix the genes, so keeping genes together (and keeping them separate from the genes for outgoing traits) would be impossible.

Genographic Project

According to the Genographic Project's website:

We are all related—descended from a common African ancestor who lived only 60,000 years ago.  When DNA is passed from one generation to the next, most of it is recombined by the processes that give each of us our individuality.

But some parts of the DNA chain remain largely intact through the generations, altered only occasionally by mutations which become "genetic markers." These markers allow geneticists like Spencer Wells to trace our common evolutionary timeline back through the ages. 

Different populations carry distinct markers. Following them through the generations reveals a genetic tree on which today's many diverse branches may be followed ever backward to their common African root.

That's why the Genographic Project has established ten research laboratories around the globe. Scientists are visiting Earth's remote regions in a comprehensive effort to complete the planet's genetic atlas.

HapMap - Finding the top 300,000 human genetic differences

In a recent article, Francis Collins, one of the leaders of the Human Genome Project, proclaimed that "the HapMap is generating a gold-standard set of [gene] variants".

So, what is this new HapMap project?  It's an international $100 million project slated for completion in 2005, and funded in the U.S. by the National Institutes of Health.  The goal of HapMap is to find many of the gene variations among humans that make us different from each other.

The HapMap project is a follow-on to the Human Genome Project.  That project, which completed a few years ago, identified the 20,000 gene locations we all share, but not the gene variants at each location.  Essentially, the Human Genome Project identified the genes of only one person (Craig Venter), a healthy, white, male, high-IQ, extroverted caucasian.

The HapMap project acknowledges that we all share over 99% of the same genetic material, but since we all have 20,000 genes comprising 3 billion "DNA letters", having a 1% genetic difference translates to millions of variations between people.  (Remember that two keys need have only 1 difference in order to open two different locks!)

The HapMap project found that "only" 300,000 or so of these differences comprise the most important set, responsible for differences in disease susceptibility, personality differences, etc.  When those differences are measured, and correlated with the results of questionnaires, we can find out which genetic difference leads to which effect.

Hot Button Issue: For example, if a significant number people who are found to have gene variant XYZ answer "yes" when asked if they have ever committed a crime, that gene variant may be responsible for a lower threshold to anger and aggressive behavior.

Genetic differences among women

"Literally every one of the females we looked at had a different genetic story," said Duke University genetics expert Huntington Willard, who co-wrote a recent study. "It is not just a little bit of variation."

The study showed that "activity level varied widely by woman, from zero in some  to varying levels in others" on their X chromosomes.  (Women and men both have the X chromosome, although women have two X copies and men have only one X and one Y).

According to a news article, "the analysis also found that the obsessively debated differences between men and women are, at least on the genetic level, even greater than previously thought ... As many as 300 of the genes on the X chromosome may be activated differently among women than among men, said molecular biologist Laura Carrel at Penn State University, the other author of the paper."

There's a gene for that!

Many people say the human body and mind are so complex, there is no way to understand them in terms of simple causes and effects. But there are two common examples where a single genetic "switch" can control complex behavior or development:

• Broadcast commands (with hormones)
• Master genes

Broadcast commands (with hormones)

One way to send a signal throughout the body is to release a hormone into the bloodstream. Throughout the body, the "troops" (i.e. hormone receptors) are listening and waiting.  They are trained to respond to this "command", like soldiers with radio receivers waiting for an order.

Releasing the hormone (often done by the brain) is a singular act. The complex part (having receptors pre-arranged throughout the body that are specially trained to respond to the hormone) was established well in advance, like soldiers who are trained and strategically positioned across a battlefield. They listen for commands (with their ears or "signal detectors"), and ignore any other commands (i.e. other hormones) for which they were not trained to respond. A single command (or signal) such as "Division 1, charge!" sets in motion a complex, coordinated behavior.

Setting up a complex system of receptors (ahead of time) in diverse locations allows a simple signal to trigger a complex response.

Master genes

Some genes are the generals of our development as well. The SRY gene, for example, issues a single command for the developing human body to develop into a male. This command is broadcast for a few hours only - before birth (as studied in mice) - then switches off forever.

Of course, the SRY master switch triggers a cascade of other genetic activity throughout the body, the same way that a general's order may have far-reaching consequences. In other words, the simplicity of the command is made possible by the prior "training" of the troups. Even though male development (or commanding an army) is an extremely complex process, it can be conducted using simple commands.

The strategic distribution of the receptors (soldiers), their pre-existing ability to recognize and respond to the signals, and the resulting cascade of activity once activated, are the truly complex aspects of this. But the general (or hormone, or master gene) who issues the simple command is the one who gets the glory of launching the battle.

Genes, and the Law of Large Numbers

When you pull the plug in a full bathtub, the water doesn't merely go straight down the drain. North of the equator, it tends to spin counter-clockwise on its way down [some people say this is a myth, but I'm just using it to illustrate the principle]. We can easily circumvent this effect, of course, by spinning the water in the opposite direction with our hand. But we aren't usually motivated to do this on each and every occasion we empty the tub. So the natural spin, without intervention, usually occurs unchanged from its natural tendency, due to gravity and the rotation of the earth.
      
So it is with free will. We have a natural genetic reaction to many situations, but in most situations we are free to consciously override our natural impulses. However, given a certain laziness or inattentiveness, we usually follow our nature.

Our innate reactions emanate from our inner eye, and are simplistic and stereotyped. But over thousands of days and experiences, we tend to do most often what resonates with our inner eye, and allow our genetic reaction to dominate by default. Thus temperament and personality develop genetically.
       
What we do most often becomes our habit, and then our expertise. We have free will in the moment only when we are self-consciously overriding our inner eye.

Our emergent personality, as well, is apparent only over many observations, so in some sense each of our actions is free in the moment. Emergent phenomena, like statistical experiments or catalytic effects, say nothing about individual observations or occurrences. Only the cumulative emergent effect is genetically determined.  Yet, if you flip a coin 1,000,000 (a large number), the ratio of heads to tails will be 1:1, with a great deal of precision.  You can count on it.

It's not of the amount of genetic difference that matters

It's true that humans share 99% of the same DNA with each other. But that statistic is not really very meaningful. Think of two keys to the same brand of automobile. Both keys appear almost identical, except for a slight difference in 1% of their metal. Perhaps one key has a slight ridge where the other doesn't. But this small difference has a dramatic effect, when trying to open the door or start the car. One key works, the other doesn't.

We humans each have 3,000,000,000 letters in our genetic code, and we only differ among each other by 1% of those pieces.  That doesn't sound like a lot, but it still means we have 3,000,000 differences among us.  That's enough to determine differences in personality and hair color and all the rest.

We don't have 23,000 genes; We have 23,000 gene variants

Scientists have discovered (to date) that humans have approximately 23,000 gene "slots" into which we receive gene variants (also called "alleles" or "polymorphisms") from our parents. Think of it as a set of 23,000 mailboxes in a long row. Into each box is deposited one gene package (variant) from our mother, and one from our father. The gene packages deposited in a particular box (say, mailbox number "GRM3") are fairly similar, but not identical; they are unique gene variants which explain human diversity.

Geneticists identify each gene location by a Hugo name, and typically refer to the specific contents of that gene (i.e. the gene variant) by letter (e.g. variant A, variant B, variant C..) or some other name.

For example, everyone has a variant of the GRM3 gene - but if you receive the 'A' variant you have a greater chance of developing Schizophrenia.

Do gene variants serve a purpose when they are responsible for causing diseases? It's hard to speculate. Do schizophrenics contribute something essential to the survival of society, perhaps once every 1,000 years, that encourages the variants to remain in the collective genome of society, even though it's a terrible price to pay for those afflicted?