Philosophy of Genetics

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.