Category: Classic Genes and Serology
You are a collection of cells (literally trillions of them), each with a specific design and function. However, with a few exceptions, your cells all have a basic architectural design. Most of the time they are depicted as looking like a fried egg cooked sunny side up, but in reality they are three dimensional beings, more akin to a golf ball that you’ve cut across its midline. The “white” of our cell model is the body of the cell, and here are found many specialized areas called organelles that do particular jobs, much like our own internal organs have specific jobs as well. The “yolk” of our cell model is called the nucleus, and in this compartment there lies the object of our affections, the chromosomes.
Chromosomes were first discovered at the end of the 19th century by a German biologist named Walther Flemming. Flemming was looking at cells under a microscope and got the idea to use colors to dye the cell to make it easier to see things. The idea must have worked better than anticipated since he at once began to see spaghetti looking things in the nucleus that dyed a very deep color. As is the fashion, he named these entities chromosomes which is Greek for “colored bodies”.
Chromosomes are one of the more dynamic faces of Nature; they have to be, since they are responsible for the passing on of the 'Baton of Life' that we call reproduction. The number of chromosome in the cell nucleus differs somewhat from species to species. We humans have 46 chromosomes; dogs have 78; alligators 32; cabbage plants 18.
Your chromosomes are both the governess and chauffeur of the most important molecule in your body: DNA --which is actually two molecules wrapped around each other. Like any blueprint, DNA needs to be read in order for the work order to be constructed. Now, DNA is a long, long molecule. If it were completely unraveled it would be about six feet long, yet so thin that it would be invisible, since you can easily fit one million cells on the head of a pin. If the entire DNA, in every cell of your body, was stretched out and laid end-to-end in a straight line, it would reach to the sun and back over one thousand times.
I think an effective way of describing the dynamic qualities of the chromosome is to use a few metaphors. My older daughter likes to knit, so we often visit the knitting supply shop in town for fresh yarn. Yarn usually comes wrapped in skeins, a length of yarn wound around a reel. Most yarn comes in lengths of 80-150 yards. One of the nice things about buying yarn this way, rather than just as one long unwound string, is that you can put it under your arm and walk to the car. This is certainly better than tying a knot to the rear bumper and pulled the unwound string all the way home. Thus, the first important lesion of chromosome dynamics; if you’re going to reproduce you’ve got to stuff that entire DNA into a very small, tight package. Chromosomes are just that: tight packages of DNA.
On the other hand, it is very difficult, if not downright impossible to knit anything if the skein of yarn still has the paper label wrapped around it. In order to use the yarn, you have to unwind it. That’s the formula: when the cell needs to use DNA to get information about how to make a protein, it has to unwind it. When it needs to reproduce, or turn off the DNA information flow, it needs to concentrate and condense it.
How this occurs is rather wondrous, and will be the subject of much discussion later on when we talk about how you can modify your genetic destiny, but for now we’ll just stick to the basics. DNA is packaged and concentrated by special proteins termed histones. This concentrated DNA is called chromatin, which is the DNA plus the histones that package DNA within the cell nucleus. Chromatin structure is also relevant to DNA replication and DNA repair.
Histones are very cool bead-like proteins that spool the DNA in a way that makes it either tighter or looser, sort of like the cardboard around which our skein of yarn is wrapped. Histones respond to changes in their structure by tightening the DNA wrap or loosening it. Whenever a cell needs to access the genetic information encoded in its DNA, the histones on the section of the DNA that is needed undergo a chemical reaction called acetylation by which a molecule called an acetyl group is stuck on the histones, causing them to relax and unravel. When business is concluded for the day, special enzymes come along and chomp off the acetyl group cause the histones to become de-acetylated, which makes them tighten up again, sending the DNA in the region back to its resting state. Think of it like this; when your DNA needs to work its histones chow down on acetyl groups for breakfast and they do yoga; when it needs to reproduce or shut down, the histones lift weights --the strain of which causes the acetyl group to pop out of their mouths.
Make sure that you’ve mastered the last paragraph, because much of the very cool stuff dealing with how you can modify gene functions pretty much requires that you know this stuff. By the way, this is very, very cutting edge material; only until recent times have we understood this mechanism, and of supremely paramount importance, that it is used by the environment to influence gene function and that influence, for either good or bad, can be passed on as inheritance.
Scientists have given each human chromosome a number, according to its size; thus chromosome number 1 is the largest, then number 2, etc. Chromosomes come in pairs, one from each parent. So there are 23 pairs, for a total of 46 in us humans. Numbers 1-22 are non-sex chromosomes called autosomes, and pair 23 contains the X and Y sex chromosomes.
In the few minutes it has taken to read up to here, this, around 400 million of your red blood cells were depleted and replaced, consistent with the set of genetic instructions contained in your DNA.
The year 1956 stands out in my mind for a variety of reasons, the most important being (at least for me) that it was the year I was born. It also marked the year of the only ‘perfect game’ even thrown in a baseball World Series. Music fans might remember that it was the year that Elvis Presley entered the United States music charts for the first time, with 'Heartbreak Hotel.'
1956 was also the year a scientist named Roger Williams published a book called Biochemical Individuality, which attempted to relate inherited individual distinctions to nutritional requirements. Although Williams was no small figure in medicine (at the University of Austin he had discovered pantothenic acid, one of the critical B vitamins, and had published skews of articles detailing some of the most basic biochemical discoveries) Biochemical Individuality attracted little, if any attention from the medical community, probably due to the fact, as Jeffrey Bland speculates in his book Genetic Nutritioneering, Williams expressed many of his ideas in biochemical terms, which doctors of the time were far less comfortable with compared with today.
How prescient is the following phrase:
“The existence in every human being of a vast array of attributes which are potentially measurable (whether by present methods or not), and often uncorrelated mathematically, makes quite tenable the hypothesis that practically every human being is a deviate in some respects.”
It’s a strange choice of words, but the word deviate in this context signifies a turning away from the normal or a variance of some sort. Of course, we tend to think of the word more as a term for individuals who deviate from some sort of social norm; but norms are norms.
Williams was certainly deviating from conventional medical wisdom. Nobody at the time was looking at peculiar and individual aspects of nutrition that might be predicted genetically. More importantly, in 1956 there wasn’t anywhere near the enormous genetic industry and technology that exists today; it had only been three years before that James Watson and Francis Crick deduced the basic structure of DNA, (Deoxyribonucleic acid) –the double helix-- that contains the genetic instructions specifying the biological development of all cellular forms of life.
Thus when Williams talked of “attributes that are potentially measurable (by present methods or not)” he is taking an amazingly huge step into the future.
So Williams’ phrase “often uncorrelated mathematically” should probably be reinterpreted to mean “we can’t see the connections because of our current puny computational abilities.” Nowadays we link supercomputers together into vast neural networks and process data at a speed and accuracy that just boggles the mind. It was just this type of muscular computing that allowed scientists like Craig Venter and his firm Celera Genomics to help crack the human genome in record time. Today, the combination of gene sequencing and supercomputers is a day to day event in hundreds of laboratories worldwide, and is a prime part of a vast new field called bioinformatics.
In 1956, nutrition science was still in its infancy, concerned mostly with deficiency types of diseases such as pellagra and anemia, and making sure that we all ate “balanced meals.” There was no link between diet and cholesterol or between cholesterol and hardening of the arteries and medical journals often featured cigarette ads on their back pages. Ulcers were often treated by telling the patient to drink copious amounts of milk, the so-called “sippy-diet.” In other words, nutritional thinking at the time was predominantly disease-based, which is odd, since almost everything we do with food has absolutely nothing to do with disease. This resulted in what my friend and colleague Jonathan Wright used to call "The Association Diets.'
This is not to say that pieces of the puzzle weren’t evident, or that intelligent people were not already beginning to ask the right questions. It’s just that the questions could only be based on what was thought to be known, and what was known was not very much.
I can remember taking a computer class in high school (already well into the 1960’s) where we were taught to diligently inscribe a series punch cards with a 'number 2' pencil, which were then collated and fed to a machine the size of a large refrigerator, which then hacked and coughed for a while, finally yielding a half page printout of a list of fifty prime numbers.
Unless, of course, you had the misfortune to have penciled in the wrong box, in which case you just started all over again; a frustrating experience, which lead to one of my young colleagues, in a rage of frustration, placing one of the cards on the floor and proceeding to stomp on it repeatedly with his shoed foot, sending it on to the card reader --and probably producing the first computer virus-- a trick many of us would repeat when similarly frustrated. Your home computer can do these functions in micro-seconds, and the software to do it is considered so basic that it is usually packaged for free with the operating system.
No single diet theory can address all aspects of our individuality, and only a fool would claim that soy, red meat, grains, coconut oil or anything else is universally good or universally bad for everyone.
For example, people who are blood type O appear to derive significant benefit from a diet including hormone and antibiotic free meats and poultry. There is a very basic physiologic reason for this: those with type O blood have almost three times the levels of an enzyme in their intestines called ‘intestinal alkaline phosphatase’ (IAP) . This enzyme performs two very important functions in the body. First, IAP splits dietary cholesterol into smaller fragments, allowing for their proper breakdown. Second, IAP enhances the absorption of calcium from the diet. Now you'd think this was cutting-edge, late-breaking news since it is obviously of tremendous interest in these nutrigenomic times. However, the first observations were made over four decades ago.
In addition to these two critical functions IAP is an important influence on the ability of the digestive tract to heal. Thus in most of our type O patients (44% of the population) we see a marked improvement in their IBS, colitis and Crohn’s disease when they increase their protein and cut back on their carbohydrates. 
Blood type B makes considerable amounts of IAP as well, but type A’s make very little. This probably explains why most studies that have looked at heart disease and blood type show a significantly higher rate of problems with blood type A individuals. These folks really should follow a Mediterranean-type diet.
Later studies showed that type A not only secreted almost no alkaline phosphatase in their intestines, but whatever little they did secrete was in and of itself inactivated by the presence of their own A antigen. 
Thus, we have here one of the strongest indications for the long term benefit of a low-fat diet in type A, both with regard to the susceptibility to cardiovascular disease, and (although not mentioned here) their additional susceptibility to cancer. Following the type A eating plan, with its emphasis on a healthy fats, low animal protein and the avoidance of foods high in phenylalanine, is the best method to maximize digestive efficiency in type As, lower their level of intestinal dysfunction, and to influence their susceptibility to cardiovascular disease.
One of the great chin-scratchers of modern physical anthropology revolves around blood type, in particular why most indigenous populations of the New World have such incredibly high percentages of the gene for type O. Sometimes, especially as you move south of the modern US-Mexico border, the percentages almost reach 100%.
Since almost everyone agrees that human habitation of the New World began with migrations out of the Siberia, across the Bering Sea, and the population on the Russian Asiatic side shows no similar high percentage of type O; if anything the percentage frequency of the type O gene drops as we move further and further north and east. Several theories have been advanced to explain the apparent 'Bering Sea Bottleneck'.
The most often suggested is the genetic drift theory. The basic idea behind genetic drift is easy enough to understand. If you flip a coin two hundred times, there is a very good chance that your results will be somewhere close to 100 times coming up heads, and another 100 times coming up tails. Indeed, the more you flip a coin, the more likely (given that you have an honest coin) the results will be 50% head and 50% tails.
However, suppose that you instead only flipped the coin seven times; would it not be feasible on any given Sunday to flip five heads and two tails? Sure it is. That is how Las Vegas stays in business. Genetic drift is like that: A small population may have an uncharacteristic gene distribution simply because the genetic coin did not flip enough to have things even out.
So the Genetic Drift Theory of the 'Bering Bottleneck Type O Anomaly' posits that a small band of folks swam, walked or boated over the Bering Strait, and because their numbers were so small, the genes for A and B did not come along with the coin flip. This small number of colonist determined the future gene pool for the continent due to their exerting a 'founder effect'.
It's not a bad theory, except that in order to accomplish this, the numbers of Asian immigrants to the New World must be very small; along the order of a dozen or less, so that there is an even slight statistical chance that they could all be type O. However, even if the original colonizers of the New World numbered, say ten or eleven, the odds of those entire ten or eleven colonist being type O is about one in a thousand. Even if the number of colonists is dropped to five the odds only drop to one in thirty-two. (1) And that also assumes that there was one boatload or band of colonists, when common sense tells us that there must have been numerous attempts, though perhaps not all successful, to migrate to the New World.
The second theory is that of Natural Selection, which a lot of people equate with evolution, but it's not. Natural selection posits that perhaps a mixture of all blood types were part of the original migration, but for some reason, probably infectious disease, the type A and type B colonists died out. Of the two, Natural Selection is perhaps the stronger theory since there a definite likes between ABO type and susceptibility to small pox, syphilis, E. coli and tuberculosis, all of which probably killed lots of people back then.
However, as any honest exterminator will tell you, it's hard to kill them all.
A.E. Mourant addressed this issue in his book Blood Relations
"Like the absence of B in the Australian aborigines, the lack of B in the northern zone and of A and B in the southern zone raises a problem of world-wide importance. Was the B gene totally absent from the original populations from eastern Asia that ultimately reached Australia and America, or was the gene lost on the way? If so, was this due to genetic drift in relatively small isolated populations, or to natural selection? Early blood-group workers suggested that when man left Asia for Australia and America mutations for the A and B genes had not yet occurred. However, analogous if not identical genes occur in the higher apes at least, and so are several million years old. In the light of the discussion of O frequencies in Europe it is not difficult to see how, as a result of the elimination of A and B fetuses of O mothers, first the gene B (which is rarer than A) could have tended to disappear, and then A itself."(2)
Now, it has been know for a while (3) that human and primate ABO genes are somewhat analogous, let's just say that they are similar enough for our purposes, which is to say that the individual genes for A, B and (by default) O are 'old'. However, does it automatically lead us to assume that just because genes share a long history, does that mean we can assume that they will always exist in the percentage numbers? Of course not, we just say that with Genetic Drift: percentages change.
With apologies to Edward Tufte, let's take a look at the snazzy graphic I just did:
What you are looking at is the northeast corner of Asia and the northwest corner of North America at the Bering Strait, across and under-which one day your kids may be able to drive their cars. Not surprisingly, the colors of the map mean things: For example, the darker green the land is colored, the higher the frequency of the gene for type O; the lighter the color, the lower the percentage (less type O genes)
Now, first of all, note that these are indigenous populations, so the modern-day Alaskans and Siberians don't figure here that much here. What sticks out at you? Yup, there is lots of O gene the further east (the right side of ther map) you travel! But what else? Normally we might expect the trail of O genes to drift nicely along, but in our map the distribution is bi-modal: The incidence of O gene is higher at both ends of the map and lower in the middle. You can see that by looking at the bar graphs below, which not only looks at the relative 'percentage if each percentage' but also the percentage of land versus water: Each bar graph is actually a snapshot of one of the sixteen 'slices' of the map, the black lines.
So if anything, the more constricted that land mass became, the less you find the type O gene.
Interestingly, look at the red numbers on the map. They are the percentages of type B gene. Notice as well that the Asian side of the Strait has some of the highest percentage of Type B gene on the planet. What about on the American side?
Virtually no type B gene.
Now, to me this implies that there may well have been two waves, a 'First Wave' that contained very high percentages of type O gene and which had a relatively easy time getting across the Bering Strait (which may well have still been a land bridge) and who created the 'Founder Effect' in America, and a 'Second Wave' somewhat higher in Type A and much higher in Type B which followed but got stymied by the ecological changes and the closing of the land bridge.
So what I think is that both the Genetic Drift and the Natural Selection theories are correct, but I'm more inclined to move both of their occurrences with regard to blood type further back in time and much further west. In that case, rather than having crossed before the advent of the genes for A and B, our first American colonists would have walked across before the rest of Asia had a chance to recover from the results of its own initial 'flip of the coin.'
By which time there was no more walking there.
1. L. Luca Cavalli-Sforza. Genes People and Languages. University of California Press, 2000
2. Mourant, AE. Blood Relations, Blood Groups and Anthropology. Oxford University Press, Oxford, UK 1983.
3. Saitou N, Yamamoto F. Evolution of primate ABO blood group genes and their homologous genes. Mol Biol Evol. 1997 Apr;14(4):399-411.
Growing up in Brooklyn I remember many exciting and fun filled trips to Manhattan --or as anyone from Brooklyn calls it, “The City.” One of the features I always looked forward to seeing was a huge advertisement for a paint company that featured a can of paint pouring itself over a globe of the world, its byline proclaiming “We Cover the Earth with Our Paints.”
Excepting the obvious question as to why anyone would ever want to cover the world in it, paint is not a bad metaphor for how most scientists viewed inheritance before Mendel, it being a sort of “blended essence” --a mix of the features of both mom and dad, much like how we might combine white and black paints to make gray. In the late 1800s Charles Darwin proposed a mechanism of inheritance by means of gemmules, imaginary granules or atoms which are continually being thrown off from every cell or unit, and circulate freely throughout the system. Yet Mendel’s research showed that it was nothing of the sort; being in fact much more digital, like how a computer makes all sorts of interesting stuff out of what are essentially zeros and ones. Mendel’s theory nixed that notion completely, although after a while things started to be observed that appeared to indicate that genetics wasn’t all that black and white, on and off after all, but I’ll save that for a later story.
I’ve married a blue eyed woman, and have two daughters. The first daughter has brown eyes just like me. Simple enough: My brown-eyed alleles squash my wife's blue-eyed ones. However, my second daughter has greenish-hazel eyes, much lighter than mine or her sister, but certainly not bright blue like those of my wife, so it would seem like a little blending is going on over there after all. Eye color is not a simple dominant-recessive trait, although knuckle hair and tongue rolling are. The eye color trait is what geneticists call polygenic, which simply means that it is not decided by one single gene. In order to account for my younger child’s green-hazel eyes, we have to add other factors to the mix.
My wife is pure Irish on her mother’s side and a mix of Slovakian and Hungarian on her father’s. Hungarians have the highest percentage of green eyes of any population, close to 20%, so something in my wife’s blue-eyed world (the blue-eyed allele of her Hungarian father) produced a variant that refused to role over and die, but instead made alliances with other genes --including a recently discovered one that may go back to the Neanderthals--- that slips green eyes and red hair in between things, ultimately producing my younger daughter’s wonderful green eyes. Given that, you'd think I'd get the tongue rolling gene and she the knuckle hair, but alas, the results are quite opposite.
Many traits are polygenic, and when when added to the tremendously under-appreciated epigenetic effects on gene expression, explain why we have never found a single gene for diabetes, or cancer or Alzheimer’s disease. If it were that simple, we’d have had the answers to these questions already.
Another type of inheritance is very close to my heart. The allele (the set of alternate genes for any trait) for type O blood is recessive to the alleles for type B and type A. Again using my family as an example, biologically I am type A blood and my wife is type O. My daughters are both type A blood, so we know that they must have received a type O allele from mom and a type A allele from me. Their genotype for ABO blood type is A/o (recessive alleles are usually depicted in lower case, dominant in capitals, and genetic things are usually rendered in italics).
If I was instead type B blood and had provided a type B allele, the children would have type B, as type B is dominant to type O as well.
But here is where things get interesting. What happens if you were to receive one type A allele and one type B allele? Why, you would be blood type AB! The reason behind this is that although both B and A clobber O, they strike a tentative truce between themselves and split the kingdom and declare a dual monarchy. This is called co-dominance. There are not many instances of co-dominance in genetics, and ABO inheritance is almost always given as the example.
You may well ask why, if type O is recessive to types A and B, why hasn’t it disappeared, leaving only A and B to slug it out, and eventually producing a world of only type AB people? The reasons and proofs for this are mathematical, so I won’t bore you with them, but suffice it to say that if a population is large enough, and the individuals in that population tend to mate randomly, and there are no other major influences (such as one type being more resistant to an infectious disease), after one generation the gene pool will stabilize and reach a sort of equilibrium.
Since there is such a huge amount of o allele in the human population (so much so, in fact, that even though it is the recessive allele, individuals with type O blood constitute the majority of most populations around the world) it will keep propagating itself, whereas the type you’d have though would be replacing everyone else by now, AB, comprises at best about 2% of the population.
Most people probably have a negative concept of mutation, spawned by a slew of admittedly great science fiction. However, it might surprise you to learn that that vast majority of mutations, at least the ones that get incorporated into our genetic heritage, are not lethal and often don’t do very much at all. For example, let’s again turn to our trusty blood types. As we will explore in more later on in this book, genes are chunks of DNA that do things, like code for specific proteins. Although DNA is an incredibly long molecule (if all the DNA in all your cells was unwound and placed end to end it would produce a string capable of reaching to the sun and back several times) it is composed of a simple string of four repeating nucleotides abbreviated A,T,C and G. The sequence of these four repeating nucleotides is what contains the instructions for the protein.
The difference between having the gene for type A blood or type B blood is a variation of a mere seven letters out of the total of 1,062 that make up the entire gene. We even know exactly where they differ: letters number 523, 700, 793 and 800. If you are type A blood, you have C,G,C,G in these locations, whereas if you are type B blood you have G,A,A,C there instead. Yet however slight this difference is, it is enough to cause a major problem if you were to receive the wrong blood in a transfusion. These are called point mutations because they are a simple one-letter misspelling in a gene, unless as in the case of blood type it is a consistent variation that is inheritable, in which case it is called a polymorphism.
The type O gene mutation is even more interesting. It derives from a frame shift mutation. If you are type O you may be surprised to discover that rather than having a difference of letters, like A and B, you're just missing one letter, number 258, entirely.
So hopefully by now you are comfortable with the notion that mutations are just part of life, unless of course you are unfortunate enough to have gotten a lethal one (and there are many) which probably would never have allowed you to get so far in life as to be able to read this blog. Many, if not most, of these mutations are spontaneously terminated while the sufferer is still an embryo in utero. Virtually all of the well-known genetic disorders are semi-lethal.
There are may causes of mutations, including viruses and radiation, but the most common cause is the simple fact that when our cells reproduce, they must make a complete copy of there DNA, and sometimes the copies don’t turn out so great. Think about the photocopy of that great joke that circulated around the office cubicle the other day. If it was barely legible, with bloated letters that ran one into the other, it was probably because someone made a photocopy of the original, which was quite likely a photocopy of the previous copy. Each time a copy was made of a copy, the writing was degraded a bit more.
Genes are like that. Often as we get older, we tend to get more and more of this “photocopy effect”. Perhaps what was once a word string of CAG became CAA. Even if it is copied correctly, it will be CAA from there on. Perhaps not unexpectedly these mutations are called “copying errors” and given the enormous amount of cell division that goes on over the course of a lifetime it is the real surprise is just how good of a job we do at it.
Fascinating presidential election; certainly a very unique and historic outcome. It will be interesting to see --given the perilous state of affairs we find ourselves in-- whether 2008 is also the first presidential election in which (come January) it is the winner rather than the loser who demands a recount.