Human Genetics Analysis

Every day in the office I deal with the issues involved in human genetics. Making a human baby involves the union of the genetics of a mother and a father. A man and a women. Benjamin Franklin (one of the American Founding Fathers) used to like to say that only two things in life are certain. They were, in order of importance, Death and Taxes. Americans repeat that phrase often. We usually say it fast without any pause in between.  I would add that there are a few other certain things in life. At the beginning of life, there is Birth. One cannot have a death without having a birth. There is a Franklindian certainty (of the Death and Taxes type) that a human being must have one genetic mother, to be born. One mother must provide the genetics. Every person who is born has one genetic mother.

Similarly, every human that is born has a genetic father. 

What are genes? They are the information storage system of all known life. The DNA system is astonishingly the same for all known life. The Scientists Watson and Crick received a Nobel prize for discovering that the genes live on a helical molecule called DNA. Deoxyribonucleic Acid.  They discovered it in the 1950's.  A normal structure of the DNA molecules in a living human cell is for each of these molecules to be coiled up into Chromosomes. An uncoiled DNA molecule is several meters long. Coiled up, 46 of them fit into the nucleus of a cell, and the chromosomes are millions of times shorter. Chromosomes are easily visible under a microscope. I see pictures of actual human baby chromosomes all the time. This is the end result of a genetic amniocentesis. A normal cell has exactly 46 chromosomes. 23 chromosomes come from the mother, via her egg, and 23 from the father, via his sperm. The woman always contributes 23 chromosomes. Since every women (and human) has 23 pairs, or 46 total, every egg has to choose one of the pair of each 23 pairs. This has some astonishing statistical implications. For instance, each woman can make 2 to the 23rd power different kinds of human eggs. No more, and no less (unless there is chromosomal "pathology"). 2 to the 23rd is 8,388,608 different kinds of human eggs for each woman. Each human woman is born with about 300,000 human eggs. They are created before she is born, and she will create no more during her life. Statistically speaking, every one of those 300,000 eggs is completely different, genetically and chromosomally unique. The odds of any two eggs having the same chromosomal material is about one in 8.4 million. The odds of there being two identical eggs in a woman, out of her whole complement of 300,000, is about one in 28. This is 8.4 million divided by 300,000. 

The statistics for sperm are exactly the same, but for the fact that men make trillions of sperm throughout their life. But they can only make 8,388,608 different kinds of sperm.  

How many different kinds of human siblings can a specific man and women make? This is an easy statistic. It is, choose one of the different kinds of eggs, and choose one of the different kinds of sperm. The math is 8,388,608 times 8,388,608. Equivalently, 8,388,608 squared. This equals 70,368,744,177,664. Not one more or one less. Lets just call it 70 trillion. So a couple would have to have about 35 trillion children before they had a 50 percent chance of having genetically identical children. Obviously identical twins are much more common than that. The reason there are more identical twins is because the human embryo sometimes splits into two or more, before the third day of conceptional life.  

Therefore, chromosomally speaking, it is vanishingly unlikely that any two humans have anywhere near the same identical chromosomes, unless they are identical twins. 

And unrelated humans have even less likelihood of having common DNA. 

If a single family can make 70 trillion different kinds of offspring, then how many genetically different kinds of humans can be made? It boggles the mind. 

There are a lot more interesting genetic facts and conclusions. 

Lets get started with some more interesting analysis. 

Everyone has two of the first chromosome, called chromosome number one. It is the largest chromosome, so it contributes a lot of genetic material. Everyone gets one from their father, and one from their mother. The one they got from their mother is a genetic identical copy of her mother's. And the other is an identical copy of their father's first chromosome. Her mother got one from her mother. And her mother got a perfect copy from her mother. And so on and so on. The only changes that exist are "mutations". Mutations are spontaneous changes in genetic material that happen when a child gets a different chromosome that their parent had. Mutations happen because of an error in the copying mechanism that creates cell division. They might happen, for instance, when a gamma ray hits the chromosome and changes it. Or when the wrong biological molecule gets stuck in the copying machine. 

Mutations happen at a statistically predictable rate. Most mutations are "bad", but some are favorable. Mutations are important because they are one source of genetic evolution. The other, more important source, is simply which chromosomal rearrangements of the 70 trillion possible, are "better"? Which one makes a human smarter, bigger, stronger, more resistant to disease, etc? Which one will survive, and therefore survive long enough to make even better children? 

Because we know how many mutations there seem to be, we can extrapolate backwards in time to a genetic "Adam and Eve", that was the first set of humans. Genetics professors have done this, and have decided that the first human tribe consisted of about 40 human females, or "Eves", and they existed about 200,000 to 250,000 years ago. Most likely this tribe was in North Africa, and spread out from there. Since then the human species has grown in number. Most of the growth is recent. There have been about 120,000,000,000 humans born since then. 120 billion. The reason I say Eves and not Adams, is that it is easier to do these statistics with women, because of some genetic implications of the mitochondrial DNA, which is a different set of DNA, and only comes from the mother. 

A similar analysis has been done with the "Y" chromosome, that only comes from fathers, and the fathers father, and his father, and so one. 

The fossil record, and anthropology, is consistent with the human species being this old. All of recorded history begins about 8000 years ago. But we know that modern human culture, with words, art, tribe hunting, of large and dangerous game, and oral histories, began at least 50,000 years ago. 

Anyway, I was looking at a photograph of human chromosomes today, with a new patient to the practice, and she had a bunch of really interesting questions to ask. She had already had a genetic amnio, and this was the report on the baby. The baby had normal looking chromosomes. The baby had 23 pairs of human chromosomes, labelled 1 to 22. All of them looked normal. There were two X chromosomes, and no Y chromosomes, so we knew it was a girl. 

One of the most common abnormalities of the amnio result is a triplication of the 21st chromosome. This is the second smallest chromosome. Somehow, when a sperm or egg is created, the chormosome sorting machinery goes awry. This means an egg or a sperm gets an extra chromosome This means that this human fetus would have trisomy 21, or Down's syndrome. Down's is quite common. It is not a mutation. A 35 year old women has a one in 300 chance of having a Down's baby. A 40 year old has about a one in 30 chance. It is much more common as a women gets older. 

There are trisomies of all the chromosomes. Most are incompatible with human life, and never create pregnancies. Trisomy 21 is  one exception in that these pregnancies create a human with Down's syndrome. Trisomy 13 and 18 do create pregnancies, but the fetuses never survive more than a few days of life, if they even get to full term. They are highly abnormal. On the other hand Trisomy of the X chromosome is much less abnormal. In a female with an extra X chromosome, she is completely normal. It will likely even never get diagnosed. Even her children will likely be normal. Men with an extra X are called Klinefelters. They are tall, they are tend to have weak muscles, they may have an emotionally tough puberty, and they don't make sperm. So they cannot have their own children. Trisomy of the Y is called XYY. These are normal males. The teaching used to be that these boys were troublemakers, had high testosterone, and wound up in prison a lot. More modern thinking is that they are about 3 inches taller than usual, and about 5 IQ points smarter than average. They are basically normal people, like the XXX females are normal. 

Finally, I would like to say that that the scientific quantity of knowledge in the field of genetics is exploding. There is so much to know about genetics analysis of individuals, and their children, and the means of inheritance, that it is literally impossible to keep up with current knowledge, recommendations, and the science. I have spoken with our genetics consultants, and I am continually surprised by the new genetics testing that is possible. And these possibilities continue to expand. The geneticists themselves have to frequently hit the books to figure out any individual case. 

Myself, I frequently refer to geneticists because there is just too much to know. 

There are a couple of advancements to note, though: 

About 1990, the US Federal Government funded the genetic sequencing of an individual. The cost to do this was about 3 billion dollars. The wikipedia page is here: http://en.wikipedia.org/wiki/Human_Genome_Project 

The first draft of the genome was printed about the year 2001. 

Now, the cost to do the sequencing continues to decrease. 

There is a report of a company that can do an individual's sequencing using "system on a chip" technology borrowed from the computer industry. This company claims to be able to entirely sequence a human for about a thousand dollars. I reported about this in a prior blog post. 

Right now it costs my patients, or their insurance companies, about 3 or 4 thousand dollars to test for a few breast cancer genes. Do the math and you will  see that the cost of genetics analysis will continue to plummet over the next few years. 

Also, the Genetic Amniocentesis may be going to way of the dodo bird. I mean, it may be going extinct. Or, it is going to become increasingly rare, and used only at the end stage of a diagnostic workup. Women hate doing the amnio because it pokes a needle very near their baby. And it has a miscarriage risk quoted to be somewhere between one in 300 and one in 1500. Nowadays, I can order a simple blood test that can tell me if the pregnancy has a trisomy 13, 18, or 21.  These are the most useful trisomies to test for. The one that I do in my office is the Materna T-21 test. I recently ordered it for a pregnant women who was found to have a downs risk of about 1 in 350. In the past, this women would have faced a very difficult choice between risking the amnio, with it's inherent risks, or risking the Down's, with a risk of about one in 350. Technically, her Downs risk was completely normal, because we don't call it elevated risk until the risk is about one in 300 or more. But, in this day and age, where a common Down's syndrome risk assessment is one out of a quarter million, I don't see how couples are going to be happy living with a risk of Down's of one in 350 when I can do a noninvasive nearly risk free amnio alternative. 

We can only hope that the insurance companies will pay for the noninvasive modern T21 style tests. I think they will ultimately come along and pay for it, but it will take some time and work to convince them. 

Thank you for reading my blogs. Comments are very welcome. 

Dr John W Marcus MD FACOG PC 

89 North Maple Ave 

Ridgewood, NJ 07450 

Phone 201-447-0077 

Fax    201-447-3560 

Blog at : Http://doctorjohnmarcus.blogspot.com/ 

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