Mind-Blowing, Life-Saving Research

My mother's father died of cancer before I was born. My mother was pregnant with me, but had not told her father that she was to have a second child. The story I've been told is that they opened him up to remove the cancer -- and found it everywhere. They closed him back up and sent him home to die.

Both of my mother's brothers died of cancer. All three of these men were heavy smokers, one ignored the signs of potential trouble for years, and all three died from cancer.

My mother was diagnosed with cancer in 1978 and beat it. She was diagnosed a second time in 2005, but again beat cancer. She went to heaven last fall, but not due to cancer. She was not a smoker -- so what was the cause?

Her sister, my aunt, has never had cancer. I've often wondered, what genetics, lifestyles and triggers can make a difference in the cause of cancer?

There are some scientific discoveries so mind blowing that when you first hear about them you know that they are really, really big. That there will be ramifications for decades, even though you don't know what the ramifications will be.

The grandness of the discovery captures your imagination and changes your thoughts about relationships and life, even thought you don't quite understand the details, the underpinnings of the discovery.

Such is the discovery noted in The New York Times article this week, "Seeing X Chromosomes in a New Light," by Carl Zimmer. The article captured my imagination and broadened my mind.

The last time that I dealt with chromosomes was in college biology, when I had the mistaken belief that biology was my future and my major. A few chemistry labs later and one histology class, and I knew that my future was not in biology, but in business, where getting an A did not involve donning goggles and aprons for hours at a time.

As a quick review, the female chromosomes are XX and males are XY. Children receive one of their mother's X-chromosomes and either the X, or Y-chromosome from their father. The transmission of the father's chromosome determines whether the child is a male or female. This is not new news, but old.

Females, having two X-chromosomes, shut down one of the chromosomes at a cellular level. Which X-chromosome is shut down varies by cell -- in some it's the one passed down by the father, in others it's the chromosome that is passed down by the mother.

OK -- so scientists have known about this for over five decades, and it's just now coming to my attention -- but why the press now?

A recent study was published in "Neuron," that included maps of the X-chromosome inactivation. "They found a remarkable complexity to the pattern in which the chromosomes were switched on and off," according to Zimmer.

Females have two copies of the X-chromosome, each of which has different versions of the genes not found on the other. This allows for one or the other to be used in the cell, leading to more genetic diversity than males. If one of the genes has a weakness -- the other can be used.

"Females simply have access to realms of biology that males do not have," Huntington Willard, the director of Duke University's institute of Genome Sciences & Policy noted.

The recent published research led by Dr. Nathans showed illuminated maps of where different X-chromosomes were activated in various cells within the bodies of mice. Nathans "speculates that using chromosomes from both parents is especially useful in the nervous system. It could create more ways to process information. 'Diversity in the brain is the name of the game.'"

What shuts down the second X-chromosome? It's a number of molecules, led by what has been named the Xist.

Dr. Lee, a Howard Hughes Medical Institute investigator at Harvard Medical School, has found that when the Xist is inactivated and the second X-chromosome is allowed to be active, it creates extra proteins. These extra proteins can drive a cell to grow uncontrollably. This additional uncontrollable growth makes cancer is more likely.

Women's brains are created differently, on the molecular, cellular level. What does this mean? I'm not sure, but I'm fascinated. Now that we know Xist exists, maybe we can determine how it becomes inactive -- and ensure it remains inactive.

exDemMom said: "... and eventually won the Nobel Prize. "

Excellent. Are you working on yours?

Up for more questions?

You state that we have "thousands of viruses living in our genome". Are these viruses "free-ranging"; that is, can they move from cell to cell within a person and replicate? Can they move from one person to another and replicate?

You also state, "the mitochondrial DNA uses a slightly different triplet code than the nuclear DNA".

I'm aware that each triplet codes for a particular amino acid and that a sequence of triplets codes for the sequence of amino acids making up a particular protein.

I'm also aware that there is some redundancy in the code, in that, in at least one case, there can be more than one triplet used to code for a particular amino acid.

The question then is, when you speak of a "different triplet code", just how different is the code? Is the connection with viruses confirmed, at least in part, by the details of this alternative coding? How exacting is the match between this alternative coding and that of viruses? Do all viruses use the same coding which is different from that used in human cells?

For that matter, do most non-viral organisms use the same coding or are there differences.

I recall reading about inheritable markers left in DNA by viral infections being used to confirm evolutionary relationships. I found the argument for evolution based on these markers very convincing. Has this research continued to confirm evolution? I would expect at least some surprises when using this technique to confirm evolutionary relationships versus other means to relate different species.

Excellent. Are you working on yours?

Haha, no. I chose a career path that is highly unlikely to result in a Nobel Prize. However, I have met a number of Nobel Prize winners.

No, these viruses have permanently become fixed in our chromosomes and are incapable of moving around. They became integrated in chromosomes as a result of ordinary viral infection--some (not all) viruses routinely insert themselves into the host DNA during the course of infection. When this happens in the germ cells, and if the virus does not disrupt essential genes, the progeny from those germ cells will have a copy of that virus in every cell in their body. Sometimes, viruses will remove themselves from the chromosome as a result of some trigger (a number of things can be a trigger). But if a virus is stably integrated in a chromosome so that it is passed to the offspring, it eventually (after generations) loses the ability to remove itself. Right now, a retrovirus causing disease in koalas in Australia is showing evidence of becoming a permanent part of the koala genome.

You also state, "the mitochondrial DNA uses a slightly different triplet code than the nuclear DNA".

...

First of all, viruses that infect humans use the same triplet code as humans. The mitochondria use a slightly different code, where triplets that mean one thing in nuclear DNA mean another thing in mitochondrial DNA. For example, the "start site" where protein synthesis is initiated is almost always ATG (AUG in the messenger RNA), which codes for the amino acid methionine. But mitochondria can also initiate protein synthesis at AUA, AUC, and AUU--in other words, at any codon that begins with "AU." In addition, a handful of codons that mean one amino acid in nuclear DNA mean a different one in mitochondrial DNA. Mitochondria have their own RNA polymerases and ribosomes, so they do make a few of their own proteins.

There are 64 different codon "words" of 3 letters each, which stand for 20 amino acids and "stop", with most amino acids coded for by more than one codon. For the most part, the codons mean the same thing in all organisms--but there are a handful of known exceptions, like the mitochondria. I can engineer bacteria to make proteins using mouse or human DNA, and I do not have to change any codons for the bacteria to make the correct proteins.

I should take a moment to point out here that the viral DNA in our genome was found by homology matches with known virus genes. There are very powerful computer programs that help us to search these huge sequences for these homologies.

The viral remnants in our DNA very much help to delineate evolutionary relationships. It is possible to find a virus in the genome of one species, but not in that of another closely related species, which helps to pin down exactly when that virus became permanently embedded in that genome. I find looking at evolutionary relationships fascinating, and I love generating phylogenetic trees. As for finding surprises in evolutionary data--those always show up. We scientists just love to find new things!

exDemMom said: "The viral remnants in our DNA very much help to delineate evolutionary relationships."

Thanks for your responses.

My understanding from years ago is that whales, being mammals, are thought to have evolved from land based animals. I don't know how controversial such a theory would have been prior to the discovery of these viral DNA markers, but I would think that it might now be possible to be more certain.

Another fact I ran across recently is that mushrooms can be a dietary source of vitamin D if the mushrooms are exposed to sunlight.

I believe that not all organisms are able to synthesize vitamin D from sunlight. Is the presence of this capability consistent with viral DNA, or am I barking up the wrong phylogenetic tree?

Thanks for your responses.

Thank you!

The virus remnants are just one genetic tool. We have several ways of establishing these relationships. Paleontologists piece together phylogenies based on bone measurements, for instance, by measuring the ratios of various parts of a bone and comparing those ratios between species. They also look at other bone features. Since I never studied paleontology, what they do really looks like magic to me. However, by doing what I know best--molecular biology--I look at DNA homologies, not just of the viral remnants, but of any part of the genome that I want to study, and I can reconstruct the same phylogenetic tree that the paleontologist constructed. I love phylogenetic trees; they can be used to examine any evolutionary relationship, no matter how closely or distantly related the organisms are.

This picture is the phylogeny of a single gene on Y chromosomes of European men. These men are all related. I would guess that the alphanumeric code is an identifier for each man in the tree.

Another fact I ran across recently is that mushrooms can be a dietary source of vitamin D if the mushrooms are exposed to sunlight.

I believe that not all organisms are able to synthesize vitamin D from sunlight. Is the presence of this capability consistent with viral DNA, or am I barking up the wrong phylogenetic tree?

Interesting! I do not know enough about mushrooms to know how much of their metabolism is affected by the presence of viral genes. The thing is, viruses and more complicated organisms rely on each other. We exchange genes with each other, and we are true symbiotes in that we perform biological functions for viruses, bacteria, and fungi, and they perform vital functions for us. Although most people think of germs as destructive invaders, the truth is that most of them are not pathogens and have mutual cooperation agreements with their hosts.

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