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05/27/2010

What's in Your DNA?

Svante Pӓӓbo is a Neandertal! You may also be a caveman or a cavewoman! Me too! Not so if you're black and of purely African heritage. OK, I must admit to some exaggeration - we "cavemen" only have a bit of uniquely Neandertal DNA, as I understand it. You've probably seen or heard in the media that a draft of the Neandertal genome has been published and it seems that the question as to whether our early Homo sapiens ancestors had sex with Neandertals when first they met has now been answered.  The answer is yes!
 
It isn't just Neandertal DNA that's been in the news. Recently, Walgreens announced they would be selling DNA test kits that would enable one to have his or her DNA analyzed for genetic features predisposing one to various diseases or maladies. Then the FDA and others voiced objections and Walgreens pulled back the offer. Even so, it's probably only a matter of time before a person's DNA is routinely checked, possibly at birth. 
 
Another DNA item that has intrigued me is an article titled "The Insanity Virus" by Douglas Fox in the June issue of Discover magazine. If psychiatrist Fuller Torrey is right, our DNA carries not only possible genetic contributions from the Neandertals but also contains DNA sequences derived from long ago contacts with viruses; these viral DNA sequences may be like Trojan horses, giving rise to schizophrenia, bipolar disorders or even muscular dystrophy. 
 
But first let's elaborate on the Neandertal affair. The question of whether or not there was interbreeding between modern man and the Neandertals has been bugging scientists almost from the time of the discovery of Neandertal fossil remains back in the 19th century. Clearly, one way to approach the problem is to compare the DNA in the genome of us Homo sapiens with the genome of Neandertals. With the relatively recent decoding of our own Homo sapiens genome, the question became: Is it possible to decode the Neandertal genome from material taken from Neandertal fossils tens of thousands of years old?
 
This question has now been answered. In the May7 issue of Science the achievement of a draft sequence of the Neandertal genome is reported in two papers. Accompanying interpretive articles by Ann Gibbons and by Elizabeth Pennisi provided much needed help for my feeble brain to understand the substance of these highly technical articles describing the unraveling of the Neandertal genome. To understand the immense challenges inherent in this remarkable achievement, consider that some (all?) of the samples that were analyzed consisted of 99.8% microbial material and only 0.2% Neandertal material. After all, when a person has been dead for tens of thousands of years, the remains have been food for all kinds of microbes and other critters. Not only that but some samples were contaminated with modern human DNA, introduced I would imagine in the digging up and handling of the fossils.
 
I find it interesting that the first author on the paper titled "A Draft Sequence of the Neandertal Genome" is Richard Green and the last is Svante Pӓӓbo, with somewhere around 50 authors in between them. I'm glad to see that Pӓӓbo, Director of the Department of Genetics at the Max Planck Institute for Evolutionary Anthropology and the fellow who seems to have been the key player in getting the Neandertal genome project going, put himself last in the author list. Judging from one of the articles by Pennisi, Richard Green truly earned his first spot on the author list. He apparently contributed greatly to the mathematical/modeling challenge of sorting through and figuring out how to separate out those parts of the DNA sequences that belonged to the Neandertal from all the overwhelming majority of DNA sequences from microbes and modern humans. Somehow, by chopping up the sequences of DNA sufficiently and applying analytical techniques beyond my comprehension, the workers could decode the Neandertal segments and then virtually assemble them in their proper order in the genome. Amazing! 
 
So, what did the researchers accomplish? They sequenced DNA from Neandertals from four different sites in Europe and Russia. They compared the Neandertal DNA with the DNA of five present day humans from Southern Africa, West Africa, New Guinea, China and France. The key finding is that the present day non-African humans share with the Neandertals certain segments of their DNA, somewhere between 1 and 4 percent of the total; these particular segments were not found in the Africans' DNA. The conclusion is that the modern homo sapiens coming out of Africa first met the Neandertals when the latter were coming to the Middle Eastern area to escape the cold weather in Europe at that time. The scenario is that our modern human ancestors and the Neandertals indulged in some interbreeding, at which time our ancestors picked up those additional Neandertal segments of DNA and passed them along to their offspring. At that point some of us moderns went east and others went west, populating Europe and Asia and, eventually Australia and islands in the Indian and Pacific Oceans. The Neandertals never got back down to Africa and hence did not add any of their DNA to the DNA of native Africans.
 
So, it seems that some of us carry in our DNA bits of DNA resulting from our ancestors getting together, if only briefly, with our Neandertal cousins. But it turns out that we also carry with us in our DNA the results of other encounters, not with hominids, but with so-called retroviruses. The HIV virus responsible for AIDS is a retrovirus. If you look up the definition of a retrovirus you'll find it to be a virus composed of RNA, ribonucleic acid, instead of DNA. RNA is a single stranded compound as opposed to DNA, with its famous two stranded structure in which the "letters" (bases) A,G,C and T link up across the two strands. In RNA the base T is replaced by another base, U. Let's not go into the chemistry here except to note that in a retrovirus there's a sneaky enzyme, reverse transcriptase, that can transform the retrovirus's RNA into DNA and slip this "retro-DNA" into the DNA of the cell into which the retrovirus has penetrated.
 
Now the scary part. If that cell does what many cells do, it divides and passes along the retro-DNA into the other cell. If the cell happens to be a sperm or ovum, Voila! Whatever critter that sperm or ovum gives rise to now has the retroDNA in its own DNA. Just such encounters with retroviruses are thought to have happened throughout our history, even going back to some of our ancestors that were not yet human! One such ancestor is thought to have been a lemur. In fact, according to Fox, we carry around in our DNA about a hundred thousand of these retrovirus sequences in our DNA; that means that about 40 percent of our human DNA is parasitic retrovirus related! In the trade, these are known as human endogenous retroviruses (HERVs). Apparently, our genome does a good job of isolating these viral remnants from doing us harm by folding up to block the exposure of the remnants or by other means of keeping any ill effects to a minimum.  However, it now appears that these efforts do not always succeed. One of these HERVs, HERV-W, is of special interest.
 
A fellow in France, Hervé Perron, had the feeling that retroviruses might have something to do with muscular dystrophy, MS. Others had similar ideas but failed to link MS with any known virus. After some eight years of hard work, culturing cells from MS patients and finally finding a retrovirus, Perron sequenced the retrovirus gene in 1997. Perron was shocked to find that, instead of being a virus that spread through the air or from person to person, the gene sequence, HERV-W, was there in the patients' own DNA! Since that time a number of other studies have confirmed that HERV-W is present in MS patients.
 
Let's turn from MS to schizophrenia and Fuller Torrey, director of the Stanley Medical Research Institute in Maryland. Torrey's sister was about to enter college when she was diagnosed with schizophrenia, a disease that is typically diagnosed in patients in their late teens to mid twenties. This no doubt influenced Torrey's interest in starting research aimed at finding the cause of the disease. If you've known someone with schizophrenia or bipolar disorder, as I have, you can appreciate what a terrible disease a mental illness is. Going against the traditional view that schizophrenia is a mental disease due to genetic or to psychological problems, Fuller and others are convinced schizophrenia is actually caused by infection, initiated by an infection early in life. 
 
There are a couple of intriguing examples that helped lead Torrey to this conclusion. Although it's only a small effect, 5 to 8 percent, there's been a consistent correlation of schizophrenia with the birth month. In over 200 studies, there is this consistent finding that schizophrenia is more prevalent in people born in winter or early spring. These are the months when infections, notably the flu, are most prevalent. Or, take the actual case of two specific identical twin boys, one of whom came home from the hospital after birth in good health. On the other hand, his twin brother contracted a life-threatening infection in the hospital, putting him in the intensive care unit and an incubator for a month. When he finally came home he was lethargic and, after learning to walk, had balance problems, falling and bumping into things. However, by the time the two boys entered grade school all seemed well. The two looked like the identical twins they were, both played basketball and were good students, earning B+ grades. 
 
All was going smoothly until the twins were 17, at which point the "infected" twin began to hear voices and was diagnosed with schizophrenia. Torrey's studies of schizophrenics, including other identical twins, showed the schizophrenics to have signs of inflammation, physical problems such as not being able to walk a straight line, differences in brain structure when compared with their twin, etc. Although not a popular concept, Torrey maintained that schizophrenia is not a psychological problem but is instead a brain disease. 
 
As did Perron with MS, Torrey and Robert Yolken, at Johns Hopkins, began looking for a retrovirus associated with schizophrenia and in 2001 came up with a candidate, none other than HERV-W! And, in 2008, Perron himself published a paper showing that in one study half the people with schizophrenia had HERV-W in their blood, compared to only 4 percent for healthy people. 
 
Various experiments with mice have led Perron to suggest the following scenario for MS and schizophrenia. In MS the initial infection is thought to awaken or activate the HERV-W segment of the genome. When the immune system of the newborn detects the HERV-W it springs into action with T-cells spewing out cytokine molecules that in turn attract more immune cells and the inflammation gets out of control. Eventually the immune system attacks and kills brain cells causing MS or damages neurons by overstimulating them and, over a period of time and perhaps other infections, the effects build up to the point where the emitting of neurotransmitters leads to hallucinations, paranoia and other symptoms of schizophrenia or bipolar disorder. 
 
Finally, in the interest of full disclosure, I should point out that both the infection and the sex-with-Neandertal claims have their critics who doubt the conclusions discussed here. For those who've read my columns over the years, would you expect otherwise? Any exciting discovery or postulate has its critics and that's probably good in that it spurs more work and, hopefully, the truth emerges. 
 
As for me, I find it rather exciting to think I might have some caveman in me. As far as the possible link between infection and MS, schizophrenia or bipolar disorder, I hope the link is indeed proved, perhaps paving the way for some sort of routine vaccination or other medical intervention at birth to prevent or address the effects of early infection. 
 
Next column on or before July 1, hopefully.

 
Allen F. Bortrum



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-05/27/2010-      
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Dr. Bortrum

05/27/2010

What's in Your DNA?

Svante Pӓӓbo is a Neandertal! You may also be a caveman or a cavewoman! Me too! Not so if you're black and of purely African heritage. OK, I must admit to some exaggeration - we "cavemen" only have a bit of uniquely Neandertal DNA, as I understand it. You've probably seen or heard in the media that a draft of the Neandertal genome has been published and it seems that the question as to whether our early Homo sapiens ancestors had sex with Neandertals when first they met has now been answered.  The answer is yes!
 
It isn't just Neandertal DNA that's been in the news. Recently, Walgreens announced they would be selling DNA test kits that would enable one to have his or her DNA analyzed for genetic features predisposing one to various diseases or maladies. Then the FDA and others voiced objections and Walgreens pulled back the offer. Even so, it's probably only a matter of time before a person's DNA is routinely checked, possibly at birth. 
 
Another DNA item that has intrigued me is an article titled "The Insanity Virus" by Douglas Fox in the June issue of Discover magazine. If psychiatrist Fuller Torrey is right, our DNA carries not only possible genetic contributions from the Neandertals but also contains DNA sequences derived from long ago contacts with viruses; these viral DNA sequences may be like Trojan horses, giving rise to schizophrenia, bipolar disorders or even muscular dystrophy. 
 
But first let's elaborate on the Neandertal affair. The question of whether or not there was interbreeding between modern man and the Neandertals has been bugging scientists almost from the time of the discovery of Neandertal fossil remains back in the 19th century. Clearly, one way to approach the problem is to compare the DNA in the genome of us Homo sapiens with the genome of Neandertals. With the relatively recent decoding of our own Homo sapiens genome, the question became: Is it possible to decode the Neandertal genome from material taken from Neandertal fossils tens of thousands of years old?
 
This question has now been answered. In the May7 issue of Science the achievement of a draft sequence of the Neandertal genome is reported in two papers. Accompanying interpretive articles by Ann Gibbons and by Elizabeth Pennisi provided much needed help for my feeble brain to understand the substance of these highly technical articles describing the unraveling of the Neandertal genome. To understand the immense challenges inherent in this remarkable achievement, consider that some (all?) of the samples that were analyzed consisted of 99.8% microbial material and only 0.2% Neandertal material. After all, when a person has been dead for tens of thousands of years, the remains have been food for all kinds of microbes and other critters. Not only that but some samples were contaminated with modern human DNA, introduced I would imagine in the digging up and handling of the fossils.
 
I find it interesting that the first author on the paper titled "A Draft Sequence of the Neandertal Genome" is Richard Green and the last is Svante Pӓӓbo, with somewhere around 50 authors in between them. I'm glad to see that Pӓӓbo, Director of the Department of Genetics at the Max Planck Institute for Evolutionary Anthropology and the fellow who seems to have been the key player in getting the Neandertal genome project going, put himself last in the author list. Judging from one of the articles by Pennisi, Richard Green truly earned his first spot on the author list. He apparently contributed greatly to the mathematical/modeling challenge of sorting through and figuring out how to separate out those parts of the DNA sequences that belonged to the Neandertal from all the overwhelming majority of DNA sequences from microbes and modern humans. Somehow, by chopping up the sequences of DNA sufficiently and applying analytical techniques beyond my comprehension, the workers could decode the Neandertal segments and then virtually assemble them in their proper order in the genome. Amazing! 
 
So, what did the researchers accomplish? They sequenced DNA from Neandertals from four different sites in Europe and Russia. They compared the Neandertal DNA with the DNA of five present day humans from Southern Africa, West Africa, New Guinea, China and France. The key finding is that the present day non-African humans share with the Neandertals certain segments of their DNA, somewhere between 1 and 4 percent of the total; these particular segments were not found in the Africans' DNA. The conclusion is that the modern homo sapiens coming out of Africa first met the Neandertals when the latter were coming to the Middle Eastern area to escape the cold weather in Europe at that time. The scenario is that our modern human ancestors and the Neandertals indulged in some interbreeding, at which time our ancestors picked up those additional Neandertal segments of DNA and passed them along to their offspring. At that point some of us moderns went east and others went west, populating Europe and Asia and, eventually Australia and islands in the Indian and Pacific Oceans. The Neandertals never got back down to Africa and hence did not add any of their DNA to the DNA of native Africans.
 
So, it seems that some of us carry in our DNA bits of DNA resulting from our ancestors getting together, if only briefly, with our Neandertal cousins. But it turns out that we also carry with us in our DNA the results of other encounters, not with hominids, but with so-called retroviruses. The HIV virus responsible for AIDS is a retrovirus. If you look up the definition of a retrovirus you'll find it to be a virus composed of RNA, ribonucleic acid, instead of DNA. RNA is a single stranded compound as opposed to DNA, with its famous two stranded structure in which the "letters" (bases) A,G,C and T link up across the two strands. In RNA the base T is replaced by another base, U. Let's not go into the chemistry here except to note that in a retrovirus there's a sneaky enzyme, reverse transcriptase, that can transform the retrovirus's RNA into DNA and slip this "retro-DNA" into the DNA of the cell into which the retrovirus has penetrated.
 
Now the scary part. If that cell does what many cells do, it divides and passes along the retro-DNA into the other cell. If the cell happens to be a sperm or ovum, Voila! Whatever critter that sperm or ovum gives rise to now has the retroDNA in its own DNA. Just such encounters with retroviruses are thought to have happened throughout our history, even going back to some of our ancestors that were not yet human! One such ancestor is thought to have been a lemur. In fact, according to Fox, we carry around in our DNA about a hundred thousand of these retrovirus sequences in our DNA; that means that about 40 percent of our human DNA is parasitic retrovirus related! In the trade, these are known as human endogenous retroviruses (HERVs). Apparently, our genome does a good job of isolating these viral remnants from doing us harm by folding up to block the exposure of the remnants or by other means of keeping any ill effects to a minimum.  However, it now appears that these efforts do not always succeed. One of these HERVs, HERV-W, is of special interest.
 
A fellow in France, Hervé Perron, had the feeling that retroviruses might have something to do with muscular dystrophy, MS. Others had similar ideas but failed to link MS with any known virus. After some eight years of hard work, culturing cells from MS patients and finally finding a retrovirus, Perron sequenced the retrovirus gene in 1997. Perron was shocked to find that, instead of being a virus that spread through the air or from person to person, the gene sequence, HERV-W, was there in the patients' own DNA! Since that time a number of other studies have confirmed that HERV-W is present in MS patients.
 
Let's turn from MS to schizophrenia and Fuller Torrey, director of the Stanley Medical Research Institute in Maryland. Torrey's sister was about to enter college when she was diagnosed with schizophrenia, a disease that is typically diagnosed in patients in their late teens to mid twenties. This no doubt influenced Torrey's interest in starting research aimed at finding the cause of the disease. If you've known someone with schizophrenia or bipolar disorder, as I have, you can appreciate what a terrible disease a mental illness is. Going against the traditional view that schizophrenia is a mental disease due to genetic or to psychological problems, Fuller and others are convinced schizophrenia is actually caused by infection, initiated by an infection early in life. 
 
There are a couple of intriguing examples that helped lead Torrey to this conclusion. Although it's only a small effect, 5 to 8 percent, there's been a consistent correlation of schizophrenia with the birth month. In over 200 studies, there is this consistent finding that schizophrenia is more prevalent in people born in winter or early spring. These are the months when infections, notably the flu, are most prevalent. Or, take the actual case of two specific identical twin boys, one of whom came home from the hospital after birth in good health. On the other hand, his twin brother contracted a life-threatening infection in the hospital, putting him in the intensive care unit and an incubator for a month. When he finally came home he was lethargic and, after learning to walk, had balance problems, falling and bumping into things. However, by the time the two boys entered grade school all seemed well. The two looked like the identical twins they were, both played basketball and were good students, earning B+ grades. 
 
All was going smoothly until the twins were 17, at which point the "infected" twin began to hear voices and was diagnosed with schizophrenia. Torrey's studies of schizophrenics, including other identical twins, showed the schizophrenics to have signs of inflammation, physical problems such as not being able to walk a straight line, differences in brain structure when compared with their twin, etc. Although not a popular concept, Torrey maintained that schizophrenia is not a psychological problem but is instead a brain disease. 
 
As did Perron with MS, Torrey and Robert Yolken, at Johns Hopkins, began looking for a retrovirus associated with schizophrenia and in 2001 came up with a candidate, none other than HERV-W! And, in 2008, Perron himself published a paper showing that in one study half the people with schizophrenia had HERV-W in their blood, compared to only 4 percent for healthy people. 
 
Various experiments with mice have led Perron to suggest the following scenario for MS and schizophrenia. In MS the initial infection is thought to awaken or activate the HERV-W segment of the genome. When the immune system of the newborn detects the HERV-W it springs into action with T-cells spewing out cytokine molecules that in turn attract more immune cells and the inflammation gets out of control. Eventually the immune system attacks and kills brain cells causing MS or damages neurons by overstimulating them and, over a period of time and perhaps other infections, the effects build up to the point where the emitting of neurotransmitters leads to hallucinations, paranoia and other symptoms of schizophrenia or bipolar disorder. 
 
Finally, in the interest of full disclosure, I should point out that both the infection and the sex-with-Neandertal claims have their critics who doubt the conclusions discussed here. For those who've read my columns over the years, would you expect otherwise? Any exciting discovery or postulate has its critics and that's probably good in that it spurs more work and, hopefully, the truth emerges. 
 
As for me, I find it rather exciting to think I might have some caveman in me. As far as the possible link between infection and MS, schizophrenia or bipolar disorder, I hope the link is indeed proved, perhaps paving the way for some sort of routine vaccination or other medical intervention at birth to prevent or address the effects of early infection. 
 
Next column on or before July 1, hopefully.

 
Allen F. Bortrum