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BTD Forums  /  Golden Threads  /  9Q34 Questions
Posted by: Tom1964, Thursday, October 13, 2005, 8:12pm
My niece has asked me to help her learn the blood type theory (she's seen the difference it has made for me).

I know one of the key truths underlying the blood type is the fact that your blood type is determined at gene 9Q34.  I also know that it is significant what the genes in the immediate vicinity of 9Q34 control.

What I don't know is why proximity is so significant.  What makes two genes being in immediate or close proximity any more significant than two genes which are far apart?

Tom
Posted by: Lola, Thursday, October 13, 2005, 8:26pm; Reply: 1
here s more on this:
http://www.dadamo.com/forum/archive9/config.pl?read=51637

have you read this?
http://www.dadamo.com/knowbase/disease/disease3.htm

and this quote:
''We already know of some intimate relationships between the blood type gene, located on chromosome 9 at band q34, and other genes that impact on our health and well-being. For example, in 1984, researchers reporting in the journal, Genetic Epidemiology, presented evidence of a family pedigree in which a major gene for breast cancer susceptibility is located near band q34 on chromosome 9. There is a clear connection between blood type and breast cancer.

Heres another intriguing link that suggests a relationship between blood type and the brain. The gene for the enzyme dopamine beta hydroxylase (DBH), which converts dopamine to noradrenaline, is located right at 9q34. Its literally sitting on top of the gene for blood type. As we will see later, this has vast implications for the association between blood type and stress, mental health, and even personality characteristics.''
Posted by: Cheryl_O_Blogger, Thursday, October 13, 2005, 8:53pm; Reply: 2
The relationship is because of something called genetic linkage.

http://www.ndsu.nodak.edu/instruct/mcclean/plsc431/linkage/linkage2.htm

Basically, when two genes are very close together they tend to be inherited together.  There is some recombination between chromosomes during reproduction, but the closer the genes are together the less likely they will be separated by recombination.  Before DNA sequencing technology was available, genetic linkage was used to estimate the position of genes on a chromosome.

Let's pretend the gene for hair color was close to the gene for blood type.  We might find that a gene for brown hair was on most chromosomes with the O antigen, so most people with Type O blood had brown hair.  The gene for blood type would not be responsible for the brown hair, it would just be a coincidence that the two are inherited together in most cases.

I think this is one reason people don't accept BTD.  They think Dr. D is saying that blood type is directly affecting things like personality.  They haven't read the whole book and don't understand the concept of genetic linkage.
Posted by: Tom1964, Thursday, October 13, 2005, 9:02pm; Reply: 3
I understand what Cheryl wrote about genes in vicinity and inheritance, but what about day-to-day.  For example, I know being a type O that I have trouble clearing the catecholamines adrenaline and noradrenaline.  I also know some of the hard wired genetic truth about why I have this problem clearing catecholamines is because there is a gene which influence DBH which is in close proximity to 9Q34.  

But I still don't understand why just because the gene effecting DBH is "close" to 9Q34 that this means there is an effect.  For example, lets say i have a neighbor who lives 5 houses down from me.  Let's say he's an alcoholic and his house is a mess.  Being 5 houses down it doesn't really effect me, other than maybe slightly loweting my house's market value.

I'm really trying to understand this in a way I can explain it simply, because I think it really enhances anyone's understanding of why 9Q34 is significant.
Posted by: Cheryl_O_Blogger, Thursday, October 13, 2005, 9:17pm; Reply: 4
It doesn't have an effect on you day to day because it's close to the blood type gene.  You inherited it because it's close to the blood type gene.  All the genes you inherited are expressed.  At that point it doesn't matter how close they are on the chromosome.  Everyone has a gene for dopamine hydroxylase.  Type Os just usually get one that doesn't process adrenaline very well.
Posted by: Melissa_J, Thursday, October 13, 2005, 9:37pm; Reply: 5
Here's something to chew on, look at how close some of these genes are, DBH which Os have trouble with and TTP for the As (blood clotting)...

http://www.ncbi.nlm.nih.gov/Omim/getmap.cgi?d4328
Posted by: Cheryl_O_Blogger, Thursday, October 13, 2005, 11:08pm; Reply: 6
http://darkwing.uoregon.edu/~tasa/Anthropology%20362%20-%20Week%20VI.pdf

Interesting info on details of the blood group system.  The Duffy antigen gives an example where a particular genotype confers resistance to malaria.  Some regions in Africa have almost 100% of the resistant phenotype.  This kind of info really supports Dr. Ds explanation that blood groups are primarily present to help us deal with microbes.  Many instances of association of HLA type with various diseases because of genetic linkage.  In my prior job at a blood bank, during the time when AIDS was emerging, the director noted some association of HLA type with susceptibility to AIDS.  For a time, blood with that HLA type was not used to help reduce the possibility of AIDS transmission by transfusion.  This was before the HIV had been identified, so there was no way to test the blood.  I don't think that connection was strong enough that it ever came to common usage, but prior to the availability of a test it was a reasonable action to take.  It was a very forward thinking group there.  That experience was another thing that made me take a second look at BTD.
Posted by: Melissa_J, Thursday, October 13, 2005, 11:17pm; Reply: 7
That's interesting...which HLA type was that?  I see a few listed when I search, one is associated with celiac disease.
Posted by: 903 (Guest), Friday, October 14, 2005, 5:24am; Reply: 8
Hi Tom,

Part of the answer you are seeking has to do with how DNA at the chromosomal level is packaged and how gene expression occurs and is controlled as a local phenomenon at a gene locus, ex. 9q34. Simply put, there are several levels of organization and packaging of DNA in our cells; if it were all accessible to gene transcription cellular machinery, it would be in the way and possibly damaged. Gene expression is very dynamic and is controlled at one level by this packaging. Genes that aren't being expressed, ie aren't being transcribed into RNA, and aren't being replicated, are wrapped around proteins and condensed into nucleosomes. These nucleosomes are condensed further and the resulting structure is chromatin.

The genes in a segment of condensed chromatin are not "open", preventing proteins involved in transcription or replication from binding to the DNA sequences. Stearic hindrance. Now, when it is time for a gene to be expressed, the nucleosomes  (the "packaging material") within the chromatin are modified, altering the structure of the chromatin, and loosening it. Other proteins then gain access and open the chromatin even further.

Once the chromatin is open (this is a local phenomenon), a "transcription bubble" forms. Transcription factor proteins bind to regulatory elements of the genes and initiate gene expression. If several genes are tightly linked in this region, very close to each other, their likelihood of being transcribed increases as well (since they are located within the transcription bubble and transcription protein machinery is locally available). The ABO blood group locus is a very busy locus and therefore is found in a loose chromatin configuration a majority of the time. Genes neighboring the ABO locus are included in the ABO transcription bubble and their likelihood of being transcribed into RNA (and then translated into a protein product) increases.

Now there are other levels of control over gene expression, like gene-specific transcription factors, however, without a transcription bubble and the recruitment of nuclear machinery, it is safe to say a gene will not be expressed! It is interesting that genes within a transcription bubble often share transcription factors so that the majority of genes within the bubble are co-expressed. This co-expression can be at differing levels/efficacy as compared to the transcription of the "targeted" ABO locus; perhaps the transcription factors recruited to the bubble act "full strength" on the ABO locus but aren't as strong initiating neighboring gene transcription as other, absent "neighboring gene-specific" transcription factors would be. But first things first, there has to be access, and the ABO locus is usually open for business!  ;D

Hope this helps, BTW, if your neice needs scientific detail, let me know!
Posted by: Dr. D, Friday, October 14, 2005, 10:38am; Reply: 9
What a great thread. This should be archived!
Posted by: Cheryl_O_Blogger, Friday, October 14, 2005, 3:48pm; Reply: 10
Quoted from Melissa_J
That's interesting...which HLA type was that?  I see a few listed when I search, one is associated with celiac disease.


I don't know, that was probably 20 years ago.  The data was probably not published, but it was a primary blood bank in Dallas with a relatively large population of gay men, so the blood bank had a lot of internal data to draw from.  They would also not use blood from someone using aspirin, because it affected white cells.  That may be standard now, but I haven't donated blood for many years, so don't know what the exclusion criteria are these days.
Posted by: 547 (Guest), Friday, October 14, 2005, 5:56pm; Reply: 11
Hey Judy!

Awesome explanation of genetic linkage and transcribing! :o
I am going to print this thread! ;D
I have a  lecture to deliver tomorrow and no doubt questions will arise about this..
Thanks for the explanation.

As Peter says: a thread to be archived!!  ;D ;D

What is your profession by the way?? You are awesomely knowledgeable about this..
Take care and stay well

Cocky 8)
Posted by: 903 (Guest), Saturday, October 15, 2005, 5:33am; Reply: 12
I am a Molecular Geneticist, Cocky. Glad I could help. It is a rare treat to be asked about the mechanisms of genetics, so thank Tom!   8)

What is your lecture's subject??
Posted by: 547 (Guest), Saturday, October 15, 2005, 3:25pm; Reply: 13
Hi Judy!

That explains it!!  ;D ;D

I had a lecture today in Amsterdam in the Vitamin Advice Shop...
It was a closed lecture. 20 people present who listened to my explanation of the basics of bloodgroups and the diseases they are prone to and the foods they have to consume to get better! Talked also about the 9q34 chromosome and the meaning of that thick band of DNA on it.
Had 2 AB's in my audience!!! They confirmed the trait that AB have no antibodies in their system.. They were both troubled by loss of energy and inflammation, 'inviting' bacteries and viruses so voluntarily in their system!! For those AB's Bromelain and Proberry will do the trick next to the Diet of course!! ;D ;D

The audience was stupefied!! Such nice talks I had with most of them..
I think some of them will visit my in my practice.
Sold some Dutch books of Live Right and many Eldoncards!!
The BTD is being revisited in Holland... People see this Diet has not vanished like many others. No, Peter keeps 'surprising' us all the time with his research!! :o
This way of life is getting ahead here!!

Thanks again for your explanation, so clarifying.
Take care and stay well!

Cocky 8)
Posted by: 903 (Guest), Saturday, October 15, 2005, 4:29pm; Reply: 14
Excellent Cocky! Keep up the good work!!  :) So gratifying, eh?
Posted by: Cheryl_O_Blogger, Thursday, November 10, 2005, 10:59pm; Reply: 15
Judi or Dr. D or anyone else with an opinion,
Is it known in the case of dopamine beta hydroxylase for example, whether the blood type difference is related to simple genetic linkage or to the "transcription bubble" influence that Judi described.  I could understand that the ABO locus might be a transcriptionally active region, but it would have to be more or less active in the different blood types to result in altered expression.

I understand the dominant relation to blood type that a specific allele is more frequently inherited by individuals of a particular blood type.  The additional possibility of transcriptional influence is interesting though.
Posted by: 903 (Guest), Friday, November 11, 2005, 8:56pm; Reply: 16
Hi Cheryl,

I am on my way out right now but, give me a day or two and I will put together a summary of what is known about the very complex genetic regulation at the DBH locus.

Cheers,

Judi
Posted by: resting, Friday, November 11, 2005, 9:36pm; Reply: 17
Hi folks,

For us laymen the critical word is 'bond'.  [What is meant by this word?]  A neighbour 5 houses away is a loose bond, but a brother/sister/mother/father have a 'tight' bond.  So too does one's mate and their children, and even children of children.  Non chemical people have a definite loss of appreciation when a chemist talks about a genetic bond ... one that it it truely close.  If however, a scientist talks about the water 'bonded' in a crystal lattice, this might be considered a close cousin.  A neighbour might be as close as two fish in the same lake.

The issue of bonding may become evident if there was a toxin entering the lake and killing all the fish.  A genetic-bond is extremely tight.  Even being close means 'being affected'.  It is somewhat like being close to fire: you don't have to be 'on-fire' but 'near' means 'getting singed'.

I hope this helps some ...........

John
Posted by: Cheryl_O_Blogger, Friday, November 11, 2005, 9:48pm; Reply: 18
Thanks Judi,
That would be very interesting.  I had thought it would be unrealistically expensive to test the Blood Type Diet theory, but I was thinking of nutritional studies, with people actually on the diet.  In fact, it should be possible demonstrate many of the principles through molecular techniques such as SNP analysis.
Posted by: 903 (Guest), Wednesday, November 23, 2005, 6:22pm; Reply: 19
You are right Cheryl, it would be easy to do the work you suggest; the sequencing is all done! Problem is, no researchers doing peer reviewed work are looking for an association with blood type. This is what I was able to find (and I apologize for the time it took to put this together for you). Very complex regulation at the DBH locus and it is easy to see there would be a huge range of expression levels in all populations.

DBH is the enzyme that converts dopamine to norepinephrine. Low DBH protein (detectable in the plasma and cerebrospinal fluid, CSF) leads to elevated ratios of dopamine to norepinephrine (hormones contribute to flight-flight endocrine responses), which explains associations between low DBH activity and neurobehavioral disorders like attention deficit hyperactivity disorder (ADHD) or psychotic symptoms, etc.

A single major quantitative trait locus, QTL, accounting for about half the heritability of DBH activity was initially mapped to chromosome 9q34 by linkage analysis in 1982 and again in 1988. Later studies identified the DBH gene, located within this region, as this QTL (1997-1998. The structural gene encoding DBH is ~23kb long and contains 12 exons.

A functional SNP (-1021 C/T), located within the promoter of the DBH gene, accounts for 35%52% of the total variation in plasma DBH activity levels in three distinct populations (couldnt retrieve entire article therefore exact populations unknown). One single polynucteotide polymorphism accounts for up to 50% of the variance seen in DBH plasma levels (again, populations studied unknown). This is a g/a substitution in exon 2 (exon2 *444g/a discussed further below). These above two polymorphisms are thought to account for the majority of variance in plasma DBH activity .

The exon 2 *444 g/a polymorphism and an intron 5 (Taq I) polymorphism, were studied in the same population (Indian). Lack of a significant association was reported between transmission of both polymorphisms and ADHD in the Indian study group. Lack of association may hint towards a unique genotypic pattern in the Indian study group as compared to other ethnic groups since significant association was reported between DBH*444g/a and cerebrospinal fluid DBH activity, but not plasma activity, in European-American patients with mood or anxiety disorder. It should be noted here that not all of the research looked into CSF levels as plasma samples are easier to obtain.

In an Irish population study, in contrast to the Indian findings, significant association was observed between ADHD and the intron 5 Taq I A2 allele. Another report on Brazilian subjects showed similar association between the Taq I A2 allele and ADHD. Finally, a Milwaukee study in caucasians found that the Taq I A1 allele is significantly associated with the disorder (ADHD).

There is also a GT-repeat polymorphism (in the 5 untranslated region) with two out of four possible alleles associated with low plasma DBH activity. The occurrence of these alleles differs in various populations but was not been found to be statistically significant in one limited population study. A second study found this GT polymorphism to be associated with variance in both plasma and CSF DBH activity.

Two expressed alleles of the gene encoding DBH, containing either G or T at nucleotide position 910, resulting in specification by codon 304 of alanine (DBH*304A) or serine (DBH*304S), respectively. Genotyping estimates of the frequencies of the alleles in African-Americans, European-Americans, and in several geographically dispersed populations (Mbuti, Danes, Adygei, Chinese, Japanese, Surui, Maya, and Nasioi) were determined. DBH*304A was the most common allele in all populations tested, with allele frequencies greater than 0.80 in each case. There was significant heterogeneity in allele frequency across population groups. The DBH*304S allele was most common in subjects of African descent, and least common in East Asians and individuals from indigenous populations of North and South America. The frequency of DBH*304S was significantly higher in African-Americans (0.16) than in European-Americans. Of the four DBH*304S homozygotes observed, all were Europeans and three of the four were Danes. While quite interesting as an analysis of mutation at this polymormism across different populations, association studies were not performed to determine if the mutation affects DBH activity. I have included it here to demonstrate how important study group selection is!

The above was a listing of known genetic mutations at the DBH locus and their affect on DBH activity. There is another level of genetic regulation that affects DBH activity, mRNA regulation. While the following work was performed in rats, the same regulation applies to humans. mRNA levels of dopamine beta-hydroxylase can be regulated by glucocorticoids and cyclic AMP (cAMP) analogues. To begin to characterize the regulation of DBH mRNA, genomic clones for rat DBH were isolated, and 1 kb of the 5' flanking region was sequenced. Several putative regulatory elements, which may be involved in cAMP and glucocorticoid regulation, were identified, including two adjacent cAMP response elements, another element that can also bind members of the ATF/CREB family of transcription factors, a NF-kappa B-like sequence, several AP-2 sites, and three core glucocorticoid receptor binding sequences.

Phox2a (a paired homeodomain protein) as well as its functional synergism with other transcription factors (e.g., CREB, AP2, and Sp1), play a critical role in the transcriptional activation of the DBH gene (rats, humans, chickens, pigs ETC!). These are relatively ubiquitous transcription factors with the exception of Phox2a. Therefore, the mostly open and active transcription bubble found at 9q34, as discussed above, would allow these transcription factors and other proteins to initiate and influence transcription whenever present.

All QTLs demonstrate very complex regulation. I did not go into regulation of the mRNA through miRNA or smRNA mechanisms as these are newly discovered fields of research and there is probably nothing known yet about these mechanisms specifically for DBH RNA.

I hope this exercise demonstrated the complexity of regulation I referred to in the opening paragraph. Unfortunately, there is no clear answer to the question that prompted this perusal of the literature, specifically, how ABO determination affects DBH activity. We will have to wait until those doing the genetic research of DBH ask this question and design their studies to address it.

Posted by: ISA-MANUELA (Guest), Sunday, November 27, 2005, 8:17pm; Reply: 20
;) :D ::) :B  ;D  must be honest... it doesn't disturb me to be *stinknormal*
but before I've got this possibilities as an option... and you know how it hurts to loose something  ;)........ :D .... I never possessed :D ;)

hey Madl... Judy do you spaek teutonic ??) .....
Posted by: Dr. D, Sunday, November 27, 2005, 10:44pm; Reply: 21
I'll make it a sticky. Great thread and hats off to JK for a magnificent tome.

Isa, I'll take a look at the permissions for your group and add sticky function to it.

Interesting that wheat and protein have two opposite effects on DBH.
Posted by: ISA-MANUELA (Guest), Monday, November 28, 2005, 8:41am; Reply: 22
:K) :K) :K) grazie so much Peter :D I am happy again :D yeeeeeeeeehhhhhhhaaaaaa ;D
Posted by: 903 (Guest), Monday, November 28, 2005, 6:32pm; Reply: 23
:B


I was able to dig a bit deeper. The three populations used for the -1021 C/T transition mutation determined to account for up to 50% of variance in DBH plasma levels were European Americans, African Americans, and ethnic Japanese. In all three populations, very low DBH individuals carried two copies of the T allele. Heterozygotes showed intermediate DBH levels and homozygotes for the C allele had the highest mean DBH levels. The simplest explanantion is that the T allele lowers expression of DBH by lowering transcription since this SNP resides in the enhancer region of the gene.

The exon 5 (Taq1) polymorphism was also found to explain small but significant additional variation in the same three populations as part of the same study (in addition to the studies performed in other populations discussed above).

BTW, there were numerous and various mutations found in small numbers of patients, littered throughout the DBH locus, that are believed to be functional but are not seen in great enough numbers of individuals to be determined functional by statistical means. This makes perfect sense too, in that a region of the chromosome that is usually in an open chromatin configuration is more liable to collect mutations than a more tightly regulated region would be.

OK, now I'm done! :X ;)


Teutonic, Isa?

Of a more or less German nature; somewhat German
"formidable volumes Teutonic in their thoroughness"
- German, Germanic

Of or pertaining to the ancient Teutons or their languages
"Teutonic peoples such as Germans and Scandinavians and British"
- Germanic


I do try to be thorough! ;) ;D However, it seems most likely to me that you really mean I am speaking in Babel!! My apologies. My only defense is that I have been busy and wanted to get the answer up as quickly as I could. I expected some questions afterwards! Please let me where I should start the clarification!
Posted by: ISA-MANUELA (Guest), Monday, November 28, 2005, 6:45pm; Reply: 24
ok.. dear Judy... eastward of the Limes ;)  ::)
and thanks for the enlightnend paraphrase named above :X ;)
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