DNA: Defects you can fix with vitamins and minerals

[Guest guest]

June 02, 2008

http://physorg.com/news131645933.html

The good news in our DNA: Defects you can fix with vitamins and minerals

As the cost of sequencing a single human genome drops rapidly, with one company

predicting a price of $100 per person in five years, soon the only reason not to

look at your " personal genome " will be fear of what bad news lies in your genes.

University of California, Berkeley, scientists, however, have found a welcome

reason to delve into your genetic heritage: to find the slight genetic flaws

that can be fixed with remedies as simple as vitamin or mineral supplements.

" I'm looking for the good news in the human genome, " said Jasper Rine, UC

Berkeley professor of molecular and cell biology.

" Headlines for the last 20 years have really been about the triumph of

biomedical research in finding disease genes, which is biologically interesting,

genetically important and frightening to people who get this information, " Rine

said. " I became obsessed with trying to decide if there is some other class of

information that will make people want to look at their genome sequence. "

What Rine and colleagues found and report this week in the online early edition

of the journal Proceedings of the National Academy of Sciences (PNAS) is that

there are many genetic differences that make people's enzymes less efficient

than normal, and that simple supplementation with vitamins can often restore

some of these deficient enzymes to full working order.

First author Marini, a UC Berkeley research scientist, noted that

physicians prescribe vitamins to " cure " many rare and potentially fatal

metabolic defects caused by mutations in critical enzymes. But those affected by

these metabolic diseases are people with two bad copies, or alleles, of an

essential enzyme. Many others may be walking around with only one bad gene, or

two copies of slightly defective genes, throwing their enzyme levels off

slightly and causing subtle effects that also could be eliminated with vitamin

supplements.

" Our studies have convinced us that there is a lot of variation in the

population in these enzymes, and a lot of it affects function, and a lot of it

is responsive to vitamins, " Marini said. " I wouldn't be surprised if everybody

is going to require a different optimal dose of vitamins based on their genetic

makeup, based upon the kind of variance they are harboring in vitamin-dependent

enzymes. "

Though this initial study tested the function of human gene variants by

transplanting them into yeast cells, where the function of the variants can be

accurately assessed, Rine and Marini are confident the results will hold up in

humans. Their research, partially supported by the Defense Advanced Research

Projects Agency (DARPA) and the U.S. Army, may enable them to employ U.S.

soldiers to test the theory that vitamin supplementation can tune up defective

enzymes.

" Our soldiers, like top athletes, operate under extreme conditions that may well

be limited by their physiology, " Rine said. " We're now working with the defense

department to identify variants of enzymes that are remediable, and ultimately

hope to identify troops that have these variants and test whether performance

can be enhanced by appropriate supplementation. "

In the PNAS paper, Rine, Marini and their colleagues report on their initial

analysis of variants of a human enzyme called methylenetetrahydrofolate

reductase, or MTHFR. The enzyme, which requires the B vitamin folate to work

properly, plays a key role in synthesizing molecules that go into the nucleotide

building blocks of DNA. Some cancer drugs, such as methotrexate, target MTHFR to

shut down DNA synthesis and prevent tumor growth.

Using DNA samples from 564 individuals of many races and ethnicities, colleagues

at Applied Biosystems of City, Calif., sequenced for each person the two

alleles that code for the MTHFR enzyme. Consistent with earlier studies, they

found three common variants of the enzyme, but also 11 uncommon variants, each

of the latter accounting for less than one percent of the sample.

They then synthesized the gene for each variant of the enzyme, and Marini, Rine

and their UC Berkeley colleagues inserted these genes into separate yeast cells

in order to judge the activity of each variant. Yeast use many of the same

enzymes and cofactor vitamins and minerals as humans and are an excellent model

for human metabolism, Rine said.

The researchers found that four different mutations affected the functioning of

the human enzyme in yeast. One of these mutations is well known: Nearly 30

percent of the population has one copy, and nine percent has two copies.

The researchers were able to supplement the diet of the cultured yeast with

folate, however, and restore full functionality to the most common variant, and

to all but one of the less common variants.

Since this experiment, the researchers have found 30 other variants of the MTHFR

enzyme and tested about 15 of them, " and more than half interfere with the

function of the enzyme, producing a hundred-fold range of enzyme activity. The

majority of these can be either partially or completely restored to normal

activity by adding more folate. And that is a surprise, " Rine said.

Most scientists think that harmful mutations are disfavored by evolution, but

Rine pointed out that this applies only to mutations that affect reproductive

fitness. Mutations that affect our health in later years are not efficiently

removed by evolution and may remain in our genome forever.

The health effects of tuning up this enzyme in humans are unclear, he said, but

folate is already known to protect against birth defects and seems to protect

against heart disease and cancer. At least one defect in the MTHFR enzyme

produces elevated levels in the blood of the metabolite homocysteine, which is

linked to an increased risk of heart disease and stroke, conditions that

typically affect people in their post-reproductive years.

" In those people, supplementation of folate in the diet can reduce levels of

that metabolite and reduce disease risk, " Marini said.

Marini and Rine estimate that the average person has five rare mutant enzymes,

and perhaps other not-so-rare variants, that could be improved with vitamin or

mineral supplements.

" There are over 600 human enzymes that use vitamins or minerals as cofactors,

and this study reports just what we found by studying one of them, " Rine said.

" What this means is that, even if the odds of an individual having a defect in

one gene is low, with 600 genes, we are all likely to have some mutations that

limit one or more of our enzymes. "

The subtle effects of variation in enzyme activity may well account for

conflicting results of some clinical trials, including the confusing data on the

effect of vitamin supplements, he noted. In the future, the enzyme profile of

research subjects will have to be taken into account in analyzing the outcome of

clinical trials.

If one considers not just vitamin-dependent enzymes but all the 30,000 human

proteins in the genome, " every individual would harbor approximately 250

deleterious substitutions considering only the low-frequency variants. These

numbers suggest that the aggregate incidence of low-frequency variants could

have a significant physiological impact, " the researchers wrote in their paper.

All the more reason to poke around in one's genome, Rine said.

" If you don't give people a reason to become interested in their genome and to

become comfortable with their personal genomic information, then the benefits of

much of the biomedical research, which is indexed to particular genetic states,

won't be embraced in a time frame that most people can benefit from, " Rine said.

" So, my motivation is partly scientific, partly an education project and, in

some ways, a partly political project. "

Marini and Rine credit Bruce Ames, a UC Berkeley professor emeritus of molecular

and cell biology now on the research staff at Children's Hospital Oakland

Research Institute, with the research that motivated them to look at enzyme

variation. Ames found in the 1970s that many bacteria that could not produce a

specific amino acid could do so if given more vitamin B6, and in recent years he

has continued exploring the link between micronutrients and health.

" Looked at in one way, Bruce found that you can cure a genetic disease in

bacteria by treating it with vitamins, " Rine said. Because the human genome

contains about 6 billion DNA base pairs, each one subject to mutation, there

could be between 3 and 6 million DNA sequence differences between any two

people. Given those numbers, he reasoned that, as in bacteria, " there should be

people who are genetically different in terms of the amount of vitamin needed

for optimal performance of their enzymes. "

This touches on what Rine considers one of the key biomedical questions today.

" Now that we have the complete genome sequences of all the common model

organisms, including humans, it's obvious that the defining challenge of biology

in the 21st century is not what the genes are, but what the variation in the

genes does, " he said.

Rine, Marini and their colleagues are continuing to study variation in the human

MTHFR gene as well as other folate utilizing enzymes, particularly with respect

to how defects in these enzymes may lead to birth defects. Rine also is taking

advantage of the 1,500 students in his Biology 1A lab course to investigate

variants of a second vitamin B6-dependent enzyme, cystathionine beta-synthase.

He also is investigating how enzyme cofactors like vitamins and minerals fix

defective enzymes. He suspects that supplements work by acting as chaperones to

stabilize the proper folding of the enzyme, which is critical to its catalytic

activity. " That is a new principle that may be applicable to drug design, " Rine

said.

Source: University of California - Berkeley