Good News In Our DNA: Defects You Can Fix With Vitamins And Minerals

[Guest guest]

Good News In Our DNA: Defects You Can Fix With Vitamins And Minerals

http://medicalnewscenter.com/out/out.cgi?

http://www.sciencedaily.com/releases/2008/06/080602214135.htm

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 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.

Coauthors with Rine and Marini are UC Berkeley research assistant

Gin and Janet Ziegle, Hunkapiller Keho,

Ginzinger and Dennis A. Gilbert of Applied Biosystems, which also

funded part of the study. The work was supported by a University of

California Discovery Grant, DARPA and the National Institutes of

Health.