Can compensate for genetic defects with vitamins and minerals

In the next five years, the cost of establishing a human gene sequence will decrease rapidly, predicting a price of about $ 100 per person. Soon the only reason why you don't want to see individual 'genetic maps' is to fear seeing defects in your genome.

However, UC Berkeley scientists have come up with a positive cause to encourage understanding of each of our genetic genetic resources to find a small genetic defect that can be recovered with simple measures. with vitamins or minerals.

Professor of cell and molecular biology Jasper Rine (California Berkeley University) said: 'I am looking for positive information in the human genome'.

'Newspapers over the past 20 years have been constantly talking about success in the field of biomedical research in search of biologically pathogenic genes, which are of great genetic importance to people. receive information. I'm obsessed with finding other genetic information that encourages people to conduct their genome analysis. ' What he and his colleagues discovered was presented on the online issue of the Proceedings of the National Academy of Sciences (PNAS). In a paper with a large genetic difference that makes one's enzymes less effective than usual, vitamin supplements can restore defective enzymes to return to action with maximum effectiveness.

Scientist Nicholas Marini (University of California Berkeley) and the first author of the article stressed that doctors often prescribe drugs with vitamins to cure many rare, potentially fatal metabolic defects. People caused by some important enzymes are mutated. Those who suffer from metabolic diseases are the ones who must receive two 'poor quality' copies (or two alleles) of a key enzyme. Many others only receive a bad gene or two copies of a slight faulty gene but still reduce the enzyme rate, which can be difficult to see, although it can still be treated with vitamin supplements.

Marini said: 'The research has convinced us that there are many variants of enzymes in the population, many of which affect the function of enzymes and also many variations that respond to vitamin. I'm not surprised if someone requires the optimal vitamin dose depending on their genetic makeup, based on the type of vitamin-dependent enzyme they are carrying in their body. '

Saccharomyces cerevisiae enamel micrograph is reproducing.Researchers at the University of California Berkeley have introduced many enzyme enzymes to see if these enzymes can be compatible with vitamins.(Photo: California Berkeley University)

Although the original study tested the function of the human gene variant by transplanting into yeast cells where their function was correctly evaluated, Rine and Marini were confident that the results were still true for the human body. . Their research is partly funded by the Advanced Research Project Defense Agency (DARPA) and the US military. The study helped them facilitate the team to test their hypothesis on soldiers that vitamin supplementation can restore defective enzymes. Rine said: 'Our soldiers, like the top athletes, must operate in extremely harsh environments but the physiological function of the body can limit their ability. We are currently collaborating with the defense agency to identify the enzyme variant that can be recovered in the hope of detecting a variant that exists in the military and at the same time testing whether appropriate additions can be enhanced. work for the military or not '.

In PNAS, Rine, Marini and colleagues published their first analysis of the human enzyme variant called methylenetetrahydrofolate reductase (MTHFR). This enzyme requires vitamin B to function normally, which plays a key role in the synthesis of molecules that make up the nucleotide block of DNA. Some cancer drugs, such as methotrexate, target MTHFR to inhibit DNA synthesis and prevent tumor growth.

With the sample DNA source of 564 participants of different races, different population groups, the research team at the Department of Applied Biological Systems (Foster City, Calif) has set up the sequences of two coding alleles. MTHFR enzymes in each person. Corresponding to previous studies, they discovered three common variants of the enzyme, accompanied by 11 rare variants with a ratio of less than 1% of each variation in the sample.

Then they synthesized genes for each enzyme variant. Marini, Rine and their UC Berkeley colleagues then put these genes into separate yeast cells to test the activity of each variant. Men use many variants of the same enzyme along with vitamins and minerals like humans. According to Rine, yeast is the ideal model to study metabolic activity in humans.

They found four different mutations that affect the function of the human enzyme in yeast. One of the above mutations is very common: nearly 30% of the population has an allele, about 9% of the population has 2 alleles. Add vitamin B folate to the yeast culture medium to restore all functions to all the most common variants except for rare variants.

During the experiment, 30 additional variants of MTHFR enzymes were discovered, and tested 15 of them. 'More than half of enzymatic dysfunction, forming a number of enzymatic activities that are hundreds of times larger. Most of them can be partially or completely recovered by folate (folic acid). What a surprising thing '.

Most scientists think that harmful mutations will evolve, but Rine points out that this is only true for mutations that affect fertility. The health impact mutation has not been evolved since then but still exists in our genome forever.

The health impact of recovering undetectable human enzyme functions, however folate - has been known for its ability to prevent congenital defects - apparently even preventing heart disease and cancer too. A defect in the MTHFR enzyme that promotes high blood metabolism of homocysteine ​​production increases the risk of heart disease and stroke - the disease usually occurs in people of reproductive age.

Marini said: 'In older people, dietary folate supplementation may reduce the rate of the above metabolite and reduce the risk of disease'.

Marini and Rine estimate that a middle-aged person carries five rare enzyme mutations, although it may not be very rare, but the condition can still be improved by supplementing vitamins and minerals. 'There are over 600 enzymes in the human body that use vitamins and minerals as a substrate. This study only shows what we found when we studied one of these enzymes. This means that even if the rate of a person with a defect occurs on one gene is low, but with 600 genes we can all experience mutations that adversely affect the function of one or more enzymes in the muscle. can '.

The hard-to-detect effect of the enzyme variant may explain the incompatibility of some medical trials, including inconsistent data on the effects of vitamin supplementation. In the future, the enzyme profile of the study subjects will be taken into account when analyzing the effectiveness of medical testing.

In the article, the researchers stated: if we don't just take vitamin-dependent enzymes but account for 30,000 proteins in the human genome, 'each individual will have about 250 harmful substitutions while phenomenon only occurs with low frequencies. This figure shows that the combined effect of low frequency variants also has a tremendous physiological effect. '

One more reason that encourages us to learn about our own genome. Rine said: 'If we do not give a compelling reason for people to care about their genome, and to be satisfied with personal genetic information, then the benefits that biomedical studies bring depending on certain genetic characteristics, most people will not be confined to the time frame. My motive is partly science, the other part is the education project, the other is the political project '.

Marini and Rine agreed with the study of Bruce Ames that encouraged the two men to look for genetic variations. Bruce Ames is a retired professor at the University of California Berkeley in molecular and cellular biology, and is currently on the research team at Oakland Children's Hospital Research Institute. At the time of the 1970s, Ames found that many bacteria that were unable to produce a certain amino acid could function when given vitamin B6. In recent years, he has continued to explore the link between micronutrient and health.

Rine said: 'Bruce found it possible to cure genetic diseases in bacteria through vitamins.' Because the human genome contains about 6 billion base pairs on DNA, each pair can mutate so there exist 3 to 6 million points of DNA sequence difference between any two people. Given this number, he explained, like bacteria 'humans also have a need for the number of different enzymes in terms of genetics for their enzymes to achieve maximum effectiveness'.

The problem, according to Rine, is related to one of the major biomedical questions today.'We now have the perfect genetic sequence of common model organisms, including humans. Obviously the biological challenge posed in the 21st century is not the identification of genes but gene variants. '

Rine, Marini and colleagues continue to study variants of human MTHFR genes as well as other folate-used enzymes, particularly interested in the link between defects of these enzymes and birth defects. Thanks to the large number of students - 1500 students - studying at his biological laboratory 1A, Rine has the advantage in understanding the variation of the second vitamin B6-dependent enzyme called cystathionine beta-synthase .

He also explored how enzymes such as vitamins and minerals restore defective enzymes. He suspects that vitamin and mineral supplements act as an additive to stabilize the enzyme's structural folding process, which is a key factor for enzyme's catalytic activity. 'This is a new principle that can be applied in pharmaceutical manufacturing.'

Co-author of the study, in addition to Rine and Marini, there are also research assistants Jennifer Gin and Janet Ziegle of California Berkeley University, Kathryn Hunkapiller Keho, David Ginzinger and Dennis A. Gilbert of the Applied Biological System. The agency also funded part of the research. In addition, the research was funded by the University of California, DARPA and the National Institutes of Health.