We all know that exercise can make us fitter and reduce our risk for illnesses such as diabetes and heart disease. But just how, from start to finish, a run or a bike ride might translate into a healthier life has remained baffling.
Now new research reports that the answer may lie, in part, in our DNA. Exercise, a new study finds, changes the shape and functioning of our genes, an important stop on the way to improved health and fitness.
The human genome is astonishingly complex and dynamic, with genes constantly turning on or off, depending on what biochemical signals they receive from the body. When genes are turned on, they express proteins that prompt physiological responses elsewhere in the body.
Scientists know that certain genes become active or quieter as a result of exercise. But they hadn’t understood how those genes know how to respond to exercise.
Enter epigenetics, a process by which the operation of genes is changed, but not the DNA itself. Epigenetic changes occur on the outside of the gene, mainly through a process called methylation. In methylation, clusters of atoms, called methyl groups, attach to the outside of a gene like microscopic mollusks and make the gene more or less able to receive and respond to biochemical signals from the body.
Scientists know that methylation patterns change in response to lifestyle. Eating certain diets or being exposed to pollutants, for instance, can change methylation patterns on some of the genes in our DNA and affect what proteins those genes express. Depending on which genes are involved, it may also affect our health and risk for disease.
Far less has been known about exercise and methylation. A few small studies have found that a single bout of exercise leads to immediate changes in the methylation patterns of certain genes in muscle cells. But whether longer-term, regular physical training affects methylation, or how it does, has been unclear.
So for a study published this month in Epigenetics, scientists at the Karolinska Institute in Stockholm recruited 23 young and healthy men and women, brought them to the lab for a series of physical performance and medical tests, including a muscle biopsy, and then asked them to exercise half of their lower bodies for three months.
One of the obstacles in the past to precisely studying epigenetic changes has been that so many aspects of our lives affect our methylation patterns, making it difficult to isolate the effects of exercise from those of diet or other behaviors.
The Karolinska scientists overturned that obstacle by the simple expedient of having their volunteers bicycle using only one leg, leaving the other unexercised. In effect, each person became his or her own control group. Both legs would undergo methylation patterns influenced by his or her entire life; but only the pedaling leg would show changes related to exercise.
The volunteers pedaled one-legged at a moderate pace for 45 minutes, four times per week for three months. Then the scientists repeated the muscle biopsies and other tests with each volunteer.
Not surprisingly, the volunteers’ exercised leg was more powerful now than the other, showing that the exercise had resulted in physical improvements.
But the changes within the muscle cells’ DNA were more intriguing. Using sophisticated genomic analysis, the researchers determined that more than 5,000 sites on the genome of muscle cells from the exercised leg now featured new methylation patterns. Some showed more methyl groups; some fewer. But the changes were significant and not found in the unexercised leg.
Interestingly, many of the methylation changes were on portions of the genome known as enhancers that can amplify the expression of proteins by genes. And gene expression was noticeably increased or changed in thousands of the muscle-cell genes that the researchers studied.
Most of the genes in question are known to play a role in energy metabolism, insulin response and inflammation within muscles. In other words, they affect how healthy and fit our muscles — and bodies — become.
They were not changed in the unexercised leg.
The upshot is that scientists now better understand one more step in the complicated, multifaceted processes that make exercise so good for us.
Many mysteries still remain, though, said Malene Lindholm, a graduate student at the Karolinska Institute, who led the study. It’s unknown, for example, whether the genetic changes she and her colleagues observed would linger if someone quits exercising and how different amounts or different types of exercise might affect methylation patterns and gene expression. She and her colleagues hope to examine those questions in future studies.
But the message of this study is unambiguous. “Through endurance training — a lifestyle change that is easily available for most people and doesn’t cost much money,” Ms. Lindholm said, “we can induce changes that affect how we use our genes and, through that, get healthier and more functional muscles that ultimately improve our quality of life.”
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DNA is a dynamic and adaptable molecule. As such, the nucleotide sequences found within it are subject to change as the result of a phenomenon called mutation. Depending on how a particular mutation modifies an organism's genetic makeup, it can prove harmless, helpful, or even hurtful. Sometimes, a mutation may even cause dramatic changes in the physiology of an affected organism. Of course, in order to better understand the varying effects of mutations, it is first necessary to understand what mutations are and how they occur.
Where do mutations occur?
Mutations can be grouped into two main categories based on where they occur: somatic mutations and germ-line mutations. Somatic mutations take place in non-reproductive cells. Many kinds of somatic mutations have no obvious effect on an organism, because genetically normal body cells are able to compensate for the mutated cells. Nonetheless, certain other mutations can greatly impact the life and function of an organism. For example, somatic mutations that affect cell division (particularly those that allow cells to divide uncontrollably) are the basis for many forms of cancer.
Germ-line mutations occur in gametes or in cells that eventually produce gametes. In contrast with somatic mutations, germ-line mutations are passed on to an organism's progeny. As a result, future generations of organisms will carry the mutation in all of their cells (both somatic and germ-line).
What kinds of mutations exist?
Mutations aren't just grouped according to where they occur — frequently, they are also categorized by the length of the nucleotide sequences they affect. Changes to short stretches of nucleotides are called gene-level mutations, because these mutations affect the specific genes that provide instructions for various functional molecules, including proteins. Changes in these molecules can have an impact on any number of an organism's physical characteristics. As opposed to gene-level mutations, mutations that alter longer stretches of DNA (ranging from multiple genes up to entire chromosomes) are called chromosomal mutations. These mutations often have serious consequences for affected organisms. Because gene-level mutations are more common than chromosomal mutations, the following sections focus on these smaller alterations to the normal genetic sequence.
Base substitution Base substitutions are the simplest type of gene-level mutation, and they involve the swapping of one nucleotide for another during DNA replication. For example, during replication, a thymine nucleotide might be inserted in place of a guanine nucleotide. With base substitution mutations, only a single nucleotide within a gene sequence is changed, so only one codon is affected (Figure 1).
Although a base substitution alters only a single codon in a gene, it can still have a significant impact on protein production. In fact, depending on the nature of the codon change, base substitutions can lead to three different subcategories of mutations. The first of these subcategories consists of missense mutations, in which the altered codon leads to insertion of an incorrect amino acid into a protein molecule during translation; the second consists of nonsense mutations, in which the altered codon prematurely terminates synthesis of a protein molecule; and the third consists of silent mutations, in which the altered codon codes for the same amino acid as the unaltered codon.
Insertions and deletions Insertions and deletions are two other types of mutations that can affect cells at the gene level. An insertion mutation occurs when an extra nucleotide is added to the DNA strand during replication. This can happen when the replicating strand "slips," or wrinkles, which allows the extra nucleotide to be incorporated (Figure 2).
Strand slippage can also lead to deletion mutations. A deletion mutation occurs when a wrinkle forms on the DNA template strand and subsequently causes a nucleotide to be omitted from the replicated strand (Figure 3).
Insertion or deletion of one or more nucleotides during replication can also lead to another type of mutation known as a frameshift mutation. The outcome of a frameshift mutation is complete alteration of the amino acid sequence of a protein. This alteration occurs during translation because ribosomes read the mRNA strand in terms of codons, or groups of three nucleotides. These groups are called the reading frame. Thus, if the number of bases removed from or inserted into a segment of DNA is not a multiple of three (Figure 4a), the reading frame transcribed to the mRNA will be completely changed (Figure 4b). Consequently, once it encounters the mutation, the ribosome will read the mRNA sequence differently, which can result in the production of an entirely different sequence of amino acids in the growing polypeptide chain.
To better understand frameshift mutations, let's consider the analogy of words as codons, and letters within those words as nucleotides. Each word itself has a separate meaning, as each codons represents one amino acid. The following sentence is composed entirely of three-letter words, each representing a three-letter codon:
THE BIG BAD FLY HAD ONE RED EYE AND ONE BLU EYE. Now, suppose that a mutation eliminates the sixth nucleotide, in this case the letter "G". This deletion means that the letters shift, and the rest of the sentence contains entirely new "words":
THE BIB ADF LYH ADO NER EDE YEA NDO NEB LUE YE. This error changes the relationship of all nucleotides to each codon, and effectively changes every single codon in the sequence. Consequently, there is a widespread change in the amino acid sequence of the protein. Lets consider an example with an RNA sequence that codes for a sequence of amino acids:
AUG AAA CUU CGC AGG AUG AUG AUG With the triplet code, the sequence shown in figure 5 corresponds to a protein made of the following amino acids:
Now, suppose that a mutation occurs during replication, and it results in deletion of the fourth nucleotide in the sequence. When separated into triplet codons, the nucleotide sequence would now read as follows (Figure 6):
AUG AAC UUC GCA GGA UGA UGA UG This series of codons would encode the following sequence of amino acids:
Each of the stop codons tells the ribosome to terminate protein synthesis at that point. Consequently, the mutant protein is entirely different due to the deletion of the fourth nucleotide, and it is also shorter due to the appearance of a premature stop codon. This mutant protein will be unable to perform its necessary function in the cell.
What causes mutations?
Mutations can arise in cells of all types as a result of a variety of factors, including chance. In fact, some of the mutations discussed above are the result of spontaneous events during replication, and they are thus known as spontaneous mutations. Slippage of the DNA template strand and subsequent insertion of an extra nucleotide is one example of a spontaneous mutation; excess flexibility of the DNA strand and the subsequent mispairing of bases is another.
Environmental exposure to certain chemicals, ultraviolet radiation, or other external factors can also cause DNA to change. These external agents of genetic change are called mutagens. Exposure to mutagens often causes alterations in the molecular structure of nucleotides, ultimately causing substitutions, insertions, and deletions in the DNA sequence.
What are the consequences of mutations? Mutations are a source of genetic diversity in populations, and, as mentioned previously, they can have widely varying individual effects. In some cases, mutations prove beneficial to an organism by making it better able to adapt to environmental factors. In other situations, mutations are harmful to an organism — for instance, they might lead to increased susceptibility to illness or disease. In still other circumstances, mutations are neutral, proving neither beneficial nor detrimental outcomes to an organism. Thus, it is safe to say that the ultimate effects of mutations are as widely varied as the types of mutations themselves.
The chemists aren’t going to be happy about this one. Over the last decade, the Nobel Prize in Chemistry has often gone to biochemistry, which to chemists is only sort-of real science. And this year’s prize, announced today, is no exception.
The winners: three scientists who parsed the molecular mechanisms that drive the repair of damaged DNA. The stuff of genetic code, the long chains of bases that are the chemical blueprints of life, doesn’t just stay filed away in some cellular safe deposit box. Even when cellular machinery isn’t reading it to make proteins—that’s what genes are for—DNA is dynamic, copying itself when cells divide. And living things have so much DNA, getting copied so many times, that the system is bound to mess up a letter here or there. It’s also constantly under assault from environmental mutagens like radiation and free radicals.
Those mistakes, sadly, don’t turn you into an X-Man. In fact, one of today’s laureates, Tomas Lindahl, discovered just how big of a problem those built-up errors really are. Genetic information decays, and the mistakes add up fast enough that without built-in repair mechanisms, humans wouldn’t be here. Evolution itself would break. After realizing that, Lindahl figured out one of the repair systems: base excision repair, in which an assembly of proteins slices an erroneous base out of a stretch of DNA and replaces it with the right one.
Those single-base errors usually occur spontaneously. But another mechanism of DNA repair, nucleotide excision (discovered by Aziz Sancar), targets more extensive genetic damage caused by UV radiation. (When the system fails, you can end up with skin cancer.) The third recipient of the prize, Paul Modrich, discovered how cells correct errors introduced during DNA copying. When that mismatch repair system goes haywire, people can end up with colon cancer.
All of those discoveries are essential biochemical knowledge—they’re happening in your body right now, and if you’re really quiet, you might be able to hear them. (Not really.) But in the end, thanks to their carcinogenic connections, they may have just as much influence in medicine as in chemistry. Time for a new classification scheme, Stockholm?
I have quite different opinion than this.
DNA may seem to be damaged to current researchers but they are just reflecting the changes of the owner's body (not only just physical organism but also emotions and spirits).
What DNA is dynamic is mentioned in the above article, however, how dynamic doesn't seem to be known. Is it as fast as speed of light? I believe so. Maybe even faster than speed of light.
Until the science advances good enough to acknowledge the existence of Bonghan Ducts and Living Eggs, the western medicine has long way to find cure for all kinds of pains and diseases.
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