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What is Variation in the Genome?


Lecture Ļ 3.

Gene Testing for Cancer

More and more often, headlines boast of new cancer genes found.

No wonder people are left with many unanswered questions. What is the connection between such gene discoveries and cancer? Is there a connection between genes and cancerís diagnosis or treatment?

The answers to these and other gene questions lie in understanding gene discovery, the science behind gene testing--the ability of researchers to identify changes within genes that may predict the future development of specific diseases, help diagnose existing diseases, or, someday, make it possible to treat or even ward off disease.

To understand a personís genetic background, one needs to start with the human genome, including all 25,000 genes. The human genome is the complete set of instructions for life as we know it. The human genome is located in the nucleus of every cell in the body, except for red blood cells, which have no nuclei. Only about 3 percent of this genome actually provides the set of instructions called genes that are used to build the bodyís proteins. These regions are called coding regions, and they are scattered throughout the chromosomes. In addition to coding regions, close to each gene are regulatory sequences of DNA, which are able to turn the gene "on" or "off.Ē Scientists have discovered some functions for the remaining 97 percent of the genome, areas called noncoding regions, but most of this region remains a mystery.

An amazing aspect of a personís genome is that there is so little variation in the DNA sequence when the genome of one person is compared to that of another. Of the 3.2 billion bases, roughly 99.9 percent are the same between any two people. It is the variation in the remaining tiny fraction of the genome, 0.1 percentóroughly several million basesóthat plays a powerful role in deterring or encouraging cancer.

What is Variation in the Genome?

Variation occurs whenever bases in a personís DNA sequences change. Variations can involve only one base, many bases, or even large segments of chromosomes. If the two strands of a chromosome are thought of as nucleotides threaded on a string, then, for example, a string can break, resulting in a re-ordering of the beads. One or more nucleotides may be changed, added, removed, or exchanged. In chromosomes, these changes are called polymorphisms, insertions, deletions, or translocations.In addition to these changes, some persons have DNA sequences called "repeats" that like to insert extra copies of themselves several times. Chromosomes can also undergo more dramatic changes called translocations. These occur when an entire section of DNA on one chromosome switches places with a section on another. Not all variations in a personís DNA sequences have an effect. Among the variations that do cause effects, some are more serious than others. The outcome depends on two factors: where in the genome the change occurs (i.e., in a noncoding, coding, or regulatory region) and the exact nature of the change.

Cancer researchers think that, in addition to inherited or acquired mutations, tiny variations in a personís genome called single nucleotide polymorphisms, or SNPs ("snips") for short, may play a role in cancer. A SNP is defined as a single base change in a DNA sequence that occurs in a significant proportion (more than 1 percent) of a large population. The single base is replaced by any of the other three bases. Here is an example: In the DNA sequence TAGC, a SNP occurs when the G base changes to a C, and the sequence becomes TACC. SNPs are scattered throughout a personís genome and are found in both coding AND noncoding regions. They can cause silent, harmless, harmful, or latent effects. They occur with a very high frequency, with estimates ranging from about 1 in 1000 bases to 1 in 100 to 300 bases. This means that there could be millions of SNPs in each human genome

Most SNPs occur in noncoding regions and do not alter genes. So most variations in the human genome have no known effect at all because they occur in noncoding regions of the DNA. In addition, there are some changes that do occur in coding and regulatory regions, yet the effect is not entirely understood. All these are silent variations

The remaining SNPs occur in coding regions. They may alter the protein made by that coding region, which in turn could influence a personís health. Some of the variations that occur in the coding and regulatory regions of genes simply contribute to the normal variation observed among people. They can, for example, change the way a person looks. Some people have blue eyes, others brown; some are tall, others short. Other variations in coding regions are harmless because they occur in regions of a gene that do not affect the function of the protein made.

An individual may also harbor genetic variations that have "latent" effects. These variations, found in coding and regulatory regions, may have small effects on their own, but over time, in the context of other genetic changes, infections, or environmental exposures, they may eventually alter a personís risk for cancer. They may also explain why one person responds to a drug while another does not. These variations are very difficult to study, but populations studies are attempting to unravel their effects. Here is part of the genome from two people who are both smokers, but only one of them gets cancer. The zoom into the chromosomes of these two men shows just a sampling of the differences in variation that are responsible for their individual cancer risk. The variations themselves do not cause cancer. They only affect each personís susceptibility to the damaging effects of tobacco smoke after exposure.

Date: 2015-12-24; view: 884

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