PSEUDOGENES
What are they, where do they come from and what can we learn from them?
PSEUDOGENESWhat are they, where do they come from and what can we learn from them?
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Creation vs. Evolution:
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The poly(ADP-ribose) polymerase (PADPRP) pseudogene and cancer risk (in humans)One practical application of pseudogenes is to use them as genetic markers. Recent developments in the field of genomics have allowed this new use of pseudogenes. Because the human genome is now mapped, pseudogene sequences have been found because of their similarity to functional genes. Some other organisms such as the fruit fly (Drosophila) and nematode (C. Elegans) have also been mapped, and much research is devoted to determining the function of all DNA sequences. Beyond the simple pursuit of knowledge, there are applications for forensics, medicine, and evolutionary studies, to name a few (see our other links). Here, a pseudogene polymorphism was used to predict genetic cancer risk in humans. Poly(ADP-ribose) polymerase is an important enzyme involved in DNA repair, replication, and recombination. It is activated in response to DNA-damaging agents such as chemical carcinogens and ultraviolet and ionizing radiation. Inhibition of the gene that codes for the enzyme is correlated with increased cancer risk (human and mouse studies). This is because DNA-repair mechanisms are suppressed. Thus mutations that could lead to the development of cancer are maintained in the genome. The active gene has been mapped to human chromosome 1, and no polymorphism has been found for the active gene.
Two pseudogenes have been associated with the poly(ADP-ribose) gene. The pseudogenes have been mapped to chromosomes 13 and 14. No polymorphism was found on chromosome 14, but a two allele (A/B) polymorphism was found on chromosome 13. It results from a deletion in the B allele. The pseudogene's sequence similarity to the functional gene's cDNA suggests that it arose from retrotransposition (see the section on pseudogene function). In a number of studies, the pseudogene has been used to study genetic susceptibility to cancer. Since no polymorphisms have been found on the original poly(ADP-ribose) gene, it was hypothesized that pseudogene polymorphism could possibly play a role. Since the pseudogene has been previously assumed to be non-functional (hence it's nomenclature), it can be asked why pseudogene polymorphism would matter. The polymorphism may simply function as a marker, or it might possibly have a functional role. This finding would raise questions as to whether or not the term "pseudogene" was appropriate in this case, or in fact at all. In it's role as a marker, it might signify that there may be other genes involved that have not yet been identified. These undiscovered genes may be associated with the pseudogenes, in that each polymorphism is likely to be inherited with a particular set of other genes. This association is most likely due to chromosomal proximity, thus reducing the likelihood of recombination events. On the other hand, the pseudogene may actually have a functional role. It has been speculated that the pseudogene protein product plays a role in DNA repair (Wu et al. 1997). If this is so, it may or may not actually be a pseudogene. It has also been proposed that the protein product of the pseudogene may compete for binding sites with the PADPRP (Hu et al., 1997). It could have a functional binding site, but a dysfunctional catalytic site. This would interfere with DNA repair. Studies so far have looked at differences between ethnic groups. This methodology is used for two main reasons. Certain ethnic groups have higher incidences of certain cancers. For example, African-American populations are at increased risk for lung and prostate cancer (Doll et al, 1996). This strategy also increases the probability that the pseudogene polymorphism is associated with the same set of unknown other genes. There is a greater degree of genetic relatedness among ethnic groups than in the general population because of relative geographical isolation until the past few hundred years. One of the first studies along this line of research was conducted in 1993 by Lyn et al. They hypothesized that there was a correlation between higher frequency of the B allele and a higher incidence of multiple myeloma, prostate and lung cancer among the U.S. African-American population. They found that there was an increased frequency of the B allele in patients that developed prostate and multiple myeloma cancer, but no relationship was found for lung cancer. They proposed that the B allele could be used as a genetic marker to predict these cancers in African-Americans. The study was criticized for its methodology, particularly it's small sample size, and thus many studies expanded on their work. Other groups looked at African American, Caucasian and Mexican populations, and other forms of cancer. For example, Doll et al. found that the A allele was statistically significant with respect to the development of prostate cancer. Smulson (1994)'s work supports that of Lyn et al. (1993) in that a positive correlation between B allele frequency and prostate and multiple myeloma cancer was found in blacks, but not in whites. Wu et al. (1998) found that the B allele frequency was associated with lung cancer risk for Mexican-Americans and black-Americans. The frequency of the BB and AB genotypes was much higher in black than in Mexican populations, but Mexicans with the pseudogene showed a statistically significant elevated lung cancer risk. There was no such correlation with blacks, as predicted by earlier research. Gu et al. (1999) increased the sample size and compared black, Mexican, and white groups. They also found that the B allele was correlated with increased lung cancer risk in Mexicans only. Finally, a related study examined the correlation of the PADPRP pseudogene with breast cancer in white women (Hu et al., 1997). It was found that the B allele was associated with a decreased risk for cancer, and that A allele homozygosity was associated with higher incidences of breast cancer. A few general conclusions can be drawn from the above research. One, is that the frequency of each of the pseudogene polymorphisms varies among groups. Second, allele homozygosity was associated with more cancer risk. Third, there is a positive correlation between B allele frequency and prostate and multiple myeloma cancer in African-Americans. There is also a positive correlation between B allele frequency and lung cancer risk in Mexicans, but there are contradictory results for lung cancer in African-Americans. In general, as there were differing and contradictory results, more research is necessary. Research implications: Many more studies are possible, as there are many other ethnic groups and many other forms of cancer. Obviously, more research might lead to a better understanding of genetic cancer risk and also might lead to treatments. There are some sociopolitical implications as well. Hopefully, the research may lead to decreased racism in public health policy, due to previously held assumptions that socioeconomic factors contributed to increased cancer risk in certain groups. This is very significant for the United States. Finally, the exact mechanisms of how PADPRP functions are still unknown. It may or may not have a functional role, and thus it is not strictly being used as a marker for other genes. This role may be antagonistic, as in competing for binding sites with poly(ADP-ribose) polymerase. Hopefully elucidation of this mechanism may lead to new treatments for cancer.
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