Pharmacogenomics Paper 4

You have read a couple of epigenetics papers now, but this last one had a decidely different twist. In this paper the authors focus on an X linked gene so they can ask a complex question.

In your response please address the following points.

1) Why is the fact that the gene of interest is located on the X chromosome important.

2) What is inactivation? How is this process involved in this study?

3) What were the conclusions of the authors? What do they suggest happens next? What experiment would you do next?

21 thoughts on “Pharmacogenomics Paper 4

  1. It is believed that monoamine oxidase A (MAOA)is related in multiple central nervous system disorders. It is important to know that this gene of interest is located on the X-chromosome because every person has an X-chromosome. Although in females one out of the two X-chromosomes is inactivated or silenced and will not direct or dictate any cellular processes, research has shown that in somatic cells one X-chromosome is likely to be inactivated over the other and that X-chromosome inactivation is not merely a random selection.

    The significance of studying MAOA is that the gene is among top 15% of X-linked genes that escape X-chromosome inactivation, leaving the question: Do X-chromosome inactivation and epigenetic factors contribute to MAOA regulation and ultimately mental disorders?

    The study compares one allele to the other allele of the same target tissue. Due to the fact that the study only used DNA and RNA extract and only a small sample size was studied, relationships between MAOA protein or enzyme activity, methylation status or genotype were unable to be determined. However, the agreement in allelic expression imbalance (AEI)ratio did ensure epigenetic factors as well as genetic factors’ role in mental disorders.

    In order to further investigate diseased subjects and controls, experiments should be conducted on whole tissue samples of a larger population of people to reflect on the various genetic variations. Future studies should incorporate greater amount of tissue samples of large population.

  2. In this paper, researchers were studying to determine whether epigenetic changes on the MAOA gene are responsible for the condition of mental disorders such as schizophrenia and bipolar disorder. Researchers chose to study this particular gene because the MAOA gene is known as a monoamine oxidase which is the target for antidepressant drugs. By studying this gene, scientists are able to see if the way the gene is changed could result in a mental disorder and if these types of drugs are needed to get that original shape of the gene back.
    Although we have read some other papers based on epigenetic changes, this paper is interesting because the chromosome being studied is that of a sex chromosome. X linked chromosomes are present in both males and females but females do have a second X chromosome. Because X linked chromosomes are being studied, it brings up the concept that males and females can have differences in these mental disorders based solely on the fact that they have a different number of chromosomes to begin with. Do men or women have a higher chance over the other based on the number of X chromosomes that they have and the ability of them to possess these epigenetic changes? That seems to be the question at hand.
    Throughout the paper, the authors make the point to say that in the female samples, the used one of the X chromosomes as a control for the other chromosome. The X chromosome that is seen as the “control” for the other one is known as the inactivated chromosome. Inactivation of one of the x chromosomes in females occurs during development and specialization and is important because without inactivation, genetic problems and disorders can occur. Because the chromosome has been inactivated, epigenetic and genetic changes won’t occur on that particular chromosome. Researchers can than compare the other chromosome that is said to have the polymorphisms occurring to what the actual makeup of the chromosome should be.
    The authors concluded at the end of paper that there weren’t a lot of correlations between all of the calculations taken and that more future research does need to be done. I felt like in this paper, there was a lot going on between the three different groups- control, bipolar and schizophrenia- and the two genders and then all of the different assays. Future research was mentioned throughout the paper, one idea being to study MAOA protein activity and take it into consideration with the other assays. The reason this wasn’t done in this particular study was because the samples were taken from brain autopsies and don’t have protein activity occurring in the samples.
    Overall, I found the content of the paper interesting but confusing to follow at times because of all of the techniques going on. I found the structure of the paper, putting the results and then discussion first, as a surprise because I’ve never seen authors do this in a paper before. It definitely made it easier to read and understand the paper though.

  3. The fact that the gene of interest, MAOA, is located on the X-chromosome is vital information because it involves multiple CNS disorders that can affect males and females differently due to their sex chromosomes. Males only have one X chromosome whereas females have two. The fact that it is located in the X chromosome is also important because the X-linked MAOA gene has a pVNTR repeat polymorphism located on its promoter region that can also be associated to mental disorders. It is also an important asset that the gene of interest is located on the X- chromosome because one allele could be compared to the other on the same subject. A study shows that CpG methylation in the promoter region of the gene of interest was substantial in females compared to males. Another study has shown that alternative dosage compensation in females in which both X chromosomes in females is considered one X chromosome in the male. Genotyping of MAOA polymorphisms in females specifically with a haplotype block showed a strong association. There are also different enzymatic levels of the gene in the activated X chromosome and in the inactivated X chromosome, conclusively showing variable epigenetic and genetic events in gene expression. For this article, having the MAOA gene on the X chromosome is important because one allele serves as a control for the other gives us more “robust” allelic expression ratios in which the study focuses more on the two X chromosomes in females.
    Inactivation in terms of genes means to “turn off” a gene or to “silence” it from gene expression until it is needed. Inactivation of the X chromosome happens through compact packaging of the chromosome into heterochromatin that is transcriptionally inactive. Without the inactivation of one of the X-chromosomes that females have, there would be double the expression of X-chromosome gene products compared to males where “dosage compensation” is necessary. One X chromosome is always chosen to be active while the other one remains inactive for the lifetime of the organism. Only the MAJORITY of the X-inactivated chromosome does not express its genes. By being tightly packed into heterochromatin, the majority of genes are repressed from being expressed but the MAOA genes present in the inactivated X chromosome “escape”…which shows that the AEI is independent of the unequal X-inactivation.
    In the X inactivated chromosome there is a higher level of DNA methylation and varying levels of histone, acetylation, etc… that contribute to the silencing of the gene. The studies they performed supported the hypothesis that the MAOA promoter methylation modulates or regulates transcription.
    The authors had many hypotheses that ended up not being true but they studied the “genetic and epigenetic mechanisms in the X-linked gene implicated in multiple CNS disorders involved in the regulation of allelic expression.” They did this by comparing one allele to the other but they were unable to determine genotype, methylation status, or MAOA protein or enzyme activity because of the small sample size they used for their studies. They suggested that for future studies, there should be a largepopulation cohort of patients and controls to determine the differences in allelic expression and MAOA protein activity. Allelic Expression ratios, however served well in these studies because they seemed to be “robust” since one could be looked as the control for the other in a tissue: the study focused on the “mechanisms underlying differential expression from the two chromosomes in females. The regulation of gene expression is the gene silencing in the X-inactivation chromosome caused by CpG island methylation of MAOA which “occurs exclusively in females”. There is also a large variation of promoter methylation between the three and four-repeat alleles in the same person which proved that MAOA modulates transcription instead of abolishing it completely. Another conclusion the authors reached in this article is that both genetic and epigenetic factors are part of the variable mRNA expression in females but in males there was no methylation so only genetic factors played a role. This is why there is a large sex difference in susceptibility and presentation of mental disorders. Overall, epigenetic factors are the purpose for the modulation of biogenic amine tone in the CNS of females causing the mental activity and disorders to function the way they do. If I were given the chance to do an experiment next, I would compare one allele against the other in a target tissue because there was need of a larger population cohort to “address the biological relevance of differences in allelic expression and reflection of MAOA protein activity.

  4. Researchers suggest that the monoamine oxidase gene (MAOA)is found on the x chromosome and is associated with mental disorders such as anti-social behavior, anorexia nervosa, and bi-polar disorders where inactivation of certain chromosomes in specific cells plays an important role of individuals being genetically predisposed to the above mentioned diseases. This paper explores the idea of how epigenetic processes influence the MAOA gene regulation.
    The gene being located on the x chromosome is important in the methodology of researchers studying the effects of gene regulation on the expression of certain traits. The methodology of the research would be based on case studies of women. Women possess two x chromosomes, making it possible for researchers to more efficiently study how inactivation of specific genes, in the same person, effects mRNA expression. Because the study is being done within one person, all other genome wide factors would be comparable and controlled. The inactivation of the x chromosomes would mean that the genes of this chromosome would be silenced and therefore would not be expressed. By silencing genes in specific errors, researchers can narrow their study on exactly how expression of MAOA affects the body and dosages of medication overall.
    The authors state that the study was inconclusive and that it still requires attention in the future. They suggest that pVNTR alleles were not broad enough to be accurately representative of an individual. The authors suggest that the next experiments should be conducted in vivo and that MAOA transcription variance indicates epigenetic factors play a significant role although no methylation could be found in male subjects.

  5. The general idea of this paper is to address the relationship between monoamine oxidase A (MAOA) and a number of central nervous system disorders such as drug abuse, aggression, antisocial behavior, anxiety, attention deficit hyperactivity disorder, anorexia nervosa, bipolar disorder and Alzheimer’s disease. Due to the fact that the gene of interest is located on the X chromosome researchers were allowed to take an interesting approach with studying this gene, it is known that males have one X chromosome with the exception of men with Klinefelter syndrome and females on the other hand have two X chromosomes which is the prime significance to this interesting approach.

    In slightly more detail due to X-Inactivation which is the process of “turning off” one of two X chromosomes, females provide both a control and a variable for X-Linked Chromosomal activity, this is possible because inactivated X chromosomes do not undergo genetic or epigenetic changes thus acting as the control. The variable chromosome would of course be the activated chromosome, this sets up a great environment for the comparisons because unlike in other studies where subject A and subject B are in a different host containing a wider variety of variables that may have some effect on the results subject A (activated chromosome) and subject B (inactivated chromosome) are both in the same host with the same tissue and overall the same environment increasing the possibility of a more accurate study.

    Although it seemed like a near perfect experimental study the authors did not manage to pull through with ground breaking results but they do believe with further attention something note worthy may be discovered. For further research the authors basically suggested having a larger sample size to be able to derive more from the experiment than they were able to. This paper did not seem as engaging to me as the other papers nevertheless it had some interesting points.

  6. It has been proven that the MAOA gene is highly associated with mental disorders within the central nervous system. Disorders such as bipoloar, anorexia nervousa, and bulimia are commonly found in patients proven to have this disorder. Epigenetic factors have proven to show that there is a imbalance in rare human female brian tissue showing not only one X sex gene chromosome, but another. Although most humans have generally one sex gene, which is active at the time, there are certian cases in which one has two x chromosomes, one active, and one inactive. Which has a high probability of leading to disorders.

    The expierment consisted of 35 samples taken from autopsies with previously noted disorders, and 35 control samples. The samples were taken from mulitipe parts of the brian, and all samples were genotyped for 13 common poluymorphisms. The conclusion was determined by using methylation in the MAOA promoter region to compare inactivated X-linked androgen receptor locus. The inactivated cells

    So is it possible that women are more prone to these mental disorders of the central nervous system than men? And why? How is it that only SOME women are born with an inactivated X sex chromosome? And why does this inactivation of a cell lead to such dramatic disorders? Something as simple as a cell not undergoing an epigenetic change can affect a persons everyday life and outlook. Amazing. Although this procude appeared flawless, every experiment has room for improvment. It has been suggested that to further and expand this knowledge, perhaps one may try to get a larger, more equipped sampling group of predisposed disease. It is interesting how something so minor within us can have such an interesting affect on us, something that is so uncontrollable to our own free will. This paper was extremely interesting to me.

  7. The MAOA gene has been linked the CNS disorders such as aggression, ADHD, and bipolar disorder. The relation between X-linked genes and the MAOA genes can be linked to different cases of gene expression such as AEI (allele expression imbalance) which is seen in female chromosomes since females possess two x genes. The X gene has been an important factor when it comes to studying disorders since some diseases are X linked since they only appear in the x gene. The presence of two x genes in females can increase the chance of there being only active x gene that is normal and inactivating the mutated one. Such advantages are not found in males and x linked mutant expressions are more likely to appear in males than in females. The use of female chromosomes in the study of the MAOA gene is important since females have the aforementioned advantage and can provide better experimental results.
    Inactivation of genes in the female x chromosome ensures for proper bodily functions since the copy of the x gene that is unfavorable is inactivated while the other one is used. The study of inactivation in the MAOA gene study is important due to the different epigenetic circumstances that contribute to somatic inactivation. The factors of AEI can help explain why certain cells in the body exhibit the unwanted gene expressions while others don’t.
    The study mentioned in the paper contributes to the different factors that are linked to disorders and disease. Though studies are done to find these factors, there are improvements to experiments that the author mentions. The samples used in the experiment were mentioned to have been better if a larger population size was used. Larger tissue samples also would have been better since the differences between somatic cells also contribute to the calculations they seem to have been looking for.

  8. The importance of the X chromosome location is; that genetic traits can be linked to it; considering females have two x chromosomes it makes them better candidates for research- its like having the control and the experimental group in one person.
    Inactivation is masking or inhibiting a genetic feature within the brain in this case causing mental disorders like schizophrenia and bipolar disorder. In this study the inactivation occurs from the chromatin from the x chromosome being so tightly packaged into the heterochromatin, therefore making it unavailable to any proteins or enzymes and inhibiting transcription.
    The study suggests that epigenetic and genetic factors contribute relaltivy equally to mRNA expression in females. But for males there is no methylation- and as we learned from our previous paper- therefore no epigenetic effects. T they suggest more studies are done on male genetic factors for the various mental illnesses. I would do this and also try to obtain a more varied sample of brain tissue from many parts of the country- not just one foundation.

  9. Many CNS disorders like bipolar disorder and Alzheimer’s disease have been related to the MAOA gene, which is located on the X chromosome. The most important fact about the X chromosome is that in males there is only one, while in women there are two. Since men only have one X chromosome they are not ideal for this study which compares the two alleles. Another interesting fact is that in women one of their X chromosomes is inactivated. These facts show that there are different ways the MAOA gene is expressed differently both in men and women. Men aren’t really affected because they only have one; women have two but as they grow random X chromosomes are inactivated.
    This random inactivation is when an X chromosome is silenced. This inactivation occurs so that the female does not have twice as many X chromosomes gene products than men. In this study they compare both alleles of X chromosomes, which in males cannot be done. Because women silence one of their genes, they express different genes that are found in one or the other. Thus this is why this study focuses on their different mechanisms of expression, so as to understand how the MAOA gene causes all of the mental disorders.
    The authors concluded that there weren’t many good conclusions out of this study and that there should be more experiments done. According to the authors this study provided evidence for presence of genetic factors affecting mRNA expression in human brain tissue. And after their study they were no able to determine how differences in allelic expression of MAOA affect the functional expression. The authors suggested making the samples bigger, instead of taking from different cells one should focus in one tissue. Once the sample sizes have been increased one should be able to reflect on the various variations of genes each individual could posses. Although this paper confused me a bit about how women X chromosomes are expressed, I did learn the reason for men to be as likely to get these diseases.

  10. The MAOA gene is an x-linked gene that is believed to be associated with causing CNS disorders such as bipolar disorder and Alzheimer’s disease. It is important that this gene of interest is located on the X- chromosome. X linked traits appear in both males and females, but males only contain one while females receives two. The fact that women receive two x chromosomes, allows more variation of which allele of the gene is expressed.
    Inactivation is the silencing (compacting of the chromatin) of one of the two X chromosomes in females, if not, disorders can occur. The chromosome that is not silenced is known as the control and is the chromosome that is used. This process is involved in this study because the genes on the silenced or inactivated chromosome are not used or expressed so they are not studied. With a silenced and controlled chromosome, scientists can compare how MAOA affects the body by studying the effects of the gene on the chromosome it is expressed from. So this case study must be done on women, to show how the inactivation of genes effect mRNA expression in the same person.
    The purpose of this study was to study epigenetic and genetic effects by comparing one allele against the other to see the association between MAOA and mental disorders. The samples in this study used only DNA and RNA, they were unable to determine the correlation between the genotype and the activity of the MAOA protein; also the sample size used was too small for accurate results. For future experiments studies should be done on whole tissue samples taken from a big population to see genetic variation.

  11. This week’s paper studied the x-linked MAOA gene which has been shown to be associated with many CNS disorders. The fact that women have 2 X-chromosomes is very important to this research because instead of having to test two different people with two different genomes they did the tests in multiple women. They were able to do this because women have two different X-chromosomes which they could test one is inactivated and the other is the. This would make it as though the control and the experiment were in the same person. Because of the fact that one X-chromosome in women is inactivated they were able to look at which chromosome is on and which is off in the different.

    One of the X-chromosomes in females is silenced because there can only be one chromosome expressed. The X-chromosome gets inactivated by getting packed into heterochromatin and once an x-chromosome becomes inactivated it will stay inactivated in every cell in that organism until it dies. In the experiment the primer was labeled with a dye that had fluorescent properties so that the products can be viewed.

    In the paper the authors conclude that, “both genetic and epigenetic factors contribute to nearly similar extents to variable mRNA expression in females.” They also suggest that more research be done on males. One thing that I would suggest to do for future research is to take a larger sample of women this would then give you a greater sampling of brain tissues.

  12. The study is mainly on monoamine oxidase(MAOA), a gene found in promoter region of the human brain tissues. The study focuses on how how genetic and epigenetic processes interect to regulate this gene expressions. this gene is a X-linked choromosome, and is associated with disorders such as drug abuse, aggression, antisocial behavior, anxiety, attention deficit hyperactivity disorder, anorexia nervosa, bipolar disorder and Alzheimer’s disease.
    The fact that MAOA is a X-linked chromosome is important for this study because allelic expression imbalance (AEI)results provide an evidence that of the two X choromosomes in females, one allele serves as the control for the other. The location of
    MAOA on the X-chromosome also simplified the haplotype analysis because males have only a single X-chromosome.
    X-Chromosome inactivation is the process where one of the two copies of the X chromosome present in female is inactivated so that the females does not have twice as many X chromosome gene products as the male.This is important for this study since there is comparion between the male and female chromosomes and how they are not randomly inactivated as they are thought sometimes.
    Because the researchers only used samples used DNA and RNA extract, they were unable to determine the relationship between genotype or methylation status and MAOA protein or enzyme activity. Also the
    subject sizes were too small to comapre between diseased subjects and controls. For future studies, they suggest to work on whole tissue samples obtained from a large population sample to address allelic expressions.

  13. This paper focuses on the MAOA gene, a gene that may be associated with several abuse and mental disorders.

    The fact that the gene of interest is located on the X-chromosome is important because it affects who the subjects for this study are and how the investigation will be performed. Men have an X chromosome and Y chromosome, while women have two X chromosomes. Because women have two X chromosomes, one of them is often inactivated and silenced to prevent duplicate genes for the entire lifetime. Because one of the X chromosomes is silenced, it can be considered as a control subject because genetic changes will not occur on this chromosome. At the same time, the activated X chromosome acts as the experimental subject. This allows the researchers to a) use women as their test subjects and b) have a control and experimental subject in one person—this avoids complications with different genes and gene expression between two different people.

    Because women have two X chromosomes, one of them is randomly chosen to be inactivated during development in order to prevent genetic complications and duplicates. The chromosome that is inactivated remains inactivated during the woman’s entire lifetime and does not undergo any genetic or epigenetic changes. This process is vital to this study because the researchers use the inactivated X chromosome in women as the control subject. The researchers then compare this “untouched” chromosome to the active one, which has undergone genetic and epigenetic changes which ultimately affect gene expression of the MAOA gene.

    I feel that the authors’ conclusion was very inconclusive. They kept saying that their results were “too variable” to determine an answer. It seems that their only solid information was the differences found in allelic gene expression ratios. The authors found that one allele compared to the other had significantly higher gene expression for MAOA than the other. The authors also suggested future experiments be conducted on MAOA protein activity. I would try to conduct the same experiment but with live samples and a larger population. The authors used brain tissue from autopsies, which prevents them from studying protein activity. If you study gene expression, and also have samples of protein activity associated with the MAOA gene, I’m sure some more solid results could be concluded.

    The topic of this paper was interesting but it was difficult to read and understand since the authors didn’t present real conclusive results.

  14. First and foremost the gene of interest is MAOA which monoamine oxidase which is associated with mental disorders such as anxiety and bipolar disorder. The significance of this gene and its location on the X chromosome is because The location of MAOA on the X-chromosome simplifies the froup of alleles of linked genes study, because males have only a single X-chromosome. In addition for females, the X chromosome is randomly inactivated and has been hypothesized that in humans that the MAOA gene is the issue to X-chromosome inactivation.
    Inactivation means to be not active or not operating and in this case refers to the X-chromosome and it’s relation to the MAOA gene. In this study, they experimented with the promoter region of MAOA in comparison to X-inactivation. Using methylation in the CpG location of the promoter part of MAOA results concluded that it was associated with the inactivation of the X-chromosome.
    Unfortunately the authors didn’t find any concrete conclusions to their experiement. I suggest in the near future they just keep experimenting. Practice makes perfect! And eventually they’ll hit gold with the X-chromosome and the MAOA gene. This study should include a larger population to experiment on and should be done over a long period of time. Overall, I found it a bit more interesting than the last articles. I found it interesting that mental disorders is regulated by sex.

  15. The purpose of this study was to assess epigenetic effects of a gene by comparing one allele against another within the same subject. The scientists were researching something known as a pVNTR, which is a polymorphism present on the X-linked monoamine oxidase, or MAOA. This polymorphism of the X- chromosome may or may not play a role in genetic occurrences that are responsible for mental disorders such as drug abuse, anti-social behavior, Alzheimer’s disease, anorexia nervosa, and ADHD. The fact that the gene is located on the X chromosome is important because a female contains two copies of this chromosome, while a male only contains one. Scientists are wondering if this explanation has anything to do with the fact that statistics show an increased susceptibility to impulsive behaviors and early experiences of substance abuse in males. Also, by making the study gene of interest the X chromosome, it allows them to utilize two frequent marker SNP’s that you can compare one allele against another in the same subject. Because women have two copies of the X- gene, the test subject can contain the control as well as the variable. The study measured the allelic expression of mRNA in one chromosome and how it compares to one allele in a relevant autopsy target tissue of the same individual.

    Inactivation is when one X chromosome is active, hence possesses gene expression; while the other X chromosome remains inactive during the organism’s lifetime. In females, when the X chromosome is inactivated, one remains active. Sometimes the inactive X chromosome is silenced. The reason why X inactivation occurs is so that a female, who possesses two X chromosomes will not have twice as many gene copies as a male; she will one possess a single copy. This is so that an individual contains half of their genes from their father and half from their mother. This process is used in this study because the scientists are using females as the test subjects because they possess an inactive X chromosome while possessing an active one. Therefore, they can check the polymorphism on the active MAOA.

    The main purpose of this study was to research epigenetic and genetic effects by comparing one allele against the other in a target tissue. By checking the potential limits of these genetic associations on the X chromosome, scientists can find a link between MAOA and these specific and other mental disorders. The author’s concluded that because they only studied DNA and RNA extract, they were inconclusive in determining the relationship between the methylation status and the MAOA protein activity. They also explain that the reason their results were inconclusive was because the sample sizes were too small to properly analyze the difference between diseased subjects and the control. They suggest that more studies can be done because they are aware that DNA and RNA extracts obtained from defined brain regions contains several typed of neurons as well a glial supporting cells. An experiment I would perform next would be on a wider range of test subjects and perhaps test males and females.

  16. It has been discovered that monoamine oxidase A (MAOA)is an enzyme that breaks down the monoamine neurotransmitters norepinephrine, serotonin, and dopamine, produces aggressive phenotypes across various species. This enzyme has been linked to different phenomenons such as CNS disorders, hyperactivity disorder, bipolar and Alzheimer’s disease. The MAOA is bound to the outer membrane of most cell types in the body.

    The fact that this gene is located on the short arm of the X chromosome is vital because the X chromosome can be found in both the male and female genotype. However, females have two X chromosomes, whereas males have one X and one Y chromosome. Due to the different number of chromosomes, it has been determined that the mental disorders will vary between the sexes.

    The X inactivation is an occurence in a female by which one X chromosome (either the maternally or paternally derived X) is randomly inactivated in an early embryonic cell. As a result, the inactivation of that same X will be fixed for all the cells that descend from that cell. This is also known as epigenetic in which the change in gene function is heritable without an alteration in the DNA sequence.In this article, scientists attempt to address the question how genetic and epigenetic processes interact to regulate MAOA gene expression using human autopsies from brain tissues. This factor provides the opportunity for great case studies on women because researchers would have the control and the experiment in one person. It is a good mechanism to discover what is driving these disorders. Through the utilization of women, researchers can see how MAOA is being modified and get some information on how it is mutating. It is also a process that would help eliminate errors.

    At the end of the article, scientists conclude that both genetic and epigenettic factors contributed to variable mRNA expression in females. While in males on genetic factors played a vital role. The scientists believe that there should be further study that utilizes larger sample sizes of in vivo mechanisms. A larger population is necessary in order to establish a more accurate study. This was an interesting paper. It was very informative in explaining how MAOA dysfunction can cause different CNS disorders. The methods that were taken in order to prove their theory was also interesting as well.

  17. This paper is focused on how the genetic and epigenetic mechanisms affect the regulation of allelic expression of the X-linked monoamine oxidase A (MAOA) gene relate in multiple central nervous system (CNS) disorders. This research analyzed 105 individually autopsied brains, including female and male samples, which had been diagnosed for bipolar disorder or schizophrenia, to find out characteristics of MAOA in different sorts of disorders. They compared allelic expression ratios and absolute mRNA levels, studied the comparison between CpG metylation and AEI, studied genotypes, and studied the relationship of mRNA levels with CpG methylation and genotypes. In particular, the female samples proved the most useful to the experiment because the females had two X-chromosomes which meant two different alleles (CpG methylation occurs in X-linked MAOA). In other words, because of the female samples, the researchers could try different combinations of tests in this experiment.
    Unlike males, females have two X-chromosomes, but as soon as the female embryo is formed, one of X-chromosomes become dormant or silenced. The dormant chromosome plays an important role in this study. Based on the study, the dormant X-chromosome controls genes on the active X-chromosome. If the dormant X-chromosome is not working well, it promotes an allelic expression imbalance. By combination of MAOA and MAOA, one MAOA escape X-inactivation and the MAOA is affected by CpG methylation as well as epigenetic phenomena. In other words, gene expression is affected by epigenetic events.
    This paper is researching many different aspects of MAOA gene expression which are implicated in several CNS disorder like aggression, antisocial behavior, bipolar disorder, schizophrenia, and Alzheimer’s disease. The research group used diverse methods to find the relationship between MAOA and CNS. They look not only at the prefrontal cortex but also at the other regions of the brain and compare the results. They found that there are differences in every individual in promoter methylation. According to their experiment, they found support of their hypothesis that X-chromosome inactivation is directly related to MAOA promoter methylation. However, the researchers had a hard time collecting data due to the lack of a large population of CNS patients. Through further research, the research group wants to find out how MAOA mRNA effects the enzyme’s functional expression in human body. Since the human genome project is complete, I think we can easily compare different style of alleles and can get better result and will bring better treatment for CNS disorders. For the next experiment, I will test and compare the all the results from this paper with the human genome.

  18. While conducting research many scientists have come to the conclusion that mental disorders contain many genes but they are still unsure as to what the cause or what the correlation might be. One reason that does sound promising is the fact that polymorphism which is when two different phenotypes exist in the same species, by altering the encoded amino acid sequence. In this research they focus on one which is the mono amine oxidase gene (MAOA) which is involved in a numerous amounts of Central Nervous System disorders. They also propose the fact that this gene is linked to many psychological phenomenons. Among these disorders there is drug abuse, which is the highest, anxiety, anorexia, bi-polar disorder, and ADHD.
    Females carry two copies of the X chromosome, therefore making it twice as likely to contain toxic X-linked genes. X-Inactivation is the process when one of the two chromosomes in female mammals is silenced in a complex and highly coordinated manner. While conducting their research they discovered that “X-inactivation found that MAOA ranks among the15% of X-linked genes that escape inactivation”. The MAOA gene is located on the X-Chromosome is important because makes it more predisposed to sex-linked differences where females have two copies of this chromosome and males only have one. With this it has also been said that the MAOA gene has had a much greater affect on females than males.

    The basis for the this experiment is to identify how genetic and epigenetic
    Processes integrate to regulate the MAOA gene expression. Measuring the amounts of
    mRNA produced by each of the two alleles in the female subjects, using two marker single nucleotide polymorphisms (SNPs) in the transcribed region. The allelic expression imbalance (AEI) illustrates whether there is any cis-acting factors in the gene regulation.

    What makes this a good experiment is that it has a good control group and this makes for a good case study and these control groups where all previously diagnosed with schizophrenia and bipolar disorder. There were 105 individuals (36 females and 69 males) and 35 controls obtained from the Stanley Foundation. Now in order to explain epigenetic effects of MAOA, they determined the methylation in the MAOA promoter region in two loci, in contrast to the X-inactivation measured at the X-linked androgen receptor locus. I would suggest that they have larger sample sizes because the larger the sample size with the disease the more effective and accurate your data will be. Overall this paper was very interesting and I appreciated the way the broke down the different methods of regulating the MAOA gene expression.

  19. This particular research article focuses on the allelic mRNA expression of X-linked monoamine oxidase a (MAOA) gene in human brain which is revealed to expose negative effects on the several brain tissues. The study focuses on MAOA, a candidate gene implicated in multiple CNS disorders, most notably drug abuse, aggression, antisocial behavior, and anxiety etc. Since MAOA is an X-linked gene it is important to study this gene of interest.

    Since women contain two X chromosomes, therefore one X chromosome tends to be inactivated and another one takes part in all the cellular and metabolic processes of the cell. Thus, inactivation of another X chromosome is not a random process and the genetic changes do not seem to show up in the inactivated chromosome. That’s why inactivated chromosome serves as a control group whereas activated one is considered to be an experimental group. Likewise, scientists were able to pinpoint their group of study as women to avoid complications of varying subjects and factors of genes involved. The main purpose of this study was to dissect epigenetic and genetic effects by comparing one allele against the other in a target tissue, which can provide important insight into the potential and limits of genetic association between MAOA and mental disorders. Therefore, it involved the experimentation with promoter region of MAOA in comparison to X-inactivation. The methylation in CpG location of the promoter part of MAOA resulted in variance between the three- and four repeat alleles in the same individual. Because allele-specific methylation is significantly correlated with allele-specific mRNA expression, the findings support the hypothesis that MAOA promoter methylation modulates transcription and thus represents a mechanism of partial dosage compensation independent of X-chromosome inactivation.

    Although scientists were not able to conclude on their experiment performed, the results of this study have implications for future clinical genetic association studies, which provide evidence for the presence of genetic factors effecting mRNA expression in human brain tissues. Also, the finding that promoter methylation affects allelic MAOA transcription and varies considerably between females indicates that epigenetic factors also play a significant role in modulating biogenic amine tone in CNS of female subjects, and hence mental activity and disorders. It was interesting to find the correlation between the disorders and sex.

    Though the authors suggest on addressing the biological and clinical significance of these findings, I would recommend on performing this experiment on large sample of population and then comparing the results to obtain a concrete standpoint on this particular finding.

  20. The monoamine oxidase A (MAOA)is directly related to the occurrence of mental disorders and central nervous system disorders. The fact that the gene of interest is located on the X chromosome is important because the X chromosome is a sex chromosome. Males have one X chromosome while females have two chromosomes. This brings an interesting angle to the experiment because we can now observe and study the gender effects on In this experiment one of the X chromosomes in the female is inactivated. This means that the chromosome is silenced. This allows the chromosome to serve as a control. It also prevents disorders and any genetic modifications.
    Thus, this allows researchers to observe and study the other chromosome containing the polymorphisms. Inactivation is important during processes such as development so that disorders are prevented. At the conclusion of the study not many correlations were found.
    Further research has to be performed. Future experiments are suggested to be performed on whole tissue samples. A larger pool should be taken into consideration to account for the genetic variations in the population. The pVNTR alleles, which were used in this experiment, were not broad and did not account for a large pool.

  21. It is important for the gene of interest to be located on the X chromosome because of its separate affects on males and females. Since males and females have different chromosome combinations (one X and one Y for males, and two X for females) this affects the different mental disorders that can vary between the sexes. (MAOA) Monoamine oxidase A an enzyme that breaks down the monoamine neurotransmitters (norepinephrine), serotonin, and dopamine) is located in the X chromosome, it is responsible for a lot of the CNS disorders that exist in people. Women result as better experiment subjects cause of their chromosome sequence of having only an X chromosome. Scientists compared allelic expression ratios and mRNA levels between males and females and studied the comparison between CPG methaylation and AEI, and came to the conclusion that women are better test subjects than men in studying CNS disorders because of different alleles in both the X chromosomes.
    Inactivation occurs in females when one X chromosome is active, while the other X chromosome remains inactive during the female’s lifetime. The reason why X inactivation occurs is to avoid the duplicate copying of genes. Women will possess one set of genes , instead of having the same two sets which can complicate things.
    The reason this study was performed is to research genetic anomalies by comparing alleles against the other s in a different part of the body. The X chromosome can be used by scientists to find a link between MAOA and these specific and other mental disorders. I would suggest a experiment that included a wide range of male and female subjects which tests specific alleles on the X chromosomes.

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