Last week I talked about the ways in which environmental factors influence the epigenome, and I wanted to expand on the topic a little more this week. We are currently in a period where obesity levels are rising and people are constantly watching what they eat, trying different diets in order to lose the extra weight. I thought it would be interesting to see how diet effects the epigenome and what consequences this has on the phenotype of the individual. Mischke and Plosch (2013) believe that a mother's diet while pregnant as well as the baby's diet when it is newly born influence the type of gut microbials that develop in the microbiome which effect the epigenetics of the individual.
Mischke and Plosch (2013) found that babies that are breast-fed tend to have lower levels of body fat than babies that have only been formula-fed. This initial diet is thought to effect the epigenetics of babies and result in lower body weights on average throughout life compared to individuals that were given a formula diet (Mischke & Plosch 2013). Different foods influence the content of the gut microbiome which affects the person's metabolism (Mischke & Plosch 2013). Folate and butyrate were observed in this study as both of them are metabolites that control epigenetics of the gut microbiome (Mischke & Plosch 2013). They are specifically involved with DNA methylation and histone modifications associated with intestinal cells, and play major roles in metabolism (Mischke & Plosch 2013). Microbials in the gut develop from the time a baby is born and diet has a large impact on the type of microbes that will form (Mischke & Plosch 2013). Breast milk introduces a type of bacteria that produces metabolites such as folate, while formula attempts to provide the same amino acids which causes there to be more proteins present in the microbiome (Mischke & Plosch 2013). The formula causes increased levels of butyrate to develop in the microbiome (Mischke & Plosch 2013). Folate regulates DNA methylation while butyrate inhibits histone deacetylases, so the two diets influence the epigenome in different manners (Mischke & Plosch 2013). Higher levels of the bacteria (bifidobacteria) which produced more folate were observed in people with lower body weight (Mischke & Plosch 2013).
The expression of genes through transcription is effected by the metabolites of the gut microbiota. DNA methylation helps regulate metabolism of lipids and glucose, and folate is needed for methylation to occur (Mischke & Plosch 2013). In order to produce enough folate, people need to maintain a diet that contains bifidobacteria (Mischke & Plosch 2013). This bacteria allows the gut microbiota to produce the metabolite which alters gene expression and allows the body to metabolize food more efficiently (Mischke & Plosch 2013). The addition of butyrate within the microbiome (possibly from formula diets) resulted in higher levels of fat as well as being associated with cancer and sickle cell anemia (Mischke & Plosch 2013). More research needs to be done on the effects of butyrate, but this metabolite was found to control the activity of genes (Mischke & Plosch 2013).
Miscke and Plosch (2013) determined that a baby's nutrition caused the development of certain gut microbiota and that the metabolites formed from the microbiota regulate the epigenetics of intestinal cells. Differences in transcriptional activity due to epigenome coding, resulted in specific phenotypes. Formula diets are thought to be linked to higher chances of the individual becoming obese through the alteration to the epigenome (Mischke & Plosch 2013).
Wednesday, 28 May 2014
Thursday, 22 May 2014
Environmental Influence on Epigenetics
Over the past few weeks, I have discussed how epigenetics causes differences in the phenotypes of individuals. Its effects are demonstrated through the observation of new behaviours and diseases, which gives the impression that epigenetics is in control. This isn't the case though. There are factors that influence epigenetics, and I wanted to know where the environment came into play in all of this.
There is evidence that different environmental events within an organism's life can increase or decrease the epigenetic modifications that occur to DNA sequences. Some of these alterations are then passed down to offspring, resulting in similar phenotypes observed through multiple generations. Impact from diet and toxins on the epigenome were studied (2010) in an attempt to determine how changes in the environment influence DNA methylation of an individual, and what that does to the organism's phenotype (Feil 2006; Franklin & Mansuy 2010). Their studies demonstrated that the altered expression of certain genes through DNA methylation can be passed down to offspring (Feil 2006; Franklin & Mansuy 2010). Although more research needs to be conducted, Franklin and Mansuy's study (2010) negates the idea that changes to the epigenome were lost from one generation to the next.
When a DNA sequence is epigenetically modified, it affects whether the associated gene is expressed or silenced. As cell replication occurs, these alterations need to be maintained in order for the resulting phenotype to remain consistent (Feil 2006). A methyltransferase known as DNMT1 regulates the DNA methylation of newly replicated sequences so that they are the same as the original (Feil 2006). Environmental factors can sometimes inhibit the DNMT1, altering the DNA methylation pattern in the gene and in turn, causing changes to the phenotype of the organism (Feil 2006). Feil (2006) found that changes in an organism's diet can have present these consequences. Humans with hyperhomocysteinaemia, a disease classified by high levels of homocysteine in the blood, were studied, and it was determined that these individuals showed lower levels of DNA methylation than normal DNA sequences (Feil 2006). The increase of this chemical in the cell inhibited DNMT1 causing a disease which could lead to heart problems (Feil 2006). Intake of more folic acid was found to alter the problem and increase the levels of DNA methylation (Feil 2006). In this scenario, implementing a change in diet through the introduction of more folic acid, caused a shift in the epigenetic pattern which resulted in a beneficial phenotypic change (Feil 2006).
Toxins, such as methoxychlor which is used as a pesticide on crops, are also believed to alter levels of DNA methylation in organisms exposed to them (Feil 2006; Franklin & Mansuy 2010). Animals experienced a decrease in fertility after exposure to these chemicals, and it was observed that they displayed changes in the levels of DNA methylation (Feil 2006). This phenotypic change was passed down the male germ line of rats as far as 4 generations (Feil 2006). Although more research is needed to fully understand what is causing these changes, alterations to the epigenetic patterns of organisms is thought to play a major role (Feil 2006; Franklin & Mansuy 2010). It is believed that toxins could cause similar alterations to humans and result in deformities or cancer (Feil 2006).
There is evidence that different environmental events within an organism's life can increase or decrease the epigenetic modifications that occur to DNA sequences. Some of these alterations are then passed down to offspring, resulting in similar phenotypes observed through multiple generations. Impact from diet and toxins on the epigenome were studied (2010) in an attempt to determine how changes in the environment influence DNA methylation of an individual, and what that does to the organism's phenotype (Feil 2006; Franklin & Mansuy 2010). Their studies demonstrated that the altered expression of certain genes through DNA methylation can be passed down to offspring (Feil 2006; Franklin & Mansuy 2010). Although more research needs to be conducted, Franklin and Mansuy's study (2010) negates the idea that changes to the epigenome were lost from one generation to the next.
When a DNA sequence is epigenetically modified, it affects whether the associated gene is expressed or silenced. As cell replication occurs, these alterations need to be maintained in order for the resulting phenotype to remain consistent (Feil 2006). A methyltransferase known as DNMT1 regulates the DNA methylation of newly replicated sequences so that they are the same as the original (Feil 2006). Environmental factors can sometimes inhibit the DNMT1, altering the DNA methylation pattern in the gene and in turn, causing changes to the phenotype of the organism (Feil 2006). Feil (2006) found that changes in an organism's diet can have present these consequences. Humans with hyperhomocysteinaemia, a disease classified by high levels of homocysteine in the blood, were studied, and it was determined that these individuals showed lower levels of DNA methylation than normal DNA sequences (Feil 2006). The increase of this chemical in the cell inhibited DNMT1 causing a disease which could lead to heart problems (Feil 2006). Intake of more folic acid was found to alter the problem and increase the levels of DNA methylation (Feil 2006). In this scenario, implementing a change in diet through the introduction of more folic acid, caused a shift in the epigenetic pattern which resulted in a beneficial phenotypic change (Feil 2006).
Toxins, such as methoxychlor which is used as a pesticide on crops, are also believed to alter levels of DNA methylation in organisms exposed to them (Feil 2006; Franklin & Mansuy 2010). Animals experienced a decrease in fertility after exposure to these chemicals, and it was observed that they displayed changes in the levels of DNA methylation (Feil 2006). This phenotypic change was passed down the male germ line of rats as far as 4 generations (Feil 2006). Although more research is needed to fully understand what is causing these changes, alterations to the epigenetic patterns of organisms is thought to play a major role (Feil 2006; Franklin & Mansuy 2010). It is believed that toxins could cause similar alterations to humans and result in deformities or cancer (Feil 2006).
Saturday, 17 May 2014
Epigenetic Differences Between Twins Used to Detect Breast Cancer
Identical twins share the exact same DNA, yet at times, one twin may develop different characteristics or diseased than the other. Epigenetics makes this phenomenon possible as the DNA sequences remain the same but are modified in a number of different ways. DNA methylation is an example in which a methyl group is added to a site on the DNA causing the gene to be turned off. The activity affects whether the gene is expressed or not and determines the corresponding phenotype of the individual. Modification of DNA occurs differently in each person, whether they have the same sequence of DNA or not. Dr. Esteller used this understanding of epigenetics and gene expression to compare the levels of DNA methylation between twins with and without breast cancer (IDIBELL-Bellvitge Biomedical Research Institute 2012). He found that women who developed breast cancer also had a higher level of DNA methylation in the DOK7 gene than their healthy twin (IDIBELL-Bellvitge Biomedical Research Institute 2012).
The goal of Heyn et al.'s (2013) study was to look for a marker in the blood of an individual that would allow them to determine whether the person was going to develop breast cancer. By comparing the blood of identical twins the researchers could detect different levels of epigenetics and determine what functions it had within the gene (Heyn et al. 2013). A cause of cancer is the hypermethylation of promoters of tumor-suppressor genes (Heyn et al. 2013). This process would turn off the suppressors, allowing the development and continued growth of tumors. The discovery of a difference in amount of methylation occurring between twins could provide a marker to predict the onset of cancer as well as create a target for scientists to develop preventative care and treatment for cancer.
Heyn et al. (2013) discovered that hypermethylation of the DOK7 gene took place in the blood of twins that developed cancer at different times, in breast tumors, and in breast cancer cell lines. The fact that DOK7 was methylated in varying amounts before and after the development of cancer allowed scientists to study the gene further and use it as a marker to detect breast cancer (Heyn et al. 2013). The difference in the amount of methylation of the gene was very small which made it difficult for Heyn et al. (2013) to determine exactly how much methylation causes breast cancer. Genes that have already been determined to influence breast cancer as well as new genes, like DOK7, were found to display differences in levels of DNA methylation between the pairs of twins (Heyn et al. 2013). From the results of their study, Heyn et al. (2013) proposed that increased methylation of DOK7 prevented transcription factors from binding and resulted in abnormal regulation of the gene. There is a possibility that this could alter the expression of the gene and result in the development of tumors and breast cancer (Heyn et al. 2013). More research is needed to determine the exact effects of the varying levels of methylation of DOK7, but this gene could become a marker to predict breast cancer in individuals (Heyn et al. 2013).
The goal of Heyn et al.'s (2013) study was to look for a marker in the blood of an individual that would allow them to determine whether the person was going to develop breast cancer. By comparing the blood of identical twins the researchers could detect different levels of epigenetics and determine what functions it had within the gene (Heyn et al. 2013). A cause of cancer is the hypermethylation of promoters of tumor-suppressor genes (Heyn et al. 2013). This process would turn off the suppressors, allowing the development and continued growth of tumors. The discovery of a difference in amount of methylation occurring between twins could provide a marker to predict the onset of cancer as well as create a target for scientists to develop preventative care and treatment for cancer.
Heyn et al. (2013) discovered that hypermethylation of the DOK7 gene took place in the blood of twins that developed cancer at different times, in breast tumors, and in breast cancer cell lines. The fact that DOK7 was methylated in varying amounts before and after the development of cancer allowed scientists to study the gene further and use it as a marker to detect breast cancer (Heyn et al. 2013). The difference in the amount of methylation of the gene was very small which made it difficult for Heyn et al. (2013) to determine exactly how much methylation causes breast cancer. Genes that have already been determined to influence breast cancer as well as new genes, like DOK7, were found to display differences in levels of DNA methylation between the pairs of twins (Heyn et al. 2013). From the results of their study, Heyn et al. (2013) proposed that increased methylation of DOK7 prevented transcription factors from binding and resulted in abnormal regulation of the gene. There is a possibility that this could alter the expression of the gene and result in the development of tumors and breast cancer (Heyn et al. 2013). More research is needed to determine the exact effects of the varying levels of methylation of DOK7, but this gene could become a marker to predict breast cancer in individuals (Heyn et al. 2013).
Thursday, 8 May 2014
SINEs and LINEs
Last week I talked about retrotransposons and ended with a video that briefly discussed SINEs and LINEs. I want to spend this week discussing transposons in a little more detail and mention some of the problems that can arise from these transposable elements.
SINEs, LINEs, and LTRs are all retrotransposons that insert themselves into RNA through the copy and pasting method described last week. SINEs are made up of three different subgroups known as Alu, MIR, and MIR3, which act a little differently from the other two retrotransposon classes (Nelson et al. 2004). Reverse transcriptase doesn't act on SINEs which is necessary for the process of copying and pasting to occur (Nelson et al. 2004). Instead, SINEs must work with LINEs that have a similar 3' end sequence in order to use the activity from them to insert themselves (Nelson et al. 2004). LTRs only appear in humans in 4 different forms, and even in these cases, most of their sequences have been shortened by homologous recombination causing them to be "isolated elements" (Nelson et al. 2004).
Mills et al. (2007) stated that transposons make up about 44% of the human genome, but despite this amount, less than 0.05% of them are actually active. Retrotransposons that are still able to move are of high interest to researchers because their insertion and rearrangement of genetic material can cause differences in phenotypes that may hinder the host organism (Mills et al. 2007). Transposonase tends to favor inactive transposable elements that have deletions or mutations which causes an increase in production of these transposons. Although these transposable elements don't do anything they become more numerous and make up a large part of the genome (Nelson et al. 2004). LINEs are different in the fact that they generally interact with functional RNA which prevents them from losing any function so they can remain active (Nelson et al. 2004). Nelson et al. (2004) explained that transposons become embedded within the open reading frame region of genes through alternative splicing of introns. This causes the sequences to be lengthened or cut short, and if done in certain ways may end with transposable elements in the coding regions of genes that didn't normally have them (Nelson et al. 2004).
Focusing specifically on LINE-1 (L1) and Alu elements, Mills et al. (2007) reported that researchers had trouble finding the active retrotransposons amongst the many inactive ones until diseases linked to them were observed. L1 elements are usually sequences shortened at the 5' end making them difficult to identify within a gene (Mills et al. 2007). As they fit within the normal sequence it is hard to determine where the sequence ends and the inserted retrotransposon begins. Alu elements are controlled by L1 elements so these transposons are even harder to find because you need to be able to locate the L1 element before finding Alu (Mills et al. 2007). In order to determine which retrotransposons are still currently active and which are immobile, researchers compared human and chimpanzee genomes (Mills et al. 2007). They find where a transposon has recently inserted multiple sequences and then determine if the observed retrotransposon is in both genomes or if it is only found in the human genome (Mills et al. 2007). Any retrotransposons found in both genomes are thought to be immobile because it is believed that they became part of the genome before the evolutionary divergence between human and chimps (Mills et al. 2007). Retrotransposons solely in the human genome are thought to be more recently inserted and have a greater chance of activity (Mills et al. 2007). Of these active transposons, L1, Alu, and SVU elements have shown to be most commonly associated with human diseases (Mills et al. 2007).
Many transposable elements are found within the proteins of genes causing differences in the functions and coding of each protein (Nelson et al. 2004). This can lead to altered interactions of genes and ultimately result in a number of diseases depending on which genes are affected. LINEs can interact with mRNA from neighboring genes causing new insertions and the development of pseudogenes in many places within the genome (Nelson et al. 2004). Changes to the sequence of the genome effects the regulation of genes, and any slight change can result in mutagenic activity within the organism (Nelson et al. 2004). Alu retrotransposons have caused mis-pairing and crossing over in genes resulting in many deletions in host organisms (Nelson et al. 2004). The activity of retrotransposons which resulted in alterations to genetic sequences has been associated with a number of diseases such as muscular dystrophy, haemophilia, Huntington's disease, and some forms of breast cancer (Nelson et al. 2004).
SINEs, LINEs, and LTRs are all retrotransposons that insert themselves into RNA through the copy and pasting method described last week. SINEs are made up of three different subgroups known as Alu, MIR, and MIR3, which act a little differently from the other two retrotransposon classes (Nelson et al. 2004). Reverse transcriptase doesn't act on SINEs which is necessary for the process of copying and pasting to occur (Nelson et al. 2004). Instead, SINEs must work with LINEs that have a similar 3' end sequence in order to use the activity from them to insert themselves (Nelson et al. 2004). LTRs only appear in humans in 4 different forms, and even in these cases, most of their sequences have been shortened by homologous recombination causing them to be "isolated elements" (Nelson et al. 2004).
Mills et al. (2007) stated that transposons make up about 44% of the human genome, but despite this amount, less than 0.05% of them are actually active. Retrotransposons that are still able to move are of high interest to researchers because their insertion and rearrangement of genetic material can cause differences in phenotypes that may hinder the host organism (Mills et al. 2007). Transposonase tends to favor inactive transposable elements that have deletions or mutations which causes an increase in production of these transposons. Although these transposable elements don't do anything they become more numerous and make up a large part of the genome (Nelson et al. 2004). LINEs are different in the fact that they generally interact with functional RNA which prevents them from losing any function so they can remain active (Nelson et al. 2004). Nelson et al. (2004) explained that transposons become embedded within the open reading frame region of genes through alternative splicing of introns. This causes the sequences to be lengthened or cut short, and if done in certain ways may end with transposable elements in the coding regions of genes that didn't normally have them (Nelson et al. 2004).
Focusing specifically on LINE-1 (L1) and Alu elements, Mills et al. (2007) reported that researchers had trouble finding the active retrotransposons amongst the many inactive ones until diseases linked to them were observed. L1 elements are usually sequences shortened at the 5' end making them difficult to identify within a gene (Mills et al. 2007). As they fit within the normal sequence it is hard to determine where the sequence ends and the inserted retrotransposon begins. Alu elements are controlled by L1 elements so these transposons are even harder to find because you need to be able to locate the L1 element before finding Alu (Mills et al. 2007). In order to determine which retrotransposons are still currently active and which are immobile, researchers compared human and chimpanzee genomes (Mills et al. 2007). They find where a transposon has recently inserted multiple sequences and then determine if the observed retrotransposon is in both genomes or if it is only found in the human genome (Mills et al. 2007). Any retrotransposons found in both genomes are thought to be immobile because it is believed that they became part of the genome before the evolutionary divergence between human and chimps (Mills et al. 2007). Retrotransposons solely in the human genome are thought to be more recently inserted and have a greater chance of activity (Mills et al. 2007). Of these active transposons, L1, Alu, and SVU elements have shown to be most commonly associated with human diseases (Mills et al. 2007).
Many transposable elements are found within the proteins of genes causing differences in the functions and coding of each protein (Nelson et al. 2004). This can lead to altered interactions of genes and ultimately result in a number of diseases depending on which genes are affected. LINEs can interact with mRNA from neighboring genes causing new insertions and the development of pseudogenes in many places within the genome (Nelson et al. 2004). Changes to the sequence of the genome effects the regulation of genes, and any slight change can result in mutagenic activity within the organism (Nelson et al. 2004). Alu retrotransposons have caused mis-pairing and crossing over in genes resulting in many deletions in host organisms (Nelson et al. 2004). The activity of retrotransposons which resulted in alterations to genetic sequences has been associated with a number of diseases such as muscular dystrophy, haemophilia, Huntington's disease, and some forms of breast cancer (Nelson et al. 2004).
Thursday, 1 May 2014
Transposable Elements (Jumping Genes)
After our discussion about epigenetics in class last week, I thought it might be interesting to take a closer look at "jumping genes". Although there are both DNA transposons and retrotransposons, my focus will be on retrotransposons. Retrotransposons are thought to copy and paste themselves into different locations of the genome providing an increase in DNA of the organism. This occurs when there is a replication of a sequence through RNA, and then this copy is reverse transcribed into a sequence of DNA (Cordaux and Batzer, 2009). The DNA sequence is then placed into a different location within the genome (Cordaux and Batzer, 2009). The insertion of extra DNA sequences can cause differences in the regulation of genes, resulting in a variation of phenotypes between organisms despite the similarity in genetic make-up.
Retrotransposons are commonly found within the brain causing changes in gene expression which ultimately leads to differences in the function of neurons and human behaviours (Singer et. al, 2010). Long interspersed repeated sequences (LINE-1 or L1 elements) are a class of retrotransposons that make up about 20% of mammalian genomic DNA, although only about 150 of these elements are thought to be capable of activity (Singer et. al, 2010). These L1 elements move about during the development of the central nervous system as well as during adult neurogenesis and take place individually in certain cells (Singer et. al, 2010). This means that some cells may contain the retrotransposons while other cells next to them are void of the elements. The effects L1 elements have on the regulation of genes depends on where they are inserted in the gene (Singer et. al, 2010). Singer et. al (2010) found that L1 elements placed in the sense strand resulted in a decreased rate of transcription by that specific gene as compared to the antisense strand where no change occurred. The activation and inactivation of L1 elements also influences regulation of neuronal genes which is demonstrated through the diversity of behaviours of organisms (Singer et. al, 2010).
L1 elements possess the needed promoters for transcription, are affected by epigenetics, and are turned on and off at different times. Each of these situations has an effect on the expression of the gene containing the retrotransposon, and in some cases, other genes surrounding this one may also be affected (Singer et. al, 2010). Although retrotransposons are generally shorter sequences, they are still able to start transcription within a gene which then influences activity further along the pathway, possibly triggering other genes (Singer et. al, 2010). Retrotransposons have also been found to be a target for DNA methylation and histone modification, where the retrotransposon is silenced in both scenarios (Singer et. al, 2010). If these elements are reactivated, other genes my actually experience changes in their expression (Singer et. al, 2010). Retrotransposons promote regulation of genes at their own timing which influences the other genes around them. When they are silenced, genes are able to transcribe normally at specific times in conjunction with the other genes around them. Once the L1 elements are activated, they interrupt this schedule causing changes in the levels of expression and in turn, differences in the functions of the genes (Singer et. al, 2010).
Without changing the genetic material of an organism, Singer et. al (2010) believes that L1 elements in neuronal cells may causes random variation in behavioural phenotypes. Not only do retrotransposons occur during the development of neurons and last into adulthood, but retrotransposons have the ability to insert themselves into many different locations within the genes (Singer et. al, 2010). This leaves lots of room for alterations to the expression and regulation of neuronal genes, resulting in multiple phenotypes from the same genome (Singer et. al, 2010). L1 elements are affected by environmental factors, either increasing or decreasing the number of retrotransposons that occur in the organism in order to better the chances of survival (Singer et. al, 2010). With this in mind retrotransposons have the ability to allow organisms to respond and change quickly to the environment.
Below is a video that provides some more information on transposons, specifically talking about LINES and SINES. It sheds some light on the relationships and ancestry between different animals and their connection through transposable elements.
(https://www.youtube.com/watch?v=_Ol492CLkdY)
Video Reference:
Wowcunning 2009, Evolution: genetic evidence - transposons, online video, viewed 1 May 2014, <https://www.youtube.com/watch?v=_Ol492CLkdY>.
Retrotransposons are commonly found within the brain causing changes in gene expression which ultimately leads to differences in the function of neurons and human behaviours (Singer et. al, 2010). Long interspersed repeated sequences (LINE-1 or L1 elements) are a class of retrotransposons that make up about 20% of mammalian genomic DNA, although only about 150 of these elements are thought to be capable of activity (Singer et. al, 2010). These L1 elements move about during the development of the central nervous system as well as during adult neurogenesis and take place individually in certain cells (Singer et. al, 2010). This means that some cells may contain the retrotransposons while other cells next to them are void of the elements. The effects L1 elements have on the regulation of genes depends on where they are inserted in the gene (Singer et. al, 2010). Singer et. al (2010) found that L1 elements placed in the sense strand resulted in a decreased rate of transcription by that specific gene as compared to the antisense strand where no change occurred. The activation and inactivation of L1 elements also influences regulation of neuronal genes which is demonstrated through the diversity of behaviours of organisms (Singer et. al, 2010).
L1 elements possess the needed promoters for transcription, are affected by epigenetics, and are turned on and off at different times. Each of these situations has an effect on the expression of the gene containing the retrotransposon, and in some cases, other genes surrounding this one may also be affected (Singer et. al, 2010). Although retrotransposons are generally shorter sequences, they are still able to start transcription within a gene which then influences activity further along the pathway, possibly triggering other genes (Singer et. al, 2010). Retrotransposons have also been found to be a target for DNA methylation and histone modification, where the retrotransposon is silenced in both scenarios (Singer et. al, 2010). If these elements are reactivated, other genes my actually experience changes in their expression (Singer et. al, 2010). Retrotransposons promote regulation of genes at their own timing which influences the other genes around them. When they are silenced, genes are able to transcribe normally at specific times in conjunction with the other genes around them. Once the L1 elements are activated, they interrupt this schedule causing changes in the levels of expression and in turn, differences in the functions of the genes (Singer et. al, 2010).
Without changing the genetic material of an organism, Singer et. al (2010) believes that L1 elements in neuronal cells may causes random variation in behavioural phenotypes. Not only do retrotransposons occur during the development of neurons and last into adulthood, but retrotransposons have the ability to insert themselves into many different locations within the genes (Singer et. al, 2010). This leaves lots of room for alterations to the expression and regulation of neuronal genes, resulting in multiple phenotypes from the same genome (Singer et. al, 2010). L1 elements are affected by environmental factors, either increasing or decreasing the number of retrotransposons that occur in the organism in order to better the chances of survival (Singer et. al, 2010). With this in mind retrotransposons have the ability to allow organisms to respond and change quickly to the environment.
Below is a video that provides some more information on transposons, specifically talking about LINES and SINES. It sheds some light on the relationships and ancestry between different animals and their connection through transposable elements.
(https://www.youtube.com/watch?v=_Ol492CLkdY)
Video Reference:
Wowcunning 2009, Evolution: genetic evidence - transposons, online video, viewed 1 May 2014, <https://www.youtube.com/watch?v=_Ol492CLkdY>.
Wednesday, 23 April 2014
Rosey Cheeks from a Glass of Wine?
Do you look like you are blushing after drinking a glass of wine or beer? I know my face gets pretty flushed within those first couple of drinks. This characteristic happens to indicate part of your genotype. Depending on the genes you possess, you may be more or less susceptible to the affects of alcohol.
After consumption of alcohol, the alcohol dehydrogenase enzyme (ADH) works to break down the ethanol into acetaldehyde inside your liver (Kim et. al, 2005). Another enzyme known as aldehyde dehydrogenase-2 (ALDH2) then turns the acetaldehyde into acetic acid (Kim et. al, 2005). Acetaldehyde is the toxic byproduct of ethanol which the enzymes in the liver work to detoxify. In some cases, a mutation occurs in the ALDH2 gene where there is a substitution of a nucleotide pair (Kim et. al, 2005). The nucleotide goes from a G to an A and results in an amino acid change from Glutamine to Lysine which causes a loss of function of ALDH2 (Kim et. al, 2005). People with this mutant gene experience flushing of the face, tend to get sick, have headaches, or sweat after ingesting alcohol (Kim et. al, 2005). The build-up of acetaldehyde in the tissues and the body's inability to convert this toxin to acetic acid due to lack of ALDH2 activity causes these sickening symptoms. It has been found that many people of Asian descent possess this mutated ALDH2 genotype which is why they tend to have a much lower alcohol tolerance than people of different nationalities. Kim et. al (2005) looked into whether there may be more to the genotype than either having a fully active gene or a completely inactive gene. They believe that the ALDH2 activity could be a result of inheritance from both parents. In this case, a range of genotypes could occur where some people are homozygous for normal ALDH2, some are heterozygous (1 normal ALDH2 and 1 mutated ALDH2), and some homozygous for the defective ALDH2 (Kim et. al, 2005). Kim et. al, (2005) performed a study where they looked at people with each of these genotypes and measured whether alcohol intake resulted in a flushed face. After drinking one beer, 6.5% of the people with active ALDH2, 92.3% of heterozygotes of ALDH2, and 100% of homozygotes for the defected ALDH2 gene all demonstrated flushed faces (Kim et. al, 2005). The study showed the variation in phenotypes as a result of differing genotypes and that each genotype corresponds to a different level of ALDH2 activity (Kim et. al, 2005). Although complete inactivity of ALDH2 is commonly found in people of Asian background, members of other origins may exhibit decreased acetaldehyde detoxification as a result of a heterozygous genotype.
Next time you are drinking, look into the mirror after you first glass of alcohol. A red face may indicate that your body isn't getting rid of the acetaldehyde as fast as it should, and that it may be building up in your blood and tissues. Your visible phenotype may be a signal to what your genotype is and prevent you from drinking more alcohol than your body can tolerate.
After consumption of alcohol, the alcohol dehydrogenase enzyme (ADH) works to break down the ethanol into acetaldehyde inside your liver (Kim et. al, 2005). Another enzyme known as aldehyde dehydrogenase-2 (ALDH2) then turns the acetaldehyde into acetic acid (Kim et. al, 2005). Acetaldehyde is the toxic byproduct of ethanol which the enzymes in the liver work to detoxify. In some cases, a mutation occurs in the ALDH2 gene where there is a substitution of a nucleotide pair (Kim et. al, 2005). The nucleotide goes from a G to an A and results in an amino acid change from Glutamine to Lysine which causes a loss of function of ALDH2 (Kim et. al, 2005). People with this mutant gene experience flushing of the face, tend to get sick, have headaches, or sweat after ingesting alcohol (Kim et. al, 2005). The build-up of acetaldehyde in the tissues and the body's inability to convert this toxin to acetic acid due to lack of ALDH2 activity causes these sickening symptoms. It has been found that many people of Asian descent possess this mutated ALDH2 genotype which is why they tend to have a much lower alcohol tolerance than people of different nationalities. Kim et. al (2005) looked into whether there may be more to the genotype than either having a fully active gene or a completely inactive gene. They believe that the ALDH2 activity could be a result of inheritance from both parents. In this case, a range of genotypes could occur where some people are homozygous for normal ALDH2, some are heterozygous (1 normal ALDH2 and 1 mutated ALDH2), and some homozygous for the defective ALDH2 (Kim et. al, 2005). Kim et. al, (2005) performed a study where they looked at people with each of these genotypes and measured whether alcohol intake resulted in a flushed face. After drinking one beer, 6.5% of the people with active ALDH2, 92.3% of heterozygotes of ALDH2, and 100% of homozygotes for the defected ALDH2 gene all demonstrated flushed faces (Kim et. al, 2005). The study showed the variation in phenotypes as a result of differing genotypes and that each genotype corresponds to a different level of ALDH2 activity (Kim et. al, 2005). Although complete inactivity of ALDH2 is commonly found in people of Asian background, members of other origins may exhibit decreased acetaldehyde detoxification as a result of a heterozygous genotype.
Next time you are drinking, look into the mirror after you first glass of alcohol. A red face may indicate that your body isn't getting rid of the acetaldehyde as fast as it should, and that it may be building up in your blood and tissues. Your visible phenotype may be a signal to what your genotype is and prevent you from drinking more alcohol than your body can tolerate.
Wednesday, 9 April 2014
New Leukemia Treatment (Ma et. al, 2014)
Studying the genome of different organisms leads to the discovery of many different cellular processes and how certain phenotypes are influenced. Whenever I think about mutations or alterations in gene expression I immediately think of diseases. Genetic research does lead to the understanding of different diseases, but it also leads to knowledge on how to treat these disorders. Once scientists are able to narrow down the genes and specific gene functions that influence a particular disease, they can then work at finding a way to alter gene regulation in order to treat the disease. The study of Acute Myeloid Leukemia (AML) is an example of how scientists have taken what they know about gene expression in order to treat individuals with the disease.
Acute Myeloid Leukemia is a disease where underdeveloped blasts grow within the bone marrow and peripheral blood as a result of the cell's inability to differentiate (Ma et. al, 2014). Ma et. al (2014) explains how, "FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that is expressed in stem cells." When FLT3 binds it results in the activation of phosphorylation of proteins and also triggers other pathways within the cells (Ma et. al, 2014). A mutation occurs in individuals with Acute Myeloid Leukemia where FLT3 is activated without having to be bound to the ligand (Ma et. al, 2014). There are a couple different mutations that have been found to affect FLT3, but the most widely known case is when there is an internal replication of different lengths of the sequence (Ma et. al, 2014). This activation allows for continued growth of the cells which is seen in Acute Myeloid Leukemia. Ma et. al (2014) as well as other scientists are trying to find something that will inhibit FLT3 in order to treat individuals with this disease. Currently TTT-3002 is under observation as a possible new inhibitor that may be able to treat Acute Myeloid Leukemia (Ma et. al, 2014). Ma et. al (2014) believe that TTT-3002 prevents FLT3 activity by producing mutations on residue D835. TTT-3002 has been tested in mice, and so far, has been able to inhibit FLT3 containing multiple mutations, as well as working against blasts within the bone marrow and blood that express FLT3 (Ma et. al, 2014). It seems to be the strongest acting treatment to date that does little harm to the host (Ma et. al, 2014). This occurs as a result of TTT-3002's selectivity to FLT3 allowing it to more directly reach the target intended. Although this inhibitor is predicted to hold up against resistance from FLT3, studies have recorded that its effects are more damaging when doses are paired with chemotherapy (Ma et. al, 2014). TTT-3002 has more promising effects on Acute Myeloid Leukemia when it is the sole treatment. Trials on human patients are now under way, but there is still much research that needs to be done on this inhibitor and its capability to treat Acute Myeloid Leukemia.
Acute Myeloid Leukemia is a disease where underdeveloped blasts grow within the bone marrow and peripheral blood as a result of the cell's inability to differentiate (Ma et. al, 2014). Ma et. al (2014) explains how, "FMS-like tyrosine kinase-3 (FLT3) is a receptor tyrosine kinase that is expressed in stem cells." When FLT3 binds it results in the activation of phosphorylation of proteins and also triggers other pathways within the cells (Ma et. al, 2014). A mutation occurs in individuals with Acute Myeloid Leukemia where FLT3 is activated without having to be bound to the ligand (Ma et. al, 2014). There are a couple different mutations that have been found to affect FLT3, but the most widely known case is when there is an internal replication of different lengths of the sequence (Ma et. al, 2014). This activation allows for continued growth of the cells which is seen in Acute Myeloid Leukemia. Ma et. al (2014) as well as other scientists are trying to find something that will inhibit FLT3 in order to treat individuals with this disease. Currently TTT-3002 is under observation as a possible new inhibitor that may be able to treat Acute Myeloid Leukemia (Ma et. al, 2014). Ma et. al (2014) believe that TTT-3002 prevents FLT3 activity by producing mutations on residue D835. TTT-3002 has been tested in mice, and so far, has been able to inhibit FLT3 containing multiple mutations, as well as working against blasts within the bone marrow and blood that express FLT3 (Ma et. al, 2014). It seems to be the strongest acting treatment to date that does little harm to the host (Ma et. al, 2014). This occurs as a result of TTT-3002's selectivity to FLT3 allowing it to more directly reach the target intended. Although this inhibitor is predicted to hold up against resistance from FLT3, studies have recorded that its effects are more damaging when doses are paired with chemotherapy (Ma et. al, 2014). TTT-3002 has more promising effects on Acute Myeloid Leukemia when it is the sole treatment. Trials on human patients are now under way, but there is still much research that needs to be done on this inhibitor and its capability to treat Acute Myeloid Leukemia.
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