Lions, and Tigers, and Vampires! Oh My!

Vampires. No not the Edward Cullen type of vampire who sparkles when he gets in the sun and he only drinks the blood of animals because he is "vegan." I am talking about Dracula-type, who only can come out at night because the sun will kill them and they have to drink blood of humans to survive. These living-dead creatures are immortal with characteristically sharp teeth that help them penetrate the jugular of their midnight snacks. The sun basically turns them into a walking fireball that first starts out as small patches of burning that within seconds engulfs them in flame. In reality these beings do not exist (don't go to New Orleans or they will tell you otherwise), but there is a disease that mimics the vampire's sensitivity to light, fang-like appearance, and need for blood. Congenital erythropoietic porphyria (CEP) or Gunther's disease is marked with hypersensitivity to light, anemia, passing of dark colored urine. in some cases the gums recede making the teeth look fang-like.

CEP is an autosomal recessive disease that occurs when both parents have a copy of the mutated/abnormal gene and the baby inherits both abnormal version of it. The chance of passing CEP is higher in individuals who are closely related. According to Congenital erythropoietic porphyria: Insight into the molecular basis of the disease, having molecular conformation is crucial to the treatment of this disease. This disease is caused by the deficiency of uroporphyrinogen III cosynthase enzyme, expressed by the UROS gene. This enzyme is important in creating heme, which is the factor that allows your blood to bind to oxygen. Sequencing of this gene has found about  39 different mutations that could be the basis of this disease, although data on the mutations is limited. All of the mutations are either missense mutations, nonsense mutations, or frameshift mutations. In most cases, the genotype determines the different aspects of the disease and the severity of each. For example, patients who had the C73R/C73R mutations on exon 4 of the UROS gene showed very severe manifestations of the disease, while individuals with the T228M/C73R mutations showed a more milder form of the disease. However, what makes this disease hard to understand is that sometimes the genotype-phenotype is not present. Two individuals with the same mutations, P248Q/P248Q, showed a different clinical profile. (If you are not familiar with the way each of these mutations are set up (C73R/C73R), it is basically one mutation that is found on one chromatid and the other mutation is found on the other chromatid.)

Since the molecular basis of the disease is vague and confusing, only symptomatic treatment is being administered until scientist can figure out a way to treat it by gene therapy. Like vampires, individuals with this disease need blood to survive, frequent blood transfusions are given to those individuals that present with severe anemia. Bone marrow transplants are another, more beneficial, way to virtually cure the disease with the hope that the new bone marrow has a functional copy of the UROS gene.

For Further Reading:
http://eds.b.ebscohost.com.ezproxy.shsu.edu/eds/pdfviewer/pdfviewer?vid=14&sid=4a683f92-0d69-44d0-887b-5b95858acb25%40sessionmgr105&hid=127

http://www.porphyriafoundation.com/about-porphyria/types-of-porphyria/CEP

Nature's Deadpool

I know many of you are looking at the above picture and questioning what the heck this adorable creature is. It is called an axolotl and it is a Mexican salamander. These little guys are unique because they do not undergo metamorphosis at maturation. This means that these little amphibians stay in water for the entirety of their lives since they never grow lungs and keep their cute gills. They are also particularly interesting because they can regrow almost every one of their limbs, similar to the starfish or the lizard. Scientists believe that this could be in relation to gene expression of homeobox genes.

Hox genes, or homeobox genes, are responsible for pattern development of limbs. Since urodele amphibians, like the axolotl, have a really remarkable ability to regenerate their limbs scientists at the University of California, Irvine's Developmental Biology Center wanted to see the role Hox genes, in particular the play HoxA complex, in this ability.

These genes essentially get turned off after limbs are developed in the embryo and in humans they do not get turned on again, which is unfortunate. Within the HoxA complex, Hox9  and Hox13 are both reexpressed early within the regeneration of the axolotl limbs. Not only does the axolotl express these Hox genes, these scientists isolated 17 different genes that are similar. Along with Hox, these 17 genes are responsible for the complex regeneration system. These genes are usually expressed with temporal and spatial colinearity during embryo development, meaning that the genes at one end of the chromosome are expressed at the head while the genes at the other end of the chromosome are expressed at the tail end. This is not the case for limb regeneration. Once signaled, these genes express the same way no matter where the limb loss is located (the cells do not differentiate). It is not until the later process does the cells start to differentiate depending what place along the proximal-distal axis they are being grown from. Basically, all of the limbs and tail start out as a stump and then once they reach a certain point, they will differentiate into the correct limb.

Could we potentially use this knowledge to help amputees regrow limbs or would that be pushing science a little too far? Humans do express both the HoxA13 and the HoxA9 genes.

LSD Causes Schizophrenia???

Schizophrenia is a mental disorder that is classified by its symptoms of abnormal social behavior and the inability to discern what is real from what is not. Many symptoms are circled around having false beliefs, unclear thinking, hearing voices, and reduced social engagement. If you know anyone with schizophrenia you know that this disorder can have a detrimental effect on the individual's life. With that said, no one really knows the absolute causes of this disease. It is believed that environmental factors along with brain chemistry and genetics play a huge role in the progression of the disorder. In research regarding this topic, scientists have discovered that aromatic l-amino acid decarboxylase (AADC) concentrations in blood serum is increased. AADC is the rate limiting step in the production of 2-phenylethylamine (2PE), which is a known psychotogenic (causes the individual to experience psychosis) and dopamine agonist. This is particularly useful knowledge because it is also known that schizophrenia is a highly dopaminergic system. 

To play off the knowledge of the knowns about schizophrenia, scientists at the University of Wales College of Medicine, tested to see what two psychotogenic drugs, LSD and PCP, do to the levels of AADC  mRNA levels in rats. LSD and PCP are two known hallucinogenic drugs but they are considered non-dopaminergic, as LSD affects serotonin levels and PCP affect many neurotransmitters but mainly glutamate. The reason why these two drugs were chosen is because they are used as schizophrenia models in animals but they both have different structures and different pharmacologies.

In this study, however, it was shown that both LCD and PCP have small effects on AADC gene expression, with LCD acting as a probe for exon 8. The mechanism of the up-regulation of AADC mRNA is unclear for both of these drugs but the mRNA change patterns for both of the drugs is really similar. This study does further prove that using these drugs could cause the expression of the gene that codes for AADC and in turn produces 2PE, but the evidence in this study was not statistically significant. In humans there are two alternative exons at the 5' non-coding region of the gene one being predominate and lacks exon 3 causing it to be short 38 amino acids and does not catalyse the conversion of DOPA into dopamine. This shorter form could be the cause of phenylalanine converting to 2PE. Since rats do not experience schizophrenia then this primary version of the gene might not exist or exist in such small quantities that caused the statistical insignificance. There might have to be other types of studies that would have to be tested on individuals that actually use these drugs or other animals that experience schizophrenia to get statistically important results. 

Genes Associated with Human Interaction in Dogs

We have all heard the phrase that says dogs are a man's best friend. In many people's opinion dogs are the superior pet because they have the ability to be trained, while cats know what you are saying but they honestly do not care. Over their evolution, domestic dogs have developed social skills that allow them to communicate and cooperate with humans and even pick up on when "their" human is emotional. Even puppies seem to have this cognitive ability to process human communication; this makes scientists question that this might have a genetic basis. Persson et al. used this concept and a genome wide association study in beagles to map the genes that are responsible for their superior social skills.




One hundred and ninety laboratory beagels' genomes were mapped using an HD Canine SNP-chip and then given a device that they could manipulate to get treats. The first two were fairly easy to get but the third was one difficult and this made them seek out a human for assistance. Five possible genes on chromosome 26 were then identified that were associated with their social skills with humans. These genes are the first possible genes that corroborate that there is a genetic basis in human socializing in dogs meaning that this socialization happened over the course of their domestication and evolution.




Another interesting finding is that one of the possible genes, SEZ6L, is the same gene that has been recently found to be associated with autism spectrum disorder and polymorphisms are responsible with bipolar disorder in humans. The polymorphism of the gene COMT is also known to be the cause of susceptibility to develop schizophrenia in humans. This same polymorphism in varying degrees was found in other dog breeds suggesting that this could be the gene responsible for regulating behaviors.


While the purpose of this research is to map the genes associated with behavioral traits in dogs, the also paper cites other studies suggesting that there are breed-dependent diseases, like heart disease and epilepsy, that suggest that dogs could be used as a model organism for human disorders. This brings me to question, how would these scientists use dogs as a model for understanding disease progression and mental health disorders? Would they induce the disease process by genetic modification like they do for mice, who have shorter gestation periods and life spans? What do you think about this new information?


Reference: http://www.nature.com/articles/srep33439

Twins on Trial

When someone hears of twins, their mind usually flies right to the thought of two individuals that look alike and 50% of the time you would be right. There are two different types of twins: fraternal and identical. Fraternal twins are what you would call dizygotic twins. This means during fertilization there were two eggs produced and fertilized. These twins develop within separate placentas and usually come out looking different. On the other hand identical twins, or monozygotic twins, happen when one egg is fertilized and splits into two embryos. These twins share the same placenta and are born exact replicas.

Now with this information in mind, let's bring it down to a more molecular level. Monozygotic twins share the exact set of DNA since they are in a sense replicas of one another while fraternal twins have their own specific set of DNA. So with all the fun things that happens to our DNA throughout our lifetime, DNA methylation is really neat. This is the process when DNA methyltransferase (pretty neat name because it literally gives you a hint for what I'm about to say it does) adds a methyl group on the 5' position of the pyrimidine ring of the cytosine nucleotide. This methylation usually only occurs when there is a cytosine followed by a guanine. You might be familiar with the term CpG sites. Methylation is a cool process that usually affects the nature of a gene; it acts like a switch to turn active genes off or, during stem cell differentiation, methylation helps guide the stem cell to become a certain type of cell based on the methylation pattern. In mammals, this methylation happens pretty uniformly but the patterns can be variable from person to person based on the different environments we have encountered throughout our lifetime.

I probably have you asking by now what does methylation have to do with twins, well my friend, CRIME. We have always been told that if a biological sample is found a scene that holds DNA that that DNA can be sequenced and a suspects DNA can be sequenced to form a match with a high statistical probability. While this is true, it isn't so much true in the instances where monozygotic twins are involved for obvious reasons. Researchers have thought of a sort of solution, while it isn't perfect and there is a lot of testing to be done, of taking a look at not only the DNA but of the DNA methylation patterns to differentiate between the two individuals. The study is based on the principle that the methylation patterns will be different because the two individuals, even though they are twins, could have experienced different environmental stimuli at one time or another in their lifetime.

Using melt curve analysis Stewart et al. tested this hypothesis at the Alu sites of 5 sets of monozygotic twins. Alu sites are highly conserved throughout the human species and they are what you would call a short interspersed nuclear element meaning that they are about 300 nucleotides long and the nucleotides are in a repeated sequence (these sites are commonly mutated because of the repetition). Even though this method seems pretty solid, it is very variable. One set of twins did show a large differentiation between their methylation patterns while the others showed subtle or no differences. Age and environmental stimuli play a huge role for the success of using this kind of study. While the test itself is relatively cheap, the results might not be substantial for the use in a court of law. If anything, it could be used as a preliminary test before moving on to the more expensive mutation tests in a forensic laboratory. I believe that this there are other sites that could be tested for the differences in methylation that might yield more substantial results. On the other hand, a larger pool of twins might need to be used in order to get a truer result.

For further reading: http://www.sciencedirect.com/science/article/pii/S0003269715000500

Feet and the GDF6 Gene

Feet. No one talks about them because honestly, they are kind of gross. For humans, having feet is an advantage, our big toe especially, because without them we wouldn't be able to walk normally. Bipedalism has thought to have occurred because of the formation of our big toe throughout the evolution of humans. So what may have caused the creation of the big toe in our earlier ancestors?

Bone morphogenic proteins are molecules that control the formation of bones and joints during development. These proteins have been suspected to be the cause of evolving new structures while preserving the function of old structures. By first looking at the drastic differences in the freshwater and salt-water species of stickleback fish using genetic mapping of skeletal traits, Indjeian and his colleagues were able to find that cis-acting increase of the Growth/Differentiation Factor 6 was involved in the difference in amor plates in these fish, meaning that the freshwater species shows smaller plate size as they evolved due to the increase of GDF6. Smaller plate size has benefitted the freshwater species by facilitating in faster bursts when swimming but what does this have to do with the evolution of bipedalism in humans?

As humans evolved, multiple changes were made to benefit the species. For example, as locomotion started for humans, the hindlimb toes started to shorten and the strengthening of the first digit, our big toe. It was shown that the GDF6 gene is responsible for normal growth of the digits and the expression decreases as it moves away from the first digit, that is why our other toes are so much smaller than our big toe. This gene is also responsible for skull sutures and eye development. Deletion of a region-specific enhancer allowed this gene to alter the structure of the hindlimbs over time to adapt to the ever-changing environment without negatively impacting forelimb development. This enhancer deletion is human-unique as it is still prevalent in primates and other mammals. 

For further reading: Indjeian, Vahan B., Garrett A. Kingman, Felicity C. Jones, Catherine A. Guenther, Jane Grimwood, Jeremy Schmutz, Richard M. Myers, and David M. Kingsley. "Evolving New Skeletal Traits by Cis-Regulatory Changes in Bone Morphogenetic Proteins." Cell 164.1-2 (2016): 45-56. Web.

Methylation Markers Used to Identify Body Fluids

Each individual has their own unique genetic fingerprint and in the instance a crime has occurred, this genetic fingerprint can be useful in identifying perpetrators or even link victims to the original crime scene in an instance that the body was moved. The journal article Methylation Markers for theIdentification of Body Fluids and Tissues from Forensic Trace Evidence poses the question if there are specific methylation markers on DNA that can identify with positivity what type of bodily fluid is present at a crime scene and if exogenous or endogenous factors skew the methylation.

I found this research interesting because it was one of the first to actually take into account the exogenic and endogenic changes that body fluids come into contact with at a crime scene. The study's goals were to describe an epigenetic marker set using methylation on regions of DNA where a cytosine nucleotide is followed by a guanine nucleotide (CpG sites) for venous blood, menstrual blood, vaginal fluid, saliva, and sperm. These body fluids were chosen specifically because they are the most prevalent at a crime scene. Their hypothesis stated that because many methylated loci are involved in cell-specific gene expression, quantifying the degree of methylation at these positions could identify a cell line with accuracy.

Within the research Forat et al. tested different variables that the body fluid could undergo at a crime scene and their effects on the methylation by first finding reciprocal marker loci. This means that they wanted to find loci for which the target body fluid was unmethylated while the remaining fluids' loci were methylated. After the markers were located, the body fluids were placed in sample environments: dry on room temperature, wet in an exsiccator, outside on the ground. Each sample was tested after 1, 2, 3, and 6 months.

The discrimination power of these markers are very high because in all cases there is at least 1 marker for each kind of fluid and they show no overlap distribution of methylation rates compared to each fluid. Thus showing that each of the body fluids can be positively identified using the method explained in the article. The researchers even went on in explaining influences that made the results less clear. A large example was that tumors have an effect on the methylation patterns in women with cervix cancer.

This research is significant in the field of forensic science because it moves away from using RNA to identify body fluids since RNA is less stable in a variety of different conditions. Another surprising result was that each time a body fluid was examined, even when the body fluids were mixed, the method identified the fluids 100% of the time.