Down+Syndrome+Data+Analysis

=Data Analysis =

Phylogenetic Analysis
Genetic analysis of the Down Syndrome Critical Region 3 across several mammalian species demonstrates that it is common outside of the human species. The DSCR3 phylogenetic tree demonstrates several groupings of mammals with the DSCR3 gene. Humans are most closely related to the Sumatran Orangutan as well as the Orca Whale and the Bactrian Camel. The alignment of these genes demonstrated few gaps between them as well as high amino acid similarity, demonstratinsfg a fair ClustalW alignment. The protein UPGMA tree does not meet the criteria for a reliable tree due to low bootstrap values. These proteins are translated from the same DSCR3 genes used in the gene phylogenetic tree. The hypothetical Human II protein is an outgroup, because it is hypothetical. The Muscle alignment demonstrates many similarities between each protein sequence with no large gaps and all sequences are approximately 250 Amino Acids long. This alignment demonstrated a different grouping of mammals where the Shew is more closely related to the Bactrian Camel rather than the Prairie Vole. The difference in phylogenetic mapping concludes that the protein likeliness is different compared to their genetic likeliness. This information could be useful when determining how these species could potentially develop Down Syndrome. These differences could also produce different types of phenotypes varying on genetic makeup. For example, a Prairie Vole, Shrew and Bactrian Camel could all have a genetic makeup that causes Down Syndrome, but due to the closer protein similarity between the Shrew and the Bactrian Camel, their phenotype for Down Syndrome may be expressed differently than that of the Prairie Vole.

STRING and PDB Analysis
The STRING tool demonstrated an interesting relationship between the DSCR protein interactions compared to the APP relationships. Although both proteins are found on the 21st chromosome, neither of them demonstrate relationships with common proteins. When the DSCR and the APP proteins were entered into the STRING tool to analyze their relationship, STRING provided a diagram that showed no web or line between them. This information is interesting when analyzing the relationship between Down Syndrome and Alzheimer's Disease considering these are the main proteins that contribute to both of these diseases. The PDB 3D models provide a visual representation of both the DSCR and APP proteins which is useful for understanding their role in transcription or gene dosage effects.

=Research Conclusions =

**What genes and proteins are responsible in Down Syndrome patients for early onset Alzheimer's Disease? **
There are many genes involved in Down Syndrome because it is caused by the triplication of the 21st chromosome, therefore all the genes and proteins located on the 21st chromosome contribute in some way to Down Syndrome. The Down Syndrome Critical Region (DSCR) and the Down Syndrome Cell Adhesion Molecule (DSCAM) are the only ones named after the disease specifically. DSCR is the gene mainly responsible for the development of mental retardation and physical morphology. It is also important to note that the analysis of this gene was through the genomic investigation of individuals with trisomy 21 (Toyoda et al., 2002). DSCAM contributes to the development of the human central and peripheral nervous system. The beta-site APP-cleaving enzyme (BACE) is an important gene in the relationship between Alzheimer's and Down Syndrome. The NCBI summarizes it as an important step in the development of Alzheimer's as well as Down Syndrome. It cleaves the amyloid precursor protein (APP) into the amyloid beta mature peptide. This process contributes to the formation of the amyloid-beta plaques present in individuals with Down Syndrome, thus causing Alzheimer's Disease (Wilcock and Griffin, 2013). APP does not interact directly with the DSCAM or DSCR genes (as demonstrated by the STRING tool), but its relationship with BACE does make sense for early onset Alzherimer's Disease. The triplication of the 21st chromosome increases the quantity of all the genes compared to an individual with only two of the 21st chromosome, including the BACE gene. Due to the higher concentration of this gene, it is possible that more amyloid-beta precursor proteins are transformed into plaques much faster than the average individual and causes Alzheimer's earlier in life. Cytoskeletal proteins are also an important factor that contributes to the neuropathogenesis of Alzheimer's Disease in Down Syndrome (Letourneau & Antonarakis, 2012). Other pathogenic factors have also been predicted to explain this relationship that could be a subject of further research.

**What genes are responsible for the different phenotypes of Down Syndrome? **
The different phenotypes of Down Syndrome are unique to every individual with Down Syndrome. One individual may experience low blood pressure, hearing loss as well as a higher risk of Leukemia while another may experience high blood pressure and only mild intellectual disablement. The 21st chromosome makes up only 1.5% of the human genome and its gene content is fairly relative to its small size. However, it does include many of the genes responsible for important transcription factors that contribute to the different expression variability in Down Syndrome. It is also important to consider what genes are prone to dosage sensitivity which causes over or under expression of certain genes on the 21st chromosome. Every individual, with or without Down Syndrome, has a unique genome of their own (Letourneau & Antonarakis, 2012). A huge contributing factor to these difference is due to single nucleotide polymorphisms (SNPs). This has also been determined to be a main factor to the different Down Syndrome phenotypes. The most conclusive and widely accepted hypothesis for the different Down Syndrome phenotypes is due to the dosage-sensitive genes which are unique to every individual. Certain genes are more sensitive in one individual compared to another which will result in a difference of phenotype. The genes essentially responsible for these Down Syndrome phenotypes can not be pinpointed to any specific gene, but rather the whole 21st chromosome (Lockstone et al., 2007). Due to the trisomy, it is expected that the gene would be 1.5 times more expressed. It has been determined that how much these genes are expressed is largely due to the dosage effect for each gene depending on each individual. Further research could include researching the genes that are affected most commonly by dosage effects and if certain gene dosage effects cause affect the phenotype of another gene that may not be affected by dosage effects.

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