Abby Pelletier
aep1019@wildcats.unh.edu
University of New Hampshire - Manchester

ABSTRACT:
In this experiment, the SERPINA1 gene and Alpha-1 Antitrypsin protein for humans were analyzed and compared to those of other animal species, including gorilla, baboon, macaque, mouse, dog, etc. Blast, Mega, phylogenic tree, and 3D modeling tools were used to compare and determine which species were most related. Both the gene and the protein phylogenic trees followed similar patterns, with the pan tronglodytes, pan paniscus, humans, gorilla, pongo abelii, and nomascus leucogenys forming a clear group at the top of each tree. The chlorocebus sabeus was clearly the out-group on the nucleotide tree, and the microcebus murinus was clearly the out-group on the protein tree, both forming their own branches, respectively. The nucleotide tree showed high phylogenic similarity with values as high as 100%, but it also showed very low phylogenic similarity with values as low as 41% and 53%. The protein tree showed relatively high phylogenic similarity with values ranging from 62% to 99%. The 3D models were relatively similar with the Swiss model show greater detail than the UniProt model. Ultimately, the phylogenic tree results were as expected and showed consistency across species for how the SERPINA1 and gene and A1AT protein were expected to perform.

BACKGROUND:
-->Alpha-1 antitrypsin deficiency (ATD) is an autosomal recessive disease.
Autosomal_recessive_EN.svg.png
-->ATD is the most common genetic cause of liver and lung disease affecting 3.4 million worldwide (Campbell et al., 2007). In addition, another 116 million carry at least one abnormal A1AT allele (Campos et al., 2014).

-->Produced in the liver, A1AT circulates as an anti-protease to regulate enzymatic tissue damage caused by leukocyte-derived peptidases (Haq et al., 2015). When lacking, this serine protease inhibitor leads to uninhibited proteolytic destruction of connective tissue (Campbell et al., 2007). This often leads to liver disease, emphysema, or COPD, because the lack of circulating inhibitor permits excessive pulmonary inflammation and uncontrolled proteolytic degradation of the portion of the lungs responsible for gas exchange (Haq et al., 2015).
Conditions_associated_with_Alpha-1_Antitrypsin_Deficiency.png

-->ATD is caused by a gene mutation, on the SERPINA1 gene, leading to a defective A1AT protein (Campbell et al., 2007).gastroenterology-pancreatology-liverdisorders13-g004.gif
-->The A1AT protein is coded for on chromosome 14q31-32.3 of SERPINA1 (Matamala et al., 2017), and the deficiency is caused by a single base pair mutation that results in a lysine for glutamate substitution (Wilson et al., 2015).Human_chromosome_14_-_400_550_850_bphs.png
-->Over 120 mutations of the SERPINA1 gene are known (Haq et al., 2015), the M allele is normal, but the S and Z mutations are the two (2) documented to cause ATD, with the Z allele being the most common (Long et al., 2014).Misfolding, polymerization, and defective secretion of functional alpha-1 antitrypsin underlies the predisposition to sever liver and lung disease in alpha-1 antitrypsin deficiency (Haq et al., 2015).The M is the wild type, and S & Z are the most common deficiencies (Donato et al., 2015).The M allele produces normal levels of alpha-1 antitrypsin secretion, the S allele produces moderate levels, the Z allele produces low levels, and two (2) copies of the Z allele produce very low or no ATT levels (Parrott et al., 2016).The Z mutation delays folding and impairs secretion of the A1AT protein, which causes polymerization and aggregation of the protein (O’Reilly et al., 2014).
MSZ Alleles.PNG
-->The classical form of ATD causes lung and liver disease (Long et al., 2014).The classical form of ATD with low levels of A1AT predisposes adults to emphysema (O’Reilly et at., 2014).ATD is the most well characterized genetic risk factor for developing chronic obstructive pulmonary disease (COPD) (Campos et al., 2014).Early detection is crucial to apply effective preventive measures and early institutions of therapy for emphysema and COPD patients(Campos et al., 2014).normal vs A1AT.jpg

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