Cell and Developmental Biology Commons^™

Keratin Gene Expression Profiles After Digit Amputation In C57bl/6 Vs. Regenerative Mrl Mice Imply An Early Regenerative Keratinocyte Activated-Like State, Chia-Ho Cheng, John Leferovich, Xiangming Zhang, Khamilia Bedelbaeva, Dmitri Gourevitch, Cathy J. Hatcher, Craig T. Basson, Ellen Heber-Katz, Kenneth A. Marx

PCOM Scholarly Works

Mouse strains C57BL/6 (B6) and MRL were studied by whole mouse genome chip microarray analyses of RNA isolated from amputation sites at different times pre-and postamputation at the midsecond phalange of the middle digit. Many keratin genes were highly differentially expressed. All keratin genes were placed into three temporal response classes determined by injury/preinjury ratios. One class, containing only Krt6 and Krt16, were uniquely expressed relative to the other two classes and exhibited different temporal responses in MRL vs. B6. Immunohistochemical staining for Krt6 and Krt16 in tissue sections, including normal digit, flank skin, and small intestine, and from normal …

The Bio-Nano-Interface In Predicting Nanoparticle Fate And Behaviour In Living Organisms: Towards Grouping And Categorising Nanomaterials And Ensuring Nanosafety By Design, Hugh Byrne, Arti Ahluwalia, Diana Boraschi,, Bengt Fadeel, Peter Gehr, Arno C. Gutleb, Michaela Kendall, Manthos Papadopoulos, Iseult Lynch

Articles

In biological media, nanoparticles acquire a coating of biomolecules (proteins, lipids, polysaccharides) from their surroundings, which reduces their surface energy and confers a biological identity to the particles. This adsorbed layer is the interface between the nanomaterial and living systems and therefore plays a significant role in determining the fate and behaviour of the nanoparticles. This review summarises the state of the art in terms of understanding the bio-nano interface and provides direction for potential future research directions and some recommendations for future priorities and strategies to support the safe implementation of nanotechnologies. The central premise is that nanomaterials must …

Cancer Quasispecies And Stem-Like Adaptive Aneuploidy, Domenico Napoletani, M. Signore, Daniele C. Struppa

Mathematics, Physics, and Computer Science Faculty Articles and Research

In this paper we develop a theoretical frame to understand self-regulation of aneuploidy rate in cancer and stem cells. This is accomplished building upon quasispecies theory, by leaving its formal mathematical structure intact, but by drastically changing the meaning of its objects. In particular, we propose a novel definition of chromosomal master sequence, as a sequence of physically distinct whole or fragmented chromosomes, whose length is taken to be the sum of the copy numbers of each whole or fragmented chromosome. This fundamental change in the functional objects of quasispecies theory allows us to show that previously measured aneuploidy rates …

Menthol Binding And Inhibition Of A7-Nicotinic Acetylcholine Receptors, Abrar Ashoor, Jacob C. Nordman, Daniel Veltri, Keun-Hang Susan Yang, Lina T. Al Kury, Yaroslav M. Shuba, Mohamed Magoub, Frank Christopher Howarth, Bassem Sadek, Amarda Shehu, Nadine Kabbani, Murat Oz

Mathematics, Physics, and Computer Science Faculty Articles and Research

Menthol is a common compound in pharmaceutical and commercial products and a popular additive to cigarettes. The molecular targets of menthol remain poorly defined. In this study we show an effect of menthol on the α7 subunit of the nicotinic acetylcholine (nACh) receptor function. Using a two-electrode voltage-clamp technique, menthol was found to reversibly inhibit α7-nACh receptors heterologously expressed in Xenopus oocytes. Inhibition by menthol was not dependent on the membrane potential and did not involve endogenous Ca2+-dependent Cl− channels, since menthol inhibition remained unchanged by intracellular injection of the Ca2+ chelator BAPTA and perfusion with Ca2+-free bathing solution containing …

Facilitation Of Electroporative Drug Uptake And Cell Killing By Electrosensitization, Olga N. Pakhomova, Betsy W. Gregory, Andrei G. Pakhomov

Bioelectrics Publications

Cell permeabilization by electric pulses (EP), or electroporation, is widely used for intracellular delivery of drugs and plasmids, as well as for tumour and tissue ablation. We found that cells pre-treated with 100-mus EP develop delayed hypersensitivity to subsequent EP applications. Sensitizing B16 and CHO cells by splitting a single train of eight 100-mus EP into two trains of four EP each (with 5-min. interval) decreased the LD(50) 1.5-2 times. Sensitization profoundly enhanced the electroporation-assisted uptake of bleomycin, a cell-impermeable cytotoxic agent accepted for killing tumours by electrochemotherapy. EP exposures that were not lethal per se caused cell death in …

Induction Of Cell Death Mechanisms And Apoptosis By Nanosecond Pulsed Electric Fields (Nspefs), Stephen J. Beebe, Nova M. Sain, Wei Ren

Bioelectrics Publications

Pulse power technology using nanosecond pulsed electric fields (nsPEFs) offers a new stimulus to modulate cell functions or induce cell death for cancer cell ablation. New data and a literature review demonstrate fundamental and basic cellular mechanisms when nsPEFs interact with cellular targets. NsPEFs supra-electroporate cells creating large numbers of nanopores in all cell membranes. While nsPEFs have multiple cellular targets, these studies show that nsPEF-induced dissipation of DeltaPsim closely parallels deterioration in cell viability. Increases in intracellular Ca2+ alone were not sufficient for cell death; however, cell death depended of the presence of Ca2+. When both events occur, cell …

Regulation Of The Glycine Transporter 1 (Glyt1) By Pkca-Dependent Ubiquitination, Susana Barrera

Open Access Theses & Dissertations

Glycine is one of the major inhibitory neurotransmitters in the central nervous system. It is implicated in the regulation of motor-sensory function such as; pain perception, reflex responses, and is essential for early development of the CNS. In addition to its inhibitory actions, it acts as an obligatory co-agonist for the activation of glutamatergic NMDARs, which are of pivotal importance in the process of learning and memory, its dysfunction leads to several neurodegenerative diseases. Two high affinity Na+/Cl- dependent transporters GlyT1 and GlyT2 tightly regulate the availability of glycine present at the synapse for the activation of NMDARs and GlyRs. …

Comparison Of Ectoparasitic Mite Loads Between Gonochoristic (Aspidoscelis Marmorata) And Parthenogenic (A. Tesselata) Syntopic Whiptail Lizards (Teiidae) From The Northern Chihuahuan Desert Of Trans-Pecos, Texas, William Dawson Lukefahr

Open Access Theses & Dissertations

The objective of this study was to compare the ectoparasitic loads between two syntopic whiptail lizard species (Teiidae) that differ in their reproductive modes; Aspidoscelis marmorata (bisexual) and A. tesselata (unisexual). The study site was located on Indio Mountains Research Station (IMRS) in a Chihuahuan Desert Scrub landscape in Hudspeth County, Texas. Previous studies conducted at IMRS showed the two species having similar diets, morphology, and reproductive characteristics, but fluctuated in nematode loads. No comparative study of ecotoparasitic mites (Eutrombicula alfreddugesi) between the two species has ever been done.

Aspidoscelis marmorata (n = 141) and A. tesselata (n = 144) …

Novel Copper (Ii) Mediated Transfection Nano-Systems And Biological Properties Of Pyridinium Surfactants, Sarit Pal

Open Access Theses & Dissertations

Efficacy of gene therapy is relied upon the improvement of gene delivery vectors into mammalian cells. Although viral-based polynucleotide carriers are still considered as the most common method for gene delivery but the cost effectiveness, nonspecific lethal immune response has evoked the renaissance of non-viral synthetic delivery systems. An initial discovery by Felgnar et al showed Cationic Liposomes (CLs) (having an overall positive charge) when mixed with DNA to form CL-DNA complexes can enhance the transfer of polynucleotides into cells followed by its expression. Presently, a flurry of experimental works is taking place for the better understanding of structural characterization …

A Novel Fkbp52/Β-Catenin Complex Specifically Regulates Androgen Receptor Activity, Cheryl Lynne Storer

Open Access Theses & Dissertations

The androgen receptor complex plays an essential role in prostate cancer progression due to exploitation of the androgen receptor (AR) as a transcription factor. The final stage of the receptor complex consists of a dimerized receptor, a dimeric heat shock protein (Hsp90), the cochaperone p23, and an immunophilin. Hormone-dependent prostate cancer progresses due to key interactions between the androgen receptor complex and its ligand α dihydrotestosterone (DHT). While current treatments focus on blocking the androgen receptor-ligand interactions, these therapies are no longer effective in advanced stage, hormone-refractory prostate cancer (HRPC).

Therefore, we have been interested in targeting other members of …

Large Scale Matrix Degradation By Stromal Cells Independent Of Invadopodia, Hong Cao, Robbin Eppinga, Eugene W. Krueger, Jing Chen, Mark A. Mcniven

Faculty Work Comprehensive List

Invadopodia are actin-rich structures at the base of many neoplastic cells that sequester matrix metalloproteases that act to degrade the surrounding stroma to facilitate the invasive process. Conventional invadopodia are dependent upon Src kinase and the large GTPase dynamin 2 (Dyn 2). Whether invadopodia are the only mechanism by which cells degrade matrix is unclear. We have observed that cells of mesenchymal origin degrade matrix in an unique way different from tumor cells. The HYPOTHESIS of this study is that fibroblasts, and other cells of mesenchymal origin, degrade matrix by a mechanism distinct from that of epithelial-based tumor cells. The …

Vegf And Angiopoietin-1 Exert Opposing Effects On Cell Junctions By Regulating The Rho Gef Syx, Siu P. Ngok, Rory Geyer, Miaoliang Liu, Antonis Kourtidis, Sudesh Agrawal, Chuanshen Wu, Himabindu Reddy Seerapu, Laura J. Lewis-Tuffin, Karen L. Moodie, Deborah Huveldt, Ruth Marx, Jay M. Baraban, Peter Storz, Arie Horowitz, Panos Z. Anastasiadis

Dartmouth Scholarship

Vascular endothelial growth factor (VEGF) and Ang1 (Angiopoietin-1) have opposing effects on vascular permeability, but the molecular basis of these effects is not fully known. We report in this paper that VEGF and Ang1 regulate endothelial cell (EC) junctions by determining the localization of the RhoA-specific guanine nucleotide exchange factor Syx. Syx was recruited to junctions by members of the Crumbs polarity complex and promoted junction integrity by activating Diaphanous. VEGF caused translocation of Syx from cell junctions, promoting junction disassembly, whereas Ang1 maintained Syx at the junctions, inducing junction stabilization. The VEGF-induced translocation of Syx from EC junctions was …

Long-Term Depression Of Excitatory Inputs To Gabaergic Neurons In The Ventral Tegmental Area, Philip J. Sandoval

Theses and Dissertations

Dopamine cells within the ventral tegmental area of the brain are involved in motivation and reward. Drugs of abuse target these dopamine cells altering their activity and plasticity resulting in addiction. While dopamine cell activity is primarily involved in addiction, the GABA neurons in the VTA have also been shown to have an indirect role. By decreasing the activity of the inhibitory GABA inputs onto dopamine neurons abusive drugs can indirectly increase dopamine cell activity resulting in addictive behaviors. However, although GABA neurons are important in the perception of reward, much less is known about how the excitatory inputs to …

Doublesex Target Genes In The Red Flour Beetle, Tribolium Castaneum, Jayendra Nath Shukla, Subba Reddy Palli

Entomology Faculty Publications

Sex determination cascade in insects terminates with the production of sex-specific protein, Doublesex (Dsx). We identified the dsx homolog (Tcdsx) in Tribolium castaneum. The pre-mRNA of Tcdsx is sex-specifically spliced into three female (Tcdsxf1, Tcdsxf2 and Tcdsxf3) and one male-specific (Tcdsxm) isoforms. Cis-regulatory elements potentially involved in sex-specific splicing of the Tcdsx pre-mRNA were identified in the female-specific exon and the adjoining intronic sequences. All the three female-specific TcDsx proteins share common OD1 and OD2 domains and differ in their C-terminal sequences. Knockdown of Tcdsx resulted in a reduction in the oocyte development, egg production and hatching of eggs laid. …

Molecular Mechanisms Regulating Neonatal Oocyte Survival And Primordial Follicle Formation In The Mouse Ovary, Robin L. Jones

Biology - Dissertations

In mammals, formation of the primordial follicle is a complex process involving the breakdown of germ cell cysts, where oocytes must separate from each other and subsequently become surrounded by somatic cells. As cysts separate, a large number of germ cells are lost by apoptosis, however the mechanisms by which cyst breakdown and germ cell death occur are not well understood. We first hypothesized that two anti-apoptotic regulators from the BCL2 family of proteins, BCL2 and MCL1, may be responsible for regulating neonatal oocyte survival. To elucidate the effects of BCL2 in the neonatal ovary, we examined ovaries of both …

Early Arrest Mutant Ogre: A Defect In Cytokineis Caused By A Mutation In The Gene Racgap1, April Wicklund

Masters Theses

The early arrest mutant ogre, isolated in the Tübingen screen, has a block in cytokinesis (Kane et al., 1996). Here I use genetic and molecular techniques to demonstrate that the ogre phenotype is caused by a lesion in the gene encoding Racgap1. I performed fine mapping studies using microsatellite markers to a 0.15 cM region containing the ogre locus. DNA sequence data revealed a nonsense mutation in the Racgap1 gene of ogre mutants, and in situ hybridization experiments showed a loss of racgap1 mRNA at later stages of development, likely by nonsense mediated decay. This evidence supports the abolishment …

Biochemical Characterization Of Binding Partners Of Two Hsp70 Co-Chaperones In Saccharomyces Cerevisiae, Jacob Verghese

Dissertations and Theses (Open Access)

Cells are exposed to a variety of environmental and physiological changes including temperature, pH and nutrient availability. These changes cause stress to cells, which results in protein misfolding and altered cellular protein homeostasis. How proteins fold into their three-dimensional functional structure is a fundamental biological process with important relevance to human health. Misfolded and aggregated proteins are linked to multiple neurodegenerative diseases, cardiovascular disease and cystic fibrosis. To combat proteotoxic stress, cells deploy an array of molecular chaperones that assist in the repair or removal of misfolded proteins.

Hsp70, an evolutionarily conserved molecular chaperone, promotes protein folding and helps maintain …

A Study On The Function Of 14-3-3sigma In Regulating Cancer Energy Metabolism, Liem M. Phan, Liem M. Phan

Dissertations and Theses (Open Access)

Metabolic reprogramming has been shown to be a major cancer hallmark providing tumor cells with significant advantages for survival, proliferation, growth, metastasis and resistance against anti-cancer therapies. Glycolysis, glutaminolysis and mitochondrial biogenesis are among the most essential cancer metabolic alterations because these pathways provide cancer cells with not only energy but also crucial metabolites to support large-scale biosynthesis, rapid proliferation and tumorigenesis. In this study, we find that 14-3-3σ suppresses all these three metabolic processes by promoting the degradation of their main driver, c-Myc. In fact, 14-3-3s significantly enhances c-Myc poly-ubiquitination and subsequent degradation, reduces c-Myc transcriptional activity, and down-regulates …

Expansion Of Human Induced Pluripotent Stem Cells On Synthetic Substrate In Defined Medium, Huantong Yao

Graduate Theses and Dissertations

Human induced pluripotent stem cells (hiPSCs) have the potential to generate patient-specific cells to treat many incurable diseases by cell replacement therapy. However, so far the culture of hiPSCs depends greatly on feeder cells or Matrigel which has safety issues. Thus, chemically defined substrates that could provide niches necessary for cell attachment and proliferation are preferred for clinical application of hiPSCs. Recently, Corning Life Sciences has developed synthetic peptide-functionalized cell culture surface, referred to as Corning® Synthemax that support self-renewal and differentiation of human embryonic stem cell (hESC). In this work, we have collaborated with Corning to investigate the attachment, …

Glutaredoxin 2 (Grx2) Knockout Increases Sensitivity To Oxidative Stress In Mouse Lens Epithelial Cells, Hongli Wu, Liren Lin, Frank Giblin, Ye-Sheh Ho, Marjorie F. Lou

School of Veterinary and Biomedical Sciences: Faculty Publications

Glutaredoxin belongs to the oxidoreductase family with cytosolic glutaredoxin 1 (Grx1) and mitochondrial gluraredoxin 2 (Grx2) isoforms. Of the two isozymes, the function of Grx2 is not well understood. This paper studied the effect of Grx2 deletion on cellular function using primary lens epithelial cell cultures isolated from Grx2 gene knockout (KO) and wild type (WT) mice. We found that both cell types showed similar growth patterns and morphology, and comparable mitochondrial glutathione pool and complex I activity. Cells with deleted Grx2 did not show affected Grx1 or thioredoxin (Trx) expression but exhibited high sensitivity to oxidative stress. Under treatment …

Genetic Analysis Of The Hippo Pathway In Mouse Liver, Li Lu

Dissertations and Theses (Open Access)

Cancer therapy and tumor treatment remain unsolved puzzles. Genetic screening for tumor suppressor genes in Drosophila revealed the Hippo-signaling pathway as a kinase cascade consisting of five core components. Disrupting the pathway by deleting the main component genes breaks the balance of cell proliferation and apoptosis and results in epithelial tissue tumorigenesis. The pathway is therefore believed to be a tumor suppressor pathway. However, a corresponding role in mammals is yet to be determined. Our lab began to investigate the tumor suppression function of the potent mammalian Hippo pathway by putting floxed alleles into the mouse genome flanking the functional-domain-expressing …

Fancm And Faap24 Maintain Genomic Stability Through Cooperative And Unique Functions, Yucai Wang

Dissertations and Theses (Open Access)

Fanconi anemia (FA) is a rare recessive genetic disease with an array of clinical manifestations including multiple congenital abnormalities, progressive bone marrow failure and profound cancer susceptibility. A hallmark of cells derived from FA patients is hypersensitivity to DNA interstrand crosslinking agents such as mitomycin C (MMC) and cisplatin, suggesting that FA- and FA-associated proteins play important roles in protecting cells from DNA interstrand crosslink (ICL) damage. Two genes involved in the FA pathway, FANCM and FAAP24, are of particular interest because they contain DNA interacting domains. However, there are no definitive patient mutations for these two genes, and the …

Anti-Tumor Effects Of The Notch Pathway In Gastrointestinal Stromal Tumors, Amaury G. Dumont

Dissertations and Theses (Open Access)

Gastrointestinal Stromal Tumors (GIST) are sarcomas driven by gain-of-function mutations of KIT or PDGFRA. Although, the introduction of tyrosine kinase inhibitors has dramatically changed the history of this disease, evidences emerge that inhibition of KIT or PDGFRA are not sufficient to cure patients. The developmental pathway Notch has a critical role in the cell fate, regulating cell proliferation and differentiation. Dysregulation of Notch pathway has been implicated in a wide variety of cancers functioning as a tumor promoter or a tumor suppressor in a cell context dependent manner.

Given that Notch activation deregulates the morphogenesis of mesenchymal cells in …

Trim24-Regulated Estrogen Response Is Dependent On Specific Histone Modifications In Breast Cancer Cells, Teresa T. Yiu

Dissertations and Theses (Open Access)

In this dissertation, I discovered that function of TRIM24 as a co-activator

of ERα-mediated transcriptional activation is dependent on specific histone

modifications in tumorigenic human breast cancer-derived MCF7 cells. In the first

part, I proved that TRIM24-PHD finger domain, which recognizes unmethylated

histone H3 lysine K4 (H3K4me0), is critical for ERα-regulated transcription.

Therefore, when LSD1-mediated demethylation of H3K4 is inhibited, activation of

TRIM24-regulated ERα target genes is greatly impaired. Importantly, I

demonstrated that TRIM24 and LSD1 are cyclically recruited to estrogen

responsive elements (EREs) in a time-dependent manner upon estrogen

induction, and depletion of their expression exert corresponding time-dependent

effect …

Regulation Of The Heat Shock Response By Thiol-Reactive Compounds In The Yeast Saccharomyces Cerevisiae, Yanyu Wang

Dissertations and Theses (Open Access)

Cells govern their activities and modulate their interactions with the environment to achieve homeostasis. The heat shock response (HSR) is one of the most well studied fundamental cellular responses to environmental and physiological challenges, resulting in rapid synthesis of heat shock proteins (HSPs), which serve to protect cellular constituents from the deleterious effects of stress. In addition to its role in cytoprotection, the HSR also influences lifespan and is associated with a variety of human diseases including cancer, aging and neurodegenerative disorders. In most eukaryotes, the HSR is primarily mediated by the highly conserved transcription factor HSF1, which recognizes target …

Characterization Of A Novel Role For The To Usled- Like Kinase In Kinetochore Assembly And Function In Caenorhabditis Elegans, Jessica M. De Orbeta

Dissertations and Theses (Open Access)

Chromosome segregation is a critical step during cell division to avoid aneuploidy and promote proper organismal development. Correct sister chromatid positioning and separation during mitosis helps to achieve faithful transmission of genetic material to daughter cells. This prevents improper chromosome partitioning that can potentially result in extrachromosomal fragments, increasing the tumorigenic potential of the cells. The kinetochore is a protenaicious structure responsible for the initiation and orchestration of chromosome movement during mitosis. This highly conserved structure among eukaryotes is required for chromosome attachment to the mitotic spindle and failure to assemble the kinetochore results in aberrant chromosome segregation. Thus elucidating …

Tet1: A Unique Dna Demethylase For Maintenance Of Dna Methylation Pattern, Chunlei Jin

Dissertations and Theses (Open Access)

DNA methylation at the C5 position of cytosine (5-methylcytosine, 5mC) is a crucial epigenetic modification of the genome and has been implicated in numerous cellular processes in mammals, including embryonic development, transcription, X chromosome inactivation, genomic imprinting and chromatin structure. Like histone modifications, DNA methylation is also dynamic and reversible. However, in contrast to well defined DNA methyltransferases, the enzymes responsible for erasing DNA methylation still remain to be studied. The ten-eleven translocation family proteins (TET1/2/3) were recently identified as Fe(II)/2-oxoglutarate (2OG)-dependent 5mC dioxygenases, which consecutively convert 5mC into 5-hydroxymethylcytosine (5hmC), 5-formylcytosine and 5-carboxylcytosine both in vitro and in mammalian …

Reactive Oxygen Species Mediated Dna Damage In Human Lung Alveolar Epithelial (A549) Cells From Exposure To Non-Cytotoxic Mfi-Type Zeolite Nanoparticles, Kunal Bhattacharya, Pratap Naha, Izabela Naydenova, Svetlana Mintova, Hugh Byrne

Articles

Increasing utilization of engineered nanoparticles in the field of electronics and biomedical applications demands an assessment of risk associated with deliberate or accidental exposure. Metal based nanoparticles are potentially most important of all the nanoparticles in terms of health risks. Microporousalumino-silicates and pure silicates named as zeolites and zeo-type materials with variety of structures, chemical compositions, particle sizes and morphologies have a significant number of industrial uses such as in catalysis, sorption and ion-exchange processes. In particular, the nanosized particles due to their unique properties are used in hybrid organic-inorganic materials for photography, photonics, electronics, labeling, imaging, and sensing. The …

Phenotypic Plasticity Of Rattlesnake Trophic Morphology, Matthew Thomas Smith

Graduate Theses and Dissertations

The trophic morphology of gape-limited predators constrains the shape and size of prey items they can ingest. Trophic morphology consists of any morphological feature that is involved in the handling and ingestion of food. Diet has a profound effect on the morphology of many gape-limited predators. Identifying how prey type and resource level affect the morphology of different populations is an essential step in understanding the mechanisms contributing to patterns of morphological diversity. Species interactions (Chapter 1) induce plasticity in morphology that can lead to increased fitness, morphological divergence, and eventually speciation.

In Chapter 2, a laboratory study tested the …

The Principal Genetic Determinants For Nasopharyngeal Carcinoma In China Involve The Hla Class I Antigen Recognition Groove, Minzhong Tang, J. A. Lautenberger, Xiaojiang Gao, Efe Sezgin, Sher L. Hendrickson, Jennifer L. Troyer, Victor A. David, Li Guan, Carl Mcintosh, Xiuchan Guo, Yuming Zheng, Jian Liao, Hong Deng, Michael Malasky, Bailey Kessing, Cheryl Winkler, Mary Carrington, Guy De The, Yi Zeng, Stephen J. O'Brien

Biology Faculty Articles

Nasopharyngeal carcinoma (NPC) is an epithelial malignancy facilitated by Epstein-Barr Virus infection. Here we resolve the major genetic influences for NPC incidence using a genome-wide association study (GWAS), independent cohort replication, and high-resolution molecular HLA class I gene typing including 4,055 study participants from the Guangxi Zhuang Autonomous Region and Guangdong province of southern China. We detect and replicate strong association signals involving SNPs, HLA alleles, and amino acid (aa) variants across the major histocompatibility complex-HLA-A, HLA –B, and HLA -C class I genes (P_{HLA-A-aa-site-62}= 7.4×10⁻²⁹; P _{HLA-B-aa-site-116}= 6.5×10⁻¹⁹; P _{HLA-C-aa-site-156} = 6.8×10 …