L7 Bioinformatics

• Bioinformatics: scientific sub discipline that involves using computer tech to collect, store, analyze biological data. interdisciplinary field.
• Kerendia (fineronone)- Bayer (selective, non steroidal mineralocorticoid receptor antagonists).

  function use: chronic kidney disease from type 2 diabetes

  microalbuminuria: increased levels of the urinary albumin to creatinine ratio. early sign of chronic kidney disease
• NR3C2: gene encodes the mineralocorticoid receptor.

  kerendia blocks the MR, reduces the risk of CDK and slows CKD from getting worse.
• software tools:

  sequence alignment tools (BLAST, CLUSTALW)

  function analysis tools (GEO, pathway tools)

  image analysis software

  clinical tools (oracle)
• sequence alignment: process of comparing and detecting similarities between biological sequences
• how to determine if a seq is a part of a protein coding gene: align to reference genome

  how to determine whether a new seq has a strong similarity to known gene/protein: predict protein structure

  how to determine whether seq from dif organisms are homogenous: trace evolutionary relationships
• alignment: task of locating equivalent regions of two or more sequences to maximize
• sequence similarity: the degree of likeness between 2 sequences, calculated by comparing the number of identical and different bases

  homology: similarity in sequence or structure specifically due to descent from a common ancestor

  homologous genes: genes derived from the same ancestral gene. during evolutionary history, they will have diverged in sequence as a result of dif mutations. high degree of similarity implies homology
• What is the minimum percentage identify that can reasonably be accepted as significant?

  30% sequence identity is generally taken as the threshold for an initial presumption of homology

  20-30% is the twilight zone.

  homology may exist but cant be reliably assumed in absence of other evidence
• Conserved sequences: identical seq in nucleic acids or a.a across species or within a genome ; can be used to find out genetic anomalies that arise as a result of changes in conserved sequences
• within a sequence, amino acids that are important for folding or that form a binding site may be more highly conserved.
• RAS mutations in highly conserved regions (meaning its necessary and important) would give rise to many cancer types.
• Lumakras(sotorasib)-originally developed as a KRAS(G12C) inhibitor. metastatic non-small cell lung cancer
• ortholog gene: gene in different species that evolved from a common ancestor. Normally they retain the same function in the course of evolution. 

  paralog: genes present in a particular organism that are related to each other through a gene duplication event.

  analog : unrelated genes in different species with separate evolutionary origin but similar functions.
• sequence similarity searching: method of searching sequence databases by using alignment to a query sequence
• Basic Local Alignment Search Tool (BLAST): the Google of biological research. an algorithm/program for comparing biological sequences. enables a researcher to compare a subject protein or nucleotide sequence (query) with a library or a database of sequences

  
  

  uses- identifying species, domain searching, phylogeny, dna mapping to known chromosome, comparison
• Blast query sequences format?

  FASTA
• Clustal Omega (Clustal W): multiple sequence alignment program for aligning 3+ sequences together in a computationally efficient and accurate manner. produces biologically meaningful multiple sequence alignments of divergent sequences. Evolutionary relationships can be seen via viewing cladograms or phylograms. ex. phylogenetic tree
• MSA(multiple sequence alignment) analysis is done to?

  • find phylogenetic relationship between more than 2 sequences
  • find when and where those sequences diverged from each other
  • help in finding mutated region in the sequence of same protein or nucleotide found in different species
  • assign a putative function to a novel sequence by comparing it with other sequences (if the sequence is known)
• Biomedical image-based analysis is the use of medical images to diagnose, monitor, and treat disease.
• Biomedical images

  • body measurements (micro and macro scope), measure physical property, interpreted by domain experts (radiologists), large impact on decisions of Dr.s

  Computer-aided image analysis (SO COOLL)

  • automatically analyze biomedical images
  • identify disease associated screenable phenotypes
  • understand disease mechanisms
  • predict drug's activity, toxicity/MOA
• image-based profiling

  • healthy and diseased pt. cell lines
  • drugs/genetic perturbations
  • high-throughput staining and imaging: cell painting assay
  • image analysis and feature extraction
  • morphological profiles
  • downstream analysis: mapping relationships
• cell image analysis software

  • reads microscopy images
  • generates quantitative measurements (size, morphology, intensity, texture)
• mutation detection using image-based analysis: image-based analysis is a technique that uses image processing to detect mutations in DNA. advantageous in settings when tumor tissue is limited or unavailable for direct testing. important for choosing therapy.
• disease detection from retinal images: diagnostic device IDx-DR (cool)

  1st FDA approved medical device that uses AI to detect a mild level of diabetic retinopathy. elevated blood sugar levels can damage the delicate blood vessels in the retina, the light-sensitive layer at the back of the eye. most common cause of vision loss among diabetic pts. *provides a screening decision without the need for a clinician to interpret the image or results. usable for non eye drs.
• pharmacogenomics: a field of medicine that investigates how a person's genetic makeup may affect how their body processes certain medications. role in identifying responders and non responders to medications, avoiding adverse events, optimizing drug dose. (EVERYONE RESPONDS TO MEDICATIONS DIFFERENTLY, DEPENDS ON GENETIC MAKEUP)
• genomic biomarkers: genetic markers that can be used to diagnose or predict disease.

  
  

  drug labeling

  • drug exposure and clinical response variability
  • risk for adverse events
  • genotype-specific dosing
  • MOA
  • trial design features
  • polymorphic drug target and disposition genes
• drug biotransformation (metabolism) = the metabolic breakdown of drugs within the organism. it gives metabolites with physicochemical and pharmacological properties that differ significantly from those of a parent drug. safety and efficacy. predict toxicity and metabolic conversion of compounds
• QSAR (quantitative structure-activity relationship): assumes that molecules with similar structures exhibit similar chemical and biological activities. employs- experimental dataset, chemical/physical features, statistical methods
• machine learning in QSAR: accelerates the process of scanning and filtering out ineffective compounds. reduces significant time and cost compared with experimental screening methods
• sequence alignment : helps identify homologous genes or conserved regions within protein sequences
• 2 types of sequence alignment programs : clustalW and BLAST
• bioinformatics: helps predict drug toxicities and effectiveness. scientific field that provides tools for managing large datasets and computational approaches that accelerate drug discovery and advance medical care