L13 - Bioinformatics

Pharmacogenomics

A field of medicine that investigates how a persons genetic makeup affects how their body processes certain medications

• iding responsers + non-responders to medications

• avoiding adverse events

• optimizing drug dose

Drug Labeling - may contain info on genomic biomarkers and can describe:

• drug exposure + clinical response variability

• risk for ADEs

• genotype-specific dosing

• MoA

• polymorphic drug target and disposition genes

• trial design features

Sequence Alignment

the process of comparing and detecting similarities between biological sequences

Applications

• detects gene expression

• predict protein structure/understand possible functions

• trace evolutionary relationships between species or within a family of proteins

Alignment is the task of locating equivalent regions of two+ sequences ato maximize their similarity

Sequence similiarity - degree of likeness between two sequences often expressed as a percentage

Alignment can reveal homology - similarity in sequence/structure due to descent from a common ancestor

• homologous genes - derived from the same ancestral gene

• diverged in sequences due to accumulation of mutations

• high degree of similarity implies high probablity of homology

• minimum % that can be reasonably accepted as significant = 30% (initial presumption of homology)

• 20-30% SId implies homology may exist but cannot be reliably assumed in the absence of other evidence

Conserved sequences - identical sequences in nucleic acids or amino acids across species or within a genome

• indicates that a sequence has been maintained by natural selection/ has important biological functions

• amino acids important for folding or forms binding sites are more highly conserved

• can be used to find out underlying genetic anomalies that arise as a result of changes in conserved sequences

Sequence analysis demonstrated the clinical effectiveness of existing drugs in diff groups of patients benefiting a broader pop.

Ortholog gene - in diff species that evolved from a common ancestor; usually retains the same func. in course of evo.

Paralog gene - present in a particular organism that are related to each other through gene dup event

analog gene - unrelated genes in diff species with separate evolutionary origins but similar functions

Sequence Similarity searching - method of searching sequence databases by using alignment to a query sequence

Basic Local Alignment Search Tool (BLAST) - a search engine for biological sequences; enables researcher to compare a subj. protein or nucleotide seq. w/ a library or database of sequences

• can be used to identify species or homologous species

• locating known domains within sequences of interest to predict the function of the protein

• establish phylogeny - can create a phylogenetic tree

• DNA mapping to a known chromosome

• comparisons

BLAST queries seq. given as character strings of single letter nucleotides or AA codes after a “>[definition line]” known as the FASTA format

Clustal Omega (ClustalW) - a multiple seq. alignment (MSA) program for aligning 3+ sequences together

• produces biologically meaningful MSA of divergent seq that showcase evolutionary relationships via cladograms/phylograms

Biomedical Image Based Analysis

Biomedical images - measurements of the body (microscopic/macroscopic)

• wide variety of imaging modalities

• measure a physical property

• interpreted by domain experts

• large impact on physician decisions

Computer-Aided image analysis - can automatically analyze images to id disease associated screenable phenotypes

• understand disease mechs

• predicts drug activity, toxicity, or moa

CellProfiler - cell image analysis software

• reads microscopy images

• generates quantitative measurements

  • size

  • morphology

  • intensity

  • texture

Deep learning analyses - mutation detection

• advantageous in settings where tumor tissue is limited/unavailable for direct testing

• important for choosing therapy

Disease Detection from Retinal Images

• Diagnostic device IDx-DR - first FDA approved tool that uses AI

• can detect mild lvl of diabetic retinopathy

  • high blood sugar leading to damage in blood vessels in retina

  • most common cause of vision loss in diabetic americans

• provides screening decision w/o need for clinician to interpret results

• usable by providers who don’t normally work in eyecare

Bioinformatics in Drug Metabolism

breakdown of a parent drug into metabolites with diff physiochemical and pharmacological properties

• usually investigated by experimental/computational approaches

Quantitative Structure-Activity Relationships (QSAR) - assumes that molecules with similar structure exhibit similar chemical/biological activities

• experimental dataset comprising the biological activity of chemical compounds

• chemical and physical features represented as molecular descriptors

• statistical methods for correlating molecular descriptors w/ biological activity

Machine Learning in QSAR

• accelerates process of scanning and filtering out ineffective compounds

• reduces time + cost compared w/ experimental screening methods

Networks and Systems Biology

System - a network of mutually dependent and interconnected components comprising a unified whole

System Biology - an approach in biomed research to understand the larger picture

• analysis and modeling of complex biological systems

  • molecular interactions

  • protein-protein complexes

  • protein-ligand/drug complexes

  • spatial organization of elements

  • response of molecules to external stimuli

• Importance

  • understand physiology and disease form level of networks, cells, tissues, organs, and whole organism

  • helps to prioritize targets

  • design clinical trials

  • improve decision making in pharmaceutical development

Gene Ontology (GO) resource - world’s largest database of info on the functions of genes

STRING - database of known and predicted protein-protein interactions