Lecture 1 + 2 Flashcards by Brooke Thornburg

Actionable Signature

-info used to make tx decision
-genetic markers help dosing and efficacy
-ex VKOCR1, CYP2C9, CYP4F2 polymorphisms in pt taking warfarin
-150 pharmacogenomic drug labels in 2018 to 517 entries in 2023

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Genetic factors affect PK and PD

-PK (ADME)
-PD (receptor, targeting, enzymes, etc)

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DNA

-thin (2nm)
-linear polymer fiber, double helix
-ATGC
-A=T
-G≡C (3 H bonds)

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Genome

-complete set of one’s DNA
->3 billion base pairs in human
->21k genes
-contained in all cells w nucleus

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Genes

-seq of DNA or RNA that codes for a molecule that has a function
-can be a few hundred to 2 million BP long
-21k in humans, similar to mice
-protein coding or noncoding

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Protein coding genes

-expressed to be proteins
-1-3% of genome (~20,000genes)

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Noncoding genes

-final product is RNA not protein
-tRNAs (transfer aa to RNA to make protein)
-rRNAs (ribosome)
-microRNAs (miRNA): regulate protein-coding gene expression

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Gene nomenclature

-genes italicized, proteins not
-abbreviation, family based, or arbitraty assignment

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Structure of gene

-promoter
-5’ untranslated region (UTR)
-exons and introns
-3’ UTR

-flanking sequences

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Structure of real gene (SCN2A)

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Sequence position

-each nucleotide has unique position (locus) in reference genome

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Chromatin

-unwound
-interphase
-DNA available for transcription

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Chromosome

-tightly packed
-cell division
-DNA not in use

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Human genome

-46 chromosomes (23 pairs)
-karyotype

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karyotype

-complete pic of genome in cell

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Why chromosome pairs?

-half from each parent
-inc genetic diversity

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Expression of Genetic information (central dogma)

Transcription (DNA to RNA)
Translation (RNA to protein)

-viruses can go from RNA to DNA w reverse transcription or use RNA replication
-prion disease (virus replicating protein)

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Transcription

-mRNA maturation process
-mRNA precursor: DNA but w poly A tail and cut out introns
-matured mRNA: in cytoplasm with alll introns removed and poly a tail (AUCG)

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Translation

-RNA to protein
-starts with AUG (makes methionine)
-stops at UAG, UAA, UGA
-open reading frame (ORF)

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Open reading frame

-coding DNA seq (CDS)
-AUG to the codon before stop codon
-protein starts w methionine

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SLIDE 24-25

v important yes

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Genetic coding system

-64 codons (1 starts, 3 stop)
-20 amino acids
-chart

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start codon

-ATG

Stop codons

-UAA
-UAG
-UGA

Sequence variations (polymorphism)

-genetic variation at the SAME position of HOMOLOGOUS CHROMOSOMES -NO polymorphisms in SINGLE GERM cell (haploid genome) -ex: Single nucleotide polymorphism (SNP) -

allele

DNA seq at locus of ONE of two HOMOLOGOUS chromosome

Genotype

combo of alleles at SAME locus of the homo chromo in a genome/cell

Homozygote

pair of identical alleles at the locus -genotype=homozygous

Heterozygote

-2 diff alleles at same locus -genotype = heterozygous

Hemizygous

-one allele present while the other allele is missing -genotype= HETEROZYGOUS

Mendel's Law

-each parent passes random allele to offspring (law of segregation)

Single Nucleotide polymorphisms (SNP)

-one nucleotide is changed to another -most common DNA seq variation -55mil SNPs in SNP database

most common polymorphisms

-SNPs

cSNP

-SNP in coding region -nonsynonymous or synonymous

Non-synonymous SNP

-change aa in the protein -missense (substitute) -nonsense (stop codon)

Missense SNP (cSNP)

-amino acid substitution -can lead to gain or loss of function

Nonsense SNP

-aa changes to stop codon -usually loss of function

Synonymous SNP

-does not change aa -usually doesnt change function -silent SNP = no aa change

Noncoding region SNPs

-intronic -SNPs in gene flanking regions and intergenic regions -SNPs in UTR region

Copy Number Variation (CNV)

-DNA region has 0-n copies in a population -structural variation -1kb-several Mb -making each chromosome longer or shorter -ex: CYP2D6 has 0-13 copies

Insertion/Deletion (Indel)

-NTs present or absent from locus: 0 or 1 copy -can be 1 to N NTs -single indel is a specific form of SNP -large ones are usually CNVs -frameshift of reading fram = truncated protein

Truncated protein

-loss of function -sent to degradation

Repetitive DNA variations

-Short Tandem Repeat (STR): short seq (1-1000bp) repeats N times (X)n -Variable number of tandem repeat -micro-satellite/mini-satellite (1-4bp) -not starred

Multi allelic polymorphisms (no star)

-often in the UTR region!!!! -some cases of neurogenetive disorders like Huntington's disease

UGT1A1-53 (TA)n polymorphism (no star)

-(TA)n, n=5-8 -occurs in TATA box of promoter -common alleles: 6 and 7 -Reduced UGT1A1 gene expression

Reference comparison

-DNA: 1 copy of CYP2C19 in genome makes 100 copies mRNA -100 copies of mRNA makes 1000 copies of protein -1000 copies of proteins metabolize 10k drug molecules

CNV comparison

-7 copies of CYP in genome = 700 mRNA = 7000 protein - 70k drug molecules metabolized =gain of function

Genen expression (repetitive DNA variation)

-1 copy CYP2C19 makes 50? -loss of function

Missense comparison

Nonsense comparision

-1 to 100 -100 makes 1000 TRUNCATED proteins =0 drug molecules metabolized -loss of function

rs number

-ID for SNPs -assigned number follows

Nomenclature

-gene/allele name: itallics -protein name regular -asterisk (gene) vs dot (protein)

CYP2C19 nomenclature

-CYP2C19*1A (no SNPs, normal function) -*2D: splicing defect (99C>T) loss of function -*3A: nonsense (stop codon) loss of function -*17: missense, gain of function

slide 17

slide 17 -*=different phenotypes= metabolize drug differently