6: Foundations Of Genomic Medicine Flashcards
How does Genomics change treatment?
Don’t forget environment
Early detection: active surveillance, prophylactic intervention
Pharmacogenomics: *monitor side effects and toxicities because of different susceptibilities to drugs and different metabolisms, modify medication choices/dosages
Genetic Counseling: patient’s healthcare/reproductive decisions, children’s health
Translations Genomics (steps)
Discover gene that causes disease
Diagnose patients at both clinical and molecular level (determine variants)
Understand mechanisms and phenotype-genotype relationship
Translate understanding to therapeutics
Disease Causing Mutations (list)
In coding, promoter, exon/intron, UTRs, ncRNAs
Monogenic mutation-linked: CF, PKU…
Multigenic mutation-linked: cancer, CVD…
50% disease causing mutations- noncoding
Specific tissue mutations- Huntington, Retinoblastoma, BRCA1/2 breast cancer
Point Mutations (substitution or transitions)
Missense- new Amino Acid
Nonsense- stop codon
Point Mutations (phenotypes)
Silent or have phenotype
Coding or noncoding regions:
- synonymous or non-synonymous a.a substitution and generation of stop codon
- splicing defects
- promoter changes
If no splice introns, 3/64 will be stop codon
Molecular Surveillance Systems (quality control of mRNA)
Nonsense Mediated Decay
-detects premature stop codons (mutation or failure to remove intron)
Non-Stop Mediated Decay
-detects absence of stop codons
Non-Go Mediated Decay
-detects absence of start codons
Nonsense Mediated Decay
Degrades mRNAs with premature stop codons (PTCs)
Proteins on interior say it’s in the wrong place. Machinery to bring in nucleases to get rid of it.
Non-Stop Decay
Degrade mRNAs with no stop codon
Lack of stop codon detected then trashed
No-Go Decay
Degrades mRNA with no start codon
MRNAs with no start codon trashed.
Splicing Mutations
Disastrous consequences
Common because of large amount of genome with introns
Deletion and Insertion Mutations (indels)
Single nucleotide or thousands of bp
Indel in protein coding region causes a ribosome reading frameshift (mostly won’t see truncated proteins)
Indels in Coding Can Cause Stop Codon Mutations
UAG, UGA, UAA
NMD (decay pathway) degrades transcripts
Failure of pathway results in shortened protein that can be toxic to cell
Truncated Protein Degradation (how)
Via the Ubiquitin-Mediated Unfolded Protein Response (UPR)
Ends up in proteasome
Expansion Mutations
Trinucleotide repeat expansion
Can happen in coding region, 5’ and 3’ UTR and promoter
Ex. OPMD and other expansions
Translocation and Duplication Mutations
Reciprocal or non-reciprocal
Usually happens during crossing over
Translocations usually deleterious
Duplications can lead to evolution of genomes
Mendelian Genetic Disorders
Mutations in single genes or chromosomal aberrations
Loss or gain of function
- Duchenne muscular dystrophy- X recessive
- CF- autosomal recessive
- Huntington’s- autosomal dominant
Modifiers- genes that modify the expressivity of a monogenic genetic disease
Mendelian Genetic Disorders (therapeutic strategies)
Characterize genes and proteins associated with mutation and modifier genes
Target single gene/gene product or modifier
Prevention: prenatal and adult genetic testing
Complex Multifactorial Genetic Disorders (strategies)
Therapeutic Strategy: can’t use gene replacement, have to use combination approaches
Prevention/Management: use genetic testing, clinical information, environmental exposure evaluation and age to make clinical decisions
Model for Mechanism of Disease
Environmental Exposures and Life Style
Genetics, Development and Aging
Heath Care Systems
Family Medical History (FHx)
Patient accuracy of memory and knowledge (of their health and of lineage health)
Physician’s knowledge of FHx in etiology of given disease
Physician’s allocated time and quality of questions
“All of Us” Initiative
NIH
Triad model data from 1 million US people
Epigenetics
Heritable changes in the genome and its expression that do not involve changes in DNA sequence
Allows somatic cells to establish and maintain their differentiated stated with the same complement of DNA.
Histone modification, RNA interference (microRNAs), DNA methylation
Transgenerational Epigenetic Inheritance
Not all epigenetic marks are erased before fertilization
Hypothesis: some marks in parental gametes may be transmitted to offspring
Dilated Cardiomyopathy (DCM)
Heart becomes enlarged (hypertrophy), portion of myocardium is dilated and can’t efficiently pump blood to kings and tissues
Significant cause of heart failure
25-35% have familial forms of DCM
Mutations in genes for: cardiac actin, deamination, nuclear lamins A and B
Breast Cancer
Most breast cancer is sporadic:
Genetic, hormonal, lifestyle, environmental risk factors
High Risk Familial Breast Cancer Genes
Usually protein truncating mutations
PTEN, BRCA1/2
Moderate Risk Familial Breast Cancer Genes
Protein truncating or INDEL
ATM, Check2
Low Risk Familial Breast Cancer Genes
MLH1, MSH2, MSH6 (DNA mismatch repair genes)
Also SNPs in non-coding regions
Metabolic Pharmogenetics
Can predict poor, intermediate extensive and ultra-rapid metabolizers
- defective and inactive enzymes (poor or no response)
- hyperactive and over expressed enzymes (increase effect or toxicity)
Radiation Sensitivity Genes
Base excision repair pathway
If you have genomic variants, should be cautioned to avoid unnecessary x-ray exposure
Genetic Variation in Humans
Two humans vary in sequence about
0.1-0.4%
Most variation in intergenic regions where most mutations are silent
Sources of Genome Variation
SNVs (SNPs)- polymorphisms in genes and integenic regions CNVs- copy number variants Repetitive DNA lengths INDELs Translocations
50% mutations in intergenic regions
Clinical Genetic Testing
Genomics (WGS, WES, SNV, DNA methylation)
Transcriptomics (RNA sequencing)
Proteomics (proteins)
Chromosome and Single Gene Analysis (PCR/targeted sequencing, CGH, FISH)
Incidental Findings
A finding that goes beyond original test or research
VUS
Variant of unknown significance
23andME and Direct-to-Consumer Genetic Testings
Do not sequence DNA
Took DNA, put on microarray (oligonucleotides complimentary to SNPs)
SNP profiling
SNPs
A single DNA base pair change
SNP is point mutation present in at least 1% of population
30 million, only 3-5% functional significance
1-2% associated with human disease
Tells you about ancestry (and Neanderthal), relatives, some basic genetic traits.
Tells you about increased risk for certain diseases, carrier of some conditions (CF, Tay-Sach’s), how you metabolize certain drugs (statins, opioids)
Prometheseus
Third Party that takes extra information for 23AndMe and does what first party used to before ban.
