6: Foundations Of Genomic Medicine

Question 1

How does Genomics change treatment?

Don’t forget environment

Answer 1

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

Question 2

Translations Genomics (steps)

Answer 2

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

Question 3

Disease Causing Mutations (list)

Answer 3

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

Question 4

Point Mutations (substitution or transitions)

Answer 4

Missense- new Amino Acid

Nonsense- stop codon

Question 5

Point Mutations (phenotypes)

Answer 5

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

Question 6

Molecular Surveillance Systems (quality control of mRNA)

Answer 6

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

Question 7

Nonsense Mediated Decay

Answer 7

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.

Question 8

Non-Stop Decay

Answer 8

Degrade mRNAs with no stop codon

Lack of stop codon detected then trashed

Question 9

No-Go Decay

Answer 9

Degrades mRNA with no start codon

MRNAs with no start codon trashed.

Question 10

Splicing Mutations

Answer 10

Disastrous consequences

Common because of large amount of genome with introns

Question 11

Deletion and Insertion Mutations (indels)

Answer 11

Single nucleotide or thousands of bp

Indel in protein coding region causes a ribosome reading frameshift (mostly won’t see truncated proteins)

Question 12

Indels in Coding Can Cause Stop Codon Mutations

Answer 12

UAG, UGA, UAA

NMD (decay pathway) degrades transcripts

Failure of pathway results in shortened protein that can be toxic to cell

Question 13

Truncated Protein Degradation (how)

Answer 13

Via the Ubiquitin-Mediated Unfolded Protein Response (UPR)

Ends up in proteasome

Question 14

Expansion Mutations

Answer 14

Trinucleotide repeat expansion

Can happen in coding region, 5’ and 3’ UTR and promoter

Ex. OPMD and other expansions

Question 15

Translocation and Duplication Mutations

Answer 15

Reciprocal or non-reciprocal

Usually happens during crossing over

Translocations usually deleterious

Duplications can lead to evolution of genomes

Question 16

Mendelian Genetic Disorders

Answer 16

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

Question 17

Mendelian Genetic Disorders (therapeutic strategies)

Answer 17

Characterize genes and proteins associated with mutation and modifier genes

Target single gene/gene product or modifier

Prevention: prenatal and adult genetic testing

Question 18

Complex Multifactorial Genetic Disorders (strategies)

Answer 18

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

Question 19

Model for Mechanism of Disease

Answer 19

Environmental Exposures and Life Style

Genetics, Development and Aging

Heath Care Systems

Question 20

Family Medical History (FHx)

Answer 20

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

Question 21

“All of Us” Initiative

Answer 21

NIH

Triad model data from 1 million US people

Question 22

Epigenetics

Answer 22

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

Question 23

Transgenerational Epigenetic Inheritance

Answer 23

Not all epigenetic marks are erased before fertilization

Hypothesis: some marks in parental gametes may be transmitted to offspring

Question 24

Dilated Cardiomyopathy (DCM)

Answer 24

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

Question 25

Breast Cancer

Answer 25

Most breast cancer is sporadic:

Genetic, hormonal, lifestyle, environmental risk factors

Question 26

High Risk Familial Breast Cancer Genes

Answer 26

Usually protein truncating mutations

PTEN, BRCA1/2

Question 27

Moderate Risk Familial Breast Cancer Genes

Answer 27

Protein truncating or INDEL

ATM, Check2

Question 28

Low Risk Familial Breast Cancer Genes

Answer 28

MLH1, MSH2, MSH6 (DNA mismatch repair genes)

Also SNPs in non-coding regions

Question 29

Metabolic Pharmogenetics

Answer 29

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)

Question 30

Radiation Sensitivity Genes

Answer 30

Base excision repair pathway

If you have genomic variants, should be cautioned to avoid unnecessary x-ray exposure

Question 31

Genetic Variation in Humans

Answer 31

Two humans vary in sequence about
0.1-0.4%

Most variation in intergenic regions where most mutations are silent

Question 32

Sources of Genome Variation

Answer 32

SNVs (SNPs)- polymorphisms in genes and integenic regions
CNVs- copy number variants
Repetitive DNA lengths
INDELs
Translocations

50% mutations in intergenic regions

Question 33

Clinical Genetic Testing

Answer 33

Genomics (WGS, WES, SNV, DNA methylation)

Transcriptomics (RNA sequencing)

Proteomics (proteins)

Chromosome and Single Gene Analysis (PCR/targeted sequencing, CGH, FISH)

Question 34

Incidental Findings

Answer 34

A finding that goes beyond original test or research

Question 35

VUS

Answer 35

Variant of unknown significance

Question 36

23andME and Direct-to-Consumer Genetic Testings

Answer 36

Do not sequence DNA

Took DNA, put on microarray (oligonucleotides complimentary to SNPs)

SNP profiling

Question 37

SNPs

Answer 37

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)

Question 38

Prometheseus

Answer 38

Third Party that takes extra information for 23AndMe and does what first party used to before ban.