Genomic medicine Flashcards
Situations in which genomic medicine is useful?
- Diagnosis
- Identifying people at increased risk
- Tracking epidemics
- Personalising drug treatments (including cancer)
- Developing new therapies
Three types of gene mutation?
1) Inherited – autosomal/ X-linked recessive/dominant
2) De novo dominant mutation
3) Mosaic mutation
What is a mosaic mutation or mosaicism?
Two or more populations of cells with different genotypes in one individual
Limits to sequencing by synthesis?
- Poor at capturing simple repeats, and GC rich areas
- Misses promoters, UTRs, microRNAs
- Targeted panels may be better
Main principle behind sequencing by synthesis?
Recordign energy given off by marked base pairing
Are mixed race families more or less likely to have the same recessive allele?
Less likely
What is a germline mutation and a somatic mutation?
Germline: is a mutation in an egg or sperm cell itself
Non-germ-line tissue mutation, so can’t be inherited
Are many inherited cancers due to oncogenes or tumour suppressant gene mutations?
tumour suppressant
What are DNA repair genes, what could their mutation lead to?
Genes responsible for correcting the mutations in DNA, a mutation in a DNA repair gene can lead to cancer through the propagation of mutated onco/tunour suppressant gene.
Why can next-gen sequencing be difficult in cancers?
- Cancer genomes are complex and diverse
- Most cancers are aneuploid (abnormal chromosome number)
- Limited biopsy DNA
- Whole genome amplification might be needed to identify certain mutations (e.g. fusions)
- Often has necrotic, apoptotic cells in sample
- Formalin can damage DNA
- Tumours can contain normal DNA, tumour DNA, and different tumour clones
What are driver and passenger gene mutations?
Drivers give the clone a selective advantage and contribute to oncogenesis
Passengers have no effect on clone survival
Why would next-gen sequencing be useful in cancer?
Identify the exact gene mutations causing the cancer
What is minimal residual disease and how is this useful in cancer?
measures the proportion of tumour cells with a defining mutation
e.g. If the ratio of allele A:allele B is no longer 50:50 then this suggests a loss of heterozygosity, therefore clonal expansion, therefore cancer
Use of minimal residual disease testing in cancer?
- Prognosis
- Quantifying drug response
- Monitoring remission and relapse
- Guiding treatment
What is SCID?
Severe combined immunodeficiency
What are PIDs?
Primary immune deficiency
Some treatments for PIDs?
Folinic acid
bone marrow transplant
Types of next generation sequencing (NGS)?
Whole genome sequencing
Whole exome sequencing
Targeted gene panels
What percentage of disease causing variants are in the exome?
85%
What are SNIPS?
Single nucleotide polymorphisms
Heterozygous - different
How much roughly would it cost to have your genome sequenced now?
About £1000
Problems when not doing whole genome sequencing?
Simple repeats are poorly captured
Whole exome is not the WHOLE exome - some will be missing
Clinical exome evolves over time
Best choice in individuals to sequence if a child has a genetic disease to find the cause?
Either closely related and unaffected individuals
Or distantly related affected individuals
What is tiered analyses?
When you have a patient with a specific condition and you first look at the genes we know are involved in that condition
How can you filter data?
Tiered analysis
Mode of inheritance e.g. it’s X linked so look at things only on X
Synonymous variants - codes for the same amino acid
Look specifically at things we know make a big difference e.g. like Frameshifts, stop codon.
Concordant variants - if the mutation is seen in unaffected individuals it can be discarded
Conservation metrics - whether it has been the same in evolution
What is the genomics england programme?
Sequence rare disease and cancer patients
Put it behind a safe firewall
Allow access from selected individuals who can then feed back into treatment/drug design
What is JMML what mutations are associated with it?
Germline CBL mutations
