Flashcards in Medical Genomics Deck (41)
When was the human genome mapped?
When did next generation sequencing begin?
What is NGS?
Next generation sequencing
The rapidly advancing technology that makes it economically viable to sequence individuals rather than species
What % of the genome is the exome?
What does studying the transcriptome RNA allow us to study?
How many base pairs in a genome?
About 3200 million
How many base pairs in an exome?
Negatives of exome sequencing
Only picks up 85% of disease causing variants
Requires additional sample prep
No assessment of non coding regions
Simple repeats, GC rich and highly homologous regions are poorly captured
Clinical exome develops over time
Negatives of genome sequencing
Much more expensive
Massive data (storage?)
Interpretation more expensive and difficult
Steps in exome sequencing
Shotgun library-> fragments
Pull down and wash
Captured DNA is sequenced
Mapping, alignment and variant calling
What does variant calling rely on?
Accurate alignment to a reference sequence from the Human Genome Reference
No read is the full gene
Who should be sequenced?
Distantly related concordantly affected individuals (share very few mutations)
Closely related discordant individuals (very few differences)
What is a compound heterozygote?
The presence of two different mutant alleles at a particular gene locus, one on each chromosome of a pair
Different mutations in mum and dad but on same allele
Offspring has no functioning copies of that gene
What does consanguineous mean?
The quality of being descended from the same ancestor as another person.
What are the 6 main types of mutations?
Inherited (autosomal recessive, autosomal dominant, X linked recessive, consanguineous autosomal recessive)
What is needed for bioinformatics?
4Gb data for each sample
Biologists skilled in programming
What affects the quality of sequencing?
What is tiered analysis?
Prioritised analysis on basis of clinical presentation
Use known targeted gene panels
Top candidate genes first then pathway, system, others
Minimises incidental findings
How can you filter data?
Mode of inheritance
Concordance/discordance to affected relatives
Frequency in control populations
Give an example of an 'in silico' tool
Name 2 reference databases
UK10K, in-house, ESV
What do genetic libertarians believe about incidental findings in genome analysis?
"Return comprehensive data"
Patient has right to know
Return all data on known and unknown risk variants
What does the ACMG recommend about incidental findings in genome analysis?
"Return data on a limited number of conditions and genes"
20 diseases, 60 genes
What do genetic empiricists believe about incidental findings in genome analysis?
"Only return data that is truly significant"
Don't create burden of 'patient in waiting'
Penetrance for most variants is unknown
Who is involved in a medical genomics/bioinformatics MDT?
What are the issues with big data?
Safety/confidentiality of data
Identifiable data refreshed for clinical life-course registry
Need data on cancer registries, rare diseases, mortality data
All data needs to be kept behind a firewall until processed
Then it can be given to clinicians, academics and industry
What are the options for a patient when they get their data back?
Info about patient's main condition
Info about 'serious and actionable' conditions (optional)
Info on carrier status for non-affected parents of children with rare diseases (optional)
What can genomics be used for?
Identifying people and increased risk of developing a condition
Diagnosing infections and tracking epidemics
Personalising drug treatments
Identifying appropriate cancer treatments
Developing new therapies
How can genomics be used to personalise drug treatments?
Genetic variation can impact drug metabolism.
-> adverse reactions