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Flashcards in Medical Genomics Deck (41)
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1

When was the human genome mapped?

2003

2

When did next generation sequencing begin?

2010->

3

What is NGS?

Next generation sequencing
The rapidly advancing technology that makes it economically viable to sequence individuals rather than species

4

What % of the genome is the exome?

1%

5

What does studying the transcriptome RNA allow us to study?

Gene expression
Gene fusions
Splice variants

6

How many base pairs in a genome?

About 3200 million

7

How many base pairs in an exome?

5--70million

8

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

9

Negatives of genome sequencing

Much more expensive
Massive data (storage?)
Interpretation more expensive and difficult

10

Steps in exome sequencing

Genomic DNA
Shotgun library-> fragments
Rehybridisation
Pull down and wash
Captured DNA is sequenced
Mapping, alignment and variant calling

11

What does variant calling rely on?

Accurate alignment to a reference sequence from the Human Genome Reference
No read is the full gene

12

Who should be sequenced?

Distantly related concordantly affected individuals (share very few mutations)
Closely related discordant individuals (very few differences)

13

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

14

What does consanguineous mean?

The quality of being descended from the same ancestor as another person.

15

What are the 6 main types of mutations?

Inherited (autosomal recessive, autosomal dominant, X linked recessive, consanguineous autosomal recessive)
De novo
Mosaic

16

What is needed for bioinformatics?

4Gb data for each sample
Biologists skilled in programming
IRIDIS4 supercomputer

17

What affects the quality of sequencing?

Read depths
Standard bias
PCR duplicates

18

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

19

How can you filter data?

Mode of inheritance
Variant type
Concordance/discordance to affected relatives
Frequency in control populations

20

Give an example of an 'in silico' tool

Computerised predictors
Logit
Mutationtaster

21

Name 2 reference databases

UK10K, in-house, ESV

22

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

23

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

24

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

25

Who is involved in a medical genomics/bioinformatics MDT?

Genomicists
Clinicians
Immunologists
Bioinformaticians
Lab techs
Registrars
Research nurses
PhD students
Molecular biologists
Pathologists

26

What are the issues with big data?

Storage space
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

27

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)

28

What can genomics be used for?

Making diagnoses
Identifying people and increased risk of developing a condition
Diagnosing infections and tracking epidemics
Personalising drug treatments
Identifying appropriate cancer treatments
Developing new therapies

29

How can genomics be used to personalise drug treatments?

Genetic variation can impact drug metabolism.
-> dosage
-> frequency
-> SEs
-> adverse reactions

30

How can NGS be used for monitoring of disease?

Measure minimal residual disease by liquid biopsy-> quantifies disease, monitors remission and detects relapse