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Genetics, genomics and the 100,000 genomes project
Dr George Burghel – Principal Clinical Scientist Galton Institute Teacher’s conference
26/06/2019
Basic Genetics - Genes
• Gene is the basic physical and functional unit of heredity
• Made up of DNA
• Instructions to make proteins
• Every person has two copies of most genes, one inherited from each parent
• Genes reside on chromosomes
46 chromosomes
Exon 1 Exon 2 Exon 3 DNA
RNA Exon 1 Exon 2 Exon 3
Protein M Y T C A
Introns
Exons Coding and non-coding regions
Basic Genetics - Genes
Basic Genomics - Exomes and Genomes
• >20 000 genes
• All exons together = Exome (30 000 000 ACTG)
• Genome (100x bigger)
– 3 000 000 000 ACTG
– Sequenced for participants of 100KGP
– A genome is an organism’s complete set of DNA, including all of its genes.
The Human Genome
BIG
BIG
The Human Genome
BIG
BIG 46 chromosomes
The Human Genome
BIG 46 chromosomes
The Human Genome
BIG 46 chromosomes
Quiz
If your genome was printed in size 4 font how many A4 pages would it be?
78,000
780 78
7,800
If your genome was printed in size 4 font how many A4 pages would it be?
78,000
780 78
7,800 78,000
The Library of life
The Library of life
Instructions manual
The human genome project
• 13 years (1990-2003)
• Sanger sequencing
• 20 centres from 6 countries; US, UK, France, Germany, China and Japan
• Cost: ~$3billion
• Enabled the discovery of disease-causing genes
• Paved the way for large-scale diagnostic genetics and genomics
Sanger DNA sequencing
G G T T C A C C T G A A G A A A A A A T C A C T A
patient’s DNA
CTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGA
Next Generation Sequencing
CTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGACTGAGAATGCTTCGGCAAGACTCAAAAAATAGCTGGA
G G T T C A C C T G A A G A A A A A A T C A C T A
G G T T C A C C T G A A G A A A A A A T C A C T A
G G T T C C C G A A G A A A A A A T C A C T A G C G G T T C A C C T G A A G A A A A A T C A C A G A G G T T C C C T G A A G A A A A A A T C A C T A G G G T T C A C C T G A A G A A A A A A T C A C T A
G T T C C C G A A G A A A A A A T C A C T A G C T G G T T C A C C T G A A G A A A A A A T C A C T A
G G T T C A C C T G A A G A A A A A A T C A C T A
G G T T C C C G A A G A A A A A A T C A C T A G C G G T T C A C C T G A A G A A A A A T C A C A G A G G T T C C C T G A A G A A A A A A T C A C T A G G G T T C A C C T G A A G A A A A A A T C A C T A
G T T C C C G A A G A A A A A A T C A C T A G C T
JIGSAW
Alignment
A A A T G G T T A C A C C C T T
GCTGTGAAATGGTTACACCCTTTATGGCCCTTGGTT
A A T G G T T A C A C C C T T T A T G G T T A C A C C C T T T A
A A T G G T T A C A C C C T T
DNA sequence
reference
150 LETTERS
Spot the difference – variant calling
A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T
A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T
A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T
A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T A A T G G T T A C A C C C T T C A T G G T T A C A C T C T T
A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T
A A T G G T T A C A C C C T T A A T G G T T A C A C T C T T
REFERENCE
PATIENT DNA
Spot the difference – variant calling
1500 LETTERS
Reference Sequence
Spot the difference – variant calling
1500 LETTERS
Patient Sequence
THE VARIANTS CHALLENGE
If we sequence two people at random, how many differences would we find?
3,000,000 - 5,000,000
30,000 - 50,000 3,000 - 5,000
300,000 - 500,000
If we sequence two people at random, how many differences would we find?
3,000,000 - 5,000,000
30,000 - 50,000 3,000 - 5,000
300,000 - 500,000 3,000,000 - 5,000,000
The Good, the bad……
How do we do it?
• Published literature
• Gene and disease databases
• Population databases
• In silico analysis
• Family studies
• Functional studies
• Research
Genetics
Genomics
Single gene
Small panels (5-10)
Large panels (50-100s)
Clinical exome (5000)
Whole exome (20 000)
Whole genome
COST TIME
Genome Sequence >3 billion bases
~3-5 million variants (1/1000)
Mostly non-coding (~99.7%)
~10 000 protein coding (within Exome – 20 000 genes)
Mostly no known disease association (~17000 genes)
~200 variants in disease causing genes (~3000 genes)
Complex disease, cancer, mendelian,
behavioural
What do we do? Report? Further investigation? Follow up, cascade testing? Family
history?
• The Watson genome 2008 • 32 variants in disease causing
genes
(1) Wright BMJ 2013;347:f6845 (2) Gonzaga-Jauregui et al Rev Med, 63, pp.35-61
Genetics
Genomics
Single gene
Small panels (5-10)
Large panels (50-100s)
Clinical exome (5000)
Whole exome (20 000)
Whole genome
COST TIME
What is the value of genetic/genomic diagnosis?
• Better diagnosis – Avoid unnecessary testing – Avoid invasive tests – Quick and accurate answer
• Prevent disease – Cancer
• Better treatment – Personalised therapy – Gene therapy
• Research
UK 100,000 Genomes Project
• Launched by David Cameron in 2012
• Delivered by Genomics England, a company wholly owned and funded by the Department of Health
• Aim to transform healthcare to incorporate the use of genomics into mainstream medicine
UK 100,000 Genomes Project
• Launched by David Cameron in 2012
• Delivered by Genomics England, a company wholly owned and funded by the Department of Health
• Aim to transform healthcare to incorporate the use of genomics into mainstream medicine
Genomics England - the mission • 100,000 Whole Genome Sequencing (WGS) on NHS
patients • Rare diseases • Cancer • And pathogens
• Working with NHS, academics and industry to make the UK a world leader in Genomic Medicine
• Transformation of NHS so that NGS can become routine investigation
• Kick start the genomics industry in the UK • Generate health and wealth • Leave a legacy of infrastructure, human capacity and
capability
100KGP – Outcomes and benefits
• 97,993 samples recruited by NHS GMCs for WGS sequencing (69,379 RD across 209 disease groupings 28,554 cancer across 15 cancer types)
• 1,500 NHS Staff involved and are leading change at core of NHS GMCs
• Collaborations with >3000 researchers & trainees from around the world & 70+ industry partners
• 100s of NHS services working closely together – cancer, clinical genetics, paediatrics and other specialisms
• 1000s of individuals engaged in genomics
• Broad mix of ethnicity (1/3rd non-white in RD samples)
• New pathways within the NHS including Genomic multidisciplinary teams for interpretation, validation & feedback
From CSO report
100KGP – Outcomes and benefits
• Diagnostic yield of 25% in RD – 50%+ for some conditions
• 50% of cancer cases show actionable mutations, increased eligibility for clinical trials
From CSO report
Challenges
• Interpretive challenges: novel and unclassified variants
• Secondary findings: report or not report
• Counselling challenges (pre- and post- testing) and “informed” consenting
• Ethical issues: privacy, confidentiality and discrimination
The Future • Mainstream introduction of genomic medicine across the
NHS allowing improvements to population health and increasing personalisation of care and management approaches
• Create NHS genomic medicine service delivered by 7 Genomics hub – Drive personalised care
– Equitable access
– Improve quality and standards
– Reduce cost (Economy of scale)
– Drive research and industry collaboration
QUESTIONS?
Acknowledgments