Genetics, genomics and the 100,000 genomes project · UK 100,000 Genomes Project •Launched by David Cameron in 2012 •Delivered by Genomics England, a company wholly owned and

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