Jeong-Sun Seo, M.D., Ph.D

Precision Medicine Center

Seoul National University Bundang Hospital

Macrogen Founder

Nov. 19th, 2019 Global Leaders Forum 2019

Korean Reference Genome

for Asian Precision Medicine

아시안 정밀의학을 위한 한국인 게놈 지도 완성

PART I

From Human Genome Project to Precision Medicine

인간게놈계획에서 정밀의학까지

left-handed:17%

Auricle feature:44%

Wet earwax: 88%

Family history of male boldness

in western : 56% anxietas tibiarum(restless legs):13%.

Images from http://www.23andme.com

Lactose intolerance: 22%

Family history in migraine:41%.

Absolute pitch:14%

도서관에 있는 책의 정보 풀기는 가능한가.

인류는 자신의 몸에 있는 생명암호를 풀 수 있을까.

인간이 자신에게 도전하다.

Human Genome Project (1990. 10. ~ 2000. 6)

June 26, 2000

Human Genome Project (1990-2000)

Francis Colins

Craig Ventor

Crown jewel

in health science

Major characteristics of 21st century 1. Globalization 2. Technology 3. Increase of aging population

Can the U.S. Meet

Its Aging Population’s Health Care Needs?

Chronic disease: $3 out of every $4 of U.S health care spending

Annual cost (2009); $1.875 Trillion

Healthcare as share GDP: from 17.6% of GDP (2009) to 37% of GDP(2050)

2015, The Year of Precision Medicine

President Obama’s State of the Union Address:

January 20, 2015

“Tonight, I'm launching a new Precision Medicine Initiative to bring us closer to

curing diseases like cancer and diabetes — and to give all of us access to the

personalized information we need to keep ourselves and our families healthier.”

President Barack Obama, State of the Union Address, January 20, 2015

Beery Twin’s Story

DRD(Dopa Responsive Dystonia)

Nic Volker’ Story

Nic underwent 160 surgeries before having his genome sequenced to diagnose his intestinal disease.

XIAP gene, inflammatory bowel disease

“ We ended up doing a core blood transplant; 42 days later he was eating. He had been on total parenteral nutrition for 9 months; after treatment, he enjoyed steak. Nic is now 9. It's coming up on 4 years since his transplant and his gut disease completely resolved. It's a great story."

Advancing Healthcare Through Personalized Medicine

Precision Medicine

For every person they do help (blue) , the ten highest-grossing drugs

in the US fail to improve the conditions of between 3 and 24 people (red)

“ One size does not fit all “

For every person they do help (blue) , the ten highest-grossing drugs

in the US fail to improve the conditions of between 3 and 24 people (red)

Precision Medicine

EMR Big data analysis

Genomics

Lifelog

Precision Medicine?

유전체정보, 질병기록 그리고 모바일 헬스 정보를 빅데이터 기술로 처리하여 질병을 예측함

Participatory Medicine

Preventive,

Predictive,

Personalized Medicine

Genomics is Failing on Diversity

Nature 538:161 (2016)

Asian

“In 2009 analysis, 96% of

participants in GWAS were of

European descent.”

Asian populations are still left behind on the road to precision medicine.

“Much of this rise, is a result of

studies on populations of Asian

ancestry.”

“The proportion of non-European

decent in GWAS increased up to

nearly 20% in 2016”

NIH Director Dr. F. Collins’ s Visit to GMI-SNU, Korea

Sep. 8th 2015. at GMI-SNU

Dr. Collins

Asian Precision Medicine Initiative

PART II

Korean Genome Map Completed

한국인 게놈 지도 완성:세번의 시도

First Approach(2009): Mapping to reference genome

Second Approach(2016): De novo Assembly

Third Approach(2019): GenomeAsia 100K Project

한국인 게놈 지도 완성:세번의 시도

Nature (2009)

SNPs of each ethnic group

Stephen Kingsmore Rady Chilidren’s Hopsital Jong Il Kim

SNUMC

Northern Asian Genome Sequencing and Analysis, Nature 2009

북방계 아시아인 게놈 분석

Green et al., Nature 470 (7333) 10 Feb. 2011

2011년 2월, 인간 게놈 프로젝트 10주년 기념 네이처 특집호

북방계 아시아인 유전체 논문 (서울의대)

백인 유전체 논문

흑인 유전체 논문

남방계 아시아인 유전체 논문

First Approach(2009): Mapping to reference genome

Second Approach(2016): De novo Assembly

Third Approach(2019): GenomeAsia 100K Project

한국인 게놈 지도 완성:세번의 시도

De Novo Assembly of Korean Human Genome

De novo assemblies are orders of magnitude slower and more memory intensive than

mapping to assemblies.

Sequencing De novo Assembly Complete genome

PacBio (~101 X)

Long reads 303 Gb

Illumina (~72 X)

Short reads 216 Gb

BioNano (~200 X)

Optical maps 600 Gb

32,026

AK1 BAC Clones

Gap Closing by AK1 Scaffold and BAC Clones

Seo JS, et al, Nature; 538:243-247, Oct, 2016

• The size of Gap_367 and Gap_368 is 50kb.

• 144 kb of novel sequences, indicated in yellow, are added to the human

reference.

• BAC clones and BioNano Genome map validate this novel sequence.

De Novo Assembly of Korean Genome

“This is the most contiguous human genome mapped to date, providing a population-specific reference genome and vital data for genetic scientists generally”

Nature Press, Oct. 2016

아시안 표준유전체 연구결과 네이처지에 발표 (2016. 10)

First Approach(2009): Mapping to reference genome

Second Approach(2016): De novo Assembly

Third Approach(2019): GenomeAsia 100K Project

한국인 게놈 지도 완성:세번의 시도

Towards diversity in genomics: GA100K

Significance of Asian genome in precision medicine

GA100K (2016-2020) Project:

Indigenous Asian Genome Project

Founding Member

Partner

- 1,739 population scale

genome sequencing

- 64 countries

- More than 200 ethnic

group

113

598

156 68

70

70

52

152 35

100

Northern Mongolian Cohort

Genetic Admixture in Asian Populations Asians have diverse population structures

AFR EUR SAS SEA OCE NEA AMR

Mongolians share ancestry with East Asian, Siberian, and native American populations

Asian is the population with diverse genetic admixtures relative to other ethnic groups.

M

Maternal Ancestry

from Asian Mitochondrial Whole Genomes

1,178 Individual mitochondrial genome

GA100K unpublished data

• 4 distinguishable

patterns of

mitochondrial whole

genomes

(European, African,

SAS, and NES)

• Mongolian data

reveals that the

maternal ancestry

of NES is related to

SAS and Native

American.

PART III

Digital Transformation & Genome Industry

디지털 전환과 게놈 산업

1. 3D Metal Printing

2. Artificial Embryo

3. Sensing City

4. AI for Everybody

5. Dueling Neural Networks

6. Babel-Fish Earbuds

7. Zero-Carbon Natural Gas

8. Perfect Online Privacy

9. Genetic Fortune-Telling

10. Material Quantum Leap

10 Breakthrough Technologies 2018

2018 March-April

Abdominal Aortic

Aneurysm

Age-related Macular

Degeneration Alzheimer’

disease

Asthma

Celiac disease

Colorectal Cancer

Crohn’s disease

Exfoliation Glaucoma

Atrial Fibrillation

Direct to Consumer Genetic Testing Personal genome service

0.51

0.77 0.14

0.23

2.99

1.00

0.86

0.60

0.18

Atrial Fibrillation 2.99 ?

Your lifetime risk of Atrial Fibrillation

This report is for people of European ancestry, which does not match for people of unknown gender and ethnicity.

When in Doubt, Spit It Out “알고 싶으면 침을 뱉어라”

“23andMe” DNA test

Home DNA Kit

- More than 20M people have a DNA story now -

AncestryDNA has 10 million

customers in their database,

adding over 2 million so far this

year

23andMe and AncestryDNA are

the two largest and well known

direct-to-consumer (DTC)

genetic testing services.

23andMe has grown to 5 million

customers in the 10 years.

Everybody’s doing DNA tests

Genome Biology 2018 19:120

북미지역 2000만명 유전자 검사 결과 보유

Growth in DTC Genetic Testing

Psomagen* Personal DNA testing in Amazon Black Friday 2019. 11.29

*Psomagen was formerly Macrogen US

10M Korean Peninsula Asian Genome Project Consumer-driven Genome Project ($50/person)

10M People in Korean Peninsula

- 4M South Korean

- 4M North Korean

- 2M Asian who live in Korea

Establishment of telemedicine in North Korea

Establishment of Unified-Korean precision medicine through

10M Korean Peninsula Genome Project

Seoul National University Bundang Hospital

Healthcare Innovation Park

“ Connecting the dots ”