[BIOINFO 2022] John Quackenbush 교수님 기조강연

Why does AI struggle?

Inefficient training data
No robust underlying model
The way we train AI is fundamentally flawed (MIT technical report, 2020)
No Free Lunch Theorems for Optimization

Networks beyond simple differences

Conventional statistical analysis
DEG 분석
Regulatory network를 도입
다만, condition-specific regulatory network이 필요하다. (Individual의 차이, cell type의 차이를 반영)
Analyze network topology and structure
compare network topologies
compare structure and expression
Use individual networks as biomarkers!
netZoo: An integrated platform

Can we solve the “GWAS Puzzle?”

Rare variants = Dust?
eQTL analysis
Which SNPs are correlated with the degree of gene expression
Most people concentrate on cis-acting SNPs

eQTL Networks

Standard eQTL analysis
SNP와 gene의 association을 나타내는 bipartite graph를 구성한다.
Network의 특성: 하나의 유전자와만 연관된 SNP가 많고, 여러 유전자와 연관된 SNP는 매우 적다 (hubs) (~scale free?)
근데 Disease와 연관된 SNP는 hub SNP가 아니다! Hubs are GWAS desert!
Network comunity modularity에 기여하는 정도를 score로 하여 각 SNP에 할당. (core score)
Significant SNPs 의 core score는 non-significant SNP보다 median이 20.3배 높더라.
→ In most instances it isn’t a single gene controlling a single traint, but a family of genetic variants that influence a process


Defining the role of common variation in the genomic and biological architecture of adult human height
250,000 individuals, GWAS reveals 697 explain 20% of height, ~10,000 SNPs explain 30% of height → Individual variants have very small effect size
A saturated map of common genetic variants associated with human height
12,111 SNPs account for 40%!

Can we model gene regulatory processes?

Integrative Network Inference: PANDA → Infers gene regulatory network
Template은 motif 기반의 TF-TG network
Co-expression is evidence for regulation → Expression data tkdyd
PPI is evidence for regulation → Interaction data 사용


Understanding tissue-specific gene regulation, Cell Reports

Reconstructing gene regulatory network

Single-sample Networks (LIONESS)
Sample i 를 제외하고 network를 만들었을 때 차이가 나는 network의 일부가 sample i의 contribution 이라는 아이디어
Sexual Dimorphism in Colorectal Cancer → Gene regulatory network이 drug metabolism 관련 pathway에서 차이가 나더라


Estimating Sample-specific regulatory network, iScience
Sex differences ~ , Cell Reports

Does this tell us something that co-expression does not?

Differential expression vs Differential co-expression


Gene targeting in Disease Neteworks, Front Gen

How do SNPs and TFs alter gene regulation?

EGRET: Extending the model to include genotype, Gen Res
CAD, CD → Differential regulatory activity에 의해 발생한다는 증거

GRAND: Gene regulatory network database