Investigating the molecular mechanisms of GWAS signals

How many disease-associated variants map outside protein-coding sequences?

more than 90%

What are the applications of second-generation sequencing technology?

RNA seq, ChIP-seq, high-throughout chromosome conformation capture (Hi-C), chromatin accessibility profiling

What does RNA-seq allow for?

detection of gene expression level, identification of new transcripts

What does ChIP-seq do?

pull down DNA fragments protected by a specific protein

What is step 1 of Hi-C?

formaldehyde fixation and crosslinking of chromosomal regions in close spatial proximity

What is step 2 of Hi-C?

digested DNA fragments are labelled with biotin, ligated and then fragmented further by sonication

What is step 3 of Hi-C?

all ligated DNA fragments are pulled-down with streptavidin beads

What is step 4 of Hi-C?

sequencing to measure how frequent two genomic regions interact

What is the goal of the genotype-tissue expression project?

to study human gene expression and regulation and its relationship to genetic variation in 54 tissues of ~1000 individuals

What is the goal of the human cell atlas?

to create comprehensive reference maps of all human cells

What does functional omics propose?

the molecular mechanisms of GWAS signals in non-coding regions

What is the first purpose of functional omics?

identifying cell types and subtypes enriched with traits-associated signals at candidate cis-regulatory elements

What is the second purpose of functional omics?

prioritizing candidate causal variants at disease-associated loci

What is the third purpose of functional omics?

linking disease variants to putative target genes

What do genetic screens reveal?

the function of genes and regulatory variants

What are the common types of CRISPR screening methods?

survival, fluorescence-activated cell sorting based. arrayed, single-celled

What are the CRISPR-based strategies to link GWAS-identified SNP variants to gene expression?

high-density tiling flow cytometry screens, single-cell functional genomics screen