High-throughput identification of noncoding functional SNPs via type IIS enzyme restriction

Nature Genetics
Gang LiPeter A Nigrovic

Abstract

Genome-wide association studies (GWAS) have identified many disease-associated noncoding variants, but cannot distinguish functional single-nucleotide polymorphisms (fSNPs) from others that reside incidentally within risk loci. To address this challenge, we developed an unbiased high-throughput screen that employs type IIS enzymatic restriction to identify fSNPs that allelically modulate the binding of regulatory proteins. We coupled this approach, termed SNP-seq, with flanking restriction enhanced pulldown (FREP) to identify regulation of CD40 by three disease-associated fSNPs via four regulatory proteins, RBPJ, RSRC2 and FUBP-1/TRAP150. Applying this approach across 27 loci associated with juvenile idiopathic arthritis, we identified 148 candidate fSNPs, including two that regulate STAT4 via the regulatory proteins SATB2 and H1.2. Together, these findings establish the utility of tandem SNP-seq/FREP to bridge the gap between GWAS and disease mechanism.

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Citations

Mar 24, 2018·Arthritis & Rheumatology·Sebastiaan J Vastert, Peter A Nigrovic
Jun 7, 2019·Current Opinion in Rheumatology·Peter A NigrovicSusan D Thompson
Dec 11, 2020·Human Genome Variation·Madhavi K GanapathirajuKalyani B Karunakaran
Mar 19, 2021·Nature Reviews. Rheumatology·Peter A NigrovicAlberto Martini
Apr 3, 2021·American Journal of Human Genetics·Minal CaliskanJoseph C Maranville
Jul 1, 2021·Nature Reviews. Rheumatology·Yuriy BaglaenkoSoumya Raychaudhuri

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Methods Mentioned

BETA
dissection
pulldown
PCR
pull down
SNP-seq
electrophoretic mobility shift assay
transfection
Flow cytometry
ChIP
immunoprecipitation

Software Mentioned

EMSA
R
R function lm
FlowJo
HaploReg

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