Apr 1, 2020

Investigating structure function relationships in the NOTCH family through large-scale somatic DNA sequencing studies

BioRxiv : the Preprint Server for Biology
Wen HuangTrudy Mackay

Abstract

The recent development of highly sensitive DNA sequencing techniques has detected large numbers of missense mutations of genes, including NOTCH1 and 2, in ageing normal tissues. Driver mutations persist and propagate in the tissue through a selective advantage over both wild-type cells and alternative mutations. This process of selection can be considered as a large scale, in vivo screen for mutations that increase clone fitness. It follows that the specific missense mutations that are observed in individual genes may offer us insights into the structure-function relationships. Here we show that the positively selected missense mutations in NOTCH1 and NOTCH2 in human oesophageal epithelium cause inactivation predominantly through protein misfolding. Once these mutations are excluded, we further find statistically significant evidence for selection at the ligand binding interface and calcium binding sites. In this, we observe stronger evidence of selection at the ligand interface on EGF12 over EGF11, suggesting that in this tissue EGF12 may play a more important role in ligand interaction. Finally, we show how a mutation hotspot in the NOTCH1 transmembrane helix arises through the intersection of both a high mutation rate and re...Continue Reading

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Mentioned in this Paper

Quantitative Trait Loci
Crops, Agricultural
Genome
Genes
Drosophila melanogaster Proteins
Inbred Strain
Drosophila
Gene Expression
Pharmaceutical Preparations
Psathyrella

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