DOI: 10.1101/494914Dec 13, 2018Paper

Nucleosome positioning stability is a significant modulator of germline mutation rate variation across the human genome

BioRxiv : the Preprint Server for Biology
Cai Li, Nicholas M. Luscombe

Abstract

Nucleosome organization is suggested to affect local mutation rates in a genome. However, the lack of de novo mutation and high-resolution nucleosome data have limited investigation. Further, analyses using indirect mutation rate measurements have yielded contradictory and potentially confounded results. Combining >300,000 human de novo mutations with high-resolution nucleosome maps, we reveal substantially elevated mutation rates around translationally stable ("strong") nucleosomes. Translational stability is an under-appreciated nucleosomal property, with greater impact than better-known factors like occupancy and histone modifications. We show that the mutational mechanisms affected by strong nucleosomes are low-fidelity replication, insufficient mismatch repair and increased double-strand breaks. Strong nucleosomes preferentially locate within young SINE/LINE transposons; subject to increased mutation rates, transposons are then more rapidly inactivated. Depletion of strong nucleosomes in older transposons suggests frequent re-positioning during evolution, thus resolving a debate about selective pressure on nucleosome-positioning. The findings have important implications for human genetics and genome evolution.

Related Concepts

Biological Evolution
Genome
Histones
Virus Replication
Germ-Line Mutation
DNA, Double-Stranded
Protein Biosynthesis
DNA Transposons
Analysis
Cellular Component Organization

Related Feeds

BioRxiv & MedRxiv Preprints

BioRxiv and MedRxiv are the preprint servers for biology and health sciences respectively, operated by Cold Spring Harbor Laboratory. Here are the latest preprint articles (which are not peer-reviewed) from BioRxiv and MedRxiv.