Characteristics and possible mechanisms of formation of microinversions distinguishing human and chimpanzee genomes

Nadezhda A Potapova,Sergei M Mirkin,Alexey S Kondrashov

doi:10.1038/s41598-021-04621-w

Abstract

Genomic inversions come in various sizes. While long inversions are relatively easy to identify by aligning high-quality genome sequences, unambiguous identification of microinversions is more problematic. Here, using a set of extra stringent criteria to distinguish microinversions from other mutational events, we describe microinversions that occurred after the divergence of humans and chimpanzees. In total, we found 59 definite microinversions that range from 17 to 33 nucleotides in length. In majority of them, human genome sequences matched exactly the reverse-complemented chimpanzee genome sequences, implying that the inverted DNA segment was copied precisely. All these microinversions were flanked by perfect or nearly perfect inverted repeats pointing to their key role in their formation. Template switching at inverted repeats during DNA replication was previously discussed as a possible mechanism for the microinversion formation. However, many of definite microinversions found by us cannot be easily explained via template switching owing to the combination of the short length and imperfect nature of their flanking inverted repeats. We propose a novel, alternative mechanism that involves repair of a double-stranded break within the inverting segment via microhomology-mediated break-induced replication, which can consistently explain all definite microinversion events.

Highlights

Detection of long inversions can be hindered by incorrect genome assembly because most non-human genomes were sequenced via short-read platforms
Detection of short inversions, sometimes referred to as “ultra microinversions”5, “submicroscopic inversions”[7] or “pico inversions”[6], requires distinguishing them from products of other mechanisms that can produce segments of low similarity (“bubbles”) in genome alignments, such as clustered small-scale mutations, mutational hotspots or a large number of independent small-scale mutations that occurred by chance within a short segment of the g enome[2,9,10]
We found 59 microinversions of lengths from 17 to 33 on the evolutionary path connecting humans and chimpanzees (Fig. 1)

Summary

Introduction

Human genome sequences matched exactly the reverse-complemented chimpanzee genome sequences, implying that the inverted DNA segment was copied precisely All these microinversions were flanked by perfect or nearly perfect inverted repeats pointing to their key role in their formation. Detection of short inversions (with lengths below 100 nucleotides), sometimes referred to as “ultra microinversions”5, “submicroscopic inversions”[7] or “pico inversions”[6], requires distinguishing them from products of other mechanisms that can produce segments of low similarity (“bubbles”) in genome alignments, such as clustered small-scale mutations, mutational hotspots or a large number of independent small-scale mutations that occurred by chance within a short segment of the g enome[2,9,10]. Human and chimpanzee genomes, which are > 98% identical if long deletions and insertions are ignored, and ~ 95% identical, if all genetic differences are c onsidered[14], provide an Scientific Reports | (2022) 12:591

Methods

Results

Conclusion