There are multiple types of genetic variation, including point mutations, deletions, copy number variants, duplications, and inversions. Out of these, inversions remain particularly unexplored. Inversions are poorly understood, in part, because they are more difficult to analyze than other types of mutations. Now, taking a multi-platform approach, researchers show that inversions are one of the most common mutational processes in humans.

The work is published in Cell, in the paper, “Recurrent inversion polymorphisms in humans associate with genetic instability and genomic disorders.

The team uncovered how inversions are formed and investigated in detail a set of 40 inversions that form recurrently in the genome—where the DNA sequence flips back and forth. These “flip-flopping” inversions typically lie in regions linked to the development of certain genomic disorders.

Inversions are relevant for the development of human diseases, such as developmental delays in children or neuropsychiatric disorders in adults. “Despite their importance, these regions have been very difficult to study before because of their complexity. Showing that these inversions indeed flip-flop back and forth required a new set of computational methods,” said Tobias Marschall, PhD, director of the Institute of Medical Biometry and Bioinformatics and the Heinrich Heine University Düsseldorf. “We can now provide human geneticists with a new tool to understand the origin of disease in their patients.”

The multi-platform approach integrated multiple genomic technologies. This enabled the  discovery of 729 inversions in 41 human genomes. When analyzing the mechanisms of inversion formation, the authors found that segmental duplications and retrotransposons have a role. In addition, the excess of common balanced inversions revealed hotspots of inversion recurrence.

More specifically, the authors noted that “approximately 85% of inversions <2 kbp form by twin-priming during L1 retrotransposition; 80% of the larger inversions are balanced and affect twice as many nucleotides as CNVs.” The team described 40 recurrent inversions encompassing 0.6% of the genome.

“We found that inversions form at a much higher rate than previously thought. In humans, at least 0.6% of the genome repeatedly changes direction, making inversion one of the fastest mutational processes in humans,” said Jan Korbel, PhD, senior scientist and head of data science at European Molecular Biology Laboratory (EMBL). “At these sites, the genome is not stable—the direction of the DNA code continues to switch back and forth.”

Many important human genes lie within these unstable regions. This flipping behavior of genomic regions must be considered when researchers study long-distance gene regulation or epigenetics.

“We showed for the first time that inversions can be associated with rare genomic rearrangements found in pediatric autism, developmental delay, and epilepsy,” said Evan Eichler, PhD, professor in the department of genome sciences at the University of Washington and an HHMI investigator. “The question now is why? We hypothesize that certain configurations at the flanks of the inversions either predispose or protect individuals and their offspring from disease-associated rearrangements. This could have a practical application in the clinic, where it could be used to identify families at risk for developing these disorders.”

Graphical abstract, Porubsky et al.