Gene-Pseudogene Inversions as a Hidden Source of Missing Heritability

Area of Science:

• Genomics
• Human Genetics
• Molecular Biology

Background:

• Pseudogenes are abundant genomic elements often considered non-functional.
• Growing evidence suggests pseudogenes play roles in human diseases.
• Gene-pseudogene arrangements can facilitate genomic rearrangements like inversions.

Purpose of the Study:

• To identify gene-pseudogene pairs prone to inversions.
• To investigate the role of these inversions in human diseases, particularly Charcot-Marie-Tooth (CMT) neuropathy.
• To assess the diagnostic utility of long read sequencing (LRS) for detecting these variants.

Main Methods:

• Genome-wide screening to identify oppositely oriented gene-pseudogene pairs.
• Analysis of 1000 Genomes Project long read sequencing (LRS) data.
• Investigation of inversions involving the SORD gene and its pseudogene SORD2P in CMT patients.
• Correlation analysis with chromatin contact data (Micro-C).

Main Results:

• Identified 411 gene-pseudogene pairs, 46 linked to disease, with 3.6% of healthy individuals carrying inversions.
• Discovered recurrent inversions between SORD and SORD2P in 9% of SORD-CMT patients, explaining previously unidentified pathogenic alleles.
• Found that gene-pseudogene pairs with chromatin contact are more susceptible to inversions.

Conclusions:

• Gene-pseudogene inversions represent an underrecognized class of pathogenic structural variants.
• LRS is crucial for detecting these inversions, which are missed by short-read sequencing.
• These findings may help explain missing heritability in Mendelian diseases.