Discovery of non-reference processed pseudogenes in the Swedish population

Area of Science:

• Genomics
• Human Genetics
• Bioinformatics

Background:

• The human genome contains a vast majority of non-coding DNA, historically understudied and often termed 'junk DNA'.
• Pseudogenes, non-functional gene copies, are a significant non-coding feature, with processed pseudogenes arising from retrotransposition of mRNA.
• The variability and distribution of processed pseudogenes across human populations remain largely unknown.

Purpose of the Study:

• To develop and apply a custom pipeline for identifying processed pseudogenes in whole genome sequencing data.
• To discover novel processed pseudogenes absent from the current human genome reference (GRCh38).
• To analyze the variability and frequency of processed pseudogenes for potential applications in DNA testing and population genetics.

Main Methods:

• Applied a custom processed pseudogene pipeline to whole genome sequencing data from 3,500 individuals (1000 Genomes dataset and Swedish cohort).
• Analyzed sequence data to identify and position processed pseudogenes, including those not present in the GRCh38 reference.
• Evaluated the impact of processed pseudogenes on common structural variant calling algorithms.

Main Results:

• Discovered over 3,000 processed pseudogenes not annotated in the GRCh38 human genome reference.
• Successfully positioned 74% of detected processed pseudogenes, enabling formation analysis.
• Identified that common structural variant callers misclassify processed pseudogenes as deletions, leading to false positive truncating variant predictions.
• Documented significant variability in non-reference processed pseudogenes across populations, with potential utility as population-specific markers.

Conclusions:

• Processed pseudogenes are highly diverse and actively generated within the human genome.
• The developed pipeline effectively identifies novel processed pseudogenes and can reduce false positives in structural variation analysis.
• Non-reference processed pseudogenes represent a valuable resource for population genetics and forensic DNA testing.