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Overcoming challenges and dogmas to understand the functions of pseudogenes

Abstract

Pseudogenes are defined as regions of the genome that contain defective copies of genes. They exist across almost all forms of life, and in mammalian genomes are annotated in similar numbers to recognized protein-coding genes. Although often presumed to lack function, growing numbers of pseudogenes are being found to play important biological roles. In consideration of their evolutionary origins and inherent limitations in genome annotation practices, we posit that pseudogenes have been classified on a scientifically unsubstantiated basis. We reflect that a broad misunderstanding of pseudogenes, perpetuated in part by the pejorative inference of the ‘pseudogene’ label, has led to their frequent dismissal from functional assessment and exclusion from genomic analyses. With the advent of technologies that simplify the study of pseudogenes, we propose that an objective reassessment of these genomic elements will reveal valuable insights into genome function and evolution.

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Fig. 1: Major classes of eukaryotic pseudogenes.
Fig. 2: Examples of pseudogene functions.
Fig. 3: Challenges and solutions to understanding pseudogene functions.
Fig. 4: CRISPR–Cas9-based approaches to understanding pseudogene functions.

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Acknowledgements

The authors thank J. Mattick for feedback on the manuscript and A. Ewing for helpful discussion. S.W.C. acknowledges support from a National Health and Medical Research Council (NHMRC) Early Career Fellowship (GNT1161832) and the Mater Foundation. G.J.F. acknowledges support from a CSL Centenary Fellowship and the Mater Foundation.

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S.W.C. and M.E.D. contributed to all aspects of the article. G.J.F. revised the manuscript.

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Correspondence to Seth W. Cheetham or Marcel E. Dinger.

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Nature Reviews Genetics thanks P. Carninci and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Glossary

Expressed sequence tags

(ESTs). Short fragmented sequences of cDNAs. Mapping ESTs identifies transcribed genes.

Non-synonymous substitutions

Nucleotide substitutions that change the encoded amino acid sequence.

Positive selection

Selection for alleles that increase fitness. Positive selection results in shifts of the allele frequency.

Purifying selection

Selection against alleles that are deleterious to fitness. Purifying selection maintains the amino acid sequence.

Retrotransposition

Insertion of a sequence into the genome via the reverse transcription and integration of an RNA intermediate.

Synonymous substitutions

Nucleotide substitutions that do not change the encoded amino acid sequence.

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Cheetham, S.W., Faulkner, G.J. & Dinger, M.E. Overcoming challenges and dogmas to understand the functions of pseudogenes. Nat Rev Genet 21, 191–201 (2020). https://doi.org/10.1038/s41576-019-0196-1

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