Analyses in a number of organisms have shown that duplicated genes are less likely to be essential than singletons. This implies that genes can often compensate for the loss of their paralogs. However, it is unclear why the loss of some duplicates can be compensated by their paralogs, whereas the loss of other duplicates cannot. Surprisingly, initial analyses in mice did not detect differences in the essentiality of duplicates and singletons. Only subsequent analyses, using larger gene knockout data sets and controlling for a number of confounding factors, did detect significant differences. Previous studies have not taken into account the tissues in which duplicates are expressed. We hypothesized that in complex organisms, in order for a gene’s loss to be compensated by one or more of its paralogs, such paralogs need to be expressed in at least the same set of tissues as the lost gene. To test our hypothesis, we classified mouse duplicates into two categories based on the expression patterns of their paralogs: “compensable duplicates” (those with paralogs expressed in all the tissues in which the gene is expressed) and “noncompensable duplicates” (those whose paralogs are not expressed in all the tissues where the gene is expressed). In agreement with our hypothesis, the essentiality of noncompensable duplicates is similar to that of singletons, whereas compensable duplicates exhibit a substantially lower essentiality. Our results imply that duplicates can often compensate for the loss of their paralogs, but only if they are expressed in the same tissues. Indeed, the compensation ability is more dependent on expression patterns than on protein sequence similarity. The existence of these two kinds of duplicates with different essentialities, which has been overlooked by prior studies, may have hindered the detection of differences between singletons and duplicates.
Gene duplicates, or paralogs, serve as a major source of new genetic material and comprise seeds for evolutionary innovation. While originally thought to be quickly lost or nonfunctionalized following duplication, now a vast number of paralogs are known to be retained in a functional state. Daughter paralogs can provide robustness through redundancy, specialize via sub-functionalization, or neo-functionalize to play new roles. Indeed, the duplication and divergence of developmental genes have played a monumental role in the evolution of animal forms (e.g., Hox genes). Still, despite their prevalence and evolutionary importance, the precise detection of gene duplicates in newly sequenced genomes remains technically challenging and often overlooked. This presents an especially pertinent problem for evolutionary developmental biology, where hypothesis testing requires accurate detection of changes in gene expression and function, often in nontraditional model species. Frequently, these analyses rely on molecular reagents designed within coding sequences that may be highly similar in recently duplicated paralogs, leading to cross-reactivity and spurious results. Thus, care is needed to avoid erroneously assigning diverged functions of paralogs to a single gene, and potentially misinterpreting evolutionary history. This perspective aims to overview the prevalence and importance of paralogs and to shed light on the difficulty of their detection and analysis while offering potential solutions.
more » « less- Award ID(s):
- 2305817
- PAR ID:
- 10542418
- Publisher / Repository:
- Oxford University Press
- Date Published:
- Journal Name:
- Integrative And Comparative Biology
- Volume:
- 64
- Issue:
- 2
- ISSN:
- 1540-7063
- Format(s):
- Medium: X Size: p. 556-564
- Size(s):
- p. 556-564
- Sponsoring Org:
- National Science Foundation
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