Gene Losses during Human Origins
Open accessAbstract
Pseudogenization is a widespread phenomenon in genome evolution, and it has been proposed to serve as an engine of evolutionary change, especially during human origins (the "less-is-more" hypothesis). However, there has been no comprehensive analysis of human-specific pseudogenes. Furthermore, it is unclear whether pseudogenization itself can be selectively favored and thus play an active role in human evolution. Here we conduct a comparative genomic analysis and a literature survey to identify 80 nonprocessed pseudogenes that were inactivated in the human lineage after its separation from the chimpanzee lineage. Many functions are involved among these genes, with chemoreception and immune response being outstandingly overrepresented, suggesting potential species-specific features in these aspects of human physiology. To explore the possibility of adaptive pseudogenization, we focus on CASPASE12, a cysteinyl aspartate proteinase participating in inflammatory and innate immune response to endotoxins. We provide population genetic evidence that the nearly complete fixation of a null allele at CASPASE12 has been driven by positive selection, probably because the null allele confers protection from severe sepsis. We estimate that the selective advantage of the null allele is about 0.9% and the pseudogenization started shortly before the out-of-Africa migration of modern humans. Interestingly, two other genes related to sepsis were also pseudogenized in humans, possibly by selection. These adaptive gene losses might have occurred because of changes in our environment or genetic background that altered the threat from or response to sepsis. The identification and analysis of human-specific pseudogenes open the door for understanding the roles of gene losses in human origins, and the demonstration that gene loss itself can be adaptive supports and extends the "less-is-more" hypothesis.
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Previous studies that comprehensively discovered and characterized genes lost in humans and related primates were limited to the human genome or involved manual curation, which prevents a large-scale application to many other species.
“Previous studies that comprehensively discovered and characterized genes that are lost in humans and related primates were limited to the human genome19 or involved manual curation13,22, which prevents a large-scale application to many other species.”
From A genomics approach reveals insights into the importance of gene losses for mammalian adaptations (2018) · cites this paper as [19]
The Results/Discussion section, “Identification of Human-Specific Pseudogenes” (page unavailable), describes a study that identified 67 human-specific pseudogenes through comparisons of human and chimpanzee sequences. The Materials and Methods section describes BLAT searches and gene-tree reconstruction, but our copy does not establish that this study involved manual curation or that manual curation prevented its application to many other species. The separate claim about work limited to the human genome is attached to a different citation. (LLM, conf=0.78)
Experimental — accuracy not yet measuredGene loss in humans or human individuals can be adaptive by enhancing protection against pathogenic bacteria or diseases such as plasmodium and HIV infections, and sepsis.
“These studies also revealed that gene loss in humans or human individuals can be adaptive by enhancing protection against pathogenic bacteria or diseases such as plasmodium and HIV infections, and sepsis17–20.”
From A genomics approach reveals insights into the importance of gene losses for mammalian adaptations (2018) · cites this paper as [19]
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Self-citation
- Authors
- Wang, X., Grus, W. E., & Zhang, J.
- Affiliations
- University of Michigan (US)
- Corresponding author
- Zhang, Jianzhi
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2006-02-14
- Volume
- 4
- Issue
- 3
- Pages
- e52
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC1361800
- OpenAlex
- W1966803394
- Cited by
- 246
- References
- 80
- Citations by year
- 2026: 5 · 2025: 2 · 2024: 6 · 2023: 3 · 2022: 6 · 2021: 15 · 2020: 8 · 2019: 4 · 2018: 6 · 2017: 2 · 2016: 10 · 2015: 8 · 2014: 16 · 2013: 8 · 2012: 12
- FWCI
- 17.36
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- University of Michigan
- National Institutes of Health
- National Human Genome Research Institute (T32HG000040)
- National Institute of General Medical Sciences (R01GM067030)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Evolution and Genetic Dynamics
- Social Sciences › Anthropology › Pleistocene-Era Hominins and Archaeology
- Life Sciences › Agricultural and Biological Sciences › Plant Science › Chromosomal and Genetic Variations
- Keywords
- pseudogenization, gene loss, human evolution, positive selection, innate immunity, chemoreception, out-of-Africa migration, comparative genomics
- MeSH terms
- Animals, Pan troglodytes, Humans, Pseudogenes, Species Specificity, Genetic Variation, Evolution, Molecular, Computational Biology, Caspases
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