Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 4 (3), e52

Gene Losses During Human Origins


Gene Losses During Human Origins

Xiaoxia Wang et al. PLoS Biol.


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.


Figure 1
Figure 1. Flow Chart for Identifying the 67 Human-Specific Nonprocessed Pseudogenes
The number of pseudogenes left after each step is given in the boxes.
Figure 2
Figure 2. Evolutionary Scenarios for Human-Specific Pseudogenes and Non–Human-Specific Pseudogenes
Functional genes and pseudogenes are represented by open and closed circles, respectively. A, A1, A2, and B represent hypothetical gene names. (A) The human-specific pseudogene has a functional chimpanzee ortholog. (B) The chimpanzee functional gene is most closely related to another chimpanzee functional gene. (C) The human pseudogene is most closely related to a functional human gene. (D) The chimpanzee functional ortholog is most closely related to a human functional gene. We consider (A) and (B) as human-specific pseudogenes.
Figure 3
Figure 3. Intraspecific DNA Sequence Variation in Noncoding Regions Linked with the Human CASP12 Gene
CASPASE12 is shown in blue, with the exons depicted by solid blue bars on the chromosome. The premature stop codon generated by the C → T nonsense mutation is shown by an asterisk in exon 4. The nine noncoding regions sequenced are indicated below the chromosome. Exons, introns, the nine noncoding regions, and spaces between regions are drawn to scale as indicated. Red circles (connected by the red dotted line) show nucleotide diversity per site among African T alleles (πT) and the red boxes shows πT ± one standard error of πT. Green squares (connected by the green dotted line) show nucleotide diversity per site among African C alleles (πC) and the green boxes shows πC ± one standard error of πC. The broken green line shows the mean πC across the nine noncoding regions sequenced. Black triangles (connected by the black solid line) show the ratio between πT and πC for each region. πC is estimated from eight alleles. πT is estimated from 22 alleles for regions 4, 5, and 6 and from eight alleles for the other regions. When only eight alleles are used, πT is 0.00018 ± 0.00007, 0.00129 ± 0.00071, and 0.00145 ± 0.00057 for regions 4, 5, and 6, respectively. πT is significantly lower than πC in regions 4 and 5 (Table S2).

Comment in

Similar articles

See all similar articles

Cited by 75 PubMed Central articles

See all "Cited by" articles


    1. Chen FC, Li WH. Genomic divergences between humans and other hominoids and the effective population size of the common ancestor of humans and chimpanzees. Am J Hum Genet. 2001;68:444–456. - PMC - PubMed
    1. Ebersberger I, Metzler D, Schwarz C, Paabo S. Genomewide comparison of DNA sequences between humans and chimpanzees. Am J Hum Genet. 2002;70:1490–1497. - PMC - PubMed
    1. Britten RJ. Divergence between samples of chimpanzee and human DNA sequences is 5%, counting indels. Proc Natl Acad Sci U S A. 2002;99:13633–13635. - PMC - PubMed
    1. Wildman DE, Uddin M, Liu G, Grossman LI, Goodman M. Implications of natural selection in shaping 99.4% nonsynonymous DNA identity between humans and chimpanzees: Enlarging genus Homo . Proc Natl Acad Sci U S A. 2003;100:7181–7188. - PMC - PubMed
    1. Watanabe H, Fujiyama A, Hattori M, Taylor TD, Toyoda A, et al. DNA sequence and comparative analysis of chimpanzee chromosome 22. Nature. 2004;429:382–388. - PubMed

Publication types

LinkOut - more resources