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Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates.

Zhang ZD, Frankish A, Hunt T, Harrow J, Gerstein M - Genome Biol. (2010)

Bottom Line: Furthermore, we identify 11 unitary pseudogenes that are polymorphic - that is, they have both nonfunctional and functional alleles currently segregating in the human population.Comparing them with their orthologs in other primates, we find that two of them are in fact pseudogenes in non-human primates, suggesting that they represent cases of a gene being resurrected in the human lineage.This analysis of unitary pseudogenes provides insights into the evolutionary constraints faced by different organisms and the timescales of functional gene loss in humans.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. zdzmg@gersteinlab.org

ABSTRACT

Background: Unitary pseudogenes are a class of unprocessed pseudogenes without functioning counterparts in the genome. They constitute only a small fraction of annotated pseudogenes in the human genome. However, as they represent distinct functional losses over time, they shed light on the unique features of humans in primate evolution.

Results: We have developed a pipeline to detect human unitary pseudogenes through analyzing the global inventory of orthologs between the human genome and its mammalian relatives. We focus on gene losses along the human lineage after the divergence from rodents about 75 million years ago. In total, we identify 76 unitary pseudogenes, including previously annotated ones, and many novel ones. By comparing each of these to its functioning ortholog in other mammals, we can approximately date the creation of each unitary pseudogene (that is, the gene 'death date') and show that for our group of 76, the functional genes appear to be disabled at a fairly uniform rate throughout primate evolution - not all at once, correlated, for instance, with the 'Alu burst'. Furthermore, we identify 11 unitary pseudogenes that are polymorphic - that is, they have both nonfunctional and functional alleles currently segregating in the human population. Comparing them with their orthologs in other primates, we find that two of them are in fact pseudogenes in non-human primates, suggesting that they represent cases of a gene being resurrected in the human lineage.

Conclusions: This analysis of unitary pseudogenes provides insights into the evolutionary constraints faced by different organisms and the timescales of functional gene loss in humans.

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Unitary pseudogene relativity. Given the phylogeny of human, chimpanzee, and mouse, a human unitary pseudogenes can arise from a gene loss that occurred in different lineages, including: (a) the human lineage after the human-chimp divergence; (b) the human-ancestral lineage after the human-mouse divergence but before the human-chimp divergence; and under different circumstances, such as (c) loss of a subfunctionalized gene in the human lineage after a duplication event before the human-chimp divergence. Because the absence of a functional gene in a species is only identifiable through the comparison with another species that has the functional ortholog, the human unitary pseudogene can be identified in (a) by comparing the human gene set to either the chimp or the mouse set as both of them have the human ortholog. In (b, c), however, the human unitary pseudogene can only be identified by comparing the human gene set to one of either the mouse or chimp gene set, as the other one does not have the human ortholog given the evolutionary history of the gene under consideration.
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Figure 7: Unitary pseudogene relativity. Given the phylogeny of human, chimpanzee, and mouse, a human unitary pseudogenes can arise from a gene loss that occurred in different lineages, including: (a) the human lineage after the human-chimp divergence; (b) the human-ancestral lineage after the human-mouse divergence but before the human-chimp divergence; and under different circumstances, such as (c) loss of a subfunctionalized gene in the human lineage after a duplication event before the human-chimp divergence. Because the absence of a functional gene in a species is only identifiable through the comparison with another species that has the functional ortholog, the human unitary pseudogene can be identified in (a) by comparing the human gene set to either the chimp or the mouse set as both of them have the human ortholog. In (b, c), however, the human unitary pseudogene can only be identified by comparing the human gene set to one of either the mouse or chimp gene set, as the other one does not have the human ortholog given the evolutionary history of the gene under consideration.

Mentions: To identify unitary pseudogenes in one species, we need a reference gene set from another species. This is not a mere operational convenience or necessity: unitary pseudogenes are conceptually comparative entities as speciation and gene duplication (and the possible subsequent gene death) are two separate events that most likely happen at different times. As a result, different sets of unitary pseudogenes in a species could be identified if reference gene sets from several species are used. For example, to identify human unitary pseudogenes, we can use mouse or chimpanzee gene sets. When the human gene loss happened after the human-chimp divergence and if the mouse and the chimp orthologs are both conserved, we have the same identifiable unitary pseudogene in human corresponding to its mouse or chimp ortholog (Figure 7a). If, however, the gene loss happened between the human-mouse and the human-chimp divergences and the mouse ortholog is conserved, the human unitary pseudogene is only meaningful and identifiable when the mouse gene set is used for the comparison (Figure 7b). In a slightly more complicated evolutionary scenario, if a gene was duplicated after the human-mouse divergence and its copy was successfully neo-functionalized (with substantial sequence change) before the human-chimp divergence and pseudogenized afterwards in the human lineage, the human unitary pseudogene is relative to, and identifiable by, its chimp ortholog (Figure 7c). Under this scenario, such human unitary pseudogenes - including human ψMYH16 - cannot be identified using the mouse protein/gene set and thus will be false negatives of the identification result (Table S6 in Additional file 1). The comparison between the human and chimpanzee genomic sequences has revealed a number of gene disruptions in humans [33].


Identification and analysis of unitary pseudogenes: historic and contemporary gene losses in humans and other primates.

Zhang ZD, Frankish A, Hunt T, Harrow J, Gerstein M - Genome Biol. (2010)

Unitary pseudogene relativity. Given the phylogeny of human, chimpanzee, and mouse, a human unitary pseudogenes can arise from a gene loss that occurred in different lineages, including: (a) the human lineage after the human-chimp divergence; (b) the human-ancestral lineage after the human-mouse divergence but before the human-chimp divergence; and under different circumstances, such as (c) loss of a subfunctionalized gene in the human lineage after a duplication event before the human-chimp divergence. Because the absence of a functional gene in a species is only identifiable through the comparison with another species that has the functional ortholog, the human unitary pseudogene can be identified in (a) by comparing the human gene set to either the chimp or the mouse set as both of them have the human ortholog. In (b, c), however, the human unitary pseudogene can only be identified by comparing the human gene set to one of either the mouse or chimp gene set, as the other one does not have the human ortholog given the evolutionary history of the gene under consideration.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2864566&req=5

Figure 7: Unitary pseudogene relativity. Given the phylogeny of human, chimpanzee, and mouse, a human unitary pseudogenes can arise from a gene loss that occurred in different lineages, including: (a) the human lineage after the human-chimp divergence; (b) the human-ancestral lineage after the human-mouse divergence but before the human-chimp divergence; and under different circumstances, such as (c) loss of a subfunctionalized gene in the human lineage after a duplication event before the human-chimp divergence. Because the absence of a functional gene in a species is only identifiable through the comparison with another species that has the functional ortholog, the human unitary pseudogene can be identified in (a) by comparing the human gene set to either the chimp or the mouse set as both of them have the human ortholog. In (b, c), however, the human unitary pseudogene can only be identified by comparing the human gene set to one of either the mouse or chimp gene set, as the other one does not have the human ortholog given the evolutionary history of the gene under consideration.
Mentions: To identify unitary pseudogenes in one species, we need a reference gene set from another species. This is not a mere operational convenience or necessity: unitary pseudogenes are conceptually comparative entities as speciation and gene duplication (and the possible subsequent gene death) are two separate events that most likely happen at different times. As a result, different sets of unitary pseudogenes in a species could be identified if reference gene sets from several species are used. For example, to identify human unitary pseudogenes, we can use mouse or chimpanzee gene sets. When the human gene loss happened after the human-chimp divergence and if the mouse and the chimp orthologs are both conserved, we have the same identifiable unitary pseudogene in human corresponding to its mouse or chimp ortholog (Figure 7a). If, however, the gene loss happened between the human-mouse and the human-chimp divergences and the mouse ortholog is conserved, the human unitary pseudogene is only meaningful and identifiable when the mouse gene set is used for the comparison (Figure 7b). In a slightly more complicated evolutionary scenario, if a gene was duplicated after the human-mouse divergence and its copy was successfully neo-functionalized (with substantial sequence change) before the human-chimp divergence and pseudogenized afterwards in the human lineage, the human unitary pseudogene is relative to, and identifiable by, its chimp ortholog (Figure 7c). Under this scenario, such human unitary pseudogenes - including human ψMYH16 - cannot be identified using the mouse protein/gene set and thus will be false negatives of the identification result (Table S6 in Additional file 1). The comparison between the human and chimpanzee genomic sequences has revealed a number of gene disruptions in humans [33].

Bottom Line: Furthermore, we identify 11 unitary pseudogenes that are polymorphic - that is, they have both nonfunctional and functional alleles currently segregating in the human population.Comparing them with their orthologs in other primates, we find that two of them are in fact pseudogenes in non-human primates, suggesting that they represent cases of a gene being resurrected in the human lineage.This analysis of unitary pseudogenes provides insights into the evolutionary constraints faced by different organisms and the timescales of functional gene loss in humans.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA. zdzmg@gersteinlab.org

ABSTRACT

Background: Unitary pseudogenes are a class of unprocessed pseudogenes without functioning counterparts in the genome. They constitute only a small fraction of annotated pseudogenes in the human genome. However, as they represent distinct functional losses over time, they shed light on the unique features of humans in primate evolution.

Results: We have developed a pipeline to detect human unitary pseudogenes through analyzing the global inventory of orthologs between the human genome and its mammalian relatives. We focus on gene losses along the human lineage after the divergence from rodents about 75 million years ago. In total, we identify 76 unitary pseudogenes, including previously annotated ones, and many novel ones. By comparing each of these to its functioning ortholog in other mammals, we can approximately date the creation of each unitary pseudogene (that is, the gene 'death date') and show that for our group of 76, the functional genes appear to be disabled at a fairly uniform rate throughout primate evolution - not all at once, correlated, for instance, with the 'Alu burst'. Furthermore, we identify 11 unitary pseudogenes that are polymorphic - that is, they have both nonfunctional and functional alleles currently segregating in the human population. Comparing them with their orthologs in other primates, we find that two of them are in fact pseudogenes in non-human primates, suggesting that they represent cases of a gene being resurrected in the human lineage.

Conclusions: This analysis of unitary pseudogenes provides insights into the evolutionary constraints faced by different organisms and the timescales of functional gene loss in humans.

Show MeSH
Related in: MedlinePlus