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Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes.

Cañestro C, Catchen JM, Rodríguez-Marí A, Yokoi H, Postlethwait JH - PLoS Genet. (2009)

Bottom Line: Interestingly, results revealed asymmetric distribution of surviving ohnologs between co-orthologous teleost chromosome segments, suggesting that local genome architecture can influence ohnolog survival.We propose a model that reconstructs the chromosomal history of the Aldh1a family in the ancestral vertebrate genome, coupled with the evolution of gene functions in surviving Aldh1a ohnologs after R1, R2, and R3 genome duplications.Results provide evidence for early subfunctionalization and late subfunction-partitioning and suggest a mechanistic model based on altered regulation leading to heterochronic gene expression to explain the acquisition or modification of subfunctions by surviving ohnologs that preserve unaltered ancestral developmental programs in the face of gene loss.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience, University of Oregon, Eugene, OR, USA.

ABSTRACT
Genome duplications increase genetic diversity and may facilitate the evolution of gene subfunctions. Little attention, however, has focused on the evolutionary impact of lineage-specific gene loss. Here, we show that identifying lineage-specific gene loss after genome duplication is important for understanding the evolution of gene subfunctions in surviving paralogs and for improving functional connectivity among human and model organism genomes. We examine the general principles of gene loss following duplication, coupled with expression analysis of the retinaldehyde dehydrogenase Aldh1a gene family during retinoic acid signaling in eye development as a case study. Humans have three ALDH1A genes, but teleosts have just one or two. We used comparative genomics and conserved syntenies to identify loss of ohnologs (paralogs derived from genome duplication) and to clarify uncertain phylogenies. Analysis showed that Aldh1a1 and Aldh1a2 form a clade that is sister to Aldh1a3-related genes. Genome comparisons showed secondarily loss of aldh1a1 in teleosts, revealing that Aldh1a1 is not a tetrapod innovation and that aldh1a3 was recently lost in medaka, making it the first known vertebrate with a single aldh1a gene. Interestingly, results revealed asymmetric distribution of surviving ohnologs between co-orthologous teleost chromosome segments, suggesting that local genome architecture can influence ohnolog survival. We propose a model that reconstructs the chromosomal history of the Aldh1a family in the ancestral vertebrate genome, coupled with the evolution of gene functions in surviving Aldh1a ohnologs after R1, R2, and R3 genome duplications. Results provide evidence for early subfunctionalization and late subfunction-partitioning and suggest a mechanistic model based on altered regulation leading to heterochronic gene expression to explain the acquisition or modification of subfunctions by surviving ohnologs that preserve unaltered ancestral developmental programs in the face of gene loss.

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Evolutionary model reconstructs the history of the Aldh1a genomic neighborhoods from ancestral vertebrate chromosomes.Circles and numbers near chromosomes label Aldh1a paralogs, and their genomic neighborhoods are color-coded (Aldh1a1: red; Aldh1a2: blue; Aldh1a3: light green; and Aldh1a3-ogm: dark green). Duplication, preservation, losses and translocation of Aldh1 gene paralogs are inferred in ancestral vertebrate chromosomes (e.g. A0–A5 [26]). Step numbers in circles label chromosome rearrangements. Vertical gray bars signify rounds of whole genome duplication events (R1, R2 and R3). Transparent images signify lost genes. In addition to the ancestral status inferred directly from comparative genomic analysis of conserved syntenies (white background; see main text for details), the figure shows two hypotheses (pink and tan boxes) to explain the mechanisms by which the Aldh1a1/2/3/3-ogm gene precursor located in the pre-R1 chromosome “A” generated the genome neighborhoods of Aldh1a2 and Aldh1a3 in chromosome “A4”, and Aldh1a1 and Aldh1a3-ogm in “A0” inferred after R2 (step 1). Under hypothesis 1 (“pre-R1 duplication scenario” in the pink box), a segment from Nakatani et al.'s ancestral chromosome “A” including the original Aldh1a1/2/3/3-ogm gene was tandemly duplicated prior to R1 and gave rise to the Aldh1a1/2 and Aldh1a3/3-ogm genes. Considering the most parsimonious situation, after R1, one of the two homeologs preserved both Aldh1a1/2 and Aldh1a3/3-ogm, and the other homeolog lost both duplicated copies. After R2, the chromosome preserving the Aldh1a genes gave rise to “A4” and “A0”, from which today's Aldh1a gene family members have evolved. After R2, the chromosome that did not preserve an Aldh1a gene gave rise to “A2–A5” and “A1–A3”, explaining conserved syntenies related to the Aldh1a family observed in today's Hsa1 and Hsa19 (see Figure 2). An alternative hypothesis to explain the ancestral synteny of Aldh1a genomic neighborhoods inferred in A4 and A0 (hypothesis 2, the “translocation scenario” in the tan box) proposes a translocation event, which may have occurred either before R2 (top half of tan box) or after R2 (bottom half of tan box). In these scenarios, and in contrast to hypothesis 1, a single original gene Aldh1a1/2/3/3-ogm was present in the ancestral chromosome “A”, and after R1, aldh1a1/2 and aldh1a3/3-ogm genes originated in duplicated chromosomes. One possibility (top half in tan box) is that, before R2, a small chromosomal translocation placed Aldh1a1/2 and Aldh1a3/3-ogm on the same chromosome (dotted arrow in tan box). After R2, the chromosome “recipient” of the translocation gave rise to “A4” and “A0”, which contained all Aldh1a ancestral genes from today's Aldh1a family members, while the chromosome “donor” gave rise to “A2–A5” and “A1–A3”, which lacked any Aldh1a gene but still preserved syntenies for Aldh1a gene neighborhoods. The possibility that the translocation carrying Aldh1a3 to the same chromosome as Aldh1a2 could have occurred after R2 cannot be discarded (dotted arrow bottom half in tan box), and would be consistent with the absence of any Aldh1a paralog in Hsa5 (white box at the bottom on chromosome A0). In this case, however, we would not expect to find paralogs of genes that are tightly linked to ALDH1A2 or ALDH1A1 on Hsa5. We found, however, genes including CCNB1, GCNT4, FAM81B in Hsa5, whose paralogs CNB2, GCNT3 and FAM81A are located near ALDH1A2 in Hsa15, and GCNT1, a third GCNT3 paralog, is close to ALDH1A1 in Hsa9. Further gene translocations, however, could explain the presence of those genes in Hsa5, and therefore a hypothetical translocation after R2 cannot be discarded.
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pgen-1000496-g007: Evolutionary model reconstructs the history of the Aldh1a genomic neighborhoods from ancestral vertebrate chromosomes.Circles and numbers near chromosomes label Aldh1a paralogs, and their genomic neighborhoods are color-coded (Aldh1a1: red; Aldh1a2: blue; Aldh1a3: light green; and Aldh1a3-ogm: dark green). Duplication, preservation, losses and translocation of Aldh1 gene paralogs are inferred in ancestral vertebrate chromosomes (e.g. A0–A5 [26]). Step numbers in circles label chromosome rearrangements. Vertical gray bars signify rounds of whole genome duplication events (R1, R2 and R3). Transparent images signify lost genes. In addition to the ancestral status inferred directly from comparative genomic analysis of conserved syntenies (white background; see main text for details), the figure shows two hypotheses (pink and tan boxes) to explain the mechanisms by which the Aldh1a1/2/3/3-ogm gene precursor located in the pre-R1 chromosome “A” generated the genome neighborhoods of Aldh1a2 and Aldh1a3 in chromosome “A4”, and Aldh1a1 and Aldh1a3-ogm in “A0” inferred after R2 (step 1). Under hypothesis 1 (“pre-R1 duplication scenario” in the pink box), a segment from Nakatani et al.'s ancestral chromosome “A” including the original Aldh1a1/2/3/3-ogm gene was tandemly duplicated prior to R1 and gave rise to the Aldh1a1/2 and Aldh1a3/3-ogm genes. Considering the most parsimonious situation, after R1, one of the two homeologs preserved both Aldh1a1/2 and Aldh1a3/3-ogm, and the other homeolog lost both duplicated copies. After R2, the chromosome preserving the Aldh1a genes gave rise to “A4” and “A0”, from which today's Aldh1a gene family members have evolved. After R2, the chromosome that did not preserve an Aldh1a gene gave rise to “A2–A5” and “A1–A3”, explaining conserved syntenies related to the Aldh1a family observed in today's Hsa1 and Hsa19 (see Figure 2). An alternative hypothesis to explain the ancestral synteny of Aldh1a genomic neighborhoods inferred in A4 and A0 (hypothesis 2, the “translocation scenario” in the tan box) proposes a translocation event, which may have occurred either before R2 (top half of tan box) or after R2 (bottom half of tan box). In these scenarios, and in contrast to hypothesis 1, a single original gene Aldh1a1/2/3/3-ogm was present in the ancestral chromosome “A”, and after R1, aldh1a1/2 and aldh1a3/3-ogm genes originated in duplicated chromosomes. One possibility (top half in tan box) is that, before R2, a small chromosomal translocation placed Aldh1a1/2 and Aldh1a3/3-ogm on the same chromosome (dotted arrow in tan box). After R2, the chromosome “recipient” of the translocation gave rise to “A4” and “A0”, which contained all Aldh1a ancestral genes from today's Aldh1a family members, while the chromosome “donor” gave rise to “A2–A5” and “A1–A3”, which lacked any Aldh1a gene but still preserved syntenies for Aldh1a gene neighborhoods. The possibility that the translocation carrying Aldh1a3 to the same chromosome as Aldh1a2 could have occurred after R2 cannot be discarded (dotted arrow bottom half in tan box), and would be consistent with the absence of any Aldh1a paralog in Hsa5 (white box at the bottom on chromosome A0). In this case, however, we would not expect to find paralogs of genes that are tightly linked to ALDH1A2 or ALDH1A1 on Hsa5. We found, however, genes including CCNB1, GCNT4, FAM81B in Hsa5, whose paralogs CNB2, GCNT3 and FAM81A are located near ALDH1A2 in Hsa15, and GCNT1, a third GCNT3 paralog, is close to ALDH1A1 in Hsa9. Further gene translocations, however, could explain the presence of those genes in Hsa5, and therefore a hypothetical translocation after R2 cannot be discarded.

Mentions: Based on results obtained from the analysis of synteny conservation of the Aldh1a1 genomic neighborhoods across human and model organism genomes, we infer an evolutionary model that reconstructs the genomic history of the Aldh1a family, and integrates previous work by Nakatani et al., (2007) [26] that had reconstructed the re-organization of the ancestral chromosomes (named A to J) of the last common ancestor of vertebrates through R1, R2 and R3 genome duplications (Figure 7). Because Aldh1a2 and Aldh1a3 are syntenic (on the same chromosome) in human, zebrafish, and stickleback genomes, we conclude that this was the state in their last common ancestor (Figure 7 step 1). According to Nakatani's reconstruction, Hsa15 mostly derives from the post-R2 ancestral chromosome “A4”, which allows us to infer that Aldh1a2 and Aldh1a3 were syntenic in the ancestral chromosome A4 (Figure 7 step 1). After our comparative analysis of synteny conservation between human and mouse, which ruled out the possibility of reciprocal Aldh1a3 paralog losses (Figure 3) and showed that Aldh1a3 genes are actual orthologs (Figure 1), we conclude that the Aldh1a3-ogm was already absent in the last common ancestor of tetrapods and teleosts (Figure 7 step 1). If Aldh1a2 and Aldh1a3 were syntenic in the ancestral state, we reason that a chromosomal translocation might have occurred during the evolution of the rodent lineage to separate them into different chromosomes (e.g Mmu9 and Mmu7 in Figure 7 step 2). Because the fourth Aldh1a paralog of rodents (i.e. Aldh1a7 in mouse) is adjacent and oppositely oriented to Aldh1a1, separated only by 0.5 Mb with no intervening genes, we conclude that the fourth Aldh1a rodent paralog originated by a rodent-specific tandem gene duplication associated with a local inversion (Figure 7 step 2) that was probably followed by subsequent amino acid sequence changes that destroyed its ability to synthesize RA [64].


Consequences of lineage-specific gene loss on functional evolution of surviving paralogs: ALDH1A and retinoic acid signaling in vertebrate genomes.

Cañestro C, Catchen JM, Rodríguez-Marí A, Yokoi H, Postlethwait JH - PLoS Genet. (2009)

Evolutionary model reconstructs the history of the Aldh1a genomic neighborhoods from ancestral vertebrate chromosomes.Circles and numbers near chromosomes label Aldh1a paralogs, and their genomic neighborhoods are color-coded (Aldh1a1: red; Aldh1a2: blue; Aldh1a3: light green; and Aldh1a3-ogm: dark green). Duplication, preservation, losses and translocation of Aldh1 gene paralogs are inferred in ancestral vertebrate chromosomes (e.g. A0–A5 [26]). Step numbers in circles label chromosome rearrangements. Vertical gray bars signify rounds of whole genome duplication events (R1, R2 and R3). Transparent images signify lost genes. In addition to the ancestral status inferred directly from comparative genomic analysis of conserved syntenies (white background; see main text for details), the figure shows two hypotheses (pink and tan boxes) to explain the mechanisms by which the Aldh1a1/2/3/3-ogm gene precursor located in the pre-R1 chromosome “A” generated the genome neighborhoods of Aldh1a2 and Aldh1a3 in chromosome “A4”, and Aldh1a1 and Aldh1a3-ogm in “A0” inferred after R2 (step 1). Under hypothesis 1 (“pre-R1 duplication scenario” in the pink box), a segment from Nakatani et al.'s ancestral chromosome “A” including the original Aldh1a1/2/3/3-ogm gene was tandemly duplicated prior to R1 and gave rise to the Aldh1a1/2 and Aldh1a3/3-ogm genes. Considering the most parsimonious situation, after R1, one of the two homeologs preserved both Aldh1a1/2 and Aldh1a3/3-ogm, and the other homeolog lost both duplicated copies. After R2, the chromosome preserving the Aldh1a genes gave rise to “A4” and “A0”, from which today's Aldh1a gene family members have evolved. After R2, the chromosome that did not preserve an Aldh1a gene gave rise to “A2–A5” and “A1–A3”, explaining conserved syntenies related to the Aldh1a family observed in today's Hsa1 and Hsa19 (see Figure 2). An alternative hypothesis to explain the ancestral synteny of Aldh1a genomic neighborhoods inferred in A4 and A0 (hypothesis 2, the “translocation scenario” in the tan box) proposes a translocation event, which may have occurred either before R2 (top half of tan box) or after R2 (bottom half of tan box). In these scenarios, and in contrast to hypothesis 1, a single original gene Aldh1a1/2/3/3-ogm was present in the ancestral chromosome “A”, and after R1, aldh1a1/2 and aldh1a3/3-ogm genes originated in duplicated chromosomes. One possibility (top half in tan box) is that, before R2, a small chromosomal translocation placed Aldh1a1/2 and Aldh1a3/3-ogm on the same chromosome (dotted arrow in tan box). After R2, the chromosome “recipient” of the translocation gave rise to “A4” and “A0”, which contained all Aldh1a ancestral genes from today's Aldh1a family members, while the chromosome “donor” gave rise to “A2–A5” and “A1–A3”, which lacked any Aldh1a gene but still preserved syntenies for Aldh1a gene neighborhoods. The possibility that the translocation carrying Aldh1a3 to the same chromosome as Aldh1a2 could have occurred after R2 cannot be discarded (dotted arrow bottom half in tan box), and would be consistent with the absence of any Aldh1a paralog in Hsa5 (white box at the bottom on chromosome A0). In this case, however, we would not expect to find paralogs of genes that are tightly linked to ALDH1A2 or ALDH1A1 on Hsa5. We found, however, genes including CCNB1, GCNT4, FAM81B in Hsa5, whose paralogs CNB2, GCNT3 and FAM81A are located near ALDH1A2 in Hsa15, and GCNT1, a third GCNT3 paralog, is close to ALDH1A1 in Hsa9. Further gene translocations, however, could explain the presence of those genes in Hsa5, and therefore a hypothetical translocation after R2 cannot be discarded.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2682703&req=5

pgen-1000496-g007: Evolutionary model reconstructs the history of the Aldh1a genomic neighborhoods from ancestral vertebrate chromosomes.Circles and numbers near chromosomes label Aldh1a paralogs, and their genomic neighborhoods are color-coded (Aldh1a1: red; Aldh1a2: blue; Aldh1a3: light green; and Aldh1a3-ogm: dark green). Duplication, preservation, losses and translocation of Aldh1 gene paralogs are inferred in ancestral vertebrate chromosomes (e.g. A0–A5 [26]). Step numbers in circles label chromosome rearrangements. Vertical gray bars signify rounds of whole genome duplication events (R1, R2 and R3). Transparent images signify lost genes. In addition to the ancestral status inferred directly from comparative genomic analysis of conserved syntenies (white background; see main text for details), the figure shows two hypotheses (pink and tan boxes) to explain the mechanisms by which the Aldh1a1/2/3/3-ogm gene precursor located in the pre-R1 chromosome “A” generated the genome neighborhoods of Aldh1a2 and Aldh1a3 in chromosome “A4”, and Aldh1a1 and Aldh1a3-ogm in “A0” inferred after R2 (step 1). Under hypothesis 1 (“pre-R1 duplication scenario” in the pink box), a segment from Nakatani et al.'s ancestral chromosome “A” including the original Aldh1a1/2/3/3-ogm gene was tandemly duplicated prior to R1 and gave rise to the Aldh1a1/2 and Aldh1a3/3-ogm genes. Considering the most parsimonious situation, after R1, one of the two homeologs preserved both Aldh1a1/2 and Aldh1a3/3-ogm, and the other homeolog lost both duplicated copies. After R2, the chromosome preserving the Aldh1a genes gave rise to “A4” and “A0”, from which today's Aldh1a gene family members have evolved. After R2, the chromosome that did not preserve an Aldh1a gene gave rise to “A2–A5” and “A1–A3”, explaining conserved syntenies related to the Aldh1a family observed in today's Hsa1 and Hsa19 (see Figure 2). An alternative hypothesis to explain the ancestral synteny of Aldh1a genomic neighborhoods inferred in A4 and A0 (hypothesis 2, the “translocation scenario” in the tan box) proposes a translocation event, which may have occurred either before R2 (top half of tan box) or after R2 (bottom half of tan box). In these scenarios, and in contrast to hypothesis 1, a single original gene Aldh1a1/2/3/3-ogm was present in the ancestral chromosome “A”, and after R1, aldh1a1/2 and aldh1a3/3-ogm genes originated in duplicated chromosomes. One possibility (top half in tan box) is that, before R2, a small chromosomal translocation placed Aldh1a1/2 and Aldh1a3/3-ogm on the same chromosome (dotted arrow in tan box). After R2, the chromosome “recipient” of the translocation gave rise to “A4” and “A0”, which contained all Aldh1a ancestral genes from today's Aldh1a family members, while the chromosome “donor” gave rise to “A2–A5” and “A1–A3”, which lacked any Aldh1a gene but still preserved syntenies for Aldh1a gene neighborhoods. The possibility that the translocation carrying Aldh1a3 to the same chromosome as Aldh1a2 could have occurred after R2 cannot be discarded (dotted arrow bottom half in tan box), and would be consistent with the absence of any Aldh1a paralog in Hsa5 (white box at the bottom on chromosome A0). In this case, however, we would not expect to find paralogs of genes that are tightly linked to ALDH1A2 or ALDH1A1 on Hsa5. We found, however, genes including CCNB1, GCNT4, FAM81B in Hsa5, whose paralogs CNB2, GCNT3 and FAM81A are located near ALDH1A2 in Hsa15, and GCNT1, a third GCNT3 paralog, is close to ALDH1A1 in Hsa9. Further gene translocations, however, could explain the presence of those genes in Hsa5, and therefore a hypothetical translocation after R2 cannot be discarded.
Mentions: Based on results obtained from the analysis of synteny conservation of the Aldh1a1 genomic neighborhoods across human and model organism genomes, we infer an evolutionary model that reconstructs the genomic history of the Aldh1a family, and integrates previous work by Nakatani et al., (2007) [26] that had reconstructed the re-organization of the ancestral chromosomes (named A to J) of the last common ancestor of vertebrates through R1, R2 and R3 genome duplications (Figure 7). Because Aldh1a2 and Aldh1a3 are syntenic (on the same chromosome) in human, zebrafish, and stickleback genomes, we conclude that this was the state in their last common ancestor (Figure 7 step 1). According to Nakatani's reconstruction, Hsa15 mostly derives from the post-R2 ancestral chromosome “A4”, which allows us to infer that Aldh1a2 and Aldh1a3 were syntenic in the ancestral chromosome A4 (Figure 7 step 1). After our comparative analysis of synteny conservation between human and mouse, which ruled out the possibility of reciprocal Aldh1a3 paralog losses (Figure 3) and showed that Aldh1a3 genes are actual orthologs (Figure 1), we conclude that the Aldh1a3-ogm was already absent in the last common ancestor of tetrapods and teleosts (Figure 7 step 1). If Aldh1a2 and Aldh1a3 were syntenic in the ancestral state, we reason that a chromosomal translocation might have occurred during the evolution of the rodent lineage to separate them into different chromosomes (e.g Mmu9 and Mmu7 in Figure 7 step 2). Because the fourth Aldh1a paralog of rodents (i.e. Aldh1a7 in mouse) is adjacent and oppositely oriented to Aldh1a1, separated only by 0.5 Mb with no intervening genes, we conclude that the fourth Aldh1a rodent paralog originated by a rodent-specific tandem gene duplication associated with a local inversion (Figure 7 step 2) that was probably followed by subsequent amino acid sequence changes that destroyed its ability to synthesize RA [64].

Bottom Line: Interestingly, results revealed asymmetric distribution of surviving ohnologs between co-orthologous teleost chromosome segments, suggesting that local genome architecture can influence ohnolog survival.We propose a model that reconstructs the chromosomal history of the Aldh1a family in the ancestral vertebrate genome, coupled with the evolution of gene functions in surviving Aldh1a ohnologs after R1, R2, and R3 genome duplications.Results provide evidence for early subfunctionalization and late subfunction-partitioning and suggest a mechanistic model based on altered regulation leading to heterochronic gene expression to explain the acquisition or modification of subfunctions by surviving ohnologs that preserve unaltered ancestral developmental programs in the face of gene loss.

View Article: PubMed Central - PubMed

Affiliation: Institute of Neuroscience, University of Oregon, Eugene, OR, USA.

ABSTRACT
Genome duplications increase genetic diversity and may facilitate the evolution of gene subfunctions. Little attention, however, has focused on the evolutionary impact of lineage-specific gene loss. Here, we show that identifying lineage-specific gene loss after genome duplication is important for understanding the evolution of gene subfunctions in surviving paralogs and for improving functional connectivity among human and model organism genomes. We examine the general principles of gene loss following duplication, coupled with expression analysis of the retinaldehyde dehydrogenase Aldh1a gene family during retinoic acid signaling in eye development as a case study. Humans have three ALDH1A genes, but teleosts have just one or two. We used comparative genomics and conserved syntenies to identify loss of ohnologs (paralogs derived from genome duplication) and to clarify uncertain phylogenies. Analysis showed that Aldh1a1 and Aldh1a2 form a clade that is sister to Aldh1a3-related genes. Genome comparisons showed secondarily loss of aldh1a1 in teleosts, revealing that Aldh1a1 is not a tetrapod innovation and that aldh1a3 was recently lost in medaka, making it the first known vertebrate with a single aldh1a gene. Interestingly, results revealed asymmetric distribution of surviving ohnologs between co-orthologous teleost chromosome segments, suggesting that local genome architecture can influence ohnolog survival. We propose a model that reconstructs the chromosomal history of the Aldh1a family in the ancestral vertebrate genome, coupled with the evolution of gene functions in surviving Aldh1a ohnologs after R1, R2, and R3 genome duplications. Results provide evidence for early subfunctionalization and late subfunction-partitioning and suggest a mechanistic model based on altered regulation leading to heterochronic gene expression to explain the acquisition or modification of subfunctions by surviving ohnologs that preserve unaltered ancestral developmental programs in the face of gene loss.

Show MeSH
Related in: MedlinePlus