The chemical defensome: Environmental sensing and response genes in the Strongylocentrotus purpuratus genome

May combine two claims.

The sea urchin genome contains at least 14 predicted PAS genes representing 12 of the 14 known metazoan PAS subfamilies.

“The sea urchin genome contains at least 14 predicted PAS genes representing 12 of the 14 known metazoan PAS subfamilies”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

One sea urchin AHR gene (Sp-Ahr) is most closely related to vertebrate AHRs, while Sp-Ahrl is a partial sequence more closely related to Drosophila spineless.

“One of the AHR genes (Sp-Ahr) is most closely related to vertebrate AHRs, while the other (Sp-Ahrl/Sp-AHR-like) is a partial gene sequence that is more closely related to the Drosophila AHR homolog spineless (ss).”

May combine two claims.

One large Maf gene and one small Maf gene have been reported in urchin, and both possess conserved EHR and bZIP domains.

“One large Maf gene (Sp-Maf, SPU_025888) and one small Maf gene ( Sp-Mafs, SPU_030167) have been reported in urchin (Coolen et al., 2005) (Table 1); both possess the conserved extended homology region (EHR) and bZIP domains that characterize vertebrate Maf proteins.”

• cites Coolen et al., 2005Not checked yet

  Not checked in the free run.

May combine two claims.

The sea urchin genome contains homologs of AHR, HIF, NFE2, HSF, and nuclear hormone receptors.

“The transcription factors include homologs of the aryl hydrocarbon receptor, hypoxia-inducible factor, nuclear factor erythroid-derived 2, heat shock factor, and nuclear hormone receptors”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

The other three NR1H-like genes form a monophyletic group that may represent a new subfamily within NR1.

“The other three NR1H-like genes form a monophyletic group that may represent a new subfamily within the NR1 family”

May combine two claims.

All complete CYP3-like sea urchin genes contain 12-13 exons, similar to tunicate and vertebrate CYP3 genes and different from insect CYP6 and CYP9 genes.

“All of the complete CYP3-like sea urchin genes contain 12-13 exons, remarkably similar to the 12-13 exons in tunicate and vertebrate CYP3 genes, and distinctly different from the 1-6 exons in insect CYP6 and CYP9 genes.”

May combine two claims.

The sea urchin genome contains 16 FMO genes, divided among 4 of the 5 FMO families, with the majority most closely related to FMO5.

“The sea urchin genome contains 16 FMO genes, divided among 4 of the 5 families of FMOs, FMO1, 2, 3, and 5, with the majority most closely related to FMO5.”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Eleven CYP1-like genes are present in the urchin genome, more than twice the five in C. intestinalis or the 3-4 in most vertebrates.

“Eleven CYP1-like genes are present in the urchin genome, more than twice the five CYP1s in C. intestinalis or the 3-4 CYP1s in most vertebrates.”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

The sea urchin genome contains 30 OATP genes, mostly (60%) members of the OATP4 subfamily.

“The sea urchin genome contains 30 OATP genes, mostly (60%) members of the OATP4 subfamily.”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

One ABCC gene, Sp-ABCC9A, has been cloned from sea urchin eggs and encodes a 1519-amino-acid protein with 33 exons spanning 24 kb.

“One ABCC gene, Sp-ABCC9A, has been cloned from sea urchin eggs and encodes a protein of 1519 amino acids (SPU_025903; 33 exons spanning 24 kb of genomic DNA).”

May combine two claims.

A second ABC gene, Sp-ABCB1, has been cloned from eggs and has 27 exons spanning 32 kb.

“A second ABC gene cloned from eggs is Sp-ABCB1 (SPU_001752, 27 exons spanning 32 kb of genomic DNA).”

May combine two claims.

The urchin genome contains single homologs of MTF1 (Sp-Mtf) and HSF1 (Sp-Hsf).

“Other stress-sensing genes present in the urchin genome include single homologs of the metal-responsive transcription factor MTF1 (Sp-Mtf, SPU_016490), and the heat shock factor HSF1 (Sp-Hsf, SPU_013409).”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Sea urchins have 65 ABC genes organized into 8 subfamilies, including the three multidrug transporter subfamilies ABCB, C, and G.

“Sea urchins have 65 ABC genes organized into 8 subfamilies (Supplemental Figs.S3-S9, Table S2) including the three multidrug transporter subfamilies (ABC B, C and G).”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Two partial CYP4C genes, CYP4C19 and CYP4C20, have been isolated from Lytechinus anamesis, and orthologs exist in S. purpuratus.

“Two partial CYP4C genes, CYP4C19 and CYP4C20, have been isolated from the white sea urchin, Lytechinus anamesis (Snyder, 1998), and orthologs of these exist in the S. purpuratus genome (SPU_002380 and SPU_012081, respectively).”

• cites Snyder, 1998Not checked yet

  Not checked in the free run.

May combine two claims.

One sea urchin gene (SPU_027598, Sp-FXR) is related to both LXR and FXR; its ligand-binding domain clusters with LXR and its DNA-binding domain with FXR.

“One of these genes (SPU_027598, Sp-FXR) is related to both LXR and FXR, and is of particular interest because the ligand-binding domain clusters with the LXR in phylogenetic analyses, whereas the DNAbinding domain clusters with the FXR”

May combine two claims.

Half of the CYP4 genes exhibit embryonic or larval expression, with SPU_005931 exhibiting high expression and a subset expressed at lower levels.

“Half of the CYP4 genes exhibit embryonic or laval expression, with SPU_005931 exhibiting high expression and a subset expressed at lower levels”

May combine two claims.

S. purpuratus possesses homologs of RXR (NR2B) and HNF4 (NR2A).

“S. purpuratus also possesses homologs of RXR (NR2B) and HNF4 (NR2A)”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Sp-Shr2 exhibits ubiquitous expression throughout development and appears upregulated in eggs in response to maternal estradiol treatment.

“Sp-Shr2 exhibits ubiquitous expression throughout development (Howard-Ashby et al., 2006) but also appears to be upregulated in eggs in response to maternal estradiol treatment (Roepke et al., 2006).”

• cites Howard-Ashby et al., 2006Not checked yet

  Not checked in the free run.

• cites Roepke et al., 2006Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There are four ABCG2-like genes in the urchin genome, the same number as in tunicates and zebrafish.

“There are four ABCG2-like genes in the urchin genome ( SPU_021184, SPU_014013, SPU_024785, and SPU_014007), the same number as in tunicates and zebrafish.”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Sea urchins possess 36 cytosolic SULT genes, 49 distinct UGT genes, and 38 GST genes.

“Sea urchins posses a large number of xenobiotic-conjugating enzymes, including genes for 36 cytosolic sulfotransferase (SULT) genes, 49 distinct UGT genes, and 38 GST genes”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

In the sea urchin, the number of CYP2-like genes is expanded relative to most other known genomes, consisting of 73 predicted genes, more than 60% of the total CYP complement, in contrast to 30-49% in vertebrate genomes.

“In the sea urchin, the number of CYP2-like genes is expanded relative to most other known genomes, consisting of 73 predicted genes, more than 60% of the total CYP complement, in contrast to the 30-49% in vertebrate genomes”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Sp-ABCB1 encodes a 1329-amino-acid protein and is detected in embryos shortly after fertilization.

“Sp-ABCB1 codes for a 1329-amino-acid protein and is detected in embryos shortly after fertilization.”

May combine two claims.

In sea urchins, the ABCC family is about 25% larger than in other deuterostome genomes, with at least 30 genes, accounting for almost half of all ABC transporters.

“In the case of sea urchins, the ABCC family is about 25% larger than in other deuterostome genomes, with at least 30 genes, accounting for almost half of all the ABC transporters”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

The sea urchin genome contains 10 CYP4-like genes; Bayesian analysis shows 3 cluster with vertebrate and tunicate CYP4F genes, whereas 6 form a cluster with vertebrate CYP4V genes.

“The sea urchin genome contains 10 CYP4-like genes; Bayesian phylogenetic analysis shows that 3 of these genes cluster with the vertebrate and tunicate CYP4F genes, whereas 6 form a cluster with the vertebrate CYP4V genes (data not shown).”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Sea urchins possess 20 ALDH genes, of which 5 are ALDH1-like and 2 are ALDH3A-like.

“Sea urchins posses 20 ALDH genes (Table 2; Supplemental Table S4), of which 5 are ALDH1-like (including three ALDH2 mitochondrial precursor-like genes) and 2 are ALDH3A-like.”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

The majority of CYP2-like genes (51/73) exhibit embryonic or larval expression, with five genes exhibiting very high embryonic expression levels.

“The majority of CYP2-like genes (51/73) exhibit embryonic or larval expression, with five genes (SPU_010576, SPU_016816, SPU_020753, SPU_020756, SPU_021087) exhibiting very high embryonic expression levels”

May combine two claims.

S. purpuratus possesses two PPAR paralogs but no estrogen receptors.

“S. purpuratus possesses two PPAR paralogs (SPU_021289 and SPU_019332; Table 1), but no ERs.”

• AssumptionRests on an assumption: The current sea urchin genome assembly and EST libraries are complete enough that failure to detect a homolog indicates its absence.
• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

The sea urchin genome contains 38 GST genes, which fall into six major GST classes: alpha, pi, sigma, theta, zeta, and omega.

“The 38 urchin GSTs represent 6 of the major GST classes (alpha, pi, sigma, theta, zeta, omega; Supplemental Fig. S10, Table S5).”

May combine two claims.

All but one of the ALDH1 and ALDH3-like genes are expressed during development, the exception being one ALDH2-like gene.

“All but one of the ALDH1 and ALDH3-like genes are expressed during development, the exception being one ALDH2-like gene (SPU_007284).”

May combine two claims.

The sea urchin contains 120 CYP genes, and those related to CYP families 1-4 constitute 80% of the total.

“The sea urchin contains 120 CYP genes, and those related to CYP gene families 1-4 constitute a large proportion (80%) of the total”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Sp-ABCB1 is one of 12 ABCB genes in sea urchin and is orthologous to mammalian ABCB1/PGP.

“This gene is one of 12 ABCB genes present in the sea urchin and is orthologous to mammalian ABCB1/PGP.”

• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Although sea urchin embryos have high efflux activity, Sp-ABCC9A transcript is present at trace quantities (<1 copy/cell).

“Although there are high levels of efflux activity in sea urchin embryos, the transcript is present at trace quantities, <1 copy/ cell”

• cites Hamdoun et al., 2004Not checked yet

  Not checked in the free run.

May combine two claims.

Much of the ABCC expansion is in Sp-ABCC5 and Sp-ABCC9 families, and orthologs of vertebrate ABCC2 are absent.

“Much of the expansion is in the Sp-ABCC5 and Sp-ABCC9 families, whereas orthologs of the vertebrate gene ABCC2 (also called MRP2) are absent.”

• AssumptionRests on an assumption: The current sea urchin genome assembly and EST libraries are complete enough that failure to detect a homolog indicates its absence.
• AssumptionRests on an assumption: Predicted gene models from the GLEAN3 assembly correspond to actual genes, so gene counts reflect functional gene family sizes.

May combine two claims.

Sea urchins possess 10 AKR-like genes but no NQO-like genes.

“Sea urchins possess 10 AKR-like genes but no NQO-like genes.”

• AssumptionRests on an assumption: The current S. purpuratus genome assembly is complete enough that failure to find a homolog indicates absence from the genome.

May combine two claims.

Three sea urchin genes similar to mammalian epoxide hydrolase-related genes are present, and these genes have no known function.

“Three sea urchin genes similar to mammalian epoxide hydrolase-related genes are also present; these genes do not have a known function.”

May combine two claims.

HSP genes appear to be highly expressed during development based on tiling array data, with roughly 80% of HSPs showing significant signals on the array.

“HSP genes appear to be highly expressed during development, based on the tiling array data (Samanta et al., 2006); roughly 80% of the HSPs showed significant signals on the array.”

• cites Samanta et al., 2006Not checked yet

  Not checked in the free run.

May combine two claims.

The reducing and hydrolyzing Phase II enzymes are represented in the sea urchin genome and are slightly expanded relative to mammals.

“The reducing and hydrolyzing Phase II enzymes are also represented in the sea urchin genome, and are slightly expanded relative to mammals (Table 2, Supplemental Fig. S12).”

May combine two claims.

In untreated sea urchins, embryonic and larval expression varies among toxicologically relevant GSTs; five alpha-class, three theta-class, all four omega-class, and both zeta and pi GSTs are expressed.

“Embryonic and larval expression in untreated sea urchins varies among the toxicologically relevant GSTs, with 5 alpha class, 3 theta class, all 4 omega class, and both the zeta and pi GSTs expressed (Supplemental Table S5).”

May combine two claims.

The sea urchin genome contains one homolog of GCLC (SPU_026291) and one of GCLM (SPU_002909), which along with GSS (SPU_000830) are expressed at high levels during developmental and larval stages.

“The urchin genome contains one homolog of both GCLC (SPU_026291) and GCLM (SPU_002909) which, along with GSS (SPU_000830), are expressed at high levels during developmental and larval stages (Table 3).”

May combine two claims.

The sea urchin genome contains 36 cytosolic SULT genes, divided into 17 SULT1-like and 19 SULT3/SULT4-like genes.

“The 36 cytosolic SULT genes in the urchin genome are divided into two major divisions: 17 are SULT1-like and 19 are SULT3/ SULT4-like (Supplemental Fig. S11).”

May combine two claims.

A variety of peroxidases are present, including four glutathione peroxidase genes, one of which is a single-exon gene (SPU_014373) and one of which is expressed during development (SPU_014276).

“A variety of peroxidases are present, including 4 glutathione peroxidase genes, one of which is a single exon gene (SPU_014373), and one that is expressed during development (SPU_014276).”

May combine two claims.

Other metal-binding genes in the sea urchin genome include a ceruloplasmin homolog (SPU_027885), a transferrin homolog (SPU_026949), and both heavy and light chains of ferritin (SPU_004876 and SPU_024366).

“Other metal-binding genes in the urchin genome include a homolog of the Cu and Fe-binding protein ceruloplasmin (SPU_027885, also know as ferroxidase), a homolog of the Febinding protein transferrin (SPU_026949), and both heavy and light chains of the Fe storage protein ferritin (SPU_004876 and SPU_024366).”

May combine two claims.

Of the sea urchin MGST-like genes, nine are MGST1-like, one is MGST2-like (SPU_008286), and two full or partially assembled genes are MGST3-like (SPU_016492 and SPU_023582).

“Nine are MGST1-like, only one is MGST2-like (SPU_008286), and the remaining two full and partially assembled genes are MGST3-like (SPU_016492 and SPU_023582).”

May combine two claims.

Sea urchins have at least four HSP90 genes and two small α-crystalline HSP20s.

“Sea urchins also have at least 4 HSP90 genes and 2 small α-crystalline HSP20s.”

May combine two claims.

The sea urchin genome contains one GST-pi gene (SPU_024294) and one GST-zeta gene (SPU_025025).

“We found only one GST-pi (SPU_024294) and one GSTzeta (SPU_025025); GST-pi has been related to carcinogenesis in humans and mice (Henderson et al., 1998), whereas GST-zeta deficiency causes oxidative stress in mice (Blackburn et al., 2006).”

May combine two claims.

At least three thioredoxin peroxidase genes are present (SPU_006211, SPU_014869, SPU_022529) and are expressed at high levels during normal development.

“At least three thioredoxin peroxidase genes are present (SPU_006211, SPU_014869, and SPU_022529), and expressed at high levels during normal development.”

May combine two claims.

Three PCS genes are present in the sea urchin genome (SPU_004431, SPU_022493, SPU_023132), four PCS homologs are present in Nematostella vectensis, and one PCS gene is present in Ciona intestinalis.

“Three PCS genes are present in the urchin genome (SPU_004431, SPU_022493, and SPU_023132), four PCS homologs are present in the genome of the sea anemone Nematostella vectensis, and one PCS gene is present in the genome of the tunicate C. intestinalis.”

May combine two claims.

The sea urchin genome possesses one vertebrate-like SOD2 gene (mitochondrial manganese SOD; SPU_024657) and one manganese SOD gene more similar to bacterial Mn/Fe SodM (SPU_021817).

“The sea urchin genome possesses one vertebrate-like SOD2 gene (mitochondrial manganese SOD; SPU_024657; see Table 3) and one manganese SOD gene that is more similar to bacterial Mn/Fe SodM (SPU_021817).”

May combine two claims.

The sea urchin genome contains eleven full and one partially assembled MGST-like genes, representing all three MGST classes (MGST1, MGST2, MGST3).

“Eleven full and one partially assembled MGST-like genes were found in the current urchin genome assembly (Table 2), representing all three classes of MGSTs (MGST1, MGST2, and MGST3).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The major heat shock protein family is HSP70, containing at least 17 genes with at least 10 HSP40/DNAJ co-chaperones.

“The major family of heat shock proteins is the HSP70 family, containing at least 17 genes with at least 10 HSP40/DNAJ co-chaperones.”

May combine two claims.

There are no ABCC2 genes in either urchins or tunicates; this gene subfamily may be specific to vertebrates.

“Interestingly, there are no ABCC2 genes in either urchins or tunicates; this gene subfamily may be specific to vertebrates.”

• AssumptionRests on an assumption: The current S. purpuratus genome assembly is complete enough that failure to find a homolog indicates absence from the genome.

May combine two claims.

Orthologous relationships are discernable among PAS proteins and among ABC transporters.

“Orthologous relationships are discernable among the PAS proteins and among the ABC transporters.”

Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

The total number of ABCB genes is similar across deuterostomes, with most species containing 1 or 2 ABCB1-like genes.

“The total number of ABCB genes is similar across deuterostomes, with most species containing 1 or 2 ABCB1-like genes.”

May combine two claims.

Both CYP3- and CYP1-related genes in sea urchin show a similar or even greater degree of expansion relative to the number of CYP3 or CYP1 genes in vertebrates.

“Although far fewer in absolute numbers, both the CYP3-and the CYP1related genes in urchin show a similar, or even greater degree of expansion relative to the number of CYP3 or CYP1 genes in vertebrates.”

May combine two claims.

In sea urchins there are 73 CYP genes related to the vertebrate CYP2 family, larger than the 16 CYP2s known in humans or most other vertebrates.

“For example, in urchins there are 73 CYP genes related to the vertebrate CYP2 family, larger than the 16 CYP2s known in humans or most other vertebrates (M.musculus: 51, R. rattus: 50, B. taurus: 23, T. rubripes: 17).”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Urchins have two ABCB1 genes, the same as in fish and rodents.

“Urchins have two ABCB1 genes, the same as in fish and rodents.”

May combine two claims.

Distinct orthologous relationships are less evident among CYP genes, or amongst GST, SULT, and UGT genes.

“Such distinct relationships are less evident among the CYP genes, or amongst the GST, SULT, and UGT genes.”

May combine two claims.

While there is general conformity in the presence of higher order gene groups across taxa, in most cases gene orthology is more difficult to determine.

“While there is general conformity in the presence of higher order gene groups across taxa, in most cases gene orthology is more difficult to determine.”

May combine two claims.

PAS gene diversity in S. purpuratus is similar to that found in other invertebrate genomes, including C. intestinalis, but lower than that of vertebrates.

“In contrast to the apparent diversification in several active defense gene groups, PAS gene diversity in S. purpuratus is similar to that found in other invertebrate genomes, including the chordate C. intestinalis, but lower than that of vertebrates (Supplemental Table S1).”

May combine two claims.

The expression of more than half of defense genes during embryonic or larval stages indicates that these genes are important during development.

“indicating their importance during development.”

Probably not a substantial claim: may not pass S3 (load-bearing).

EST or cDNA evidence confirms a number of the genes presented.

“EST or cDNA evidence confirms a number of the genes presented here, as noted in the Results.”

May combine two claims.

The sea urchin chemical defense gene network shows evolutionary conservation combined with lineage-specific diversification.

“reveals evolutionary conservation of this network combined with lineage-specific diversification”

Probably not a substantial claim: may not pass S3 (load-bearing).

Biotransformation can produce toxic and mutagenic metabolites in a cell- and chemical-specific manner.

“oxidation, N-acetylation, and sulfate or glutathione conjugation can lead to toxic and mutagenic metabolites in a cell and chemical specific manner”

• cites Gamage et al., 2006Not checked yet

  Not checked in the free run.

• cites Guengerich et al., 2003Not checked yet

  Not checked in the free run.

• cites Hein et al., 1993Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

There is a balance between protective and injurious processes and between endogenous and exogenous functions.

“Thus, there is a balance of protective and injurious processes, and between endogenous and exogenous functions”

• cites Nebert, 1991Not checked yet

  Not checked in the free run.

• cites Nebert and Russell, 2002Not checked yet

  Not checked in the free run.

Classified as probably not a substantial claim. May combine two claims.

Gene identities were confirmed by reciprocal BLAST against Genbank or by comparison to cloned cDNAs.

“Gene identities were confirmed by reciprocal BLAST of the predicted genes against Genbank or, where possible, by comparison to cloned cDNAs.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Bioactivation to toxic intermediates results from chemical structural diversity and the need to create reactive sites for conjugation.

“Bioactivation to toxic intermediates is therefore a consequence of chemical structural diversity and the occasional necessity for the creation of chemically reactive sites for subsequent conjugation reactions.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

PXR, CAR, BXR, CXR, PPARs, LXR, and FXR are activated by xenobiotic and endobiotic compounds and regulate coordinated responses involving CYP2s, CYP3s, CYP4s, conjugating enzymes, and transporters.

“The pregnane-X-receptor (PXR), constitutive androstane receptor (CAR), non-mammalian PXR homologs BXR and CXR, peroxisome proliferator-activated receptors (PPARs), liver-X-receptor (LXR), and farnesoid-Xreceptor (FXR) are activated by a variety of xenobiotic and endobiotic compounds and regulate a coordinated response involving various CYP2s, CYP3s, and CYP4s, conjugating enzymes, and transporters”

• cites Bock and Kohle, 2004Not checked yet

  Not checked in the free run.

• cites Klaassen and Slitt, 2005Not checked yet

  Not checked in the free run.

• cites Xie and Evans, 2001Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

NRF2 and related CNC-bZIP proteins are activated by oxidants and electrophiles and stimulate transcription of antioxidant enzyme genes.

“A third set of sensors includes nuclear factor erythroid-derived 2 (NFE2)-related factor 2 (NRF2, NFE2-like2) and related cap'n'collar (CNC)basic-leucine zipper (bZIP) family proteins, which are activated by oxidants and electrophiles and form heterodimers with small Maf proteins to stimulate transcription of genes encoding antioxidant enzymes such as GST, NQO, glutamate-cysteine ligase (GCL), SOD”

• cites Nguyen et al., 2003bNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

AHR is activated by planar aromatic hydrocarbons and other chemicals and regulates some CYP genes and genes for conjugating and reducing enzymes.

“The primary member of this family that is a chemical sensor, but also has developmental roles, is the aryl hydrocarbon receptor (AHR), which is activated by planar aromatic hydrocarbons and a variety of other chemicals”

• cites Denison and Nagy, 2003Not checked yet

  Not checked in the free run.

• cites Nebert et al., 2004Not checked yet

  Not checked in the free run.

• cites Whitlock, 1999Not checked yet

  Not checked in the free run.

May combine two claims.

Only one CYP2-like gene can be confidently assigned to a subfamily, CYP2U, suggesting functional conservation in that subfamily.

“Only one CYP2-like gene can be confidently assigned to a subfamily, CYP2U (SPU_008632), suggesting functional conservation in that subfamily.”

May combine two claims.

These three adjacent CYP1-like genes exhibit very different embryonic and larval expression, suggesting different enzymatic roles.

“These three adjacent genes exhibit very different embryonic and larval expression during normal development (SPU_010719 is weakly expressed, SPU_010720 is strongly expressed, and SPU_010721 does not show significant expression) suggesting different enzymatic roles in the organism”

Classified as probably not a substantial claim. May combine two claims.

If PTGS is truly missing, it suggests PTGS genes were lost on the echinoderm lineage, because at least two PTGS genes are present in vertebrates and two have been cloned from coral.

“If this result holds, it would suggest that PTGS genes have been lost on the echinoderm lineage, because at least two PTGS genes are present in vertebrates, and two PTGS genes have been cloned from coral”

• cites Jarving et al., 2004Not checked yet

  Not checked in the free run.

• AssumptionRests on an assumption: The current sea urchin genome assembly and EST libraries are complete enough that failure to detect a homolog indicates its absence.

May combine two claims.

Based on Bayesian analysis, the Lytechinus sequences cluster with vertebrate CYP4Vs, suggesting reconsideration of their classification.

“Based on Bayesian analysis, the Lytechinus sequences cluster with the vertebrate CYP4Vs, suggesting a reconsideration of the Lytechinus sequence classification.”

Probably not a substantial claim: may not pass S3 (load-bearing).

In mammals, alpha, pi, and mu GSTs conjugate polycyclic aromatic hydrocarbon metabolites.

“Alpha, pi, and mu GSTs in mammals are responsible for the conjugation of polycyclic aromatic hydrocarbon metabolites (Sundberg et al., 1997).”

• cites Sundberg et al., 1997Not checked yet

  Not checked in the free run.

May combine two claims.

Nine of the urchin CYP1-like genes are single coding exon genes, and three of these are adjacent in the genome assembly, suggesting tandem duplication following reinsertion of a processed transcript.

“Nine of the urchin genes are single coding exon genes, and three of these are adjacent in the genome assembly, suggesting tandem duplication following reinsertion of a processed transcript.”

May combine two claims.

At least two FMO5 genes are located on the same scaffold, suggesting urchin FMOs may be clustered like mammalian FMOs.

“At least two of the FMO5 genes are located on the same scaffold, suggesting that urchin FMOs may be clustered, similar to the mammalian genomic FMO arrangement.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Reactive oxygen species can be derived from various cellular processes and can contribute to diseases and pathologies due to altered gene expression or damage to biomolecules.

“Reactive oxygen species (ROS), including superoxide, hydrogen peroxide, and hydroxyl radicals, can be derived from a variety of cellular processes and can contribute to diseases and pathologies generally due to altered gene expression or damage to biomolecules, including proteins, lipids, and DNA (Halliwell and Gutteridge, 1999;Lesser, 2006).”

• cites Halliwell and Gutteridge, 1999Not checked yet

  Not checked in the free run.

• cites Lesser, 2006Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

GST-pi has been related to carcinogenesis in humans and mice.

“GST-pi has been related to carcinogenesis in humans and mice (Henderson et al., 1998), whereas GST-zeta deficiency causes oxidative stress in mice (Blackburn et al., 2006).”

• cites Henderson et al., 1998Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Mammals have two EPHX genes.

“There appear to be two membrane epoxide hydrolase (EPHX) genes similar to xenobiotic-inducible mammalian EPHX1, and three EPHX genes related to the vertebrate EPHX2 (soluble EPHX) genes (mammals have two EPHX genes (Barth et al., 2004a,b; fatty acid epoxides are the major physiological substrates of EPHX2).”

• cites Barth et al., 2004a,bNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In mammals, AKR1 family products function as aldehyde and aldose reductases and dihydrodiol dehydrogenases, acting on PAH-diols formed by CYP and EPHX.

“Six of the urchin AKR-like genes are most closely related to the vertebrate AKR1 family genes (Supplemental Fig. S13), the products of which in mammals function as aldehyde and aldose reductases and dihydrodiol dehydrogenases, acting on PAH-diols formed by CYP and EPHX (Hyndman et al., 2003;Jez and Penning, 2001).”

• cites Hyndman et al., 2003Not checked yet

  Not checked in the free run.

• cites Jez and Penning, 2001Not checked yet

  Not checked in the free run.

May combine two claims.

Metallothioneins MTA, MTB1, and MTB2 are active in response to excess metal stress but may also play roles in nutrient metal homeostasis and apoptosis.

“Three of the metal complexing genes found in the genome have previously been identified in sea urchins, the metallothioneins MTA, MTB1, and MTB2 (Nemer et al., 1991), which are active in response to excess metal stress but may also play roles in nutrient metal homeostasis and in apoptosis (reviewed in Vasak and Hasler, 2000).”

• cites Vasak and Hasler, 2000Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Only three MGSTs are present in the human genome.

“Only 3 MGSTs are present in the human genome (Pearson, 2005).”

• cites Pearson, 2005Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In mammals, expression of both GCLC and GCLM is dependent on NRF2.

“In mammals, expression of both GCLC and GCLM is dependent on NRF2 (Dickinson et al., 2004;Gong and Cederbaum, 2006;Yang et al., 2005).”

• cites Dickinson et al., 2004Not checked yet

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• cites Gong and Cederbaum, 2006Not checked yet

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• cites Yang et al., 2005Not checked yet

  Not checked in the free run.

May combine two claims.

Vertebrate genomes do not contain a gene homologous to PCS, suggesting that phytochelatin synthesis ability was lost after the divergence of tunicates from the lineage leading to vertebrates.

“Vertebrate genomes do not contain a gene homologous to PCS, suggesting that phytochelatin synthesis ability was lost some time after the divergence of tunicates from the lineage leading to the vertebrates.”

May combine two claims.

The expansion of MGST1-like genes in the sea urchin may be due to tandem duplication, because at least two gene clusters of MGST1-like genes (one of four genes and one of two genes) are present.

“The expansion in MGST1-like genes in the urchin may be due to tandem duplication, because at least two gene clusters of MGST1-like genes (one of 4 genes and one of 2 genes) are present.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Ovoperoxidase is similar to human myeloperoxidase.

“Urchins also posses a heme peroxidase important during fertilization, ovoperoxidase, which has superoxide dismutase activity (Heinecke and Shapiro, 1990;LaFleur et al., 1998) and is similar to human myeloperoxidase (Nomura et al., 1999).”

• cites Nomura et al., 1999Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Cavortin and pernin are hemolymph proteins with binding affinity for Fe, Cu, Ni, Co, and Zn.

“Interestingly, sea urchins possess an SOD2-like gene (SPU_014006) that may be related to the molluscan metal-binding proteins cavortin and pernin, which are hemolymph proteins with binding affinity for Fe but also Cu, Ni, Co, and Zn (Huvet et al., 2004;Scotti et al., 2001).”

• cites Huvet et al., 2004Not checked yet

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• cites Scotti et al., 2001Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Fatty acid epoxides are the major physiological substrates of EPHX2.

“There appear to be two membrane epoxide hydrolase (EPHX) genes similar to xenobiotic-inducible mammalian EPHX1, and three EPHX genes related to the vertebrate EPHX2 (soluble EPHX) genes (mammals have two EPHX genes (Barth et al., 2004a,b; fatty acid epoxides are the major physiological substrates of EPHX2).”

• cites Barth et al., 2004a,bNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In vertebrates, MGST2 may play an important role in tert-butylhydroperoxide resistance.

“In vertebrates, MGST2 may play an important role in tert-butylhydroperoxide resistance (Ma et al., 2004).”

• cites Ma et al., 2004Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

In vertebrates, arylamine NAT enzymes catalyze the addition of an acetyl group to aromatic amines and hydrazines, generally resulting in detoxification.

“In vertebrates, arylamine NAT enzymes catalyze the addition of an acetyl group to aromatic amines and hydrazines, a reaction generally resulting in detoxification (Boukouvala and Fakis, 2005).”

• cites Boukouvala and Fakis, 2005Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Heat shock proteins have been implicated in the response to various toxicants including heavy metals such as cadmium and arsenic, and free radicals.

“Heat shock proteins (HSP) have been implicated in the response to various toxicants including heavy metals, such as cadmium and arsenic, and free radicals (Feder and Hofmann, 1999).”

• cites Feder and Hofmann, 1999Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

GST-zeta deficiency causes oxidative stress in mice.

“GST-pi has been related to carcinogenesis in humans and mice (Henderson et al., 1998), whereas GST-zeta deficiency causes oxidative stress in mice (Blackburn et al., 2006).”

• cites Blackburn et al., 2006Not checked yet

  Not checked in the free run.

May combine two claims.

An oxidative stress response involving CNC-related proteins appears to be conserved in animals, although there are differences in specific roles and mechanisms.

“An oxidative stress response involving CNC-related proteins appears to be conserved in animals, although there are differences in the specific roles and mechanisms involved (An and Blackwell, 2003;Veraksa et al., 2000;Walker et al., 2000).”

• cites An and Blackwell, 2003Not checked yet

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• cites Veraksa et al., 2000Not checked yet

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• cites Walker et al., 2000Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

HSP90 has been shown to stabilize client proteins that are targets for toxicants, suggesting that HSP90 mediates the acquisition of drug resistance by stabilization of other proteins.

“resistance by stabilization of other proteins (Cowen and Lindquist, 2005).”

• cites Cowen and Lindquist, 2005 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Vertebrate AHR is a ligand-activated transcription factor that regulates expression of xenobiotic-metabolizing enzymes such as CYPs in response to dioxins, PAHs, and other compounds.

“One of these AHR homologs (Sp-Ahr; SPU_013788) is more closely related to the vertebrate AHR, a ligand-activated transcription factor that regulates the expression of xenobioticmetabolizing enzymes such as CYPs in response to dioxins, polycyclic aromatic hydrocarbons, and a variety of other compounds (Nebert et al., 2004).”

• cites Nebert et al., 2004Not checked yet

  Not checked in the free run.

May combine two claims.

The connectivity, path-length, and interconnectivity of the stress-sensing and response network are greater in humans than in yeast.

“The connectivity, path-length, and interconnectivity of this stresssensing and response network are greater in humans than in yeast (Lee et al., 2002), an evolutionary distance bridged, in part, by sea urchins.”

• cites Lee et al., 2002Not checked yet

  Not checked in the free run.

May combine two claims.

Urchin embryos exposed to environmental levels of UV significantly upregulate SOD and undergo apoptosis.

“Urchin embryos exposed to environmental levels of UV significantly upregulate SOD and undergo apoptosis (Lesser et al., 2003).”

• cites Lesser et al., 2003Not checked yet

  Not checked in the free run.

May combine two claims.

Transcription factors governing a stress response have greater regulatory influence and regulate in simpler combinations.

“Those results indicate that transcription factors governing a stress response have greater regulatory influence, and that they regulate in simpler combinations.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Two important factors may be at work in defensome gene regulation: coregulation and redundancy.

“Two important factors may be at work in defensome gene regulation: coregulation and redundancy.”

May combine two claims.

Sp-Fxr is most closely related to vertebrate FXR and LXR, which are activated by oxysterols and bile acids, respectively, suggesting a role in endobiotic signaling.

“Sp-Fxr is most closely related to vertebrate FXR and LXR, which are activated by oxysterols and bile acids, respectively (Eloranta and Kullak-Ublick, 2005;Handschin and Meyer, 2005), suggesting a role in endobiotic signaling.”

• cites Eloranta and Kullak-Ublick, 2005Not checked yet

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• cites Handschin and Meyer, 2005Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

The sea urchin embryo produces hydrogen peroxide at fertilization to facilitate hardening of the fertilization envelope.

“The sea urchin embryo produces hydrogen peroxide at fertilization to facilitate the hardening of the fertilization envelope (Wong et al., 2004;Wong and Wessel, 2005), and their antioxidant mechanisms have been well studied (see Epel, 2003;Shapiro, 1991).”

• cites Wong et al., 2004Not checked yet

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• cites Wong and Wessel, 2005Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

In yeast, environmental responses such as stress responses have shorter regulatory cascades than endogenous functions such as cell cycle control, implying faster signal propagation.

“Recent work has shown that, in yeast, environmental responses such as stress responses have shorter regulatory cascades than endogenous functions such as cell cycle control, implying faster signal propagation (Lunscombe et al., 2004).”

• cites Lunscombe et al., 2004Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

These small molecule antioxidants are present in eggs at high concentrations and remain high throughout development.

“These small molecule antioxidants are present in eggs at high concentrations (GSH and ovothiol total ∼ 10 mM; Turner et al., 1986Turner et al., , 1988) ) and remain high throughout development (Schomer and Epel, 1998).”

• cites Turner et al., 1986Not checked yet

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• cites Schomer and Epel, 1998Not checked yet

  Not checked in the free run.

May combine two claims.

Many gene families or superfamilies that participate in the defensome in deuterostomes are found in protostomes, suggesting the origin of an orchestrated chemical defense in a bilaterian ancestor.

“Similarly, many of the gene families or superfamilies that participate in the defensome in deuterostomes are found in protostomes, suggesting the origin of an orchestrated chemical defense in a bilaterian ancestor.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

HIF proteins mediate the response to low oxygen through a signaling mechanism that is evolutionarily conserved and required for development in most metazoans.

“HIF proteins mediate the response to low oxygen through a signaling mechanism that is evolutionarily conserved and required for development in most metazoans (Lavista-Llanos et al., 2002;Shen et al., 2005).”

• cites Lavista-Llanos et al., 2002Not checked yet

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• cites Shen et al., 2005Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

The delay between activation and response in transcriptional cascades is shorter for sensory responses than for developmental patterning.

“The delay between activation and response in transcriptional cascades is also shorter (fewer cell cycles) for sensory responses than for developmental patterning, perhaps reflecting the irreversibility of patterning (Rosenfeld and Alon, 2003).”

• cites Rosenfeld and Alon, 2003Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Gene orthologies may or may not be predictive of function, as seen with Sp-ABCC9A.

“Furthermore, gene orthologies may or may not be predictive of function, as seen with Sp-ABCC9A.”

May combine two claims.

Known invertebrate AHR homologs do not bind typical ligands of the vertebrate AHR, suggesting an important distinction in AHR functions that is not well understood.

“However, unlike the vertebrate AHRs, the known invertebrate AHR homologs do not bind typical ligands of the vertebrate AHR (Butler et al., 2001;Powell-Coffman et al., 1998), suggesting an important distinction in AHR functions that is not well understood.”

• cites Butler et al., 2001Not checked yet

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• cites Powell-Coffman et al., 1998Not checked yet

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Probably not a substantial claim: may not pass S4 (based).

Receptor activation by xenobiotic ligands may interfere with endogenous ligand-dependent developmental signaling, particularly via AHR, bZIP-CNC, and NR proteins.

“Receptor activation by xenobiotic ligands may interfere with the endogenous ligand-dependent developmental signaling, particularly via AHR, bZIP-CNC, and NR proteins.”

Probably not a substantial claim: may not pass S3 (load-bearing).

Understanding the action of these genes in sea urchins should provide insights into the mechanisms that result in the lowered senescence and increased longevity (> 100 years) observed in adult sea urchins.

“Understanding the action of these genes in sea urchins should provide insights into the mechanisms that result in the lowered senescence and increased longevity (> 100 years) observed in adult sea urchins (Ebert and Southon, 2003).”

• cites Ebert and Southon, 2003Not checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

A similar relationship between defense genes and longevity genes has been seen in C. elegans genes that control dauer formation.

“A similar relationship between defense genes and longevity genes has been seen in the C. elegans genes that control dauer formation, a whole organism stress response during development (Antebi et al., 2000;Yabe et al., 2005).”

• cites Antebi et al., 2000Not checked yet

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• cites Yabe et al., 2005Not checked yet

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Probably not a substantial claim: may not pass S3 (load-bearing).

A special challenge in embryonic development may be the integration of the regulation of defensive genes with the gene programs that are active during differentiation.

“A special challenge in embryonic development may be the integration of the regulation of defensive genes with the gene programs that are active during differentiation.”

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Regulatory proteins governing the expression of many defensome genes are not known even in vertebrates, and thus there could be transcription factors yet to be described that are involved in regulation of the active stress defense genes in sea urchin.

“The regulatory proteins governing the expression of many defensome genes are not known even in vertebrates, and thus there could be transcription factors yet to be described that are involved in regulation of the active stress defense genes in sea urchin.”