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PubMed2026

The work of specialist nurses in the mainstreaming of germline genomic testing in cancer: an investigation.

BACKGROUND: Specialist nurses are increasingly working in the mainstreaming of germline genomic testing in cancer. AIMS: The study aimed to investigate the work of specialist nurses in the mainstreaming of germline genomic testing in cancer, with a focus on Lynch syndrome, and to consider the future of genomics in nursing. METHODS: Semi-structured interviews were conducted with a purposive sample of 12 specialist nurses and three genetic counsellors, and thematic analysis was carried out. FINDINGS: Prominent themes arising from the data were: the capability and capacity of specialty-based clinical nurse specialists, for whom genomics is an added part of their wider role, to deliver genomic testing; and whether these specialty-based nurses or specialist genomic nurses, who work only in genomics, are best placed to deliver genomic testing. CONCLUSION: When planning service provision in the mainstreaming of genetic testing, the capacity and capability of specialty-based clinical nurse specialists should be considered alongside the possible need for specialist genomic nurses.

Humans↗
PubMed2026

ACG Clinical Guideline: Diagnosis and Management of Adenomatous Colorectal Polyposis Syndromes.

The hereditary adenomatous colorectal polyposis syndromes are incurable, systemic, cancer risk predisposition syndromes with substantial morbidity and mortality. They differ in their mode of inheritance, age at disease onset, phenotypic expression, and cancer risk. The most common cancer risks involve the gastrointestinal tract including the colon, rectum, duodenum, ampulla, and stomach. Identifying these syndromes through personal and family history risk assessment and germline genetic testing, along with timely surgical and endoscopic management, can reduce cancer incidence and mortality. These guidelines use the Grading of Recommendations, Assessment, Development, and Evaluation methodology to provide clinical guidance on the selection of individuals who should undergo a risk assessment for a hereditary adenomatous colorectal polyposis syndrome, modality and timing of germline genetic testing, cancer risk mitigation through endoscopic and surgical interventions, and the role of chemoprevention. This document reviews the approach to genetic testing in patients with phenotypic colorectal polyposis and the impact of presymptomatic diagnosis in families with a known familial germline pathogenic variant or clinical features suggestive of a hereditary adenomatous polyposis syndrome. Management strategies for patients based on genetic test results or without genetic testing are provided. We also review colorectal and extracolonic phenotypic benign and malignant manifestations of the known hereditary syndromes with a focus on the 2 most common hereditary colorectal polyposis syndromes: familial adenomatous polyposis and MUTYH-associated polyposis. The document concludes with recommendations on polyposis and cancer risk mitigation strategies and highlights updates to management since the previous guideline was published.

Humans↗
PubMed2025

Divergent PTEN-p53 interaction upon DNA damage in a human thyroid organoid model with germline PTEN mutations.

Germline mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) cause PTEN hamartoma tumor syndrome (PHTS). PHTS is characterized by an elevated lifetime risk of differentiated thyroid cancer (DTC), 30 times higher than the general population. However, only 1 in 3 PHTS patients develop DTC, and it remains unknown whether specific PTEN variants are associated with an increased risk of DTC. PTEN antagonizes the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway, a frequently affected pathway in sporadic DTC. PTEN also acts as a guardian of the genome by interacting with other tumor suppressors. Here, we report how ionizing radiation, an environmental tumorigenic contributor, modifies the DNA damage response based on the type of germline PTEN variants. We hypothesized that certain PTEN variants associated with DTC create a pro-oncogenic molecular signature upon radiation-induced DNA damage. DTC-associated (PTEN M134R ) or DTC-non-associated (PTEN G132D ) germline PTEN mutant alleles were introduced into a human induced pluripotent cell (hiPSC) line derived from a healthy donor utilizing CRISPR-Cas9 gene editing technology. We determined radiation-induced transcriptomic changes in functional thyroid organoids induced from wild-type and both heterozygous PTEN mutant hiPSCs. Both bulk and single-cell RNA sequencing data indicated that radiation upregulated the p53 network more potently in the thyroid organoids with PTEN WT/G132D than those with PTEN WT/M134R , which could be mediated by AKT-dependent MDM2 inactivation and PTEN-p53 physical interaction. Our data suggest that the lack of p53 pathway activation through PTEN-p53 network interactions explains why PTEN M134R is a DTC-susceptible variant.

Humans↗
PubMed2026

Expert consensus on the reporting and clinical follow up of individuals with incidentally discovered germline RET variants in the UK.

Incidentally discovered pathogenic germline genetic variants refer to the finding of a pathogenic variant in a gene that is unrelated to the reason for the initial test and is not actively sought. Our clinical understanding of the risk of developing a particular medical condition and the required clinical action for a specific pathogenic gene variant is predominantly based on knowledge and information acquired from cases ascertained through a 'phenotype-first approach' rather than in clinically unselected individuals. Therefore, a modified approach is required for incidentally discovered gene variants. Data from large UK and US population-based cohorts have demonstrated that RET variants classified as moderate-risk RET variants as per the American Thyroid Association (ATA) classification have a low penetrance for medullary thyroid cancer and other RET-related conditions (e.g. phaeochromocytoma) and are not associated with excess mortality when identified incidentally in clinically unselected adult individuals. Here, we provide guidance based on multidisciplinary expert consensus opinion for the reporting and subsequent clinical surveillance and management of patients with incidentally discovered RET gene variants in the UK.

Humans↗
PubMed2026

CHEK2 Germline Variants in Cancer Predisposition: Whole Genome Sequencing Results.

While pathogenic germline CHEK2 variants are known to increase cancer risk, there is currently insufficient evidence regarding the precise risk of developing malignant neoplasms associated with specific missense variants or variants of uncertain significance. As a result, no clear clinical guidelines exist regarding consultation, monitoring and specific treatment options for those patients. For the first time in Russia, clinical data and whole-genome sequencing (WGS) results were analyzed for 3150 patients with cancer and suspected hereditary cancer syndromes (HCS) and 5163 healthy individuals. This dataset formed the basis for assessing the role of germline CHEK2 variants in the development of different cancer types. The chromosomal coordinates and coding sequence coordinates are given in accordance with the GRCh38 (hg38) genome assembly and the NM_007194.4 transcript. Pathogenic (P) and likely pathogenic (LP) variants of CHEK2 significantly increased the risk of breast cancer (OR = 2.015 [95% CI: 1.27-3.21]; p = 0.0031), but the association with colorectal cancer was not statistically significant (OR = 1.354 [95% CI: 0.42-4.42]; p = 0.616). A moderate increase in cancer risk was identified for the c.1100del variant (OR = 2.263 [95% CI: 1.19-4.32]; p = 0.0132) and for the common P/LP variants c.1100del, c.444+1G>A and c.433C>T (OR = 2.219 [95% CI: 1.40-3.51]; p = 0.0007). Notably, our study confirmed that CHEK2 c.470T>C (p.Ile157Thr) is the most common variant in the patient group, identified in 3.8% of cases (120/3150), compared with 3.0% in the control group (155/5163). Although the association between the most common CHEK2 variant c.470T>C and cancer risk reached nominal statistical significance (OR = 1.279 [95% CI: 1.00-1.63]; p = 0.0463), the effect size was minimal, suggesting that the contribution of this variant to hereditary cancer risk in the Russian population is modest. Additional studies are required before this variant can be definitively excluded from clinical interpretation.

Humans↗
PubMed2024

[Pathogenic large duplication in TP53 as a hereditary predisposing factor in breast cancer].

AIM: Germline pathogenic variants of TP53 are associated with Li-Fraumeni syndrome and represent a high risk for hereditary breast and ovarian cancer. We identified a germline, multi-exon heterozygous duplication variant in TP53, NM_000546.6:dup(ex2-5), in a young triple-negative breast cancer patient. We aimed to assign its pathogenicity. METHODS: DNA and RNA (cDNA) level specific amplification tests and sequencings were performed to identify the genomic duplication breakpoint and to detect the presence of defective transcripts. RESULTS: cDNA tests revealed aberrant transcript, which causes a shift in the reading frame. Allelic imbalance was also observed, indicating degradation of the defective RNA product. By locating the breakpoints at the DNA level, we determined that 6975 bp was repeated in tandem and in the same orientation. We also revealed the possible mechanism of the structural rearrangement. CONCLUSIONS: We established that the duplication identified at DNA level manifested in the mRNA and coded for a non-functional protein. Based on these data, we were able to classify this duplication variant as pathogenic, which affects the patient's therapeutic options and justifies genetic screening of family members.

Adult↗
PubMed1978

Mechanisms of antibody diversity: multiple genes encode structurally related mouse kappa variable regions.

The complete amino acid sequences of the variable regions of three mouse Vkappa-21 kappa chains (A22, T111, and CB101) and one partial sequence (B32) have been determined and are compared to four previously reported Vkappa-21 variable regions. These eight kappa variable region sequences have, with the exception of an amide difference at residue 1, identical amino-terminal 23-residue sequences, all are of the same length, and all have extensive amino acid sequence homology throughout the variable region. When these eight variable regions are grouped by sequence homology, five different groups (Vkappa-21A, B, C, D, and E) are present whose members share common sets of amino acids within a group. Three groups of similar homology each contains at least two members (M63 and AB22 in Vkappa-21B; M321 and T124 in Vkappa-21C; and M70 and B32 in Vkappa-21A). The repetition of these five characteristic subgroup sequences in this relatively small sample indicates that these subgroups are isotypes which are controlled by separate germline genes. It is unlikely that these sequences could have been randomly somatically generated in different animals from a single germ-line gene (parallel mutation). Although a limited number of comparisons are available, the sequence differences within the Vkappa-21A, B, and C isotypes are limited to complementarity-determining regions and may have resulted from somatic mutations. The kappa chains comprising the Vkappa-21 isotypes offer a unique opportunity to compare the genetic interpretations of the primary amino acid sequence data with the nucleic acid hybridization data.

Amino Acid Sequence↗
PubMedDate not supplied

Studies of a cross-reactive idiotype associated with anti-para-azophenylarsonate antibodies of A/J mice.

We have reviewed studies of a cross-reactive idiotype (CRI), associated with anti-para-azophenylarsonate (anti-Ar) antibodies of A/J mice, and have presented some recent data. H chains from molecules with the CRI are homogeneous through the first hypervariable region whereas L chains show heterogeneity in the first framework segment. The constancy of N-terminal H chain sequences from 10 individual mice indicates that the framework is encoded by a germ-line gene, and that mutations have little effect on the observed framework sequence. H chains lacking the CRI show great heterogeneity in the first hypervariable segment, indicating a direct relationship between sequence and idiotype. Adult A/J mice can be suppressed with respect to the production of the CRI by administration of rabbit antiidiotypic antibody. When immunized, such mice produce anti-Ar antibodies with "private" idiotypes present at extremely low concentrations, or absent, in anti-Ar antibodies of other A/J mice. These private idiotypes can be transferred adoptively to mildly irradiated (200 r) syngeneic recipients with lymphoid cells, and serial transfers can be carried out after immunization. The original CRI remains suppressed. This presents the possibility of structural studies of anti-Ar antibodies varying in idiotype from a single strain. The work should also provide information on the degree of diversity of anti-Ar antibodies within the strain.

Amino Acid Sequence↗
PubMed1979

Extrachromosomal control of mutability in Drosophila melanogaster.

Hybrid dysgenesis is a syndrome of germ-line aberrations including, e.g., sterility and mutation, found in certain interstrain hybrids of Drosophila melanogaster. Previous studies of sterility have shown that elements responsible for dysgenesis may reside on all major chromosomes, but that their dysgenesis-causing ability is controlled by an unknown extrachromosomal factor. Dysgenic hybrids also give rise to unstable visible mutations thought to be DNA insertions at certain sensitive loci. One such unstable allele at the singed bristle locus, designated snw, was found to mutate at extraordinary rates exceeding 50%. This instability was shown to be under the same extrachromosomal control as hybrid dysgenesis itself. That is, the mutability of snw was reversibly suppressed when placed in the background cytotype known to prevent sterility and other characteristics of hybrid dysgenesis. These results suggest that snw may represent an insertion at the singed locus of a hypothetical gene responsible for hybrid dysgenesis.

Animals↗
PubMedDate not supplied

The repertoire of antibodies to a hapten group in an inbred strain of mouse.

We have investigated the diversity of antibodies to the p-azophenylarsonate (Ar) hapten group in the A strain of mouse. The method used consisted of suppressing an idiotype which commonly is observed in the anti-Ar antibodies of all this strain, and then generating anti-idiotypic antisera against the anti-Ar antibodies (lacking the cross-reactive idiotype) which arose after hyperimmunization of the suppressed mice. Anti-idiotypic antibodies prepared against these anti-Ar antibodies were used as a tool to investigate the frequency of recurrence of individual idiotypes in other mice of the same strain. A highly sensitive radioimmunoassay indicated that 3 of the 4 idiotypes studied were virtually undetectable in a panel of 181 A/J mice immunized against the phenylarsonate hapten. A fourth idiotype was found but at very low frequency. The results emphasize the enormous diversity of the immune response to a single hapten group within a strain of mouse. They are interpreted on the basis of hypothesis that the diversity arises through a random series of somatic events. The common cross-reactive idiotype, which is present in the anti-Ar antibodies of all normal A/J mice, is postulated to be the product of a germ-line gene which is closely related to a germ-line gene through a small number of somatic mutations which takes place in every A/J mouse.

Animals↗
PubMed1976

Totipotency and normal differentiation of single teratocarcinoma cells cloned by injection into blastocysts.

A definitive test for developmental totipotency of mouse malignant teratocarcinoma cells was conducted by cloning singly injected cells in genetically marked blastocysts. Totipotency was conclusively shown in an adult mosaic female whose tumor-strain cells had made substantial contributions to all of the wide range of its somatic tissues analyzed; the clonally propagated cell lineage had therefore differentiated in numerous normal directions. The test cells were from "cores" of embryoid bodies of a euploid, chromosomally male (X/Y), ascites tumor grown only in vivo by transplantation for 8 years. The capacity of cells from the same source to differentiate, in a phenotypic male, into reproductively functional sperms, has been shown in our previous experiments [(1975) Proc. Nat. Acad. Sci. USA 72, 3585-3589]. Cells from this transplant line therefore provide material suitable for projected somatic and germ-line genetic analyses of mammalian differentiation based on "cycling" of mutation-carrying tumor cells through developing embryos. In some animals obtained from single-cell injections tumor-derived cells were sporadically distributed in developmentally unrelated tissues. These cases can be accounted for by delayed and haphazard cellular integration, and by a marked degree of sustained cellular developmental flexibility in early mammalian development, irrespective of certain classical "germ-layer" designations. All mosaic mice obtained have thus far been free of teratomas. In one case, the injected stem cell contributed only to the pancreas and gave rise to a malignancy resembling pancreatic adenocarcinoma. The high modal frequency of euploidy in these individually tested cells thus tends to indicate that a near-normal chromosome complement is sufficient for total restoration of orderly gene expression in a normal embryonic environment; it may also be necessary for teratoma stem-cell proliferation to be terminated there.

Alleles↗
PubMed1979

Evidence supporting somatic assembly of the DNA segments (minigenes), coding for the framework, and complementarity-determining segments of immunoglobulin variable regions.

Two sets of apparently conflicting data on the genes coding for the variable region are being accumulated. One suggests that the sets of nucleotides coding for the framework segments of immunoglobulin light and heavy (VL and VH) chains assort independently and are therefore germ-line minigenes which, together with sets of nucleotides coding for the complementarity-determining regions (CDR) or segments assemble to form complete variable (V)-region genes (15, 16, 33). The other, based on the findings with clones from 12-d-old embryo and adult mouse coding for V-regions, infer that the first three frameworks and the three complementarity-determining segments are already assembled as germ-line V-genes (17-21). It is now generally accepted that the J segment, which in the one instance sequenced (21) is made up of nucleotides coding for framework (FR)4 plus two residues of CDR3, is a minigene. An examination of sequences of human, mouse, and rabbit V-regions, assuming the latter hypothesis, indicates that individual framework sets would have to be present in many copies. The FR2 segment found in one human, 20 mice, and 13 rabbits would have to be present in at least 10/14 copies in the NZB, and 5/6 in the BALB/c mouse, and 12/13 in the rabbit. The X-ray crystallographic data show this region to be a loop, projecting out from the V-domain, capable of accommodating many substiutions and 12 and 8 alternative sequences for this FR2 segment have been found in mouse and rabbit VK chains with substitutions possible at 13 of the 15 positions. These alternative sequences occur much less frequently than the preserved FR2 segment. Thus, there is no basis in the protein structure to account for evolutionary stability of this FR2 segment if it occurs in so many copies in germ-line genes coding for residues 1-96, but its stability is easily explained if it were coded for by a separate germ-line minigene present as a single copy; the alternative forms could then have arisen by duplication and mutation of this minigene. Somatic assembly of the minigene segments for the three framework and three complementarity-determining segments during differentiation would account completely for our assortment data from which FR4 was inferred to be a minigene.

Amino Acid Sequence↗
PubMedDate not supplied

B-cell ontogeny in the chicken.

We conclude that our data are most consistent with the hypothesis that individual bursal stem cells give rise to multiple clones of B lymphocytes by a preprogrammed sequence of variable (V) region genes. The alternate hypothesis that each stem cell gives rise to one B cell expressing but one set of VH genes could only fit our data if the additional assumption is made that each stem cell is preprogrammed to give rise to an unique B-cell clonotype at a fixed time during development. Since we were unable to influence the pattern of expression of clonotypic diversity by modifying the exposure to antigens and since random somatic mutations would seem an inefficient mechanism for systematic generation of the diversity, we favor the possibility of a genetic mechanism involving an orderly pairing of germ-line VH and VL genes. The corollary of this hypothesis is that V-region diversity is generated first and Ig-class diversity is secondarily expressed within each clone by a switch mechanism for the sequential expression of CH genes.

Animals↗
PubMed1975

Normal genetically mosaic mice produced from malignant teratocarcinoma cells.

Malignant mouse teratocarcinoma (or embryonal carcinoma) cells with a normal modal chromosome number were taken from the "cores" of embryoid bodies grown only in vivo as an ascites tumor for 8 years, and were injected into blastocysts bearing many genetic markers, in order to test the developmental capacities, genetic constitution, and reversibility of malignancy of the core cells. Ninety-three live normal pre- and postnatal animals were obtained. Of 14 thus far analyzed, three were cellular genetic mosaics with substantial contributions of tumor-derived cells in many developmentally unrelated tissues, including some never seen in the solid tumors that form in transplant hosts. The tissues functioned normally and synthesized their specific products (e.g., immunoglobulins, adult hemoglobin, liver proteins) coded for by strain-type alleles at known loci. In addition, a tumor-contributed color gene, steel, not previously known to be present in the carcinoma cells, was detected from the coat phenotype. Cells derived from the carcinoma, which is of X/Y sex chromosome constitution, also contributed to the germ line and formed reproductively functional sperms, some of which transmitted the steel gene to the progeny. Thus, after almost 200 transplant generations as a highly malignant tumor, embryoid body core cells appear to be developmentally totipotent and able to express, in an orderly sequence in differentiation of somatic and germ-line tissues, many genes hitherto silent in the tumor of origin. This experimental system of "cycling" teratocarcinoma core cells through mice, in conjunction with experimental mutagenesis of those cells, may therefore provide a new and useful tool for biochemical, developmental, and genetic analyses of mammalian differentiation. The results also furnish an unequivocal example in animals of a non-mutational basis for transformation to malignancy and of reversal to normalcy. The origin of this tumor from a disorganized embryo suggests that malignancies of some other, more specialized, stem cells might arise comparably through tissue disorganization, leading to developmental aberrations of gene expression rather than changes in gene structure.

Animals↗
PubMedDate not supplied

The complete sequence of the murine monoclonal immunoglobulin MOPC 173 (IgG2a): genetic implications.

The complete amino acid sequence of the murine monoclonal immunoglobulin MOPC 173 (IgG2a, kappa) is reported. The heavy chain contains 447 amino-acid residues, and one carbohydrate prosthetic group attached to the ASX residue 299. The kappa light chain is composed of 214 residues. The H chains are covalently linked by 3 interchain disulfide bridges. The H-L bond-forming cysteine of the H chain is between the VH and the CH1 domain. Intrachain bridges are disposed linearly, according to the classical model. There is no simple relationship between the primary structure and any given function of a particular domain. This is presumably due to the fact that the selection pressure exerts itself on the three-dimensional structure which may retain a conserved general organization as a result of balanced multiple mutations. Selection seems to act in two ways: --horizontally, in a multigene system such as the immunoglobulin classes (C domains of the heavy chains), leading to interclass homologies which are particularly marked for all the COOH-terminal domains of H and L chains which have, in addition a fair degree of homology with human beta2 microglobulin (about 30% identities); --vertically, in which case strictly homologous domains appear extremely conserved between distinct animal species. Conservation of the VH domains seems just as high as conservation of the CH domains. The VH region contains 3 types of positions: invariant and subgroup characteristic ("framework") which may be accounted for by a rather small number of germ-line genes, and hypervariable for which the origin of diversity, somatic or germinal, cannot be decided from sequence data alone. Murine VK domains, although basically built according to the same pattern, show a much more marked polymorphism of the framework, which might necessitate a higher number of basic germ-line genes. Finally, a hypothetical model of the switch mechanism is proposed. Rotational symmetry regions can be deduced at the DNA level from the known amino acid sequences of the switch peptides for the three translocational systems: H, kappa and lambda. These would provide recognition signals for restriction-like enzymes such as those which operate in prokaryotes. An implication of this model is the definition of an exact limit between the V and the C regions of all immunoglobulin chains.

Amino Acid Sequence↗
PubMed1979

Demonstration of low density lipoprotein receptors in mouse teratocarcinoma stem cells and description of a method for producing receptor-deficient mutant mice.

Familial hypercholesterolemia, a widespread human genetic disorder implicated in vascular and coronary disease, has had no laboratory animal counterpart that would enable the pathogenesis to be analyzed and drugs to be tested in vivo. The primary lesion in some patients is known to occur in the cells' initial handling of the major cholesterol-carrying lipoprotein of plasma. It entails a deficiency in the specific cell surface receptor that binds low density lipoprotein (LDL), with a consequent alteration in the control of cholesterol metabolism. The present study was undertaken to devise a practical scheme for producing, from developmentally versatile mouse teratocarcinoma stem cells, whole-animal models with a comparable genetic lesion. This requires first learning whether the tumor stem cells in culture express LDL receptors, and next establishing a selection or screening procedure to identify receptor-deficient mutants in mutagenized cell cultures. The results show that the teratocarcinoma cells do in fact have specific high-affinity LDL receptors which are similar to those reported for fibroblasts and the parenchymal cells of specialized tissues and different from those of phagocytic cells. Sterols suppressed the otherwise efficient binding, internalization, and degradation of LDL ((125)I-labeled) by the cells. Acetylation of LDL blocked the binding. Only LDL and not high density lipoprotein (HDL) was bound. After LDL uptake and degradation, the liberated cholesterol led, as expected, to increased cholesteryl ester formation; it also suppressed activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase [HMG CoA reductase; mevalonate: NADP(+) oxidoreductase (CoA-acylating), EC 1.1.1.34], the rate-limiting step in cholesterol biosynthesis. Cells with LDL receptors were readily visualized by administering a fluorescent derivative of LDL; in the fluorescence microscope, labeling was seen in all cells. Cells with experimentally depressed receptors, yielding little fluorescence, were separable from those with normal fluorescence in the fluorescence-activated cell sorter. Thus, two methods for isolating receptor-deficient cells from mutagenized cultures are now available, either by visual recognition of low-fluorescing or nonfluorescing colonies in culture plates or by electronic cell sorting. Such mutants in an appropriate line of teratocarcinoma cells can then be passaged into blastocysts for full somatic tissue differentiation and germ-line development into mice.

Animals↗
PubMed1992

Selective disruption of genes expressed in totipotent embryonal stem cells.

Two retrovirus promoter trap vectors (U3His and U3Neo) have been used to disrupt genes expressed in totipotent murine embryonal stem (ES) cells. Selection in L-histidinol or G418 produced clones in which the coding sequences for histidinol-dehydrogenase or neomycin-phosphotransferase were fused to sequences in or near the 5' exons of expressed genes, including one in the developmentally regulated REX-1 gene. Five of seven histidinol-resistant clones and three of three G418-resistant clones generated germ-line chimeras. A total of four disrupted genes have been passed to the germ line, of which two resulted in embryonic lethalities when bred to homozygosity. The ability to screen large numbers of recombinant ES cell clones for significant mutations, both in vitro and in vivo, circumvents genetic limitations imposed by the size and long generation time of mice and will facilitate a functional analysis of the mouse genome.

Alcohol Oxidoreductases↗