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PubMed1984

Chromosomal organization of the human dihydrofolate reductase genes: dispersion, selective amplification, and a novel form of polymorphism.

The human dihydrofolate reductase (DHFR; tetrahydrofolate dehydrogenase; 5,6,7,8-tetrahydrofolate: NADP+ oxidoreductase, EC 1.5.1.3) gene family includes a functional gene (hDHFR) and at least four intronless genes. Three intronless genes (hDHFR-psi 2, hDHFR-psi 3, and hDHFR-psi 4) are identifiable as pseudogenes because of DNA sequence divergence from the functional gene with introns, while one intronless gene (hDHFR-psi 1) is completely homologous to the coding sequences of the functional gene. Analysis of genomic DNA from two panels of somatic human-rodent cell hybrids with specific molecular probes provide insight into the chromosomal organization and assignment of these genes. The five genes are dispersed in that each one is found on a different chromosome. The functional gene hDHFR has been assigned to chromosome 5, and one pseudogene (hDHFR-psi 4), to chromosome 3. In a human cell line (HeLa) that was selected for methotrexate resistance, the functional locus became amplified, while there was no amplification of the four intronless pseudogenes. hDHFR-psi 1 was found to be present in DNA of some individuals and absent from DNA of others, consistent with a recent evolutionary origin of this gene originally suggested by its sequence identity to the coding portions of the functional gene. The presence or absence of this intronless pseudogene represents a previously unreported form of DNA polymorphism.

Animals↗
PubMed2001

Two S-adenosylmethionine synthetase-encoding genes differentially expressed during adventitious root development in Pinus contorta.

Two S-adenosylmethionine synthetase (SAMS) cDNAs, PcSAMS1 and PcSAMS2, have been identified in Pinus contorta. We found that the two genes are differentially expressed during root development. Thus, PcSAMS1 is preferentially expressed in roots and exhibits a specific expression pattern in the meristem at the onset of adventitious root development, whereas PcSAMS2 is expressed in roots as well as in shoots and is down-regulated during adventitious root formation. The expression of the two SAMS genes is different from the SAMS activity levels during adventitious root formation. We conclude that other SAMS genes that remain to be characterized may contribute to the observed SAMS activity, or that the activities of PcSAMS1 and PcSAMS2 are affected by post-transcriptional regulation. The deduced amino acid sequences of PcSAMS1 and PcSAMS2 are highly divergent, suggesting different functional roles. However, both carry the two perfectly conserved motifs that are common to all plant SAMS. At the protein level, PcSAMS2 shares about 90% identity to other isolated eukaryotic SAMS, while PcSAMS1 shares less than 50% identity with other plant SAMS. In a phylogenetic comparison, PcSAMS1 seems to have diverged significantly from all other SAMS genes. Nevertheless, PcSAMS1 was able to complement a Saccharomyces cerevisiae sam1 sam2 double mutant, indicating that it encodes a functional SAMS enzyme.

Amino Acid Sequence↗
PubMed2005

Divergence between motoneurons: gene expression profiling provides a molecular characterization of functionally discrete somatic and autonomic motoneurons.

Studies in the developing spinal cord suggest that different motoneuron (MN) cell types express very different genetic programs, but the degree to which adult programs differ is unknown. To compare genetic programs between adult MN columnar cell types, we used laser capture microdissection (LCM) and Affymetrix microarrays to create expression profiles for three columnar cell types: lateral and medial MNs from lumbar segments and sympathetic preganglionic motoneurons located in the thoracic intermediolateral nucleus. A comparison of the three expression profiles indicated that approximately 7% (813/11,552) of the genes showed significant differences in their expression levels. The largest differences were observed between sympathetic preganglionic MNs and the lateral motor column, with 6% (706/11,552) of the genes being differentially expressed. Significant differences in expression were observed for 1.8% (207/11,552) of the genes when comparing sympathetic preganglionic MNs with the medial motor column. Lateral and medial MNs showed the least divergence, with 1.3% (150/11,552) of the genes being differentially expressed. These data indicate that the amount of divergence in expression profiles between identified columnar MNs does not strictly correlate with divergence of function as defined by innervation patterns (somatic/muscle vs. autonomic/viscera). Classification of the differentially expressed genes with regard to function showed that they underpin all fundamental cell systems and processes, although most differentially expressed genes encode proteins involved in signal transduction. Mining the expression profiles to examine transcription factors essential for MN development suggested that many of the same transcription factors participate in combinatorial codes in embryonic and adult neurons, but patterns of expression change significantly.

Animals↗
PubMed2005

Rapid evolution of genomic Acp complement in the melanogaster subgroup of Drosophila.

Unusual properties of molecular evolution in reproduction-related Drosophila genes, including atypically rapid rates of protein evolution, support the idea that natural selection plays an important role in divergence of reproductive function in Drosophila. We used subtractive hybridization to investigate another potential side of evolution of the male reproductive transcriptome. We carried out a screen for genes with much greater transcript abundance in Drosophila simulans reproductive tracts than in Drosophila melanogaster reproductive tracts. Such genes could be present in both species but diverged dramatically in transcript abundance or could be present in D. simulans but absent from D. melanogaster. Here we report data from melanogaster subgroup species for three previously unknown accessory gland protein genes (Acps) identified in this screen. We found multiple Acps that were present in some lineages yet absent from other closely related melanogaster subgroup lineages, representing several losses of genes. An Acp that may have been lost in D. melanogaster and Drosophila erecta is segregating a null allele in Drosophila yakuba, yet shows evidence of adaptive protein evolution in contrasts of polymorphism and divergence within and between D. yakuba and its close relative, Drosophila teissieri. These data suggest that turnover of Acps occurs rapidly in Drosophila, consistent with rapid evolution of seminal fluid function.

Amino Acid Sequence↗
PubMed2007

Current topics in genome evolution: molecular mechanisms of new gene formation.

Comparative genome analyses reveal that most functional domains of human genes have homologs in widely divergent species. These shared functional domains, however, are differentially shuffled among evolutionary lineages to produce an increasing number of domain architectures. Combined with duplication and adaptive evolution, domain shuffling is responsible for the great phenotypic complexity of higher eukaryotes. Although the domain-shuffling hypothesis is generally accepted, determining the molecular mechanisms that lead to domain shuffling and novel gene creation has been challenging, as sequence features accompanying the formation of known genes have been obscured by accumulated mutations. The growing availability of genome sequences and EST databases allows us to study the characteristics of newly emerged genes. Here we review recent genome-wide DNA and EST analyses, and discuss the three major molecular mechanisms of gene formation: (1) atypical spicing, both within and between genes, followed by adaptation, (2) tandem and interspersed segmental duplications, and (3) retrotransposition events.

Alternative Splicing↗
PubMed2001

The participation of AtXPB1, the XPB/RAD25 homologue gene from Arabidopsis thaliana, in DNA repair and plant development.

Nucleotide excision repair in Arabidopsis thaliana differs from other eukaryotes as it contains two paralogous copies of the corresponding XPB/RAD25 gene. In this work, the functional characterization of one copy, AtXPB1, is presented. The plant gene was able to partially complement the UV sensitivity of a yeast rad25 mutant strain, thus confirming its involvement in nucleotide excision repair. The biological role of AtXPB1 protein in A. thaliana was further ascertained by obtaining a homozygous mutant plant containing the AtXPB1 genomic sequence interrupted by a T-DNA insertion. The 3' end of the mutant gene is disrupted, generating the expression of a truncated mRNA molecule. Despite the normal morphology, the mutant plants presented developmental delay, lower seed viability and a loss of germination synchrony. These plants also manifested increased sensitivity to continuous exposure to the alkylating agent MMS, thus suggesting inefficient DNA damage removal. These results indicate that, although the duplication seems to be recent, the features described for the mutant plant imply some functional or timing expression divergence between the paralogous AtXPB genes. The AtXPB1 protein function in nucleotide excision repair is probably required for the removal of lesions during seed storage, germination and early plant development.

Arabidopsis↗
PubMed2005

Cyanobacterial psbA families in Anabaena and Synechocystis encode trace, constitutive and UVB-induced D1 isoforms.

Cyanobacteria cope with UVB induced photoinhibition of Photosystem II by regulating multiple psbA genes to boost the expression of D1 protein (in Synechocystis sp. PCC6803), or to exchange the constitutive D1:1 protein to an alternate D1:2 isoform (in Synechococcus sp. PCC7942). To define more general patterns of cyanobacterial psbA expression, we applied moderately photoinhibitory UVB to Anabaena sp. PCC7120 and tracked the expression of its five psbA genes. psbAI, encoding a D1:1 protein isoform characterized by a Gln130, represented the majority of the psbA transcript pool under control conditions. psbAI transcripts decreased upon UVB treatment but the total psbA transcript pool increased 3.5 fold within 90 min as a result of sharply increased psbAII, psbAIV and psbAIII transcripts encoding an alternate D1:2 protein isoform characterized by Glu130, similar to that of Synechococcus. Upon UVB treatment the relaxation of flash induced chlorophyll fluorescence showed a characteristic acceleration of a decay phase likely associated with the exchange from the D1:1 protein isoform encoded by psbAI to the alternate D1:2 isoform encoded by psbAIV, psbAII and psbAIII. Throughout the UVB treatment the divergent psbA0 made only a trace contribution to the total psbA transcript pool. This suggests a similarity to the divergent psbAI gene from Synechocystis, whose natural expression we demonstrate for the first time at a trace level similar to psbA0 in Anabaena. These trace-expressed psbA genes in two different cyanobacteria raise questions concerning the functions of these divergent genes.

Amino Acid Sequence↗
PubMed2003

How well is enzyme function conserved as a function of pairwise sequence identity?

Enzyme function conservation has been used to derive the threshold of sequence identity necessary to transfer function from a protein of known function to an unknown protein. Using pairwise sequence comparison, several studies suggested that when the sequence identity is above 40%, enzyme function is well conserved. In contrast, Rost argued that because of database bias, the results from such simple pairwise comparisons might be misleading. Thus, by grouping enzyme sequences into families based on sequence similarity and selecting representative sequences for comparison, he showed that enzyme function starts to diverge quickly when the sequence identity is below 70%. Here, we employ a strategy similar to Rost's to reduce the database bias; however, we classify enzyme families based not only on sequence similarity, but also on functional similarity, i.e. sequences in each family must have the same four digits or the same first three digits of the enzyme commission (EC) number. Furthermore, instead of selecting representative sequences for comparison, we calculate the function conservation of each enzyme family and then average the degree of enzyme function conservation across all enzyme families. Our analysis suggests that for functional transferability, 40% sequence identity can still be used as a confident threshold to transfer the first three digits of an EC number; however, to transfer all four digits of an EC number, above 60% sequence identity is needed to have at least 90% accuracy. Moreover, when PSI-BLAST is used, the magnitude of the E-value is found to be weakly correlated with the extent of enzyme function conservation in the third iteration of PSI-BLAST. As a result, functional annotation based on the E-values from PSI-BLAST should be used with caution. We also show that by employing an enzyme family-specific sequence identity threshold above which 100% functional conservation is required, functional inference of unknown sequences can be accurately accomplished. However, this comes at a cost: those true positive sequences below this threshold cannot be uniquely identified.

Animals↗
PubMed1997

Origin and evolution of a new gene descended from alcohol dehydrogenase in Drosophila.

Drosophila alcohol dehydrogenase (Adh) is highly conserved in size, organization, and amino acid sequence. Adh-psi was hypothesized to be a pseudogene derived from an Adh duplication in the repleta group of Drosophila; however, several results from molecular analyses of this gene conflict with currently held notions of molecular evolution. Perhaps the most difficult observations to reconcile with the pseudogene hypothesis are that the hypothetical replacement sites of Adh-psi evolve only slightly more quickly than replacement sites of closely related, functional Adh genes, and that the replacement sites of the pseudogenes evolve considerably more slowly than neighboring silent sites. The data have been presented as a paradox that challenges our understanding of the mechanisms underlying DNA sequence divergence. Here I show that Adh-psi is actually a new, functional gene recently descended from an Adh duplication. This descendant recruited approximately 60 new N-terminal amino acids, is considerably more basic than ADH, and is evolving at a faster rate than Adh. Furthermore, though the descendant is clearly functional, as inferred from molecular evolution and population genetic data, it retains no obvious ADH activity. This probably reflects functional divergence from its Adh ancestor.

Alcohol Dehydrogenase↗
PubMed1991

Complete sequence of human cardiac alpha-myosin heavy chain gene and amino acid comparison to other myosins based on structural and functional differences.

We have obtained the 5820 nucleotide sequence encoding all 1939 amino acids of the human cardiac alpha-myosin heavy chain (alpha-MHC), as established by dideoxy sequencing of cloned cDNA, genomic DNA and polymerase chain reaction (PCR) amplification products. This sequence represents overlapping fragments of the entire coding sequence. Amino acid sequence comparison of the human cardiac alpha-MHC with the published human cardiac beta-MHC have demonstrated that there are, at least, 7 isoform-specific divergent regions, including functionally important binding protein-related sites such as ATP, actin and myosin light chain. It has been reported that in the rat, there are 8 isoform-specific divergent regions. The 7th divergent area (residue area 1633-1657, which is thought to mediate thick filament formation) in the light meromyosin region in the rat is not apparent in the human. The amino acid compositions of cardiac alpha- and beta-MHCs in the human and the rat, and human embryonic skeletal muscle and chicken gizzard smooth muscles were compared. Amino acid sequences in cardiac alpha- and beta-MHCs in the human and the rat are well conserved. In the head portion, the amino acid composition divergence of human cardiac alpha-MHC is ranked between rat cardiac alpha-MHC and human cardiac beta- or rat cardiac beta-MHC; human skeletal muscle MHC is the most divergent of the myosin isoform examined. These data predict that human cardiac alpha-MHC may have undergone evolutionary changes toward obtaining the biochemical and physiological properties of cardiac beta-MHC.

Amino Acid Sequence↗
PubMed2003

Transcomplementation of core and polymerase functions of the woolly monkey and human hepatitis B viruses.

Woolly monkey hepatitis B virus (WMHBV) is a new member of Hepadnaviridae that was isolated from a New World monkey and is phylogenetically distinct from the HBV family. In this study, we explored the functional significance of sequence divergence in the HBV and WMHBV genomes. Independently expressed TP and RT domains of the WMHBV reverse transcriptase (Pol) formed a complex functional for in vitro nucleotide priming, consistent with previous results from priming reactions conducted with HBV. Transcomplementation assays between HBV and WMHBV TP and RT components for in vitro priming demonstrated functional compatibility, although priming with the combination of WMHBV RT and HBV TP was reduced. Examination of cross-species protein-protein interactions revealed that WMHBV core coprecipitated with HBV TP and RT, as well as with WMHBV TP and RT. Analysis in Huh7 cells revealed that WMHBV core and Pol complemented core-negative and Pol-negative HBV mutant genomes for replication. These results highlight the conservation of function despite significant sequence divergence in these viruses.

Amino Acid Sequence↗
PubMed2000

Functional evolution of the Ultrabithorax protein.

The Hox genes have been implicated as central to the evolution of animal body plan diversity. Regulatory changes both in Hox expression domains and in Hox-regulated gene networks have arisen during the evolution of related taxa, but there is little knowledge of whether functional changes in Hox proteins have also contributed to morphological evolution. For example, the evolution of greater numbers of differentiated segments and body parts in insects, compared with the simpler body plans of arthropod ancestors, may have involved an increase in the spectrum of biochemical interactions of individual Hox proteins. Here, we compare the in vivo functions of orthologous Ultrabithorax (Ubx) proteins from the insect Drosophila melanogaster and from an onychophoran, a member of a sister phylum with a more primitive and homonomous body plan. These Ubx proteins, which have been diverging in sequence for over 540 million years, can generate many of the same gain-of-function tissue transformations and can activate and repress many of the same target genes when expressed during Drosophila development. However, the onychophora Ubx (OUbx) protein does not transform the segmental identity of the embryonic ectoderm or repress the Distal-less target gene. This functional divergence is due to sequence changes outside the conserved homeodomain region. The inability of OUbx to function like Drosophila Ubx (DUbx) in the embryonic ectoderm indicates that the Ubx protein may have acquired new cofactors or activity modifiers since the divergence of the onychophoran and insect lineages.

Amino Acid Sequence↗
PubMed2002

Prediction of structure and functional residues for O-GlcNAcase, a divergent homologue of acetyltransferases.

N-Acetyl-beta-D-glucosaminidase (O-GlcNAcase) is a key enzyme in the posttranslational modification of intracellular proteins by O-linked N-acetylglucosamine (O-GlcNAc). Here, we show that this protein contains two catalytic domains, one homologous to bacterial hyaluronidases and one belonging to the GCN5-related family of acetyltransferases (GNATs). Using sequence and structural information, we predict that the GNAT homologous region contains the O-GlcNAcase activity. Thus, O-GlcNAcase is the first member of the GNAT family not involved in transfer of acetyl groups, adding a new mode of evolution to this large protein family. Comparison with solved structures of different GNATs led to a reliable structure prediction and mapping of residues involved in binding of the GlcNAc-modified proteins and catalysis.

Amino Acid Sequence↗
PubMedDate not supplied

Towards an understanding of the functional significance of N-terminal domain divergence in human AMP deaminase isoforms.

Human AMP deaminase (AMPD; EC 3.5.4.6) isoforms are encoded by a multigene family and have conserved C-terminal domains that contain catalytic residues and an ATP-binding site. N-terminal domains diverge dramatically, yet are conserved when compared across mammalian species. Cross-species conservation of entire gene-specific polypeptides (e.g., rat versus human AMPD1) suggests that divergent N-terminal domains may play a role in isoform-specific properties of the enzyme. It now has become evident that the majority of published data used to characterize purified AMPD isoforms were likely derived from preparations lacking significant portions of their N-terminal domains (up to nearly 100 residues). Accumulating evidence indicates that divergent N-terminal sequences do influence catalytic behavior, protein-protein interactions, and intracellular distributions of this enzyme.

AMP Deaminase↗
PubMed2004

Divergence of carbonyl ylide reactions as a function of diazocarbonyl compound and aldehyde substituent: dioxolanes, dioxolenes, and epoxides.

The products from dirhodium(II) acetate-catalyzed reactions between diazocarbonyl compounds and a series of benzaldehydes demonstrate the extent of competition between intramolecular and intermolecular trapping of carbonyl ylide intermediates and the electronic effects that govern these transformations. With dimethyl diazomalonate, competition exists between dioxolane and epoxide formation so that with p-anisaldehyde only epoxide formation is observed and with p-nitrobenzaldehyde only 1,3-dioxolane products are formed. With methyl diazoacetoacetate, intramolecular trapping of the intermediate carbonyl ylide results in the sole production of dioxolenes. However, the vinyldiazoacetate analogue of methyl diazoacetoacetate, as its tert-butyldimethlsilyloxy derivative, only produces epoxides in its reactions with substituted benzaldehydes.

Benzaldehydes↗
PubMed1996

RFX proteins, a novel family of DNA binding proteins conserved in the eukaryotic kingdom.

Until recently, the RFX family of DNA binding proteins consisted exclusively of four mammalian members (RFX1-RFX4) characterized by a novel highly conserved DNA binding domain. Strong conservation of this DNA binding domain precluded a precise definition of the motif required for DNA binding. In addition, the biological systems in which these RFX proteins are implicated remained obscure. The recent identification of four new RFX genes has now shed light on the evolutionary conservation of the RFX family, contributed greatly to a detailed characterization of the RFX DNA binding motif, and provided clear evidence for the function of some of the RFX proteins. RFX proteins have been conserved throughout evolution in a wide variety of species, including Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans, mouse and man. The characteristic RFX DNA binding motif has been recruited into otherwise very divergent regulatory factors functioning in a diverse spectrum of unrelated systems, including regulation of the mitotic cell cycle in fission yeast, the control of the immune response in mammals, and infection by human hepatitis B virus.

Amino Acid Sequence↗
PubMed2004

Divergent effects of the catalytic and bridging functions of hepatic lipase on atherosclerosis.

OBJECTIVE: Increased expression of human hepatic lipase (HL) or a catalytically inactive (ci) HL clears plasma cholesterol in mice deficient in low-density lipoprotein receptors (LDLr) and murine HL. We hypothesized that increased expression of both HL and ciHL reduces atherosclerosis in these mice. METHODS AND RESULTS: Mice deficient in both LDLr and murine HL, alone or transgenically expressing similar levels of either human HL or ciHL, were fed a high-fat, cholesterol-enriched "Western" diet for 3 months to accelerate the development of atherosclerosis. Levels of plasma lipids, insulin, glucose, and liver enzymes were measured monthly, and aortic atherosclerosis was quantitated after 3 months. Plasma insulin, glucose, and liver enzyme levels did not differ significantly from controls. After 3 months, expression of HL reduced plasma cholesterol by 55% to 65% and reduced atherosclerosis by 40%. Surprisingly, expression of ciHL did not reduce plasma cholesterol or atherosclerosis. CONCLUSIONS: High levels of HL, but not ciHL, delay the development of atherosclerosis in mice deficient in LDLr and mHL. These studies demonstrate that high levels of catalytically active human hepatic lipase (HL) reduce atherosclerosis, whereas high levels of a catalytically inactive HL do not affect atherosclerosis in mice genetically deficient in low-density lipoprotein receptor and mouse HL.

Animals↗