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PubMed1995

Reevaluation of corneal dystrophies of Bowman's layer and the anterior stroma (Reis-Bücklers and Thiel-Behnke types): a light and electron microscopic study of eight corneas and a review of the literature.

To clarify whether Reis-Bücklers' and Thiel-Behnke's corneal dystrophies are one entity or whether two distinct corneal dystrophies of Bowman's layer and the superficial stroma (CDB) exist, 28 corneal specimens with clinically suspected diagnosis of CDB were examined by light and electron microscopy, and the literature was reviewed. Eight specimens came from patients with a honeycomb-shaped pattern of opacities at the level of Bowman's layer. Study of those eight specimens disclosed destruction of Bowman's layer, a subepithelial fibrocellular tissue with an undulant configuration, absence of the epithelial basement membrane in many areas and the presence of "curly" collagen fibers with a diameter of 9-15 nm. We concluded that two distinct autosomal dominant CDB exist and propose the designations CDB type I (synonyms: geographic or "true" Reis-Bücklers' dystrophy) and CDB type II (synonyms: honeycomb-shaped or Thiel-Behnke's dystrophy). The eight corneas of our series were characterized as CDB type II. CDB I is clinically characterized by confluent geographic opacities at the level of Bowman's layer, histopathologically by bandshaped granular Masson-positive subepithelial deposits, and ultrastructurally by the presence of "rod-shaped bodies" and may be a superficial variant of granular dystrophy. Visual loss is significantly greater in CDB I, and recurrences after keratoplasty or keratectomy seem to be earlier and more extensive in CDB I. Most cases reported thus far in the literature as "Reis-Bücklers' dystrophy" are CDB II (honeycomb-shaped or Thiel-Behnke's dystrophy).

Adult↗
PubMed2005

Dynamics of hepatitis C virus NS5A quasispecies during interferon and ribavirin therapy in responder and non-responder patients with genotype 1b chronic hepatitis C.

The quasispecies nature of hepatitis C virus (HCV) may have important implications concerning resistance to antiviral agents. To determine whether HCV NS5A quasispecies composition and dynamics are related to responsiveness to combined interferon (IFN) and ribavirin therapy, extensive sequence analyses of cloned RT-PCR amplification products of HCV-1b NS5A quasispecies of sequential isolates from 15 treated (nine sustained responders and six non-responders) and three untreated patients were performed. Accumulation of mutations in NS5A during therapy was relatively frequent in the V3 domain, but unusual elsewhere. Amino acid changes were the result of the imposition of minor variants that were already present before treatment and always occurred within the first week of therapy. Before treatment, the complexity and diversity of quasispecies were lower in isolates from responders than in those from non-responders, particularly in the V3 domain, where differences in nucleotide entropy (0.35 vs 0.64, P=0.003), genetic distance (0.0145 vs 0.0302, P=0.05) and non-synonymous substitutions (0.0102 vs 0.0203, P=0.036) were statistically significant. These differences became more apparent during treatment, because complexity and diversity remained stable or tended to increase in non-responders, whereas they tended to decrease in responders. These observations suggest that the composition and dynamics of HCV NS5A quasispecies, particularly in the V3 domain, may play a role in the response to combined IFN/ribavirin therapy.

Amino Acid Sequence↗
PubMed1999

Dynamics of rabies virus quasispecies during serial passages in heterologous hosts.

To understand the mutations and genetic rearrangements that allow rabies virus infections of new hosts and adaptation in nature, the quasispecies structure of the nucleoprotein and glycoprotein genes as well as two noncoding sequences of a rabies virus genome were determined. Gene sequences were obtained from the brain and from the salivary glands of the original host, a naturally infected European fox, and after serial passages in mice, dogs, cats and cell culture. A relative genetic stasis of the consensus sequences confirmed previous results about the stability of rabies virus. At the quasispecies level, the mutation frequency varies, in the following order: glycoprotein region (21.9 x 10(-4) mutations per bp), noncoding sequence nucleoprotein-phosphoprotein region (7.2-7.9 x 10(-4) mutations per bp) and nucleoprotein gene region (2.9-3.7 x 10(-4) mutations per bp). These frequencies varied according to the number, type of heterologous passages and the genomic region considered. The shape of the quasispecies structure was dramatically modified by passages in mice, in which the mutation frequencies increased by 12-31 x 10(-4) mutations per bp, depending on the region considered. Non-synonymous mutations were preponderant particularly in the glycoprotein gene, stressing the importance of positive selection in the maintenance and fixation of substitutions. Two mechanisms of genomic evolution of the rabies virus quasispecies, while adapting to environmental changes, have been identified: a limited accumulation of mutations with no replacement of the original master sequence and a less frequent but rapid selective overgrowth of favoured variants.

Animals↗
PubMed2006

Definition of novel GP6 polymorphisms and major difference in haplotype frequencies between populations by a combination of in-depth exon resequencing and genotyping with tag single nucleotide polymorphisms.

BACKGROUND: Common genetic variants of cell surface receptors contribute to differences in functional responses and disease susceptibility. We have previously shown that single nucleotide polymorphisms (SNPs) in platelet glycoprotein VI (GP6) determine the extent of response to agonist. In addition, SNPs in the GP6 gene have been proposed as risk factors for coronary artery disease. METHODS: To completely characterize genetic variation in the GP6 gene we generated a high-resolution SNP map by sequencing the promoter, exons and consensus splice sequences in 94 non-related Caucasoids. In addition, we sequenced DNA encoding the ligand-binding domains of GP6 from non-human primates to determine the level of evolutionary conservation. RESULTS: Eighteen SNPs were identified, six of which encoded amino acid substitutions in the mature form of the protein. The single non-synonymous SNP identified in the exons encoding the ligand-binding domains, encoding for a 103Leu > Val substitution, resulted in reduced ligand binding. Two common protein isoforms were confirmed in Caucasoid with frequencies of 0.82 and 0.15. Variation at the GP6 locus was characterized further by determining SNP frequency in over 2000 individuals from different ethnic backgrounds. CONCLUSIONS: The SNPs were polymorphic in all populations studied although significant differences in allele frequencies were observed. Twelve additional GP6 protein isoforms were identified from the genotyping results and, despite extensive variation in GP6, the sequence of the ligand-binding domains is conserved. Sequences from non-human primates confirmed this observation. These data provide valuable information for the optimal selection of genetic variants for use in future association studies.

Amino Acid Sequence↗
PubMed1996

Genetic lesions associated with Muller's ratchet in an RNA virus.

The molecular basis of Muller's ratchet has been investigated using the important animal pathogen foot-and-mouth disease virus (FMDV). Clones from two FMDV populations were subjected to serial plaque transfers (repeated bottleneck events) on host BHK-21 cells. Relative fitness losses were documented in 11 out of 19 clones tested. Small fitness gains were observed in three clones. One viral clone attained an extremely low plating efficiency, suggesting that accumulation of deleterious mutations had driven the virus near extinction. Nucleotide sequence analysis revealed unique genetic lesions in multiply transferred clones that had never been seen in FMDVs isolated in nature or subjected to massive infections in cell culture. In particular, a frequent internal polyadenylate extension has identified a mutational hot spot on the FMDV genome. Furthermore, amino acid residue substitutions in internal capsid sites which are severely restricted during FMDV evolution, amounted to half of capsid replacements in the transferred clones. In addition, a striking dominance of non-synonymous replacements fixed upon large population infections of FMDV was not observed upon serial plaque transfers. The nucleotide sequence of the entire genome of a severely debilitated clone suggests that very few mutations may be sufficient to drive FMDV near extinction. The results provide an account of the molecular basis of Muller's ratchet for an RNA virus, and insight into the types of genetic variants which populate the mutant spectra of FMDV quasispecies.

Animals↗
PubMed1994

Origin and evolutionary pathways of the H1 hemagglutinin gene of avian, swine and human influenza viruses: cocirculation of two distinct lineages of swine virus.

The nucleotide sequences of the HA1 domain of the H1 hemagglutinin genes of A/duck/Hong Kong/36/76, A/duck/Hong Kong/196/77, A/sw/North Ireland/38, A/sw/Cambridge/39 and A/Yamagata/120/86 viruses were determined, and their evolutionary relationships were compared with those of previously sequenced hemagglutinin (H1) genes from avian, swine and human influenza viruses. A pairwise comparison of the nucleotide sequences revealed that the genes can be segregated into three groups, the avian, swine and human virus groups. With the exception of two swine strains isolated in the 1930s, a high degree of nucleotide sequence homology exists within the group. Two phylogenetic trees constructed from the substitutions at the synonymous site and the third codon position showed that the H1 hemagglutinin genes can be divided into three host-specific lineages. Examination of 21 hemagglutinin genes from the human and swine viruses revealed that two distinct lineages are present in the swine population. The swine strains, sw/North Ireland/38 and sw/Cambridge/39, are clearly on the human lineage, suggesting that they originate from a human A/WSN/33-like variant. However, the classic swine strain, sw/Iowa/15/30, and the contemporary human viruses are not direct descendants of the 1918 human pandemic strain, but did diverge from a common ancestral virus around 1905. Furthermore, previous to this the above mammalian viruses diverged from the lineage containing the avian viruses at about 1880.

Amino Acid Sequence↗
PubMed2005

Characterization of multiple alleles of the T-cell differentiation marker ART2 (RT6) in inbred and wild rats.

ART2 (RT6) belongs to the family of mono-ADP-ribosyltransferases (ARTs). ART2 is a T-cell differentiation marker expressed by the majority of mature peripheral T cells in the rat. The two known ART2 allotypes display approximately 95% amino acid identity. We sequenced the ART2 coding regions from 18 inbred rat strains and found two additional alleles, termed Art2 ( a2 ) and Art2 ( b2 ). Monoclonal antibody Gy12/61 specifically reacted with Art2 ( a2 ) but not Art2 ( a1 ) lymph node cells. Expression of ART2 allotypes in Jurkat cells confirmed this specificity. A polymerase chain reaction (PCR) assay using restriction fragment length polymorphisms is described, which allows the easy discrimination of Art2 alleles. All four laboratory rat alleles, as well as an additional sequence variant, were found amongst 18 wild rat DNA samples. PCR analysis confirmed the selective presence of a rodent identifier (ID) element in the Art2 ( a ) but not the Art2 ( b ) alleles in all rats studied. Analysis of Art2 ( a1 ) and Art2 ( b2 ) genes showed greater divergence in coding than in non-coding regions. Together with the finding of a high number of non-synonymous mutations leading mostly to non-conservative amino acid substitutions clustered on the side facing away from the cell surface, this suggests that the Art2 polymorphism has been subject to selection.

ADP Ribose Transferases↗
PubMed2004

The serotonin-2A receptor gene locus does not contain common polymorphism affecting mRNA levels in adult brain.

The serotonin-2A (HTR2A) receptor is a molecule of particular interest in biological psychiatry, as it is an important target for psychotropic drugs, and altered HTR2A expression has been found in several neuropsychiatric conditions, including depression and schizophrenia. Genetic association has been reported between a synonymous 102T/C polymorphism in the gene encoding HTR2A and a number of clinical phenotypes, including schizophrenia, clozapine response, psychotic symptoms in Alzheimer's disease and certain features of depression. Given that there are no known effects of the 102T/C polymorphism on the structure of the receptor, attention has switched to the possibility that the observations of both altered expression and genetic association point to functional sequence variants that alter expression of the HTR2A gene. Moreover, data have been presented recently suggesting that mRNAs containing the 102T- and C-alleles are differentially expressed. This suggests a direct effect of the variant itself on mRNA levels, or the influence of a distinct regulatory variant, such as the -1438A/G promoter polymorphism, with which it is in perfect linkage disequilibrium. The present study tested this hypothesis by employing a highly accurate quantitative allele- specific primer extension assay to measure the relative expression of brain mRNAs carrying each allele in 23 individuals heterozygous for the 102T/C polymorphism. Comparison between allele ratios derived from genomic DNA and mRNA from several cortical regions revealed that the 102C- and T-alleles are expressed identically. Furthermore, the absence of any interindividual variability in relative mRNA allele ratio suggests that the HTR2A locus is unlikely to contain common polymorphisms or epigenetic modification that alter HTR2A mRNA levels in adult brain, and essentially exclude such phenomena as a potential explanation for the altered expression and genetic associations that have been reported to date.

Adult↗
PubMed1999

Search for the mechanism of genetic variation in the pro gene of human immunodeficiency virus.

To study the mechanism of evolution of the human immunodeficiency virus (HIV) protease gene (pro), we analyzed a database of 213 pro sequences isolated from 11 HIV type 1-infected patients who had not been treated with protease inhibitors. Variation in pro is restricted to rare variable bases which are highly diverse and differ in location among individuals; an average variable base appears in about 16% of individuals. The average intrapatient distance per individual variable site, 27%, is similar for synonymous and nonsynonymous sites, although synonymous sites are twice as abundant. The latter observation excludes selection for diversity as an important, permanently acting factor in the evolution of pro and leaves purifying selection as the only kind of selection. Based on this, we developed a model of evolution, both within individuals and along the transmission chain, which explains variable sites as slightly deleterious mutants slowly reverting to the better-fit variant during individual infection. In the case of a single-source transmission, genetic bottlenecks at the moment of transmission effectively suppress selection, allowing mutants to accumulate along the transmission chain to high levels. However, even very rare coinfections from independent sources are, as we show, able to counteract the bottleneck effect. Therefore, there are two possible explanations for the high mutant frequency. First, the frequency of coinfection in the natural host population may be quite low. Alternatively, a strong variation of the best-adapted sequence between individuals could be caused by a combination of an immune response present in early infection and coselection.

Base Sequence↗
PubMed2000

Dominant role of host selective pressure in driving hepatitis C virus evolution in perinatal infection.

The dynamics of the genetic diversification of hepatitis C virus (HCV) populations was addressed in perinatal infection. Clonal sequences of hypervariable region 1 of the putative E2 envelope protein of HCV were obtained from four HCV-infected newborns (sequential samples spanning a period of 6 to 13 months after birth) and from their mothers (all samples collected at delivery). The data show that the variants detected between birth and the third month of life in samples from the four newborns were present in the HCV populations of their mothers at delivery. In the newborns, a unique viral variant (or a small group of closely related variants) remained stable for weeks despite active viral replication. Diversification of the intrahost HCV population was observed 6 to 13 months after birth and was substantially higher in two of the four subjects, as documented by the intersample genetic distance (GD) (P = 0.007). Importantly, a significant correlation between increasing GD and high values for the intersample K(a)/K(s) ratio (the ratio between anoffymous and synonymous substitutions; an index of the action of selective forces) was observed, as documented by the increase of both parameters over time (P = 0.01). These data argue for a dominant role of positive selection for amino acid changes in driving the pattern of genetic diversification of HCV populations, indicate that the intrahost evolution of HCV populations is compatible with a Darwinian model system, and may have implications in the designing of future antiviral strategies.

Amino Acid Sequence↗
PubMed2001

Host switching in Lyssavirus history from the Chiroptera to the Carnivora orders.

Lyssaviruses are unsegmented RNA viruses causing rabies. Their vectors belong to the Carnivora and Chiroptera orders. We studied 36 carnivoran and 17 chiropteran lyssaviruses representing the main genotypes and variants. We compared their genes encoding the surface glycoprotein, which is responsible for receptor recognition and membrane fusion. The glycoprotein is the main protecting antigen and bears virulence determinants. Point mutation is the main force in lyssavirus evolution, as Sawyer's test and phylogenetic analysis showed no evidence of recombination. Tests of neutrality indicated a neutral model of evolution, also supported by globally high ratios of synonymous substitutions (d(S)) to nonsynonymous substitutions (d(N)) (>7). Relative-rate tests suggested similar rates of evolution for all lyssavirus lineages. Therefore, the absence of recombination and similar evolutionary rates make phylogeny-based conclusions reliable. Phylogenetic reconstruction strongly supported the hypothesis that host switching occurred in the history of lyssaviruses. Indeed, lyssaviruses evolved in chiropters long before the emergence of carnivoran rabies, very likely following spillovers from bats. Using dated isolates, the average rate of evolution was estimated to be roughly 4.3 x 10(-4) d(S)/site/year. Consequently, the emergence of carnivoran rabies from chiropteran lyssaviruses was determined to have occurred 888 to 1,459 years ago. Glycoprotein segments accumulating more d(N) than d(S) were distinctly detected in carnivoran and chiropteran lyssaviruses. They may have contributed to the adaptation of the virus to the two distinct mammal orders. In carnivoran lyssaviruses they overlapped the main antigenic sites, II and III, whereas in chiropteran lyssaviruses they were located in regions of unknown functions.

Adaptation, Physiological↗
PubMed2006

Bias of selection on human copy-number variants.

Although large-scale copy-number variation is an important contributor to conspecific genomic diversity, whether these variants frequently contribute to human phenotype differences remains unknown. If they have few functional consequences, then copy-number variants (CNVs) might be expected both to be distributed uniformly throughout the human genome and to encode genes that are characteristic of the genome as a whole. We find that human CNVs are significantly overrepresented close to telomeres and centromeres and in simple tandem repeat sequences. Additionally, human CNVs were observed to be unusually enriched in those protein-coding genes that have experienced significantly elevated synonymous and nonsynonymous nucleotide substitution rates, estimated between single human and mouse orthologues. CNV genes encode disproportionately large numbers of secreted, olfactory, and immunity proteins, although they contain fewer than expected genes associated with Mendelian disease. Despite mouse CNVs also exhibiting a significant elevation in synonymous substitution rates, in most other respects they do not differ significantly from the genomic background. Nevertheless, they encode proteins that are depleted in olfactory function, and they exhibit significantly decreased amino acid sequence divergence. Natural selection appears to have acted discriminately among human CNV genes. The significant overabundance, within human CNVs, of genes associated with olfaction, immunity, protein secretion, and elevated coding sequence divergence, indicates that a subset may have been retained in the human population due to the adaptive benefit of increased gene dosage. By contrast, the functional characteristics of mouse CNVs either suggest that advantageous gene copies have been depleted during recent selective breeding of laboratory mouse strains or suggest that they were preferentially fixed as a consequence of the larger effective population size of wild mice. It thus appears that CNV differences among mouse strains do not provide an appropriate model for large-scale sequence variations in the human population.

Animals↗
PubMed2001

Non-synonymous single nucleotide alterations found in the CYP2C8 gene result in reduced in vitro paclitaxel metabolism.

By sequencing genomic DNA from 73 established cell lines derived from Japanese individuals, we detected 9 single nucleotide polymorphisms (SNPs) in the CYP2C8 gene. Of them, 3 exonic SNPs resulted in amino acid alterations (g416a, R139K; a1196g, K399R; c1210g, P404A). The first two alterations were detected concurrently in one cell line and thought to be the same as CYP2C8*3. To examine the effects of these amino acid alterations on CYP2C8 function, wild-type and four types of variant CYP2C8 cDNA constructs (R139K, K399R, R139K/K399R and P404A) were transfected into Hep G2 cells and their paclitaxel 6a-hydroxylase activities were determined in vitro. Km values were not significantly different from that of the wild-type in any of the variants studied. The variant R139K/K399R showed reduced values for Vmax and clearance (Vmax/Km) similar to those of its single variant, R139K. The variant P404A also showed a significantly lowered clearance due to reduced level of protein expression. These results suggest that not only the double variant (R139K/K399R, CYP2C8*3) but also our novel variant P404A in the CYP2C8 gene are less efficient in paclitaxel metabolism.

Amino Acid Substitution↗
PubMed2003

Mutation screening of the Homer gene family and association analysis in schizophrenia.

Homer proteins are a group of proteins that regulate group 1 metabotropic glutamate receptor function. As altered glutamate function has been implicated in many neuro psychiatric disorders, particularly schizophrenia, we have screened all three known Homer genes for sequence variation for use under the candidate gene association paradigm. We found seven SNPs, including three in exons. Of these, none was non-synonymous. Allele frequencies of all the detected SNPs were estimated in DNA pools of 368 schizophrenics and 368 controls. Only one (Homer 1 IVS4 + 18A > G) was associated with schizophrenia in this sample, a finding confirmed by individual genotyping (P = 0.01). However, in our extended sample of 680 cases and 671 controls, the evidence for association diminished (P = 0.05). Our results suggest it is unlikely that sequence variants in the Homer genes contribute to the aetiology of schizophrenia, but the variants we identified are plausible candidates for other neuropsychiatric phenotypes.

Adult↗
PubMed2002

Genetic diversity in the VP1 gene of foot-and-mouth disease virus serotype Asia 1.

Complete nucleotide sequence of the 1D (VP1-encoding) gene of 61 foot-and-mouth disease (FMD) serotype Asia I virus isolates recovered from different outbreaks in India between 1985 and 1999 including two vaccine strains currently used were determined. The sequences were compared with each other and those from other Asian countries. On the basis of phylogenetic analysis the viruses could be grouped into four genotypes (genotypes I-IV). All the 61 isolates from India belong to a single genotype (genotype-II) which is further subdivided into three lineages (B1, B2 and B3) under the same genotype. The viruses of the lineage B1 and B3 were found to be more prevalent before 1996 while the viruses of lineage B2 appeared to be new variants responsible for most of the recent outbreaks. Most of the isolates of lineage B1 lack one amino acid in the VP1 protein (position 44) whereas most of the isolates of lineage B2 and B3 contain it which indicates the possibility of these lineages having evolved independently. The rate of evolution of FMDV Asia 1 virus was also estimated and found to be 2.7 x 10(-2) synonymous substitutions per nucleotide per year.

Amino Acid Sequence↗
PubMed2007

Is alpha-T catenin (VR22) an Alzheimer's disease risk gene?

BACKGROUND: Recently, conflicting reports have been published on the potential role of genetic variants in the alpha-T catenin gene (VR22; CTNNA3) on the risk for Alzheimer's disease. In these papers, evidence for association is mostly observed in multiplex families with Alzheimer's disease, whereas case-control samples of sporadic Alzheimer's disease are predominantly negative. METHODS: After sequencing VR22 in multiplex families with Alzheimer's disease linked to chromosome 10q21, we identified a novel non-synonymous (Ser596Asn; rs4548513) single nucleotide polymorphism (SNP). This and four non-coding SNPs were assessed in two independent samples of families with Alzheimer's disease, one with 1439 subjects from 437 multiplex families with Alzheimer's disease and the other with 489 subjects from 217 discordant sibships. RESULTS: A weak association with the Ser596Asn SNP in the multiplex sample, predominantly in families with late-onset Alzheimer's disease (p = 0.02), was observed. However, this association does not seem to contribute substantially to the chromosome 10 Alzheimer's disease linkage signal that we and others have reported previously. No evidence was found of association with any of the four additional SNPs tested in the multiplex families with Alzheimer's disease. Finally, the Ser596Asn change was not associated with the risk for Alzheimer's disease in the independent discordant sibship sample. CONCLUSIONS: This is the first study to report evidence of an association between a potentially functional, non-synonymous SNP in VR22 and the risk for Alzheimer's disease. As the underlying effects are probably small, and are only seen in families with multiple affected members, the population-wide significance of this finding remains to be determined.

Alzheimer Disease↗
PubMed2002

Further evidence for an association of the paraoxonase 1 (PON1) Met-54 allele with Parkinson's disease.

Paraoxonase1 (PON1) is an arylesterase mainly expressed in the liver that hydrolyzes organophosphates such as pesticides, reported risk factors for Parkinson's disease (PD), and other neurotoxins. A Leu-Met 54 polymorphism in the gene for PON1-affecting enzyme activity was recently shown, employing a new restriction enzyme technique, to be associated with Parkinson's disease. We examined the same polymorphism by automated capillary sequencing in a sample of Caucasian subjects from the Stockholm area in Sweden (127 healthy individuals and 114 patients with PD) and found similar distributions and a similar difference in our sample. The genotype distribution in our PD material was LL 36.0%, LM 45.6%, and MM 18.4%; in our control material, it was LL 45.7%, LM 44.1%, and MM 10.2%. Based on the previously established increase in allele frequencies of the lower-activity Met-variant of PON1, we could confirm a significant association using a one-sided chi(2) test. Results remained significant with a two-sided chi(2) test, allowing for both increases and decreases in frequencies. Our data confirm an association between the PON1 Leu-Met 54 polymorphism and PD by demonstrating a similar association. The distribution between familial and nonfamilial PD patients was equal. No other synonymous or nonsynonymous polymorphisms were found in the sequenced coding region of PON1.

Adult↗
PubMed1990

Structure, evolution and chromosomal localization of the human pregnancy-specific beta 1 glycoprotein gene family.

Cloning and sequencing of the cDNA of a new member of the PS beta G gene family is reported. Comparison of the sequence with those of other PS beta G cDNAs reveals a remarkable conservation of their sequence (greater than 90%) and of their general structural organization: an NH2 domain is followed by 93- and 85-residue Ig-like domains termed A and B, respectively. Most PS beta G contain two domains A in tandem followed by a single domain B. In some PS beta G members described here, alternative splicing skips the AI domain in some transcripts, yielding two- and three-domain variants, respectively. Individual PS beta G members have specific short carboxyl domains displaying little sequence conservation. The PS beta G family is closely related to the CEA gene family. A detailed comparison of the sequence of both families is given and used to construct an evolutionary tree, using the method of Li, Wu, and Luo (1985, Mol. Biol. Evol. 2: 150-174). Computation of the number of substitutions of synonymous (Ks) and nonsynonymous (Ka) sites and of the Ks/Ka ratio suggests that the PS beta G gene family appeared concomitantly with the expansion of the placental mammals and belongs to the class of rapidly evolving genes. Very little selective pressure has been exerted on the body of the molecules, especially on domain A. The analysis also suggests that PS beta G genes encoding different carboxyl domains would have been positively selected and fixed during the evolution. The PS beta G gene family was assigned to chromosome 19, which also carries the CEA genes.

Amino Acid Sequence↗