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Results for “Purifying selection”

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PubMed2004

Identification and sequence analysis of chicken Toll-like receptors.

Toll-like receptors (TLRs) play an important role in the recognition of microbial components. Only chicken TLR2 and -4 have been reported in the literature. The objectives of this study were to identify new chicken TLRs and to evaluate evolutionary significance of these receptors. Searching chicken genomic databases and DNA sequencing revealed five new TLRs, TLR1 (type 1 and 2), -3, -5, and -7. No chicken orthologues of mammalian TLR8, -9, or -10 were found. As in mammals, all chicken TLRs (chTLRs) share identical protein secondary structure that consists of several leucine-rich domains, a transmembrane domain, and Toll/Interleukin-1 receptor domain(s). Phylogenetic analyses indicate that the identified chTLR genes are the orthologues of TLRs in mammals. Analyses of the number of synonymous substitutions per synonymous site and nonsynonymous substitutions per nonsynonymous site indicate that the nucleotide sequences coding for the leucine-rich repeats of chicken TLR1 type 1 and type 2 were significantly under positive Darwinian selection. In contrast, the sequences of other TLRs were under purifying selection. These results support the hypothesis that one of the major evolutionary strategies of the innate immune system is to recognize a few highly conserved microbial components with several conserved TLRs. The results also indicate that the sequence changes in the ligand-binding domains of TLR1 in chickens provide adaptive advantages during evolution.

Amino Acid Sequence↗

PubMed2005

The molecular population genetics of the Tomato spotted wilt virus (TSWV) genome.

RNA viruses are characterized by high genetic variability resulting in rapid adaptation to new or resistant hosts. Research for plant RNA virus genetic structure and its variability has been relatively scarce compared to abundant research done for human and animal RNA viruses. Here, we utilized a molecular population genetic framework to characterize the evolution of a highly pathogenic plant RNA virus [Tomato spotted wilt virus (TSWV), Tospovirus, Bunyaviridae]. Data from genes encoding five viral proteins were used for phylogenetic analysis, and for estimation of population parameters, subpopulation differentiation, recombination, divergence between Tospovirus species, and selective constraints on the TSWV genome. Our analysis has defined the geographical structure of TSWV, attributed possibly to founder effects. Also, we identify positive selection favouring divergence between Tospovirus species. At the species level, purifying selection has acted to preserve protein function, although certain amino acids appear to be under positive selection. This analysis provides demonstration of population structuring and species-wide population expansions in a multisegmented plant RNA virus, using sequence-based molecular population genetic analyses. It also identifies specific amino acid sites subject to selection within Bunyaviridae and estimates the level of genetic heterogeneity of a highly pathogenic plant RNA virus. The study of the variability of TSWV populations lays the foundation in the development of strategies for the control of other viral diseases in floral crops.

Base Sequence↗

PubMed2006

Heterozygosity and functional allelic variation in the Candida albicans efflux pump genes CDR1 and CDR2.

Elevated expression of the plasma membrane drug efflux pump proteins Cdr1p and Cdr2p was shown to accompany decreased azole susceptibility in Candida albicans clinical isolates. DNA sequence analysis revealed extensive allelic heterozygosity, particularly of CDR2. Cdr2p alleles showed different abilities to transport azoles when individually expressed in Saccharomyces cerevisiae. Loss of heterozygosity, however, did not accompany decreased azole sensitivity in isogenic clinical isolates. Two adjacent non-synonymous single nucleotide polymorphisms (NS-SNPs), G1473A and I1474V in the putative transmembrane (TM) helix 12 of CDR2, were found to be present in six strains including two isogenic pairs. Site-directed mutagenesis showed that the TM-12 NS-SNPs, and principally the G1473A NS-SNP, contributed to functional differences between the proteins encoded by the two Cdr2p alleles in a single strain. Allele-specific PCR revealed that both alleles were equally frequent among 69 clinical isolates and that the majority of isolates (81%) were heterozygous at the G1473A/I1474V locus, a significant (P < 0.001) deviation from the Hardy-Weinberg equilibrium. Phylogenetic analysis by maximum likelihood (Paml) identified 33 codons in CDR2 in which amino acid allelic changes showed a high probability of being selectively advantageous. In contrast, all codons in CDR1 were under purifying selection. Collectively, these results indicate that possession of two functionally different CDR2 alleles in individual strains may confer a selective advantage, but that this is not necessarily due to azole resistance.

ATP-Binding Cassette Transporters↗

PubMed2005

Comparative genomics and diversifying selection of the clustered vertebrate protocadherin genes.

To explain the mechanism for specifying diverse neuronal connections in the brain, Sperry proposed that individual cells carry chemoaffinity tags on their surfaces. The enormous complexity of these connections requires a tremendous diversity of cell-surface proteins. A large number of neural transmembrane protocadherin (Pcdh) proteins is encoded by three closely linked human and mouse gene clusters (alpha, beta, and gamma). To gain insight into Pcdh evolution, I performed comprehensive comparative cDNA and genomic DNA analyses for the three clusters in the chimpanzee, rat, and zebrafish genomes. I found that there are species-specific duplications in vertebrate Pcdh genes and that additional diversity is generated through alternative splicing within the zebrafish "variable" and "constant" regions. Moreover, different codons (sites) in the mammalian Pcdh ectodomains (ECs) are under diversifying selection, with some under diversity-enhancing positive Darwinian selection and others, including calcium-binding sites, under strong purifying selection. Interestingly, almost all positively selected codon positions are located on the surface of ECs 2 and 3. These diversified residues likely play an important role in combinatorial interactions of Pcdh proteins, which could provide the staggering diversity required for neuronal connections in the brain. These results also suggest that adaptive selection is an additional evolutionary factor for increasing Pcdh diversity.

Alternative Splicing↗

PubMed1990

A biological role of the carbohydrate moieties of laminin.

The ways in which the carbohydrate moieties of laminin affect its cellular interactions have been examined by two different experimental approaches. In one approach, we used lectins in order to block specific carbohydrates on laminin which previously had been dried onto a plastic surface. We found that wheat germ agglutinin and Griffonia simplicifolia agglutinin I blocked the binding of the neuron-like rat pheochromocytoma cell line PC12. However, when concanavalin A was used cell binding was unaffected but neurite outgrowth was prevented, compared to controls, over a 24-h period. In the second approach we used unglycosylated laminin as a substratum on the plastic surface. We have developed a method for the purification of unglycosylated laminin from tunicamycin treated cultures of a mouse embryonal carcinoma derived cell line, M1536 B3, and have partially characterized the purified material. A mixture of unglycosylated and glycosylated laminin was selectively purified from the M1536 B3 cell lysate by an anti-EHS laminin monoclonal antibody immunoaffinity column. The unglycosylated laminin was separated from glycosylated laminin using G. simplicifolia lectin affinity chromatography. The lectins, wheat germ agglutinin, G. simplicifolia agglutinin I, and concanavalin A, did not bind to any of the subunits of unglycosylated laminin in Western blots. The unglycosylated laminin migrated as a single band in agarose-gel electrophoresis under nonreducing conditions indicating that it is a fully assembled and disulfide bonded molecule. Circular dichroism studies showed no differences between glycosylated and unglycosylated laminin, indicating similar molecular conformations. Western blots using antibodies specific for the A, B1, and B2 chains of laminin showed that unglycosylated laminin contained each of these subunits. We then performed cell binding and spreading or neurite outgrowth assays using unglycosylated laminin. A mouse melanoma cell line, B16 F1, bound to this laminin in the same numbers as to the control glycosylated laminin, but cell spreading was minimal. When this unglycosylated laminin was used as a substrate for PC12 cells neurite outgrowth was impaired; no effect was noted on the number of cells bound, compared to glycosylated laminin. We conclude from these results that once cells become bound to laminin the carbohydrate residues of that glycoprotein must be available to enable the cells to spread or to extend neurite processes.

Adrenal Gland Neoplasms↗

PubMed1995

Cell layer-specific expression of cyclic nucleotide phosphodiesterases in rat arteries: molecular cloning using isolated cell layers from paraformaldehyde-fixed tissues.

We describe a method for the isolation of small quantities of large poly (A)+ mRNA from blood vessels of the rat as well as from distinct cell layers of the rat aorta. The poly (A)+ mRNA isolated by this method is suitable for use in reverse transcription polymerase chain reaction (RT-PCR) amplification of low abundance messages. In this method, anesthetized rats are perfused with ice-cold phosphate-buffered paraformaldehyde to allow for the in situ fixation of many of the main arteries of the rat. Following the in situ fixation of the rat vasculature, selected blood vessels can be removed, cleaned, and poly (A)+ mRNA purified. In addition, the distinct cell layers of the paraformaldehyde-fixed aorta can be mechanically separated and poly (A)+ mRNA purified selectively from each. The application of this method to the study of enzymes involved in cyclic nucleotide-mediated cell-signaling is illustrated by the cloning of two cyclic AMP phosphodiesterases from rat arteries, and from the selective amplification of message for these enzymes from different cell layers isolated from the rat aorta. This method should be applicable to determine if selected mRNAs are present in selected blood vessels of the rat, or within distinct cell layers of particular large blood vessels.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed2005

The approximately 30-million-year-old ERVPb1 envelope gene is evolutionarily conserved among hominoids and Old World monkeys.

Most human endogenous retroviruses (HERVs) are ancient and their genes are rendered nonfunctional by debilitating mutations. One exception is a recently discovered envelope gene located on chromosome 14. This envelope protein was also recently shown to be expressed in various human tissues and to mediate cell-cell fusion ex vivo. In this study, we demonstrate that this locus (designated ERVPb1) is preserved in Old World monkeys and that the reading frame is maintained. This is congruent with the entry of the HERV-P(b) group between 27 and 36 million years ago as suggested by long terminal repeat divergence. Although the coding capacity is generally lost in the HERV-IP supergroup, the analysis of nucleotide substitutions, lack of stop codons, and single-nucleotide polymorephisms strongly indicates a selective advantage of the ERVPb1 envelope genes during primate evolution. The purifying selection and tissue-specific expression of the human ERVPb1 envelope gene provide strong evidence of a beneficial role for the host.

Animals↗

PubMed1997

Divergent patterns of progression to AIDS after infection from the same source: human immunodeficiency virus type 1 evolution and antiviral responses.

The rate of progression to AIDS in human immunodeficiency virus type 1 (HIV-1)-infected individuals is determined by a complex series of interactions between the host and virus. Here we evaluate virologic properties and host responses in two men near-simultaneously infected with HIV-1 from the same sexual partner--one individual progressed to AIDS in less than 2 years, and the other remains asymptomatic 3 years postinfection. Distinct neutralizing antibody and cellular immune responses were evident, with the slower progressor exhibiting generally stronger and broader responses, except for cytotoxic T-lymphocyte responses early in infection. Virtually identical, homogeneous virus populations were found in both patients in the first sample obtained; however, a second unrelated HIV-1 virus population was also found in the fast progressor. Whether the second population emanated from an additional source of infection or the two were transmitted from the original source could not be determined. The virus population in the slower progressor turned over and diversified rapidly, whereas both virus populations in the rapid progressor evolved at a much slower rate. In addition, the character of mutational changes underlying these diversities appeared to be distinct, with a bias for diversifying selection developing in the slower progressor and a reciprocal bias towards purifying selection maintained in both populations in the fast progressor. Thus, the rapid evolution that is a hallmark of HIV replication may be a reflection of strong host resistance against emerging virus variants and a longer period of asymptomatic infection. Furthermore, rapid progression was not linked to a collapse of any appreciable immune response following attainment of some threshold of antigenic diversity but rather to a failure to drive this diversification and a condition of relatively unimpeded expansion of variants with optimized replicative capacity within the host.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Evidence for phosphorylation of serine 753 in CFTR using a novel metal-ion affinity resin and matrix-assisted laser desorption mass spectrometry.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene encodes an apical membrane Cl- channel regulated by protein phosphorylation. To identify cAMP-dependent protein kinase (PKA)-phosphorylated residues in full-length CFTR, immobilized metal-ion affinity chromatography (IMAC) was used to selectively purify phosphopeptides. The greater specificity of iron-loaded (Fe3+) nitrilotriacetic (NTA). Sepharose compared to iminodiacetic acid (IDA) metal-chelating matrices was demonstrated using a PKA-phosphorylated recombinant NBD1-R protein from CFTR. Fe(3+)-loaded NTA Sepharose preferentially bound phosphopeptides, whereas acidic and poly-His-containing peptides were co-purified using the conventional IDA matrices. IMAC using NTA Sepharose enabled the selective recovery of phosphopeptides and identification of phosphorylated residues from a complex proteolytic digest. Phosphopeptides from PKA-phosphorylated full-length CFTR, generated in Hi5 insect cells using a baculovirus expression system, were purified using NTA Sepharose. Phosphopeptides were identified using matrix-assisted laser desorption mass spectrometry (MALDI/MS) with post-source decay (PSD) analysis and collision-induced dissociation (CID) experiments. Phosphorylated peptides were identified by mass and by the metastable loss of HPO3 and H3PO4 from the parent ions. Peptide sequence and phosphorylation at CFTR residues 660Ser, 737Ser, and 795Ser were confirmed using MALDI/PSD analysis. Peptide sequences and phosphorylation at CFTR residues 700Ser, 712Ser, 768Ser, and 813Ser were deduced from peptide mass, metastable fragment ion formation, and PKA consensus sequences. Peptide sequence and phosphorylation at residue 753Ser was confirmed using MALDI/CID analysis. This is the first report of phosphorylation of 753Ser in full-length CFTR.

Amino Acid Sequence↗

PubMed2002

Mutational equilibrium model of genome size evolution.

The paper describes a mutational equilibrium model of genome size evolution. This model is different from both adaptive and junk DNA models of genome size evolution in that it does not assume that genome size is maintained either by positive or stabilizing selection for the optimum genome size (as in adaptive theories) or by purifying selection against too much junk DNA (as in junk DNA theories). Instead the genome size is suggested to evolve until the loss of DNA through more frequent small deletions is equal to the rate of DNA gain through more frequent long insertions. The empirical basis for this theory is the finding of a strong correlation and of a clear power-function relationship between the rate of mutational DNA loss (per bp) through small deletions and genome size in animals. Genome size scales as a negative 1.3 power function of the deletion rate per nucleotide. Such a relationship is not predicted by either adaptive or junk DNA theories. However, if genome size is maintained at equilibrium by the balance of mutational forces, this empirilical relationship can be readily accommodated. Within this framework, this finding would imply that the rate of DNA gain through large insertions scales up a quarter-power function of genome size. On this view, as genome size grows, the rate of growth through large insertions is increasing as a quarter power function of genome size and the rate of DNA loss through small deletions increases linearly, until eventually, at the stable equilibrium genome size value, rates of growth and loss equal each other. The current data also suggest that the long-term variation is genome size in animals is brought about to a significant extent by changes in the intrinsic rates of DNA loss through small deletions. Both the origin of mutational biases and the adaptive consequences of such a mode of evolution of genome size are discussed.

Base Sequence↗

PubMed1996

Molecular evolution of ruminant lysozymes.

The evolution of a new digestive enzyme, stomach lysozyme, from an antibacterial host defense enzyme provides a link between molecular evolution and organismal evolution. Lysozymes have been recruited at least three times (twice from a conventional lysozyme c and once from a calcium-binding lysozyme c) in vertebrates for functioning in the stomach. The recruitment of lysozyme for its new biological function involved many molecular changes, beyond those required to adapt the protein to function in the stomach. The evolution of the stomach lysozyme gene has been extensively studied in ruminant artiodactyls. In ruminants, the lysozyme c gene has duplicated to yield a family of about ten genes. These duplications allowed: (1) specialization of gene function and (2) increased levels of expression. The ruminant stomach lysozyme genes have evolved in an episodic fashion - there was a period of rapid adaptive sequence evolution, driven by positive selection in the early ruminant, that was followed by an increase in purifying selection upon the well-adapted stomach lysozyme sequence among modern species. Recombination of small portions (exons) of the genes between members of the lysozyme gene family may have aided in adaptive evolution. Evolution to a stomach lysozyme is not irreversible; at least one member of the ruminant stomach lysozyme gene family appears to have reverted to a more ancestral function, yet retains hallmarks of its history as a stomach lysozyme.

Animals↗

PubMed1992

An evolutionary model for the duplication and divergence of esterase genes in Drosophila.

The esterase 5 (Est-5 = gene, EST 5 = protein) enzyme in Drosophila pseudoobscura is encoded by one of three paralogous genes, Est-5A, Est-5B, and Est-5C, that are tightly clustered on the right arm of the X chromosome. The homologous Est-6 locus in Drosophila melanogaster has only one paralogous neighbor, Est-P. Comparisons of coding and flanking DNA sequences among the three D. pseudoobscura and two D. melanogaster genes suggest that two paralogous genes were present before the divergence of D. pseudoobscura from D. melanogaster and that, later, a second duplication occurred in D. pseudoobscura. Nucleotide sequences of the coding regions of the three D. pseudoobscura genes showed 78-85% similarity in pairwise comparisons, whereas the relatedness between Est-6 and Est-P was only 67%. The higher degree of conservation in D. pseudoobscura likely results from the comparatively recent divergence of Est-5B and Est-5C and from possible gene conversion events between Est-5A and Est-5B. Analyses of silent and replacement site differences in the two exons of the paralogous and orthologous genes in each species indicate that common selective forces are acting on all five loci. Further evidence for common purifying selective constraints comes from the conservation of hydropathy profiles and proposed catalytic residues. However, different levels of amino acid substitution between the paralogous genes in D. melanogaster relative to those in D. pseudoobscura suggest that interspecific differences in selection also exist.

Amino Acid Sequence↗

PubMed1999

Molecular evolution of cytochrome b of subterranean mole rats, Spalax ehrenbergi superspecies, in Israel.

We describe the molecular evolution of cytochrome b of blind subterranean mole rats. We examined 12 individuals for nucleotide differences in the region of 402 base pairs of mitochondrial cytochrome b. Each individual represents a different population from the entire ecological and speciational range of the four chromosomal species in Israel (2n = 52, 54, 58, and 60) belonging to the Spalax ehrenbergi superspecies. Our results indicate the following. (i) There are seven first-position transitional differences, compared to 34 variable third positions, with no observed second-position substitutions. (ii) A maximum of four amino acids differences occurs across the range. (iii) Within-species diversity increases southward. Only 1 autoapomorphic substitution characterizes either 2n = 52 or 2n = 54, but 6-11 substitutions characterize 2n = 58, and 9-13 substitutions characterize 2n = 60. (iv) Both parsimony and maximum-likelihood trees suggest two monophyletic groups: (a) 2n = 52 and 54, and (b) 2n = 58 and 60, as identified earlier by other protein and DNA markers. (v) Mitochondrial cytochrome b heterogeneity is significantly correlated with climatic factors (rainfall) and biotic factors (body size and allozymes). We hypothesize that two selective regimes direct cytochrome b evolution in the S. ehrenbergi superspecies: (i) purifying selection in the flooded, mesic, hypoxic northern range of 2n = 52 and 54 and (ii) diversifying selection in the climatically spatiotemporal, xeric, and variable southern range of 2n = 58 and 60. Thus, the molecular evolution of mitochondrial cytochrome b in S. ehrenbergi is explicable by opposite selective stresses across the range of S. ehrenbergi in Israel, associated with the ecological adaptive radiation of the complex.

Amino Acids↗

PubMed1998

High-dose chemotherapy and autologous stem cell transplantation as treatment for high-risk breast cancer.

High-dose chemotherapy with autologous stem cell transplantation has emerged as a common treatment for patients with breast cancer who have a poor prognosis. The success of this approach appears to depend on the tumor burden and the sensitivity of the disease to chemotherapy because treatment techniques have been refined and treatment-related mortality has declined. Phase II studies in patients with stage II and III disease are encouraging and suggest that treatment with high-dose chemotherapy before the development of metastatic disease may provide an advantage in terms of relapse-free and overall survival. However, tumor cells may contaminate stem cell collections and contribute to relapse after transplantation. Therefore it may be important to separate and select purified CD34+ cells which are not contaminated. It has been suggested that selection bias contributes to the favorable preliminary results observed in phase II studies of high-risk patients. Such issues, together with patient and physician bias regarding the benefits of this strategy, emphasize the need to complete the prospective randomized trials now underway.

Antineoplastic Agents↗

PubMed2003

Mammalian housekeeping genes evolve more slowly than tissue-specific genes.

Do housekeeping genes, which are turned on most of the time in almost every tissue, evolve more slowly than genes that are turned on only at specific developmental times or tissues? Recent large-scale gene expression studies enable us to have a better definition of housekeeping genes and to address the above question in detail. In this study, we examined 1581 human-mouse orthologous gene pairs for their patterns of sequence evolution, contrasting housekeeping genes with tissue-specific genes. Our results show that, in comparison to tissue-specific genes, housekeeping genes on average evolve more slowly and are under stronger selective constraints as reflected by significantly smaller values of Ka/Ks. Besides stronger purifying selection, we explored several other factors that can possibly slow down nonsynonymous rates in housekeeping genes. Although mutational bias might slightly slow the nonsynonymous rates in housekeeping genes, it is unlikely to be the major cause of the rate difference between the two types of genes. The codon usage pattern of housekeeping genes does not seem to differ from that of tissue-specific genes. Moreover, contrary to the old textbook concept, we found that approximately 74% of the housekeeping genes in our study belong to multigene families, not significantly different from that of the tissue-specific genes ( approximately 70%). Therefore, the stronger selective constraints on housekeeping genes are not due to a lower degree of genetic redundancy.

Animals↗

PubMed2004

Stabilizing selection on behavior and morphology masks positive selection on the signal in a salamander pheromone signaling complex.

Natural selection maintains the integration and coordination of sets of phenotypic characters that collectively perform a task. In functional complexes in which characters span molecular to behavioral levels of organization, we might then expect similar modes of selection to produce similar patterns in evolutionary divergence at each level. To test this expectation, we diagnosed selection at behavioral, morphological, and molecular levels for courtship pheromone signaling by plethodontid salamanders. At the levels of morphology and behavior tens of millions of years of stasis (stabilizing selection) occur on each side of a transition from vaccination to olfactory delivery modes. As a proxy for the molecular level, we used plethodontid receptivity factor (PRF), a protein that is an active component of the pheromone. We cloned PRF from 12 Plethodon spp. spanning the delivery transition and obtained multiple alleles from each individual surveyed. Analyses of 61 alleles for PRF identified elevated nonsynonymous over synonymous substitution rates along lineages in a molecular phylogeny, and at 8% of sites in the protein, indicating that positive (directional) selection has acted on this vertebrate pheromone gene. Structural models showed PRF is in a family of cytokines characterized by a four-alpha-helix bundle. Positive selection in PRF was associated with receptor binding sites that are under purifying selection in other cytokines of that family. The evolutionary dynamics of the plethodontid pheromone delivery complex consists of stabilizing selection on morphological and behavioral aspects of signal delivery but positive selection on the signal mediated by receptors. Thus, different selection modes prevail at different levels in this reproductive functional complex. Evolutionary studies of integrated sets of characters therefore require separate analyses of selective action at each level.

Amino Acid Sequence↗

PubMed2004

Positive directional selection in the proline-rich antigen (PRA) gene among the human pathogenic fungi Coccidioides immitis, C. posadasii and their closest relatives.

In this study, we investigate the possibility of selection acting on the proline-rich antigen (PRA) gene in natural populations of the two human pathogens, Coccidioides immitis and Coccidioides posadasii, and three of their close relatives, Chrysosporium lucknowense, Chrysosporium queenslandicum, and Uncinocarpus reesii. We addressed the following questions: Is diversifying selection acting on PRA in the pathogenic species as a result of avoidance of the host's immune system, and has adaptation to a pathogenic life style lead to positive directional selection and increased rate of evolution in PRA between the species? For these purposes, we amplified and sequenced from 40 individuals belonging to the five species, the entire coding region of the PRA gene, as well as partial sequences from the coding region of each of the three housekeeping genes glyderaldehyde-3-phosphate dehydrogenase, glutamine synthetase A, and hexokinase A. We used likelihood-based methods to compare models of different types of selective pressure among codons to analyze the mode of evolution of the genes and found that the PRA gene evolves under positive selection, but the investigated parts of the housekeeping genes evolve primarily under purifying selection. We found a very low level of intraspecific variability and no evidence of diversifying selection, suggesting that the increased rate of evolution in the PRA gene is not a result of avoidance of the host's immune system. Neither did likelihood-based analyses suggest that selection was stronger on the branch separating pathogenic and nonpathogenic species. Instead, we suggest that positive selection act on PRA as a consequence of spore cell-wall morphogenesis unique to each species.

Amino Acid Sequence↗

PubMed1996

Patterns of divergence during evolution of alpha 1-proteinase inhibitors in mammals.

alpha 1-Proteinase inhibitor (alpha 1-PI), a member of the serine proteinase inhibitor superfamily, has a primary role in controlling neutrophil elastase activity within the mammalian circulation. Several studies have indicated that the reactive center region of alpha 1-PI, the amino acid sequence of which is critical to recognition of and binding to target proteinases, is highly divergent within and among species. This appears to be a consequence of accelerated rates of evolution that may have been driven by positive Darwinian selection. In order to examine this and other features of alpha 1-PI evolution in more detail, we have isolated and sequenced cDNAs representing alpha 1-PI mRNAs of the mouse species Mus saxicola and Mus minutoides and have compared these with a number of other mammalian alpha 1-PI mRNAs. Relative to other mammalian mRNAs, the extent of nonsynonymous substitution is generally high throughout the alpha 1-PI mRNA molecule, indicating greater overall rates of amino acid substitution. Within and among mouse species, the 5'-half of the mRNA, but not the 3'-half, has been homogenized by concerted evolution. Finally, the reactive center is under diversifying or positive Darwinian selection in murid rodents (rats, mice) and guinea pigs yet is under purifying selection in primates and artiodactyls. The significance of these findings to alpha 1-PI function and the possible selective forces driving evolution of serpins in general are discussed.

Animals↗