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PubMed1986

Intrachromosomal gene conversion, linkage, and the evolution of multigene families.

The evolution of the probabilities of genetic identity within and between tandemly repeated loci of a multigene family is investigated analytically and numerically. Unbiased intrachromosomal gene conversion, equal crossing over, random genetic drift, and mutation to new alleles are incorporated. Generations are discrete and nonoverlapping; the diploid, monoecious population mates at random. Under the restriction that there is at most one crossover in the multigene family per individual per generation, the dependence on location of the probabilities of identity is treated exactly. In the "homogeneous" approximation to this "exact" model, end effects are disregarded; in the "exchangeable" approximation, to which all previous work was confined, all position dependence is neglected. Numerical results indicate that the exchangeable and homogeneous models are both qualitatively correct, the exchangeable model is sometimes too inaccurate for quantitative conclusions, and the homogeneous model is always more accurate than the exchangeable one and is always sufficiently accurate for quantitative conclusions.

Female↗

PubMed1996

G protein alpha subunit multigene family in the Japanese puffer fish Fugu rubripes: PCR from a compact vertebrate genome.

We compare the complexity and organization of the G protein alpha subunit multigene family in the vertebrate genomes of mammals and the Japanese puffer fish Fugu rubripes. Fourteen Fugu G alpha genes were identified of the 16 genes characterized previously in mammals, including Fugu genes from the four classes of alpha subunits Gs, Gi, Gq, and G12. Fugu and mammalian G alpha coding sequences are highly homologous, and the intron/exon structure of the fish and mammalian orthologs is identical throughout the coding regions. A novel G alpha gene, G alpha p1, was also identified in Fugu rubripes and two other species of puffer fish. The complete sequence of Gnaz and the tandemly duplicated genes Gnai2 and Gnat1 were obtained from a Fugu genomic cosmid library. Introns in the puffer fish G alpha genes lacked repeat DNA sequences, other than simple sequence length repeats, and most introns were significantly shorter in Fugu than in mammalian orthologs. The compact genome of puffer fish provides a unique vertebrate model for characterizing multigene families and identifying novel genes directly from genomic DNA by PCR amplification with degenerate primers. The fact that Fugu encodes most, if not all, of the G protein alpha subunits identified in mammals strongly supports Fugu as a model organism for vertebrate genome research.

Amino Acid Sequence↗

PubMed2002

Major outer membrane proteins of Ehrlichia ruminantium encoded by a multigene family.

Immune responses of infected animals and humans have been reported to be directed against variable outer membrane proteins of Ehrlichia species that are encoded by polymorphic multigene families. In Ehrlichia (= Cowdria) ruminantium, two immunodominant proteins have been identified, namely major antigenic protein 1 (MAP1) and open reading frame 2 (ORF2). The aim of the present study was to identify additional map1-like genes in the E. ruminantium genome. A 12 kb clone that hybridized with the map1 probe was amplified using long template PCR. The PCR product was partially digested, cloned, and sequenced. Four map1-like genes are located in tandem, namely map1-1 (orf2) and map1-2 upstream of map1 as well as map1+1 downstream of map1. A large ORF (2.4 kb) at the 3' end is homologous to secA genes of other organisms. The sequence data in this study support other findings that outer membrane proteins are located in tandem and are encoded by a polymorphic multigene family.

Amino Acid Sequence↗

PubMed1983

Hormonal regulation and expression of vitellogenin multigene family.

Yolk proteins are the most abundant egg proteins in oviparous animals. They are deposited during oocyte maturation for use after fertilization and are synthesized in the liver or fat body as a common precursor termed vitellogenin. Hybridization with cloned DNA complementary to vitellogenin messenger RNA has revealed a surprisingly high degree of evolutionary conservation of sequence of vitellogenin genes among insects, amphibians and birds. The synthesis of vitellogenin in vertebrates is directly under the control of oestrogen at the level of gene transcription. In the frog, Xenopus, vitellogenin genes occur as a multigene family, four of which are actively expressed and are grouped as A and B genes. This multiplicity offers a useful system for investigating the possible selective hormonal regulation of expression of individual members of multigene families. When X. laevis vitellogenin genes were activated by oestrogen in the liver of whole animals or in cultures of parenchymal cells, the two groups of expressed genes were not induced in an identical manner in cells from male and female animals. The activation of A and B groups of genes was non-coordinate in male hepatocytes and coordinate in female cells. Prior exposure of male hepatocytes to oestradiol in vivo or in culture caused the pattern of expression to shift to that in female cells. Since the X. laevis oocyte itself does not synthesize vitellogenin in response to oestrogen, an attempt was made to activate its dormant vitellogenin genes by transferring oestrogen-binding proteins from the liver. Preliminary results show that the microinjection into the oocyte of a preparation containing liver receptor-hormone complex led to the synthesis of vitellogenin by the oocyte. Extension of these experiments will not only enable a more precise analysis of the activation of the vitellogenin multigene family to be made but will also provide direct functional evidence for the role played by steroid hormone receptors in regulating gene expression.

Animals↗

PubMed1992

Transcriptional analysis of multigene family 110 of African swine fever virus.

A transcriptional analysis of the 3.2-kb region of the African swine fever virus genome containing the five members of the multigene family 110 is presented. The mRNAs corresponding to the genes studied have short leader sequences with no intervening AUG codons before the translational start site, and their 3' ends map within a conserved sequence motif formed by a stretch of seven or more consecutive thymidylate residues. The possible role of this sequence as a signal for the 3'-end formation of African swine fever virus mRNAs is discussed. While four of the genes studied are actively transcribed from the beginning of the infection until the onset of virus DNA replication, the transcription of one of the members of the multigene family 110, the L270 gene, is silenced at an earlier time. A detailed analysis, including in vitro translation of mRNAs isolated from infected Vero cells, revealed that the L270 gene belongs to a small subset of early genes, designated immediate early, whose transcription is silenced before the onset of virus DNA replication. The transcriptional data obtained enabled us to generate the first detailed transcriptional map of a region of the African swine fever virus genome, thus opening the possibility of studying the cis-acting sequences involved in transcriptional control of the viral genes.

African Swine Fever Virus↗

PubMed2002

Complexities in ETS-domain transcription factor function and regulation: lessons from the TCF (ternary complex factor) subfamily. The Colworth Medal Lecture.

The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.

Amino Acid Sequence↗

PubMed1988

One of the tightly clustered genes of the mouse surfeit locus is a highly expressed member of a multigene family whose other members are predominantly processed pseudogenes.

The mouse surfeit locus is unusual in that it contains a number of closely clustered genes (Surf-1, -2, and -4) that alternate in their direction of transcription (T. Williams, J. Yon, C. Huxley, and M. Fried, Proc. Natl. Acad. Sci. USA 85:3527-3530, 1988). The heterogeneous 5' ends of Surf-1 and Surf-2 are separated by 15 to 73 base pairs (bp), and the 3' ends of Surf-2 and Surf-4 overlap by 133 bp (T. Williams and M. Fried, Mol. Cell. Biol. 6:4558-4569, 1986; T. Williams and M. Fried, Nature (London) 322:275-279, 1986). A fourth gene in this locus, Surf-3, which is a member of a multigene family, has been identified. The poly(A) addition site of Surf-3 lies only 70 bp from the poly(A) addition site of Surf-1. Transcription of Surf-3 has been studied in the absence of the other members of its multigene family after transfection of a cloned genomic mouse DNA fragment, containing the Surf-3 gene, into heterologous monkey cells. Surf-3 specifies a highly expressed 1.0-kilobase mRNA that contains a long open reading frame of 266 amino acids, which would encode a highly basic polypeptide (23% Arg plus Lys). The other members of the Surf-3 multigene family are predominantly, if not entirely, intronless pseudogenes with the hallmarks of being generated by reverse transcription. The role of the very tight clustering on regulation of expression of the genes in the surfeit locus is discussed.

Amino Acid Sequence↗

PubMed1993

The ets multigene family is conserved throughout the Metazoa.

This study provides the first empirical evidence for the conservation of the ets proto-oncogene transcription factor family throughout the Metazoa. Using the polymerase chain reaction with degenerate primers corresponding to conserved sequences within the ETS DNA-binding domain, we have detected ets genes in a range of lower metazoans, including sponges, ctenophores, anemones, flatworms and nematodes, and in several higher invertebrate metazoans. Many of these sequences are significantly divergent from the original v-ets-1 oncogene, although most can be aligned with recently defined groups within the ets gene family. Multiple ETS domain sequences were detected in a number of the lower metazoan species, providing evidence for the existence of an ets multigene family at the earliest stages of metazoan evolution. In contrast, we were unable to detect any ETS sequences in fungal, plant or several protozoan DNAs. Our findings suggest that the duplication and divergence of ets proto-oncogenes responsible for generating the multigene family occurred concomitantly with the development of metazoan animals. In addition, these data corroborate other recent molecular evidence in providing strong support for the monophyletic origin of all multicellular animals, including sponges.

Amino Acid Sequence↗

PubMed2003

Low glutelin content1: a dominant mutation that suppresses the glutelin multigene family via RNA silencing in rice.

Low glutelin content1 (Lgc1) is a dominant mutation that reduces glutelin content in rice grains. Glutelin is a major seed storage protein encoded by a multigene family. RNA gel blot and reverse transcriptase-mediated PCR analyses revealed that Lgc1 acts at the mRNA level in a similarity-dependent manner. In Lgc1 homozygotes, there is a 3.5-kb deletion between two highly similar glutelin genes that forms a tail-to-tail inverted repeat, which might produce a double-stranded RNA molecule, a potent inducer of RNA silencing. The hypothesis that Lgc1 suppresses glutelin expression via RNA silencing is supported by transgenic analysis using this Lgc1 candidate region, by reporter gene analysis, and by the detection of small interfering RNAs. In this context, Lgc1 provides an interesting example of RNA silencing occurring among genes that exhibit various levels of similarity to an RNA-silencing-inducing gene. Possible mechanisms for gene silencing of the glutelin multigene family by Lgc1 are discussed.

Amino Acid Sequence↗

PubMed2005

Birth-and-death evolution of the Cecropin multigene family in Drosophila.

Cecropins are insect antibacterial peptides that are part of the insect humoral immune response and could, therefore, be potential targets of natural selection. In Drosophila, the Cec genes constitute a multigene family whose members are arranged in tandem. The complete Cec family was isolated in two obscura group species: D. subobscura and D. pseudoobscura. The chromosomal regions encompassing the Cec genes were subsequently sequenced and mapped by in situ hybridization. In D. pseudoobscura, as in species of the D. melanogaster complex and in D. virilis, the Cec genes constitute a single cluster with five genes. In D. subobscura, unlike in the rest of the species, the eight members of the family are split into two clusters located in different parts of the same chromosome. Remarkable differences in levels of divergence were observed between copies in both species. The genomic organization and the phylogenetic relationships among members of this family in the genus Drosophila indicate (i) that the presence of two clusters is the derived state of the family, (ii) repeated gene duplication within species, (iii) nonfunctionalization and loss of some Cec copies, and (iv) the presence of both highly divergent and highly similar copies within species. These features are better explained by the birth-and-death model of molecular evolution, which posits that the high instability of the Cec multigene family in Drosophila is simply determined by the duplication rate and the subsequent loss of duplicated loci.

Amino Acid Sequence↗

PubMed1999

Detecting and characterizing gene conversions between multigene family members.

We used a variety of methods to detect known gene conversions in the actin gene families of five angiosperm species, the beta-globin gene families of two primate species, and the Zfx/Zfy gene families of seven mammalian species. Our goal was to devise a working strategy which would allow the analysis of the members of a multigene family in order to determine whether there had been gene conversions between its members, identify the genes involved in the gene conversions, establish the lengths of the converted regions, and determine the polarities of the gene conversions. We show that three phylogenetic methods and the homoplasy test of Maynard Smith and Smith perform relatively poorly on our data sets because the sequences we analyzed had large levels of multiple substitutions. The method of Sawyer, the compatibility method of Jakobsen and Easteal, the partition matrix method of Jakobsen, Wilson, and Easteal, and the co-double method of Balding, Nichols, and Hunt can be used to identify the genes which have been involved in gene conversions. The co-double method is more powerful than other methods but requires orthologous sequences from related species. Compatibility, phylogenetic, and nucleotide substitution distribution statistics methods can be used to identify the location of the converted region(s). Site-by-site compatibility analyses can also be used to identify the direction of the conversion event(s). Combinations of these methods can therefore be used to establish the presence, locations, and polarities of gene conversions between multigene family members.

Actins↗

PubMed1992

Gene conversions within the skeletal myosin multigene family.

Comparisons of the nucleotide sequences of the light meromyosin (LMM) region of developmentally regulated fast chicken myosin heavy chain (MHC) isoforms indicates that chicken MHC isoforms are more similar to each other than to MHC isoforms in other species. The sequence data provide evidence that gene conversion events have occurred recently among the isoforms. An embryonic (Cemb1) isoform and neonatal isoform have the most extensive regions of sequence identity. Similar gene conversion events are present in the rat alpha- and beta-cardiac MHCs, but were not obvious in the LMM of developmentally regulated fast human MHC isoforms. The data suggest that gene conversion events can play a significant role in the evolution of the MHC multigene families and that concerted evolution of the chicken multigene family occurred after the divergence of mammals and avians.

Animals↗

PubMed2005

Identification of the novel evolutionary conserved obstructor multigene family in invertebrates.

Insects have evolved chitin-containing structures such as the cuticle or peritrophic membranes that serve to protect their bodies against the hostile environment. The specific mechanisms by which these structures are produced, are mostly unknown. We have identified a novel multigene family, the obstructor family, which encodes ten putatively secreted chitin-binding proteins that are characterized by a stereotype arrangement of a N-terminal signaling peptide and 3 chitin-binding-domains. Gene expression studies in Drosophila melanogaster embryos demonstrate that obstructor family members are expressed in cuticle forming tissues. Using computational and phylogenetic analysis, we show that obstructor genes represent an evolutionary conserved multigene family in invertebrates.

Amino Acid Sequence↗

PubMed1989

Characterization of the hsp70 multigene family of Caenorhabditis elegans.

Our laboratory has been characterizing the hsp70 multigene family from the nematode Caenorhabditis elegans as the first step to the genetic characterization of the heat shock response in a relatively simple multicellular eukaryote. Two gene members, hsp-1 and hsp-2ps have already been characterized (Snutch et al., 1988; Heschl and Baillie, 1989). The third gene member, hsp-3, is expressed constitutively and is non-heat inducible; its mRNA is most abundant at the L1 larval stage. The hsp-3 protein (hsp70C) shares a high degree of identity with the rat grp78 protein and has a long, hydrophobic leader sequence. The carboxyl terminus of hsp70C has the putative ER-retention signal, KDEL. The fourth gene member, hsp-6 is expressed constitutively and moderately heat inducible. A partial hsp-6 protein (hsp70F) sequence shares a higher degree of identity with the Escherichia coli dnaK protein than with eukaryotic hsp70 proteins. The predicted amino-terminal half of the hsp70F polypeptide also contains a long, amphiphilic leader sequence similar to mitochondrial import leader sequences. These two genes encode proteins that potentially cross intracellular membranes. We compared the 5'-flanking DNA from the C. elegans hsp-3 gene to fragment containing enhancer activity from the rat grp78 gene regulatory region (Lin et al., 1986). A 23-nucleotide sequence was conserved between the two promoter regions. This sequence shares approximately 80% identity between these two evolutionary distant organisms. A comparison to other hsp70 genes did not reveal any conservation of this 23-nucleotide sequence. We propose that this sequence may be involved in a unique aspect of the regulation of the C. elegans' grp78-like gene and the rat grp78 gene.

Amino Acid Sequence↗

PubMed1988

Proline-rich proteins and glycoproteins: expression of salivary gland multigene families.

Our recent research interests have focused on a group of unusual proteins and glycoproteins high in proline content, or the so-called proline-rich proteins (PRPs). The PRPs are tissue-specific expressions of salivary gland multigene families. Normally PRPs are not detected or are present in very low amounts in rat, mouse and hamster salivary glands, but these unusual proteins are dramatically induced by treatment with the catecholamine isoproterenol. The structures and organizations of several PRP mRNAs and PRP genes have been determined. The amino acid sequences of all PRPs show 4 distinct regions, namely, a signal peptide, a transition region, a repeat region and a carboxyl-terminal region. Glycoproteins induced by isoproterenol treatment may be N-glycosylated or O-glycosylated. The N-glycosylated glycoprotein GP-158 from rat submandibular glands has a 12 amino acid glycopeptide which repeats possibly 49 times. Proline-rich proteins of the parotid glands of rats and mice are also greatly induced by dietary tannins. The apparent unique occurrence of PRPs in saliva suggests that one biological role is to neutralize the detrimental effects of dietary tannins and other polyphenols. The upstream regions of the mouse and hamster PRP genes contain cyclic AMP-regulated sequences as demonstrated by deletions and transient transfections. The PRP multigene family members of mouse are all located on chromosome 8.

Amino Acid Sequence↗

PubMed1988

Molecular evolution of the mouse proline-rich protein multigene family. Insertion of a long interspersed repeated DNA element.

Proline-rich proteins (PRPs) in the salivary glands of mice, rats, and hamsters are encoded by tissue-specific inducible multigene families. Mouse PRP genes are located on chromosome 8, and transcription is dramatically induced (about 70-fold) by isoproterenol treatment. Clones containing two nonallelic PRP genes (MP2 and M14) were isolated from cosmid and phage libraries of CD-1 mouse genomic DNA. The cloned regions comprise a contiguous block of 77 kilobase pairs of the mouse genome. Restriction mapping established the physical lineage of PRP genes MP2 and M14, and they are tandemly arrayed. The DNA sequence analysis presented in this report suggests that genes M14 and MP2 (Ann, D. K., and Carlson, D. M. (1985) J. Biol. Chem. 260, 15863-15872) arose via a gene duplication of a common ancestor. Two major differences between M14 and MP2 were observed. PRP gene MP2 has 13 tandemly arrayed 42-nucleotide repeats in exon II, whereas M14 has 17 repeats, and PRP gene M14 has an insertion by transposition of a 2-kilobase pair member of the long interspersed repeated DNA (LINE) family (LIMd) into intron I. The evolution of this PRP multigene family has been dominated by intra-exonic amplification of repeating nucleotide units coding for these and other proline-rich repeated peptides and by gene duplication. The LIMd element gives rise to heterogenous EcoRI, BamHI, and HindIII restriction enzyme patterns, and this insertion is also present in BALB/c, C57BL/6J, and DBA/2J mice.

Amino Acid Sequence↗

PubMed2003

Combinatorial coexpression of neural and immune multigene families in mouse vomeronasal sensory neurons.

The vomeronasal organ (VNO) is a chemosensory organ specialized in the detection of pheromones in higher vertebrates. In mouse and rat, two gene superfamilies, V1r and V2r vomeronasal receptor genes, are expressed in sensory neurons whose cell bodies are located in, respectively, the apical and basal layers of the VNO epithelium. Here, we report that neurons of the basal layer express another multigene family, termed H2-Mv, representing nonclassical class I genes of the major histocompatibility complex. The nine H2-Mv genes are expressed differentially in subsets of neurons. More than one H2-Mv gene can be expressed in an individual neuron. In situ hybridization with probes for H2-Mv and V2r genes reveals complex and nonrandom combinations of coexpression. While neural expression of Mhc class I molecules is increasingly being appreciated, the H2-Mv family is distinguished by variegated expression across seemingly similar neurons and coexpression with a distinct multigene family encoding neural receptors. Our findings suggest that basal vomeronasal sensory neurons may consist of multiple lineages or compartments, defined by particular combinations of V2r and H2-Mv gene expression.

Amino Acid Sequence↗

PubMed1995

Isolation and cDNA cloning of Ksp-cadherin, a novel kidney-specific member of the cadherin multigene family.

Cadherins are recognized as the principal mediators of homotypic cellular recognition and play a demonstrated role in the morphogenic direction of tissue development. We report here the identification of a structurally unique, kidney-specific member of the cadherin multigene family (Ksp-cadherin). cDNA cloning and molecular analysis of the 130-kDa protein confirmed that it was novel and indicated that it most closely resembled members of the LI-cadherin/HPT-1 cadherin subgroup. The predicted protein possesses the definitive cadherin-specific sequence motifs LDRE, DXND, and DXD in well conserved sequential arrangement, and the characteristic cysteine residues found in the last ectodomains of almost all known cadherins. Like LI-cadherin and HPT-1, Ksp-cadherin lacks the prosequence and HAV adhesion recognition sequence typical of most classical cadherins, and possesses a truncated cytoplasmic domain (18-22 amino acids). When expressed in a transient Vaccinia/T7 expression system, Ksp-cadherin displayed the classic calcium sensitivity to trypsin proteolysis that is observed in all cadherins. Immunolocalization studies and Northern analysis indicated that expression of Ksp-cadherin was kidney-specific and limited to the basolateral membranes of renal tubular epithelial cells. In summary, we have identified and cloned a novel, kidney-specific member of the cadherin multigene family that we propose be designated Ksp-cadherin.

Amino Acid Sequence↗