The evolutionary origin of the HLA-DR3 haplotype

The human HLA-DR3 haplotype consists of two functional genes (DRB1*03 and DRB3*01) and one pseudogene (DRB2), arranged in the order DRB1... DRB2... DRB3 on the chromosome. To shed light on the origin of the haplotype, we sequenced 1480 nucleotides of the HLA-DRB2 gene and aong stretches of two other genes, Gogo-DRB2 from a gorilla, Sylvia and Patr-DRB2 from a chimpanzee, Hugo. All three sequences (HLA-DRB2, Gogo-DRB2, Patr-DRB2) are pseudogenes. The HLA-DRB2 and Gogo-DRB2 pseudogenes lack exon 2 and contain a twenty-nucleotide deletion in exon 3, which destroys the correct translational reading frame and obliterates the highly conserved cysteine residue at position 173. The Patr-DRB2 pseudogene lacks exons 1 and 2; it does not contain the twenty-nucleotide deletion, but does contain a characteristic duplication of that part of exon 6 which codes for the last four amino acid residues of the cytoplasmic region. When the nucleotide sequences of these three genes are compared to those of all other known DRB genes, the HLA-DRB2 is seen as most closely related to Gogo-DRB2, indicating orthologous relationship between the two sequences. The Patr-DRB2 gene is more distantly related to these two DRB2 genes and whether it is orthologous to them is uncertain. The three genes are in turn most closely related to HLA-DRBVI (the pseudogene of the DR2 haplotype) and Patr-DRB6 (another pseudogene of the Hugo haplotype), followed by HLA-DRB4 (the functional but nonpolymorphic gene of the DR4 haplotype). These relationships suggest that these six genes evolved from a common ancestor which existed before the separation of the human, gorilla, and chimpanzee lineages. The DRB2 and DRB6 have apparently been pseudogenes for at least six million years (myr). In the human and the gorilla haplotype, the DRB2 pseudogene is flanked on each side by what appear to be related genes. Apparently, the DR3 haplotype has existed in its present form for more than six myr.The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession number M86691–94.     

Redundancy in antigen-presenting function of the HLA-DR and -DQ molecules in the multiple sclerosis-associated HLA-DR2 haplotype

The three HLA class II alleles of the DR2 haplotype, DRB1*1501, DRB5*0101, and DQB1*0602, are in strong linkage disequilibrium and confer most of the genetic risk to multiple sclerosis. Functional redundancy in Ag presentation by these class II molecules would allow recognition by a single TCR of identical peptides with the different restriction elements, facilitating T cell activation and providing one explanation how a disease-associated HLA haplotype could be linked to a CD4+ T cell-mediated autoimmune disease. Using combinatorial peptide libraries and B cell lines expressing single HLA-DR/DQ molecules, we show that two of five in vivo-expanded and likely disease-relevant, cross-reactive cerebrospinal fluid-infiltrating T cell clones use multiple disease-associated HLA class II molecules as restriction elements. One of these T cell clones recognizes >30 identical foreign and human peptides using all DR and DQ molecules of the multiple sclerosis-associated DR2 haplotype. A T cell signaling machinery tuned for efficient responses to weak ligands together with structural features of the TCR-HLA/peptide complex result in this promiscuous HLA class II restriction.     

A clue to the origin of life: begin from making tools

The small molecules already existing on the earth can be assembled to biological macromolecules in the presence of the suitable tool. A workman must sharpen his tools if he is to do his work well. The tool must be specific, delicate and automatic. Obviously, it is enzyme. Therefore, to explore the origin of life we must understand the origin of the manufacturing tool of biological macromolecules—the origin of enzymes. We can understand more about the origin and evolution procedures of enzymes from the NO₂. NO₂ can easily form the dimmer, N₂O₄. Four N₂O₄ molecules can coordinate with a suitable metal ion and form a plane super molecule with four N₂O₄ molecules. This supramolecule provides the basis for the appearance of enzymes: (1) It is the template for producing enzymes. (2) It provides the active centers for enzymes. (3) It provides for the enzymes with specific function of chiral selection. This supramolecule reacts with formaldehyde and porphyrin compound is gradually formed. Once suitable function groups are substituted on the porphyrin ring, enzymes are formed. The primitive environment of earth can easily produce NO₂ and CH₂O. Therefore, this might be one clue to the origin of life.

Highly polymorphic products of both HLA-DR and HLA-DQ genes contribute to the polymorphism of the HLA-DR w13 haplotype

We studied the polymorphisms of HLA-DR and HLA-DQ products from HLA-DRw13 haplotypes by analyzing the restriction of influenza A-specific cloned T cells from an HLA-DRw13,DQw1,Dw19 homozygous individual. The results show that (1) some functional epitopes, which can be borne by either HLA-DR or HLA-DQ molecules, are strictly correlated with the HLA-Dw19 subtype of HLA-DRw13. This clearly indicates that both HLA-DR and HLA-DQ products contribute to the HLA-Dw19 subdivision of HLA-DRw13. (2) At least two different restricting epitopes are borne by DR products: one is correlated with the HLA-DRwl3 serologically defined specificity, which includes Dw19 and Dw18 haplotypes; the other is correlated with the only HLA-Dw19 subtype of HLA-DRwl3. (3) Restricting epitopes borne by DQ molecules have been found on Dw19 cells only. (4) DQ-restricted clones were unable to react with DQwl APC of any other haplotypes tested, including DR1, DR2-long, DR2-short, and DRw14, demonstrating a high degree of functional polymorphism among the serologically defined DQw1 specificities.Abbreviations used in this paper: APC antigen-presenting cells - cpm count per minute - HAU hemagglutinin units - IL-2 interleukin 2 - MHC major histocompatibility complex - mAb monoclonal antibody - PBM peripheral blood mononuclear cells - PHA phytohemagglutinin - pl isoelectric point - PMA phorbol myristic acetate - SD standard deviation     

Myotonic dystrophy type 2: human founder haplotype and evolutionary conservation of the repeat tract

Myotonic dystrophy (DM), the most common form of muscular dystrophy in adults, can be caused by a mutation on either chromosome 19 (DM1) or 3 (DM2). In 2001, we demonstrated that DM2 is caused by a CCTG expansion in intron 1 of the zinc finger protein 9 (ZNF9) gene. To investigate the ancestral origins of the DM2 expansion, we compared haplotypes for 71 families with genetically confirmed DM2, using 19 short tandem repeat markers that we developed that flank the repeat tract. All of the families are white, with the majority of Northern European/German descent and a single family from Afghanistan. Several conserved haplotypes spanning >700 kb appear to converge into a single haplotype near the repeat tract. The common interval that is shared by all families with DM2 immediately flanks the repeat, extending up to 216 kb telomeric and 119 kb centromeric of the CCTG expansion. The DM2 repeat tract contains the complex repeat motif (TG)(n)(TCTG)(n)(CCTG)(n). The CCTG portion of the repeat tract is interrupted on normal alleles, but, as in other expansion disorders, these interruptions are lost on affected alleles. We examined haplotypes of 228 control chromosomes and identified a potential premutation allele with an uninterrupted (CCTG)(20) on a haplotype that was identical to the most common affected haplotype. Our data suggest that the predominant Northern European ancestry of families with DM2 resulted from a common founder and that the loss of interruptions within the CCTG portion of the repeat tract may predispose alleles to further expansion. To gain insight into possible function of the repeat tract, we looked for evolutionary conservation. The complex repeat motif and flanking sequences within intron 1 are conserved among human, chimpanzee, gorilla, mouse, and rat, suggesting a conserved biological function.     

Unusual evolutionary conservation of 5S rRNA pseudogenes inAspergillus nidulans: Similarity of the DNA sequence associated with the pseudogenes with the mouse immunoglobulin switch region

Summary AllAspergillus nidulans 5S rRNA pseudogenes known so far are the result of integration of an approx. 0.2-kbp-long DNA sequence into the 5S rRNA genes. This sequence, called block C, is present in at least five copies in theA. nidulans genome and seems to be associated either with 5S rRNA genes or pseudogenes. In contrast to the 78% sequence conservation of the C-block in pseudogenes, the truncated 5 halves of the pseudogenes are very highly conserved (96.9–100%). We postulate that the 5S rRNA pseudogenes are still a subject of concerted evolution. The C-block sequence shows similarity to the switch region of the mouse heavy chain immunoglobulin gene. A characteristic motif GGGTGAG is repeated several times in both sequences; the sequence conservation is 63%.     

Functional definition of HLA-DR and -DQ epitopes specific for DR2-short,DwFJO haplotype

T-lymphocyte clones specific for the influenza A/Texas virus were obtained by limiting dilution of activated T cells from an HLA A2/3, B7/39, Cw -/-, DR2-short/2 short, DQw1/w1, DwFJO/FJO donor. Among the proliferating clones studied, and irrespective of their antigenic specificities, most of them were restricted by epitope(s) on HLA-DR molecules present only on DR2-short/DwFJO cells but not on DR2-negative or DR2-long positive (Dw2, Dw12, Dw-) cells. Two clones were restricted by epitopes borne by DQ products. Here again, these epitopes were present on DR2-short/DwFJO but not on DR2-long, DQw1 (Dw2, Dw12) cells, indicating that the DQwl molecules of DR2-long and DR2-short haplotypes are different. Taken together, these results indicate that the DR2-short, DwFJO haplotype is characterized by both HLA-DR- and DQ-specific molecules. Finally, one clone was restricted by an epitope shared by DR products from DR2 short/DwFJO, DRw11, and DRw13 haplotypes. This latter functional determinant has never been described until now.Abbreviations used in this paper APC antigen-presenting cells - HAU hemagglutinin units of influenza virus - HLA human leukocyte antigens - HTC homozygous typing cells - IL-2 interleukin 2 - mAb monoclonal antibody - MHC major histocompatibility complex - MLR mixed lymphocyte reactions - PBM peripheral blood mononuclear cells - %RR relative response percent     

On the evolutionary origin of aging

It is generally believed that the first organisms did not age, and that aging thus evolved at some point in the history of life. When and why this transition occurred is a fundamental question in evolutionary biology. Recent reports of aging in bacteria suggest that aging predates the emergence of eukaryotes and originated in simple unicellular organisms. Here we use simple models to study why such organisms would evolve aging. These models show that the differentiation between an aging parent and a rejuvenated offspring readily evolves as a strategy to cope with damage that accumulates due to vital activities. We use measurements of the age-specific performance of individual bacteria to test the assumptions of the model, and find evidence that they are fulfilled. The mechanism that leads to aging is expected to operate in a wide range of organisms, suggesting that aging evolved early and repeatedly in the history of life. Aging might thus be a more fundamental aspect of cellular organisms than assumed so far.     

On the evolutionary origin of eukaryotic DNA methyltransferases and Dnmt2

The Dnmt2 enzymes show strong amino acid sequence similarity with eukaryotic and prokaryotic DNA-(cytosine C5)-methyltransferases. Yet, Dnmt2 enzymes from several species were shown to methylate tRNA-Asp and had been proposed that eukaryotic DNA methyltransferases evolved from a Dnmt2-like tRNA methyltransferase ancestor [Goll et al., 2006, Science, 311, 395-8]. It was the aim of this study to investigate if this hypothesis could be supported by evidence from sequence alignments. We present phylogenetic analyses based on sequence alignments of the methyltransferase catalytic domains of more than 2300 eukaryotic and prokaryotic DNA-(cytosine C5)-methyltransferases and analyzed the distribution of DNA methyltransferases in eukaryotic species. The Dnmt2 homologues were reliably identified by an additional conserved CFT motif next to motif IX. All DNA methyltransferases and Dnmt2 enzymes were clearly separated from other RNA-(cytosine-C5)-methyltransferases. Our sequence alignments and phylogenetic analyses indicate that the last universal eukaryotic ancestor contained at least one member of the Dnmt1, Dnmt2 and Dnmt3 families of enzymes and additional RNA methyltransferases. The similarity of Dnmt2 enzymes with DNA methyltransferases and absence of similarity with RNA methyltransferases combined with their strong RNA methylation activity suggest that the ancestor of Dnmt2 was a DNA methyltransferase and an early Dnmt2 enzyme changed its substrate preference to tRNA. There is no phylogenetic evidence that Dnmt2 was the precursor of eukaryotic Dnmts. Most likely, the eukaryotic Dnmt1 and Dnmt3 families of DNA methyltransferases had an independent origin in the prokaryotic DNA methyltransferase sequence space.     

Identification and expression of the lamprey Pax6 gene: evolutionary origin of the segmented brain of vertebrates

The Pax6 gene plays a developmental role in various metazoans as the master regulatory gene for eye patterning. Pax6 is also spatially regulated in particular regions of the neural tube. Because the amphioxus has no neuromeres, an understanding of Pax6 expression in the agnathans is crucial for an insight into the origin of neuromerism in the vertebrates. We have isolated a single cognate cDNA of the Pax6 gene, LjPax6, from a Lampetra japonica cDNA library and observed the pattern of its expression using in situ hybridization. Phylogenetic analysis revealed that LjPax6 occurs as an sister group of gnathostome Pax6. In lamprey embryos, LjPax6 is expressed in the eye, the nasohypophysial plate, the oral ectoderm and the brain. In the central nervous system, LjPax6 is expressed in clearly delineated domains in the hindbrain, midbrain and forebrain. We compared the pattern of LjPax6 expression with that of other brain-specific regulatory genes, including LjOtxA, LjPax2/5/8, LjDlx1/6, LjEmx and LjTTF1. Most of the gene expression domains showed conserved pattern, which reflects the situation in the gnathostomes, conforming partly to the neuromeric patterns proposed for the gnathostomes. We conclude that most of the segmented domains of the vertebrate brain were already established in the ancestor common to all vertebrates. Major evolutionary changes in the vertebrate brain may have involved local restriction of cell lineages, leading to the establishment of neuromeres.     

Primate evolution of an olfactory receptor cluster: diversification by gene conversion and recent emergence of pseudogenes.

The olfactory receptor (OR) subgenome harbors the largest known gene family in mammals, disposed in clusters on numerous chromosomes. We have carried out a comparative evolutionary analysis of the best characterized genomic OR gene cluster, on human chromosome 17p13. Fifteen orthologs from chimpanzee (localized to chromosome 19p15), as well as key OR counterparts from other primates, have been identified and sequenced. Comparison among orthologs and paralogs revealed a multiplicity of gene conversion events, which occurred exclusively within OR subfamilies. These appear to lead to segment shuffling in the odorant binding site, an evolutionary process reminiscent of somatic combinatorial diversification in the immune system. We also demonstrate that the functional mammalian OR repertoire has undergone a rapid decline in the past 10 million years: while for the common ancestor of all great apes an intact OR cluster is inferred, in present-day humans and great apes the cluster includes nearly 40% pseudogenes.     

On the evolutionary origin of the chaperonins

An analysis of the apical domain of the Group-I and Group-II chaperonins shows that they have structural similarities to two different protein folds: a "swivel-domain" phosphotransferase and a thioredoxin-like peroxiredoxin. There is no significant sequence similarity that supports either similarity and the degree of similarity based on structure is comparable but weak for both relationships. Based on possible evolutionary transitions, we deduced that a phosphotransferase origin would require both a large insertion and deletion of structure whereas a peroxiredoxin origin requires only a peripheral rearrangement, similar to an internal domain-swap. We postulate that this change could have been triggered by the insertion of a peroxiredoxin into the ATPase domain that led to the modern chaperonin domain arrangement. The peroxidoxin fold is the most highly embellished member of the thioredoxin super-family and the insertion event may have "overloaded" the core, leading to a rearrangement. A peroxiredoxin origin for the domain also provides a functional explanation, as the peroxiredoxins can act as chaperones when they adopt a multimeric ring complex, similar to the chaperonin subunit configuration. In addition, several of the GroEL apical domain hydrophobic residues which interact with the unfolded protein are located in a position that corresponds to the protein substrate binding region of the peroxiredoxin fold. We suggest that the origin of the ur-chaperonin from a thioredoxin/peroxiredoxin fold might also account for the number of thioredoxin-fold containing proteins that interact with chaperonins, such as tubulin and phosducin-like proteins.     

Primate origin of the cell-derived sequences of simian sarcoma virus

We sought to identify the species of origin of the cell-derived (sis) sequences of simian sarcoma virus. A molecular clone comprised of sis DNA detected related nucleotide sequences at low copy numbers in normal cellular DNAs of species as diverse as humans and quail. The extent of hybridization and degree of base-pair matching with sis DNA were greatest with New World primate DNAs. The thermal denaturation curve midpoints of hybrids formed between sis and woolly monkey DNAs were indistinguishable from homologous sis DNA hybrids, establishing the woolly monkey (Lagothrix spp.) as the source of sis sequences. In comparative studies, sis was shown to be more conserved among mammalian species than unique-sequence woolly monkey cellular DNA. There was no detectable homology between sis and the cell-derived sequences of other fibroblast-transforming retroviruses. These findings indicate that sis is likely to be a unique onc gene among transforming retroviruses.     

Unusual chloroplast structures in endosymbiotic dinoflagellates: A clue to evolutionary differentiation within the genusSymbiodinium (Dinophyceae)

Symbiodinium microadriaticum Freudenthal is widely regarded to represent one pandemic species of endosymbiotic dinoflagellates. Thin-sectioned and freeze-fractured chloroplasts of symbionts derived from different hosts reveal the envelope to be composed of three membraneous layers, the middle one featuring an uncommon cleavage pattern. Unusual thylakoid arrangement and inclusions indicate intrinsic differences in the chloroplasts among these algae. The results are discussed in the light of evolutionary differentiation withinSymbiodinium.     

Colour vision: a clue to hue in v2

Where do our brains encode all the colours of the rainbow? We know the neural basis for colour opponency and colour contrast, and recent studies have now provided evidence for the representation of hue in cortical visual area V2.     

Shh-Bmp2 signaling module and the evolutionary origin and diversification of feathers

To examine the role of development in the origin of evolutionary novelties, we investigated the developmental mechanisms involved in the formation of a complex morphological novelty-branched feathers. We demonstrate that the anterior-posterior expression polarity of Sonic hedgehog (Shh) and Bone morphogenetic protein 2 (Bmp2) in the primordia of feathers, avian scales, and alligator scales is conserved and phylogenetically primitive to archosaurian integumentary appendages. In feather development, derived patterns of Shh-Bmp2 signaling are associated with the development of evolutionarily novel feather structures. Longitudinal Shh-Bmp2 expression domains in the marginal plate epithelium between barb ridges provide a prepattern of the barbs and rachis. Thus, control of Shh-Bmp2 signaling is a fundamental component of the mechanism determining feather form (i.e., plumulaceous vs. pennaceous structure). We show that Shh signaling is necessary for the formation and proper differentiation of a barb ridge and that it is mediated by Bmp signaling. BMP signaling is necessary and sufficient to negatively regulate Shh expression within forming feather germs and this epistatic relationship is conserved in scale morphogenesis. Ectopic SHH and BMP2 signaling leads to opposing effects on proliferation and differentiation within the feather germ, suggesting that the integrative signaling between Shh and Bmp2 is a means to regulate controlled growth and differentiation of forming skin appendages. We conclude that Shh and Bmp signaling is necessary for the formation of barb ridges in feathers and that Shh and Bmp2 signaling constitutes a functionally conserved developmental signaling module in archosaur epidermal appendage development. We propose a model in which branched feather form evolved by repeated, evolutionary re-utilization of a Shh-Bmp2 signaling module in new developmental contexts. Feather animation Quicktime movies can be viewed at http://fallon.anatomy.wisc.edu/feather.html.     

H-2 typing of mutants of thet 6 haplotype in the mouse

Mutantt haplotypes derived from thet ⁶ haplotype were typed forH-2. The mutantt ^h2 that arose fromt ⁶ due to crossing over in the region betweenT andtf had, as expected, lost theH-2 haplotype characteristic oft ⁶. The haplotypest ^h17,t ^h18, andt ^p1, which also arose by recombination, but which represent the complementary crossover products, including the distal part of thet ⁶ haplotype, carried the sameH-2 type ast ⁶. This suggests that crossing over betweentf andH-2 is suppressed int ^h17 andt ¹⁸. This in turn suggests that mutantt haplotypes suppress crossing over for that part of thet chromatin that they still retain.The origin oft ^h7, which apparently did not include any crossover distal toT, and which retains the crossover-suppressing property oft ⁶, retains thet ⁶ H-2 type. Unexpectedly, J ^h20 , which expressestf and was at first thought to have arisen due to crossing over, also retains theH-2 type oft ⁶. This provides part of the evidence thatt ^h20 arises fromt ⁶ not by crossing over, but by a small deletion, and hence that duplication and deletion are possible modes of origin of mutantt haplotypes.Abbreviations used in this paper are t haplotype mutant haplotype of the chromosome 17, often designated J allele - T Brachyury mutant - T/+ short-tailed mouse - T/T lethal during embryogenesis - T-int T interaction (characteristic oft haplotypes that interact in heterozygotes withT to produce a tailless mouse) - tf locus homozygotes showing waves of hair loss - Kb knobby, which produces a knobbly tailed heterozygote, homozygous lethal - titer reciprocal of serum dilution giving 50% kill