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Mouse H2 allele sequences

Mouse H2 allele sequences



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I've been trying to find complete sequences of mouse (Mus musculus) MHC H2 locus haplotypes for quite some time now with limited success. The EBI IMGT database has a table of mouse H2 haplotypes, yet IMGT only provides haplotype sequences for human HLA genes via an FTP sever. I've found similar data for several other species at EBI's IPD-MHC, but Mus musculus is not on the list. The MGI database provides access to H2 SNPs, but I haven't found a mapping from SNP combinations to reconstruct happlotype sequences given reference genes.


I have also hit this issue. I was interested in full length amino acid sequences for the classical class I mouse MHC alleles. I was able to find a number of them on uniprot but not all. Here is my list below. Interested if anyone knows additional sequences to extend this:

H-2 D

  • H-2 Db

  • H-2 Dd

  • H-2 Dp

  • H-2 Dk

  • H-2 Dq

H-2 K

  • H-2 Kb

  • H-2 Kd

  • H-2 Kk

  • H-2 Kq

H-2 L

  • H-2 Ld

  • H-2 Lq


Overview

NSG-Ab o DR4 mice are NOD.scid.Il2R&gammac null ("NSG") animals with a murine major histocompatibility complex (MHC) class II knock-out allele (Ab o ) and the DR4&beta(NT) transgene that encodes a human HLA-DRB1*0401 engineered to have amino acid mutations in the &beta2 domain for better interaction with murine CD4. The NSG platform is permissive for xenograft/human tumor growth. Homozygous Ab o mice do not express murine MHC class II. The DR4&beta(NT) transgene allows irradiated NSG-Ab o DR4 mice to be engrafted with HLA-DR-matched hematopoietic stem cells (HSC) - resulting in humanized T cell and B cell populations.

Donating Investigator

Dr. Leonard D. Shultz, The Jackson Laboratory


<p>This section provides any useful information about the protein, mostly biological knowledge.<p><a href='/help/function_section' target='_top'>More. </a></p> Function i

<p>The <a href="http://www.geneontology.org/">Gene Ontology (GO)</a> project provides a set of hierarchical controlled vocabulary split into 3 categories:<p><a href='/help/gene_ontology' target='_top'>More. </a></p> GO - Molecular function i

    Source: MGI <p>Inferred from Direct Assay</p> <p>Used to indicate a direct assay for the function, process or component indicated by the GO term.</p> <p>More information in the <a href="http://geneontology.org/page/guide-go-evidence-codes#ida">GO evidence code guide</a></p> Inferred from direct assay i

      GO - Biological process i

      Enzyme and pathway databases

      Reactome - a knowledgebase of biological pathways and processes


      The Mouse Genome Database: enhancements and updates

      The Mouse Genome Database (MGD) is a major component of the Mouse Genome Informatics (MGI, http://www.informatics.jax.org/) database resource and serves as the primary community model organism database for the laboratory mouse. MGD is the authoritative source for mouse gene, allele and strain nomenclature and for phenotype and functional annotations of mouse genes. MGD contains comprehensive data and information related to mouse genes and their functions, standardized descriptions of mouse phenotypes, extensive integration of DNA and protein sequence data, normalized representation of genome and genome variant information including comparative data on mammalian genes. Data for MGD are obtained from diverse sources including manual curation of the biomedical literature and direct contributions from individual investigator's laboratories and major informatics resource centers, such as Ensembl, UniProt and NCBI. MGD collaborates with the bioinformatics community on the development and use of biomedical ontologies such as the Gene Ontology and the Mammalian Phenotype Ontology. Recent improvements in MGD described here includes integration of mouse gene trap allele and sequence data, integration of gene targeting information from the International Knockout Mouse Consortium, deployment of an MGI Biomart, and enhancements to our batch query capability for customized data access and retrieval.

      Figures

      Screen shot demonstrating the new…

      Screen shot demonstrating the new gene trap allele detail page for a BayGenomics…

      Screen shot of MGI GBrowse…

      Screen shot of MGI GBrowse showing gene traps and gene targeting projects from…


      Molecule processing

      Feature keyPosition(s)Description Actions Graphical viewLength
      <p>This subsection of the 'PTM / Processing' section denotes the presence of an N-terminal signal peptide.<p><a href='/help/signal' target='_top'>More. </a></p> Signal peptide i 1 – 20 2 Publications

      <p>Manually curated information for which there is published experimental evidence.</p> <p><a href="/manual/evidences#ECO:0000269">More. </a></p> Manual assertion based on experiment in i

      Amino acid modifications

      Feature keyPosition(s)Description Actions Graphical viewLength
      <p>This subsection of the PTM / Processing":/help/ptm_processing_section section describes the positions of cysteine residues participating in disulfide bonds.<p><a href='/help/disulfid' target='_top'>More. </a></p> Disulfide bond i 45 ↔ 100

      Keywords - PTM i

      Proteomic databases

      Encyclopedia of Proteome Dynamics

      jPOST - Japan Proteome Standard Repository/Database

      PaxDb, a database of protein abundance averages across all three domains of life

      PRoteomics IDEntifications database

      ProteomicsDB: a multi-organism proteome resource

      2D gel databases

      Two-dimensional polyacrylamide gel electrophoresis database from the Geneva University Hospital

      PTM databases

      iPTMnet integrated resource for PTMs in systems biology context

      Comprehensive resource for the study of protein post-translational modifications (PTMs) in human, mouse and rat.


      <p>This section provides information on the disease(s) and phenotype(s) associated with a protein.<p><a href='/help/pathology_and_biotech_section' target='_top'>More. </a></p> Pathology & Biotech i

      Mutagenesis

      Feature keyPosition(s)Description Actions Graphical viewLength
      <p>This subsection of the <a href="http://www.uniprot.org/manual/pathology%5Fand%5Fbiotech%5Fsection">'Pathology and Biotech'</a> section describes the effect of the experimental mutation of one or more amino acid(s) on the biological properties of the protein.<p><a href='/help/mutagen' target='_top'>More. </a></p> Mutagenesis i 55K → R in K-less, no effect on ubiquitination when associated with R-92, R-155, R-170, R-197, R-210, R-220, R-267 and R-277. 1 Publication

      <p>Manually curated information for which there is published experimental evidence.</p> <p><a href="/manual/evidences#ECO:0000269">More. </a></p> Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i

      Manual assertion based on experiment in i


      Reviewer's report 1

      Stephan Beck

      In their manuscript Joly and Rouillon report new evidence for the hypothesis that MHC class I genes undergo concerted evolution through gene conversion (e.g. non-homologous recombination). In support, they analysed 8 classical class I genes (termed class Ia) and 8 non-classical class I genes (termed class Ib) from primates and rodents with focus on three class Ib genes to which they refer to as CD94L family (human HLA-E, mouse H2-Qa1 and rat RT-BM1). The results are comprehensively discussed within the context of various relevant hypotheses which adds a review-like flavour and greatly enhances the appeal of the manuscript.

      Although some conclusions (and assumptions) are better supported than others, I only take issue with one particular point. Based on evidence I do not agree with, the authors assume the above mentioned CD94L family genes to represent orthologues and their many respective paralogues are not considered in subsequent analyses which may have affected some of the conclusions.

      Author response: Following this comment, and a suggestion made by Pierre Pontarotti on the phone, I have now modified the manuscript to remove the statement about 'the clear orthologous relationship of CD94L molecules within the primate or the rodent orders'. This is now replaced by 'There is very little room for doubt that all four primate CD94L genes descend from a common ancestral gene, and similarly for all four rodent CD94L genes'.

      On page 12, for instance, the authors conclude that at least the alpha 3 domains of the CD94L genes have all undergone intra-species concerted evolution with their respective class Ia molecules but not one of the 22 informative positions is shared across species as one would expect for orthologues. The logic conclusion would have to be that gene conversion did not occur in the ancestral (e.g. pre 80 mya) CD94L genes studied here. This is unlikely, as gene conversion has been demonstrated to be a general mechanism clearly predating the species studied here.

      Author response: Thanks to the process of 'open refereeing', I have been able to discuss this point with Stephan over the phone directly. His comment sprouted from some slight misunderstanding, which has now been lifted.

      The additional section (appended to main manuscript) does not really constitute a separate manuscript but adds further interesting points to the discussion and the key points could be summarized and included in the main manuscript.

      Author response: The solution to this has been to remove a sizeable portion of the discussion and to provide it as a clearly separate manuscript.

      The paper itself now focuses on the demonstration that HLA-E and Qa1 are orthologues. It is now much shorter, easier to read, and the message is, I hope, much clearer.

      The accompanying paper is now clearly labelled as 'hypothesis', and I have used it to regroup 4 topics of discussion touching on different aspects of MHC evolution that derive from the results obtained in the paper itself, but are not directly related to these results.

      Reviewer's report 2

      Lutz Walter

      In this paper, Joly and Rouillon compare major histocompatibility complex (MHC) class I genes derived from human, non-human primates, and rodents. Based on multiple sequence alignments and phylogenetic tree reconstructions, the authors conclude that the MHC class I genes in these species are subject to concerted evolution by means of gene conversion.

      One main point of criticism refers to the fact that not all known MHC class I genes of the species studied here are compared, and only a small extract from the full repertoire of class I genes was chosen for comparison. This may bias the interpretation of data. In this respect, it might be useful to concentrate on one or two species, e.g. the 'class I-rich species, mouse, rat, or rhesus monkey. In its current form, the paper contains data from a single mouse haplotype, but from several rat haplotypes. Thus, the data set should also be updated to allow the study of both inter- and intralocus gene conversion.

      Author response: One of the main challenges we faced when we started to do the work that would allow us to write this paper was not in terms of "How many sequences for MHC class I molecules can we collect and align ?". It was, in fact, exactly the reverse, i.e. :" With how few sequences can we proceed to demonstrate, beyond reasonable doubt, that MHC class I loci do undergo concerted evolution ?" All the figures presented in the paper were obtained from the one alignment we settled for in the end. Changing just one sequence in the list would require performing the whole study all over again, which would represent several weeks of tenuous work.

      Although our observations lead us to discuss many aspects related to MHC evolution, evaluating the frequency of inter and intra-locus conversion events was not within the remit of this study. Regarding the choice of MHC sequences from several rat MHC haplotypes, and from a single mouse haplotype, we do not see why this should have any relevance to the type of work we have done, and to the conclusions we reach. Outside of particular situation where genes can co-evolve because they are closely linked (such as RT1-A and TAP), MHC haplotypes are, after all, relatively artificial sets of genes that happened to find themselves on the same chromosomal strand when inbred strains were generated.

      Starting with many more sequences, we would have faced the following problems:

      1) The alignment showed on Figure ​ Figure2, 2 , which was used to generate the trees, could not have been provided within the manuscript. We also find that the clarity of figures containing trees degrades rapidly when these trees have too many branches.

      2) The computer time required for calculation of the trees and of the ds/dn values grows exponentially with the number of sequences, and the time spent generating the alignments and the figures is also dependent on the number of sequences included.

      3) For the precise question we wanted to address, the only class Ib loci that were informative were those identified in at least two species. We also felt that it was best to restrict our analysis to those molecules for which a function had clearly been documented, and which had the same number of amino-acids as class Ia sequences (to avoid gaps in the alignment). When we embarked on this work, the only class Ib loci fulfilling these criteria were the CD94L and the murine M3 molecules. As far as we know, this is still true today.

      page 16: the sister grouping of M3 and CD94L genes is due to a limited data set (see above) and does not reflect true phylogenetic relationship (and is not supported by bootstrapping). Furthermore, it contradicts data by Hurt et al. (2004) who studied the phylogenetic relationship of all rat and mouse class I genes

      Author response: We are in complete agreement with the statement that the grouping of M3 and CD94L does not necessarily reflect phylogenetic relationship, and this despite a bootstrapping value of 63% (with the methods used for these comparisons, values above 60% are usually considered significant, and this is specified several times in the paper). Two alternative interpretations relating to this were (and still are) proposed in the manuscript. We actually pointed to this feature of the tree to underline our point of view that extreme caution must be exerted when carrying out phylogenetic analyses of members of multigene families that undergo extensive inter-genic exchanges.

      page 16 and more: it is not obvious why the authors introduce a new abbreviation for 'residues outside the antigen recognition site (ROARS)' and do not use the widely accepted 'non-PBR'

      Author response: We chose to use ROARS because we think it sounds better than 'non-PBR', and also because not all class I molecules present peptides.

      page 17, second paragraph: the authors should explain how homogenisation can be afforded in non-PBRs, particularly at those sites where PBRs and non-PBRs alternate. Is the degree of homology between the two sequences high enough to allow gene conversion to take place?

      Author response: What we witness here are signs that are very evocative of intra-species homogenisation, and gene conversion seems to be the most likely mechanism to explain this. We have no way of knowing when these events took place, and between what sequences (for example, some other genes, or pseudogenes, could have served as relay between certain sequences). Furthermore, although gene conversion is clearly favoured between homologous sequences, we are not aware of data documenting the minimal length of homologous sequences required for gene conversion to take place. Outside of the fact that this question seems to be way beyond the scope of our study, we therefore would have no way of addressing this question.

      I would not recommend adding of the additional section into the manuscript, as the manuscript might become 'unreadable'. However, certain aspects of this "additional" discussion section might be included in the manuscript. Nevertheless, I would strongly recommend considerable shortening of the manuscript.

      In my opinion, this paper should be published, but should be regarded as a 'hypothesis paper' as it contains many assumptions, which were not proven by experimental evidence, and it contains many review-like sections.

      Author response: As explained above, we have managed to comply to these slightly contradictory recommendations (i.e. including more points but shortening overall) by splitting the paper in two: One 'real' paper with the results, and one hypothesis paper.

      Reviewer's report 2

      Pierre Pontarotti

      This article hypothesizes that the Peptide Binding Region of the mouse, rat and human Class I b, that presents the leader peptide from the Class I a molecules to natural killer cells, evolved from a common ancestor while the non PBR part evolved via gene conversion.

      The arguments are based upon phylogenic analysis and upon the conserved location of these MHC class I b genes.

      This contrasts with another hypothesis: the MHC class I genes are lineage specific, they come from a common ancestor which is different in the human and mouse lineage, (in other word class I gene from mouse and human are paralogues), and HLA E and H2Qa1 PBR evolved via convergent evolution.

      In order to strengthen their hypothesis the authors should screen other mammalian lineages using ensembl data bases since some sequences of ensembl data base are not obligatory present in NCBI NR, especially those from canis, loxodanta, bos Taurus, canis Familirais and monodelphis (even if this species is out side of the eutherian group). If an "HLAE like" PBR orthologue is found in all these groups, the author hypothesis will be stronger supported.

      Author response: We would indeed have been very interested to identify MHC class I molecules with CD94L-like PBR outside of the rodent and primate genera. As was already indicated in the result section entitled "Certain residues are CD94L-specific, and others are homogenised within species" (on page 10 of the current manuscript), we have repeatedly tried to identify such molecules via several approaches in all the online databases available to us, and, as of 20 Dec 2005, we have not succeeded so far.

      Second if the conversion of the non PBR HLA E like gene is an ongoing process, this could be seen at higher taxonomic level, for example at primate level by comparing human chimp and macaque MHC class I genes: more homogenization should be seen outside the "HLA E like" PBR than within the PBR.

      Author response: This is indeed exactly what we see, and this is discussed on page 18 of the manuscript (Comparison of this tree. low support values)

      Concerning the sentence page 14 L 11: Among the classI B . years ago. I do not understand why the results confirm that CD94L molecules are much more evolutionary conserved than Class I a molecules.

      Author response: This was indeed confusing, and I have tried to clarify this point by writing the following sentence:

      "The fact that the comparison of primate sequences strongly suggests that the four CD94L are orthologues, whereas this is much less clear for the corresponding class Ia sequences confirms previous reports that primate. ".


      Rapid and efficient generation of conditional alleles using Easi-CRISPR

      A first research article from Quadros and colleagues aimed to improve the generation of conditional alleles in mice using programmable nucleases [2]. The authors made the simple observation that since the efficiency to repair DNA after DSB is higher for the homology-directed repair pathway than homologous recombination, the delivery of a longer repair template would result in a higher efficiency for generating mutant alleles. This technique, called efficient addition with ssDNA inserts-CRISPR (Easi-CRISPR), involves targeting by two sgRNAs which flank the endogenous exon and are complexed with Cas9 to form a ribonucleoprotein complex for cellular delivery. The exon is replaced after the DSB of the DNA and repaired with a long-stranded oligonucleotide template containing two loxP sites and spanning the entire exon. The authors demonstrated the power of this approach by showing a high efficiency in editing and allelic replacement, averaging a 50% success rate, and up to 100% editing for certain alleles, which is a marked improvement compared with conventional methods. Future work and replication studies from various research groups and transgenesis core facilities will confirm or disprove these observations. However, while efficient, this technique does not solve the limiting issues of CRISPR/Cas9, such as the requirement for highly trained staff and the use of an expensive microinjection apparatus only available in transgenesis core facilities.


      Microbial nutrition and basic metabolism

      6 OXIDATION-REDUCTION SYSTEMS IN ELECTRON TRANSPORT

      Generation of the proton motive force by the oxidation reactions in electron transport systems depends on the principle that oxidation reactions liberate energy. Oxidation is the loss of electrons from an atom or molecule. It can also be the loss of hydrogen atoms from a molecule, since each hydrogen atom contains an electron in addition to its proton. The opposite of oxidation is reduction, i.e. the gain of electrons or hydrogen atoms. Unlike oxidation reactions, reduction reactions do not liberate energy but instead require energy in order to proceed. The reverse of any oxidation is a reduction and, it follows, that the reverse of any reduction is an oxidation. In an oxidation-reduction reaction, a pair of substances is involved: one is the oxidized form and the other the reduced form, e.g. Fe 3+ and Fe 2+ . Each pair of such substances is called an oxidation-reduction (O/R) system. One O/R system may tend to accept electrons from another system, i.e. the first system will be reduced while the second system will be oxidized. The capacity of an O/R system to be oxidized or reduced depends on the relative oxidizing power of each O/R system.

      The oxidative power of any O/R system is called its Eh value. The ‘h‘ means that it is measured electrically in relation to the H + /H2 system, which is the standard system, and is expressed in volts. The more positive the Eh of an O/R system, the greater the oxidizing ability of the system. Knowledge of the relation of each O/R system to the standard H + /H2 system permits the comparison of one system with another. To do this, the concentrations of the oxidized and reduced forms in an O/R system, as well as the pH and temperature, must be taken into account. These variables affect the Eh value of an O/R system. When this is done, a value called EO′, the standard oxidation potential, is obtained and used. It is the particular Eh value when O and R are at the same concentration ([O] = [R]), the temperature is 25°C, and the pH is 7. Under these particular conditions, any system can oxidize any other system having an EO′ that is less positive but not more positive. These relationships are very important in recognizing the sequence in which biological oxidations occur, especially in an electron transport system, where the oxidized and reduced forms of the reactants are in approximately a 1:1 ratio.

      When one O/R system oxidizes another, energy is released (the ΔG°′ value is negative). The amount of energy released or the standard free energy change, the ΔG°′ is directly proportional to the difference in EO′ values of the two O/R systems:

      Here, n = the number of electrons transferred per molecule, usually 1 or 2 F is the Faraday (96 500 coulombs). Application of this equation to substances whose standard oxidation potentials are known, allows prediction of the direction of the reaction and the amount of energy released from it. Furthermore, the equation allows determination of whether or not the energy released from a particular oxidation is sufficient to allow formation of a molecule of ATP. The following example is instructive. Consider the oxidation of NADH by FAD. The standard oxidation potential (EO′) value for NAD is −0.32, while that for FAD is −0.22. The process involves the transport of two electrons. Substituting these values into the above equation, the amount of energy released per mole of NADH oxidation is:

      where 4.18 is the conversion factor between coulomb-volts (Joules) and calories. In this example, 4.62 kcal of energy are released per mole of NADH oxidized, an amount insufficient to produce an ATP molecule. The formation of an ATP molecule requires 7.5-8 kcal per mole. It should be remembered, however, that the actual amount of energy released from oxidative processes in cells may be different from that obtained by the kind of calculation as above using values for compounds obtained under standard conditions. Such calculations should be used with caution.


      Human Immunoglobulin Heavy Chain Locus

      FUMIHIKO MATSUDA , in Molecular Biology of B Cells , 2004

      5′ Regulatory Regions

      The 5′ flanking region of the VH segments contains two cis-acting elements, namely the octamer motif that regulates tissue-specific expression of IgH genes and the TATA box essential for the general transcription machinery. Extensive comparison of 500-bp of 5′-flanking sequences of 79 VH segments without 5′ truncation revealed striking family-specific conservation ( Haino et al., 1994 Matsuda et al., 1998) ( Table 1.2 ). Locations of the octamer motif and TATA box are conserved within the same family but are different between different families. Forty out of 44 V h segments having a complete ORF contain an octamer sequence identical to the consensus (ATGCAAAT). The V3-20, V3-53, and V6-1 segments carry slightly less conserved octamer sequence but are known to be translated. The V3-38 segment in the ORF group has completely lost octamer (and TATA) due to 5′-truncation. Of note, the octamer sequence is less conserved in pseudogenes and as many as 15 of 33 pseudogenes without 5′-truncation have diverged octamer motif.

      TABLE 1.2 . Summary of the 5′ regulatory sequences and RSS of the human VH segments

      5′ regulatory regionRSS
      VH familyHeptamcer(bp) * Octamer(bp) * TATA(bp) * 7mer(bp)9mer
      VH1CTCATGA2ATGCAAAT19TAAATAT81CACAGTG23TCAGAAACC
      VH2ATGCAAAT26TT(G/C)AAAA41CACAGAG23ACAA(A/G)AACC
      VH3ATGCAAAT18ATGAAAA101CACAGTG23ACACAAACC
      VH4ATGCAAAT39TTAAATT59CACAGTG23ACA(C/A)AAACC
      VH5ATGCAAAT18ACTTAAA79CACAGTG23CTAAAACCC
      VH6AGGCAAAT19TTTAAAT78CACAGTG23ACACAAACC
      VH7TTCATGA2ATGCAAAT8GGAATAT79CACAGTG23TCAGAAACC

      In contrast, the sequence of the TATA box is well conserved within the same VH family, but very different between different families ( Table 1.2 ). In addition, like the octamer motif, pseudogenes have a less conserved TATA motif. A heptamer sequence (CTCATGA), which is reported to be essential for full VH promoter activity in mouse lymphoid cells ( Ballard and Bothwell, 1986 Eaton and Calame, 1987 Siu et al., 1987) , is found in the human VH1 and VH7 families and, as in mice, similarly located (2- to 22-bp upstream of octamer). However, no heptamer element is found or similarly placed in the other VH families. Hence, this provided no further supportive evidence for the hypothesis that the heptamer element is involved in the activation of the H-chain promoters by the oct protein before the activation of the L-chain promoters that do not contain the heptamer motif ( Kemler et al., 1989) .

      Another interesting finding is that the 5′-flanking regions of three VH3 segments, namely V3-9, V3-20, and V3-43 have a common 65-bp deletion in the region at 251- to 315-bp upstream of the initiation codon ( Haino et al., 1994) . Since all are found in the full-length VH mRNAs, the deletion would not drastically reduce the promoter activity. No other conserved nucleotide sequences or potential candidates for a novel cis-acting element of VH transcription regulation are identified, in spite of an extensive investigation of nucleotide sequence alignment. However, future studies to correlate VH promoter activity and nucleotide sequence variation in the 5′ regulatory region may identify such elements.