Agaba, M

Anderson, S

Archibald, A

Brass, A

Hulme, H

Kemp, SJ

Noyes, HA

Ogugo, M

University of Liverpool Repository

Description External Gene IDC57BL/6AJ Balb/c129 Haplotypepeptidase inhibitor 16 [Source:MarkerSymbol;Acc:MGI:1921366] Pi16mitochondrial carrier homolog 1 (C. elegans) [Source:MarkerSymbol;Acc:MGI:1929261] Mtch1FYVE, RhoGEF and PH domain containing 2 [Source:MarkerSymbol;Acc:MGI:1347084] Fgd2proviral integration site 1 [Source:MarkerSymbol;Acc:MGI:97584] Pim1TBC1 domain family, member 22B [Source:MarkerSymbol;Acc:MGI:2681867]Tbc1d22bring finger protein 8 [Source:MarkerSymbol;Acc:MGI:1929069] 1300018I05RikRIKEN cDNA 1110021J02 gene [Source:MarkerSymbol;Acc:MGI:1915847] 1110021J02RikMdga1Small nucleolar RNA SNORA70 [Source: RFAM 8.0] [Source: RFAM 8.0] SNORA70zinc finger, AN1-type domain 3 [Source:MarkerSymbol;Acc:MGI:1096572] Zfand3BTB (POZ) domain containing 9 [Source:MarkerSymbol;Acc:MGI:1916625] Btbd9predicted gene, ENSMUSG00000052388 [Source:MarkerSymbol;Acc:MGI:3642006] ENSMUSG00000052388glyoxalase 1 [Source:MarkerSymbol;Acc:MGI:95742] Glo1dynein, axonemal, heavy chain 8 [Source:MarkerSymbol;Acc:MGI:107714] Dnahc8U6 spliceosomal RNA [Source: RFAM 8.0] [Source: RFAM 8.0] U6predicted gene, ENSMUSG00000054148 [Source:MarkerSymbol;Acc:MGI:3642051] ENSMUSG00000054148glucagon-like peptide 1 receptor [Source:MarkerSymbol;Acc:MGI:99571]Glp1rpredicted gene, ENSMUSG00000073427 [Source:MarkerSymbol;Acc:MGI:3642784] ENSMUSG00000073427uromodulin-like 1 [Source:MarkerSymbol;Acc:MGI:1929785] Umodl1ATP-binding cassette, sub-family G (WHITE), member 1 [Source:MarkerSymbol;Acc:MGI:107704]Abcg1trefoil factor 3, intestinal [Source:MarkerSymbol;Acc:MGI:104638] Tff3trefoil factor 2 (spasmolytic protein 1) [Source:MarkerSymbol;Acc:MGI:1306805] Tff2trefoil factor 1 [Source:MarkerSymbol;Acc:MGI:88135] Tff1transmembrane protease, serine 3 [Source:MarkerSymbol;Acc:MGI:2155445] Tmprss3ubiquitin associated and SH3 domain containing, A [Source:MarkerSymbol;Acc:MGI:1926074]Ubash3aradial spoke head 1 homolog (Chlamydomonas) [Source:MarkerSymbol;Acc:MGI:1194909] Rsph1solute carrier family 37 (glycerol-3-phosphate transporter), member 1 [Source:MarkerSymbol;Acc:MGI:2446181]Slc37a1phosphodiesterase 9A [Source:MarkerSymbol;Acc:MGI:1277179]Pde9apredicted gene, ENSMUSG00000053280 [Source:MarkerSymbol;Acc:MGI:3642122]ENSMUSG00000053280WD repeat domain 4 [Source:MarkerSymbol;Acc:MGI:1889002] Wdr4RIKEN cDNA 1500032D16 gene [Source:MarkerSymbol;Acc:MGI:1925580] 1500032D16RikRIKEN cDNA 4833413E03 gene [Source:MarkerSymbol;Acc:MGI:1925354] 4833413E03RikPbx/knotted 1 homeobox [Source:MarkerSymbol;Acc:MGI:1201409] Pknox1cystathionine beta-synthase [Source:MarkerSymbol;Acc:MGI:88285] CbsU2 small nuclear ribonucleoprotein auxiliary factor (U2AF) 1 [Source:MarkerSymbol;Acc:MGI:98884]U2af1crystallin, alpha A [Source:MarkerSymbol;Acc:MGI:88515] CryaaSNF1-like kinase [Source:MarkerSymbol;Acc:MGI:104754] Snf1lkheat shock transcription factor 2 binding protein [Source:MarkerSymbol;Acc:MGI:1921627]Hsf2bpribosomal RNA processing 1 homolog B (S. cerevisiae) [Source:MarkerSymbol;Acc:MGI:1919712]Rrp1bNotch gene homolog 3 (Drosophila) [Source:MarkerSymbol;Acc:MGI:99460] Notch3abhydrolase domain containing 9 [Source:MarkerSymbol;Acc:MGI:1919182] Abhd9bromodomain containing 4 [Source:MarkerSymbol;Acc:MGI:1888520] Brd4A kinase (PRKA) anchor protein 8 [Source:MarkerSymbol;Acc:MGI:1928488] Akap8A kinase (PRKA) anchor protein 8-like [Source:MarkerSymbol;Acc:MGI:1860606] Akap8lwidely-interspaced zinc finger motifs [Source:MarkerSymbol;Acc:MGI:1332638] WizRIKEN cDNA A430107D22 gene [Source:MarkerSymbol;Acc:MGI:2444128] A430107D22RikRIKEN cDNA A530088E08 gene [Source:MarkerSymbol;Acc:MGI:3603459] A530088E08Rikcytochrome P450, family 4, subfamily f, polypeptide 39 [Source:MarkerSymbol;Acc:MGI:2445210]Cyp4f39cytochrome P450, family 4, subfamily f, polypeptide 16 [Source:MarkerSymbol;Acc:MGI:1917351]Cyp4f16cytochrome P450, family 4, subfamily f, polypeptide 16 [Source:MarkerSymbol;Acc:MGI:1917351]Cyp4f16Cyp4f40cytochrome P450, family 4, subfamily f, polypeptide 15 [Source:MarkerSymbol;Acc:MGI:2146921]Cyp4f15RIKEN cDNA 9030612M13 gene [Source:MarkerSymbol;Acc:MGI:1921793] 9030612M13Rikzinc finger protein 811 [Source:MarkerSymbol;Acc:MGI:2682944] Zfp811U1 spliceosomal RNA [Source: RFAM 8.0] [Source: RFAM 8.0] U1RIKEN cDNA 6030490I01 gene [Source:MarkerSymbol;Acc:MGI:2443934] 6030490I01RikcDNA sequence BC066107 [Source:MarkerSymbol;Acc:MGI:3029586] BC066107cytochrome P450, family 4, subfamily f, polypeptide 14 [Source:MarkerSymbol;Acc:MGI:1927669]Cyp4f14cytochrome P450, family 4, subfamily f, polypeptide 13 [Source:MarkerSymbol;Acc:MGI:2158641]Cyp4f13cytochrome P450, family 4, subfamily f, polypeptide 41 pseudogene [Source:MarkerSymbol;Acc:MGI:1925125]Cyp4f41-pszinc finger protein 472 [Source:MarkerSymbol;Acc:MGI:2385049] Zfp472RIKEN cDNA C920016K16 gene [Source:MarkerSymbol;Acc:MGI:2441928] C920016K16RikRIKEN cDNA 1700065O13 gene [Source:MarkerSymbol;Acc:MGI:1920701] 1700065O13RikPHD finger protein 8 [Source:RefSeq_peptide;Acc:NP_001009544] NP_001009544.1zinc finger protein 563 [Source:MarkerSymbol;Acc:MGI:2677168] Zfp563microrchidia 2B [Source:MarkerSymbol;Acc:MGI:3045293] Morc2bpredicted gene, EG383232 [Source:MarkerSymbol;Acc:MGI:3643505] EG383232zinc finger protein 422, related sequence 1 [Source:MarkerSymbol;Acc:MGI:3028594] Zfp422-rs1zinc finger protein 81 [Source:MarkerSymbol;Acc:MGI:1890752] Zfp81zinc finger protein 101 [Source:MarkerSymbol;Acc:MGI:107547] Zfp101RIKEN cDNA 1700029I08 gene (1700029I08Rik), mRNA [Source:RefSeq_dna;Acc:NM_183282]NM_183282.2a disintegrin-like and metallopeptidase (reprolysin type) with thrombospondin type 1 motif, 10 [Source:MarkerSymbol;Acc:MGI:2449112]Adamts10myosin IF [Source:MarkerSymbol;Acc:MGI:107711] Myo1fzinc finger protein 414 [Source:MarkerSymbol;Acc:MGI:1915641] Zfp414PML-RAR alpha-regulated adaptor molecule 1 [Source:MarkerSymbol;Acc:MGI:3576625] Pram1membrane-associated ring finger (C3HC4) 2 [Source:MarkerSymbol;Acc:MGI:1925915] Mar-06RAB11B, member RAS oncogene family [Source:MarkerSymbol;Acc:MGI:99425] Rab11bangiopoietin-like 4 [Source:MarkerSymbol;Acc:MGI:1888999] Angptl4ankyrin repeat domain 47 [Source:MarkerSymbol;Acc:MGI:1098615] Ankrd47NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 7 (B14.5a) [Source:MarkerSymbol;Acc:MGI:1913666]Ndufa7CD320 antigen [Source:MarkerSymbol;Acc:MGI:1860083] Cd320Fas death domain-associated protein [Source:MarkerSymbol;Acc:MGI:1197015] Daxxzinc finger and BTB domain containing 22 [Source:MarkerSymbol;Acc:MGI:1931870] Zbtb22TAP binding protein [Source:MarkerSymbol;Acc:MGI:1201689] Tapbpral guanine nucleotide dissociation stimulator-like 2 [Source:MarkerSymbol;Acc:MGI:107483]Rgl2H2-K region expressed gene 2 [Source:MarkerSymbol;Acc:MGI:95908] H2-Ke2WD repeat domain 46 [Source:MarkerSymbol;Acc:MGI:1931871] Wdr46UDP-Gal:betaGalNAc beta 1,3-galactosyltransferase, polypeptide 4 [Source:MarkerSymbol;Acc:MGI:1859517]B3galt4ribosomal protein S18 [Source:MarkerSymbol;Acc:MGI:98146] Rps18vacuolar protein sorting 52 (yeast) [Source:MarkerSymbol;Acc:MGI:1330304] Vps52predicted gene, EG630499 [Source:RefSeq_peptide;Acc:NP_001074484] NP_001074484.1expressed sequence AA388235 (AA388235), mRNA [Source:RefSeq_dna;Acc:NM_001013793]NP_001013815.1histocompatibility 2, K1, K region [Source:MarkerSymbol;Acc:MGI:95904] H2-K1ring finger protein 1 [Source:MarkerSymbol;Acc:MGI:1101770] Ring1mmu-mir-219-1 [Source:miRBase;Acc:MI0000702] mmu-mir-219-1H2-K region expressed gene 6 [Source:MarkerSymbol;Acc:MGI:95911] H2-Ke6solute carrier family 39 (zinc transporter), member 7 [Source:MarkerSymbol;Acc:MGI:95909]Slc39a7retinoid X receptor beta [Source:MarkerSymbol;Acc:MGI:98215] Rxrbprocollagen, type XI, alpha 2 [Source:MarkerSymbol;Acc:MGI:88447] Col11a2histocompatibility 2, O region alpha locus [Source:MarkerSymbol;Acc:MGI:95924] H2-Oabromodomain containing 2 [Source:MarkerSymbol;Acc:MGI:99495] Brd2histocompatibility 2, class II, locus Mb1 [Source:MarkerSymbol;Acc:MGI:95922] H2-DMb1histocompatibility 2, class II, locus Mb2 [Source:MarkerSymbol;Acc:MGI:95923] H2-DMb2proteasome (prosome, macropain) subunit, beta type 9 (large multifunctional peptidase 2) [Source:MarkerSymbol;Acc:MGI:1346526]Psmb9transporter 1, ATP-binding cassette, sub-family B (MDR/TAP) [Source:MarkerSymbol;Acc:MGI:98483]Tap1proteasome (prosome, macropain) subunit, beta type 8 (large multifunctional peptidase 7) [Source:MarkerSymbol;Acc:MGI:1346527]Psmb8transporter 2, ATP-binding cassette, sub-family B (MDR/TAP) [Source:MarkerSymbol;Acc:MGI:98484]Tap2histocompatibility 2, O region beta locus [Source:MarkerSymbol;Acc:MGI:95925] H2-Obhistocompatibility 2, class II antigen A, beta 1 [Source:MarkerSymbol;Acc:MGI:103070] H2-Ab1histocompatibility 2, class II antigen A, alpha [Source:MarkerSymbol;Acc:MGI:95895] H2-Aahistocompatibility 2, class II antigen E beta [Source:MarkerSymbol;Acc:MGI:95901] H2-Eb1RIKEN cDNA A130038H09 gene [Source:MarkerSymbol;Acc:MGI:3588187] A130038H09Rikhistocompatibility 2, class II antigen E alpha [Source:MarkerSymbol;Acc:MGI:95900] H2-Eabutyrophilin-like 2 [Source:MarkerSymbol;Acc:MGI:1859549] Btnl2butyrophilin-like 1 [Source:MarkerSymbol;Acc:MGI:1932027] Btnl1ID     C57  AJ   Balb 129 C57BL/6 regions inTir 1 congenicsTir 2 congenicsTir 3 congenicsTir1Tir3Tir2IntroductionAfrican cattle breeds differ significantly in their ability to survive low to moderate levels of challenge with Trypanosoma congolense. Similarly the survival times of inbred mouse strains vary substantially after infection. We have previously identified three regions of the mouse genome that regulate survival after infection in two crosses (A/J x C57BL/6 and Balb/c x C57BL/6) (Kemp et al 1997 Nature Genetics). These have been designated Tir1, Tir2 and Tir3 for Trypanosoma infection response loci on mouse chromosomes 17, 5 and 1 respectively. We have now used two strategies to reduce the size of the regions that appear to be regulating survival. Firstly, congenic mice lines carrying defined regions of the C57BL/6 genome on an A/J background were developed to identify physical boundaries of the regions and confirm its effect. Secondly the response to infection has been mapped in an additional mouse strain (129J). The mapping data has been combined with haplotype maps to identify a 70kb high priority region containing just 5 strong candidates for the causative gene for resistance to trypanosomiasis in mice on chromosome 17. Identifying candidate genes for the regulation of the response to Trypanosoma congolense infectionNoyes HA1Agaba M2Ogugo M2Brass A3Anderson S4Archibald A4Hulme H3Kemp SJ11School of Biological Sciences University of LiverpoolCrown StreetLiverpool        L69 7ZB 2International Livestock Research Institute (ILRI)P O Box 30709Nairobi 00100 Kenya3Department of Computer Science University of ManchesterOxford RoadManchester  M13 9PL4Roslin InstituteRoslin BioCentreMidlothian EH25 9PSCongenic MiceSingle nucleotide poly-morphsims are not the only formof genetic variation. Regions ofthe mouse genome can beduplicated or deleted and areknown as copy number variants(CNV). CNV between C57BL/6and A/J mice were detected usingAgilent 240k whole genomeCGH arrays. An amplifcation ofthe Glo1 gene within the Tir1QTL on chromosome 17. Thisgene was not identified by thehaplotype analysis but expressionanalysis indicated that the genewas more highly expressed in A/Jand Balb/c consistent with copynumber.Effect of gene copy number on expressionAcknowledgements:  We thank John Wambugu, Moses Ogugo and Leanne Wardlesworth for technical assistance.  These studies were funded by the Wellcome TrustCongenic lines are created by crossing resistant C57BL/6 with the susceptible A/J mice. At each generation the offspring are genotyped to identify those animals that are carrying alleles from C57BL/6 in the target region of interest and these mice are then selected to be backcrossed to the recipient genome. After seven generations of backcrossing to A/J, heterozygous carriers of the C57BL/6 donor region of interest were intercrossed and homozygous carriers were selected as the congenic line and were designated TirnCC in this study. Homozygous carriers of the A/J alleles were selected as the control line and are designated TirnAA. The creation of these mouse lines makes it possible to study the effect of each locus in isolation from the other loci and most background effects.The positions of the regions of the C57BL/6 genome that were introgressed into the A/J background were determined by genotyping the three lines with the Illumina 1536 SNP marker panel (Figure 1).The introgressed regions on chromosome 5 and 17 had a significant effect on survival (Figure 2) but the C57BL/6 region on chromosome 1 had no effect on survival indicating that the genes regulating the response to infection are elsewhere on this chromosome.Survival (Days)0 20 40 60 80 100% Surviving1030507090110Tir1AATir1CCTir2AATir2CC Figure 1. Positions of QTL are shown by red arrows. Positions of regions of C57BL/6 genome introgressed into the A/J genome are shown by the coloured blocksFigure 2. Survival times. The plots show that the Tir1CC mice carrying C57BL/6 DNA at the chromosome 17 locus survived longer than the Tir1AA mice carrying A/J DNA at this locus. Also the Tir2CC mice carrying C57BL/6 DNA at the chromosome 5 locus survived longer than the Tir2AA mice carrying A/J DNA at this locus. There was no difference in survival of the Tir3CC and Tir3AA mice (not shown) indicating that the genes carrying resistance alleles on chromosome 1 are outside this region.Mapping loci controlling the response to infection in 129J miceIdentifying the regions controlling the response to infection in additional mouse strains make it possible refine the list of candidate genes that might regulate survival time.F2 C57BL/6 x 129J were bred by crossing 129J and C57BL/6 mice to create and F1 generation and then by intercrossing their offspring to create an F2.135 F2 C57BL/6 x 129J mice were genotyped with the Illumina 384 SNP mapping panel and the data was analysed with the JQTL package (Figure 3).The data confirmed the presence of QTL on chromosomes 1 and 17 but there was no evidence of a QTL on chromosome 5 suggesting that 129J might carry the C57BL/6 allele at this locus.The locus on chromosome 17 was significantly associated with survival. The locus on distal chromosome 1 was not significant after correction for multiple testing, but since it was supported by multiple SNP markers and it coincides with previously identified loci in A/J and Balb/c mice, it may be real but the effect size of the alleles may be insufficient to show a significant effect in this relatively small panel of mice.Figure 3. Plot of LOD scores for markers on chromosomes 1, 5 and 17. Showing evidence of QTL on chromosomes 1 and 17 but not on chromosome 5.The availability of mapping data from three pairs of mouse strains makes it possible to look for correlation between haplotypes across the QTL regions and response to infection. The genome of inbred mouse strains is believed to be composed of a mosaic of regions derived from three or four ancestral strains. Given that we have observed the some QTL in multiple pairs of mouse strains it is likely that the polymorphisms that make C57BL/6 more resistant are derived from one of those ancestral strains. If the ancestral strain from which gene is inherited can be identified then it should be possible to produce a short list of candidate genes for which C57BL/6 inherits its allele from one strain and A/J, Balb/c and 129J inherit their alleles from a different strain.The recent publication of 8 million SNP in the fifteen most widely used mouse strains makes it possible to identify the haplotype of origin of most regions of the mouse genome (Frazer et al. 2007 Nature). http://mouse.perlegen.com/mouse/mousehap.htmlWe have used this data to assign each gene to an ancestral haplotype (Figure 4). Only five genes were on the same ancestral haplotype in 129J, A/J and Balb/c and on a different haplotype in C57BL/6. These genes are therefore strong candidates for the gene that regulates the difference in survival after infection, Quantative Trait Genes (QTG). An additional 19 genes were on different haplotypes in 129J, A/J and Balb/c but also all different from C57BL/6. These genes are also possible candidate QTG. It is as important to exclude genes as include them and the addition of data from the 129J x C57BL/6 cross makes it possible to exclude the class 1 and 2 MHC genes. Since the chromosome 17 QTL overlaps the the MHC region these were natural candidate genes. 129J and C57BL/6 share the same MHC haplotype (b)  as can be seen in figure 4. Consequently it seems unlikely that the classical MHC genes are responsible for the large difference in survival time associated with this locus.Haplotype analysisFigure 4. Haplotypes of C57BL/6, AJ, Balb/c and 129J across the Tir1 QTL on chromosome 17. The ancestral haplotype of each strain is indicated by the coloured blocks to the right of the gene names. C57BL/6 is always shown in yellow. Where the other strains differ in ancestral haplotype they are shown in red, green or blue. ConclusionsThe combination of congenic mice, additional mapping data and discovery of copy number variations within the QTL regions has made it possible to identify a short list of genes that might regulate the response to infection with T. congolense. This list is now sufficiently short that it is practicable to undertake detailed studies on the role of individual genes in the response to infection and hence determine whether they cause the difference in survival time after infection. The identification of thesegenes is expected to give an insight into the pathways that regulate the response to infection and may lead to new approaches totreatment.

Identifying candidate genes for the regulation of the response to Trypanosoma congolense infection

Identifying candidate genes for the regulation of the response to Trypanosoma congolense infection

Abstract

Similar works

Full text

Available Versions

University of Liverpool Repository