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Molecular Mechanisms of Chronic Kidney Transplant Rejection via Large-Scale Proteogenomic Analysis of Tissue Biopsies

Aleksey Nakorchevsky,* Johannes A. Hewel,*† Sunil M. Kurian,‡ Tony S. Mondala,§ ʈ Daniel Campbell,§ Steve R. Head,§ Christopher L. Marsh, John R. Yates, III,* and ʈ Daniel R. Salomon‡

*Department of Chemical Physiology, ‡Department of Molecular and Experimental Medicine, and §DNA Microarray Core, Scripps Research Institute, La Jolla, California; †Center for Cellular and Biomolecular Research, University of ʈ Toronto, Toronto, Ontario, Canada; and Scripps Center for Organ and Cell Transplantation, Scripps Health, La Jolla, California

ABSTRACT The most common cause of kidney transplant failure is the poorly characterized histopathologic entity interstitial fibrosis and tubular atrophy (IFTA). There are no known unifying mechanisms, no effective therapy, and no proven preventive strategies. Possible mechanisms include chronic immune rejection, inflammation, drug toxicity, and chronic kidney injury from secondary factors. To gain further mechanistic insight, we conducted a large-scale proteogenomic study of kidney transplant biopsies with IFTA of varying severity. We acquired proteomic data using tandem mass spectrometry with subsequent quantification, analysis of differential protein expression, validation, and functional annotations to known molecular networks. We performed genome-wide expression profiling in parallel. More than 1400 proteins with unique expression profiles traced the progression from normal transplant biopsies to biopsies with mild to moderate and severe disease. Multiple sets of proteins were mapped to different functional pathways, many increasing with histologic severity, including immune responses, inflammatory cell activation, and apoptosis consistent with the chronic rejection hypothesis. Two examples include the extensive population of the alternative rather than the classical complement pathway, previously not appreciated for IFTA, and a comprehensive control network for the actin cytoskeleton and cell signaling of the acute-phase response. In summary, this proteomic effort using kidney tissue contributes mech- anistic insight into several biologic processes associated with IFTA.

J Am Soc Nephrol 21: 362–373, 2010. doi: 10.1681/ASN.2009060628

Kidney transplantation success has steadily im- the host and the allograft, resulting in progressive proved since the first efforts in 19541 in identical kidney tissue injury including immune- and non– twins. Nonetheless, it is now evident that long-term immune-mediated injury mechanisms. graft survival has not advanced nearly as dramati- cally as 1-yr graft survival and the reductions in Received June 17, 2009. Accepted October 13, 2009. 2 acute rejection rate. Chronic allograft nephropa- Published online ahead of print. Publication date available at thy (CAN), defined as a clinical entity by a progres- www.jasn.org. sive deterioration of kidney transplant function, is A.N. and J.A.H. contributed equally to this work the most common cause of graft loss in surviving Correspondence: Dr. Daniel R. Salomon, Department of Molec- patients. Despite more than a decade of intense ef- ular and Experimental Medicine, The Scripps Research Institute, fort, there is no single mechanistic explanation for La Jolla, CA 92037. Phone: 858-784-9975; Fax: 858-784-2121; the clinical entity of CAN; rather, it seems to repre- E-mail: [email protected] sent a spectrum of interrelated processes between Copyright ᮊ 2010 by the American Society of Nephrology

362 ISSN : 1046-6673/2102-362 J Am Soc Nephrol 21: 362–373, 2010 www.jasn.org CLINICAL RESEARCH

More recently, the clinical entity of CAN has been renamed Table 1 lists the clinical and demographic data of the pa- and redefined in histologic terms as interstitial fibrosis and tients in this study. In data set 1, there is no significant differ- tubular atrophy (IFTA) of unknown etiology.3,4 By biopsy his- ence in serum creatinine in any group, and all patients under- tology, the incidence of IFTA is as high as 50% of kidney trans- went biopsy by protocol at 2 yr. The only significant difference plants at 1 yr after transplantation, 70% at 2 yr, and nearly was that the b0 (no IFTA) group was not treated with cal- universal after 10 yr,5,6 with clear evidence that IFTA cineurin inhibitor (CNI) immunosuppression but rather had progresses and correlates with progressively diminished renal been randomly assigned to rapamycin. One interpretation is function.7,8 Conversely, it is also clear that IFTA does not al- that CNI-mediated nephrotoxicity is the predominant cause of ways progress in a linear, predictable manner, consistent with IFTA. Alternatively, de novo sirolimus-based immunosuppres- the hypothesis that elements of IFTA are dynamic. Thus, there sion is more effective in preventing IFTA. It is important to is a pressing medical need to develop new strategies to unravel note that in data set 2, all patients studied were on CNIs. Thus, the complex mechanisms of tissue injury producing this clini- to avoid any possible drug therapy–related bias, we focused on cal/pathologic entity of CAN/IFTA. proteins common to both data sets for all analyses, which also In this study, we have done the first investigation of kidney represent the majority of proteins identified. In data set 2, the transplant biopsies in patients with documented and histolog- percentage of deceased donors was significantly less in the b23 ically graded IFTA using shotgun proteomics. The principal group, surprising in that long-term outcomes are typically bet- goal of this study was a comprehensive and discovery-driven ter for living-donor recipients. As expected, time to biopsy was analysis of protein expression in transplanted kidneys compar- significantly different between groups in data set 2, and creat- ing those with normal renal function and biopsy histology with inine was significantly higher for b3. The last difference was a transplants with mild to moderate/severe stages of IFTA. One higher steroid use in b1 and b23 as compared with b0. Some immediate goal of IFTA proteomics is discovery of specific believe that steroids are antifibrotic in kidney transplants, but proteins that can be linked to functional molecular pathways this correlation is not evident here. to yield early diagnostic information and serve as metrics for The two independent proteomic data sets of kidney trans- disease progression. Another goal of these studies was to test plant biopsies were collected during a period of 2 yr, data 1 the hypothesis that mechanistically relevant information can (green) and data 2 (blue; Figure 1). Figure 1A illustrates the be obtained by shotgun proteomic analysis of a complex clin- significant overlap between the data sets for all three categories ical/pathologic entity in an equally complex and affected hu- of IFTA despite the difference in immunosuppression. As man tissue. We have also correlated our proteomic expression noted, our analysis focuses only on the overlaps where protein results with parallel genome-wide, gene expression profiling to identifications were confirmed in several technical replicates in explore the connections between the transcriptome and the both data sets. These identifications consist of two classes of proteome. Our results demonstrate the success of shotgun pro- proteins: Those that were differentially expressed and met our teomics in characterizing the histologic stages of IFTA progres- significance criteria and proteins that were uniquely identified sion and that proteins identified using these technologies can in one or more IFTA categories. Figure 1B represents differen- be mapped to molecular networks with functional significance tially expressed and unique proteins via a Venn diagram. Over- defined by relevant literature as novel insights into the mech- laps between categories represent significant differentially ex- anisms driving IFTA in kidney transplantation. Specifically, we pressed proteins, and nonoverlapping portions of the diagram demonstrate a strong set of immune rejection-associated pro- represent unique protein identifications. There are 86 unique teins and transcripts consistent with the hypothesis that an proteins in b0, 73 in b1, and 333 in b23. There are 184 signifi- ongoing chronic allograft rejection is one important mecha- cant differentially expressed proteins among all three catego- nistic element of IFTA. ries of IFTA, 182 between b0 and b1, 281 between b0 and b23, and 257 between b1 and b23 categories. The relative abun- dance levels of the differentially expressed population span RESULTS three orders of magnitude, whereas the majority (97%) of the differentially expressed proteins vary within two orders of Kidney biopsies were classified as one of four stages of IFTA magnitude (Figure 1C). In summary, we have identified a total severity, Banff 0 through Banff 3 (designated b0, b1, b2, and b3 of 904 significantly differentially expressed and 492 unique in text). The b0 samples show no histologic evidence of IFTA, proteins across three histologic categories of IFTA. in other words, an essentially normal kidney transplant biopsy. The b1 samples represent mild IFTA and reflects the early Differentially Expressed Proteins stages of a progressive tissue injury and fibrosis. The b2 and b3 We divided all differentially expressed proteins into groups samples represent moderate to severe IFTA, respectively, and (expression profiles) that reflect the expression level and/or identify a patient population with progressive injury and a high presence in b0, b1, and b23. For a complete list of the differen- risk for graft loss. We pooled the results for b2 and b3 IFTA in tially expressed categories, see the data set key in Figure 2. First, the interest of sample size and compared protein expression we clustered proteins identified at all IFTA stages but differen- changes across the three histologic stages: b0, b1, and b23. tially expressed (b0-b1-b23; Figure 1). Cluster_b0, cluster_b1,

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Table 1. Clinical and demographic data of the kidney biopsy donors Data Set 1 Data Set 2 Banff 0 Banff 1 Banff 2,3 Significance Banff 0 Banff 1 Banff 2,3 Significance Number 4 4 5 NS 4 5 10 NS Recipient age (years) 38.7 ϩ 15.9 42.7 ϩ 11.2 41.2 ϩ 16.3 NS 55.5 ϩ 10.2 51.4 ϩ 11 45.1 ϩ 12.1 NS Recipient gender (% 02520NS754060NS female) Recipient race (% 0 25 20 NS 0 20 10 NS AA) PRA Ͼ20 (%) 0 0 0 NS 0 0 20 NS HLA mismatch 2.8 ϩ 2.2 1.5 ϩ 0.6 2.2 ϩ 2.3 NS 3.7 ϩ 3.2 4.4 ϩ 1.5 3.4 ϩ 1.3 NS Deceased donor (%) 75 50 80 NS 75 100 30 Banff 1 versus 2,3 P Ͻ 0.02 Donor age (years) 42 ϩ 20.2 44.8 ϩ 10.3 40.2 ϩ 11.4 NS 33.7 ϩ 22.9 35.8 ϩ 20 41.4 ϩ 12.9 NS Donor gender (% 25060NS256060NS female) Donor race (% AA) 0 25 20 NS 0 0 10 NS Induction (%) 100 100 100 NS 75 100 100 NS Serum creatinine 1.45 ϩ 0.44 1.33 ϩ 0.45 2.14 ϩ 0.88 NS 2.28 ϩ 1.69 2.02 ϩ 0.24 3.14 ϩ 1.33 Banff 1 versus 2,3 P Ͻ 0.02 Time to biopsy 726 ϩ 125 704 ϩ 46 719 ϩ 94 NS 550 ϩ 514 1571 ϩ 1251 2767 ϩ 992 Banff 0 versus 2,3 (days) P Ͻ 0.0002 CNI (%) 0 25 80 Banff 0 versus 2,3 100 100 90 NS P Ͻ 0.05 MMF (%) 100 75 100 NS 75 100 80 NS Steroids (%) 100 100 100 NS 25 100 90 Banff 0 versus 1 P Ͻ 0.05; Banff 0 versus 2,3 P Ͻ 0.02 Values are expressed as mean ϩ standard deviation unless otherwise indicated. NS, not significant; CNI, calcineurin inhibitor treatment; MMF, mycophenolate mofetil treatment; AA, African Americans; HLA, Human Leukocyte Antigen; PRA, Panel Reactive Antibody. and cluster_b23 represent groups of upregulated proteins. The same holds true for canonical pathways where b0 ex- The b0b1_b0up group is composed of proteins that are dif- pression profiles represent a gamut of metabolic pathways ferentially expressed between b0 and b1 sets (182 proteins; whereas the b1 and b23 expression profiles are considerably Figure 1) and upregulated in b0 compared with b1 (39 of enriched for proteins that belong to phosphatidylinositol-3 182 proteins). Unique protein groups are designated kinase (PI3K)/AKT signaling, acute-phase response signal- uniq_b0, uniq_b1, and uniq_b23. Finally, we combined all ing, complement system, actin cytoskeleton signaling, fi- of the differentially expressed and unique proteins into brosis, and integrin signaling (Figure 2B). all_b0, all_b1, and all_b23. We used Ingenuity Pathway Analysis for functional annotations where the proteins were b0-b1-b23 Comparison assigned to either biologic function (Figure 2A) or canoni- We examined the differentially expressed proteins for presence cal pathways (Figure 2B) and hierarchically clustered. The of known renal disease markers as a function of the continuum color gradient in Figure 2 reflects probabilities of correct b0 to b23. The 184-protein set (b0-b1-b23 overlap; Figure 1B) functional annotations, with red being higher than black. consists of three clusters: Cluster_b0, cluster_b1, and clus- We also applied hierarchical clustering to both the protein ter_b23 (Figure 2). It is evident that whereas proteins with the categories (x axis) and protein functions (y axis) to demon- strongest expression in cluster_b0 display biologic functions strate that we have identified proteins with different sets of such as lipid metabolism and small-molecule biochemistry as- functions depending on the stage of IFTA. The expression sociated with normal kidney function, the balance shifts to- profiles that represent proteins upregulated or unique to b0 ward “cellular distress” functions such as cancer, gastrointes- (green highlights) are enriched for healthy biologic func- tinal disease, endocrine systems disease, and metabolic disease tions such as amino acid metabolism, small-molecule bio- from cluster_b1 to cluster_b23. Moreover, cluster_b1 and chemistry, and lipid metabolism, whereas proteins that are cluster_b23 are enriched for proteins known to be involved in primarily expressed in b1 (yellow highlights) and b23 (red renal apoptosis, necrosis, fibrosis, and cell death: angio- highlights) reflect cellular distress/tissue injury and repre- tensinogen (AGT),9–14 ATPase ␣ subunit,15,16 ␤ 1 integrin sent broad biologic functions such as cancer, and gastroin- (ITGB1),17 and plasminogen (PLG).18 Clusters representing testinal, immunologic, and metabolic disease (Figure 2A). later stages of IFTA are also enriched for cathepsin D associated

364 Journal of the American Society of Nephrology J Am Soc Nephrol 21: 362–373, 2010 www.jasn.org CLINICAL RESEARCH with apoptosis and keratin 8, known to pro- vide resistance to Fas-mediated apopto- sis.19 The downregulation of cathepsin B in b1 and b23 is also linked in the literature with decreased apoptosis.20,21 Annexin A1, reported to play a role in decreasing isch- emic injury,22 is upregulated in b1 and b23. Fibrinogen ␤ chain is upregulated in b1 and b23, supporting the notion that one of the distinguishing features of late-stage IFTA is fibrosis and tissue remodeling.23,24 In sum, these protein changes suggest that progres- sive IFTA represents a losing balance be- tween destructive and reparative mecha- nisms, a conclusion that is consistent with current views of tissue injury and remodel- ing in other clinical entities such as conges- tive heart failure. The 184 proteins and their clusters are listed in Supplemental Table 1. b0-b1 Comparison We analyzed three categories of differen- tially expressed proteins, b0-b1, b0-b23, and b1-b23. For example, the b0-b1 group contains proteins differentially expressed between b0 and b1. The most significant biologic functions upregulated in b0 Figure 1. (A) overlap between independently collected data sets, each composed of (b0b1_b0up; Figure 2B) are healthy bio- multiple technical replicates (data 1, green; data 2, blue) for the b0, b1, and b23 logic functions including amino acid and classes represents the consensus proteomic data. (B) Venn diagram showing the drug metabolism and molecular transport; overlap between consensus b0, b1, and b23 protein identifications. (C) Relative however, the proteins upregulated in b1 abundance distribution of differentially expressed proteins. The binary overlaps (b0- (b0b1_b1up; Figure 2B) are functionally b1, b0-b23, and b1-b23) contain proteins that are differentially expressed at P ϭ 0.05 linked to cancer, gastrointestinal disease, level of significance (two-tailed independent t test), whereas the b0-b1-b23 overlap and genetic disorders. These include tubu- represents differentially expressed proteins at P ϭ 0.05 level of significance as deter- lins, fibrinogens, thrombin, biglycan, mined with one-way ANOVA. The areas marked with arrows represent total pair-wise ITGB1, clusterin, profilin 1, heparin sulfate differentially expressed proteins between Banff categories. proteoglycan 2 (HSPG2), and angiotensin I–converting enzyme (ACE). The ACE enzyme is a key com- logic functions such as cancer, gastrointestinal disease, and cel- ponent of the renin-angiotensin system (RAS) and an angio- lular movement. Some of the proteins upregulated in b23 are tensin II regulator. RAS activation is one of the contributors to cathepsin D, profilin 1, the tubulins, decorin, ITGB1, AGT and IFTA progression,25 and ACE inhibitors are commonly used clusterin. AGT is further overexpressed in b23 samples com- clinically to attenuate decline of renal function and increase pared with b1. Decorin, ITGB1, AGT, and clusterin are linked graft survival.26,27 Upregulated biglycan and ITGB1, a com- with renal necrosis and apoptosis.30–33 We have also identified mon chain of one class of integrin adhesion molecules, have a large set of b23 upregulated proteins that belong to the com- been reported to decrease apoptosis of kidney cells, mesangial plement system: Complement components 3, 5, 6, and 9; com- cells, glomerular cells, and proximal tubules.17,28 The cell ad- plement factors D and H; and serpin peptidase inhibitor. The hesion protein HSPG2 was previously reported to increase glo- complement system plays an important role in immunity and merular and mesangial kidney proliferation.29 The 182 differen- inflammation, and, specifically, C3, C5, and complement fac- tially expressed proteins between b0 and b1 are listed in tor H are linked to renal damage in mouse models.34–38 The full Supplemental Table 2. list of 281 differentially expressed proteins between b0 and b23 is shown in Supplemental Table 3. b0-b23 Comparison There are 281 differentially expressed proteins in b0-b23 (b0- b1-b23 Comparison b23 overlap; Figure 1B). Similar to the b1 stage, the proteins There are 257 differentially expressed proteins between b1 and upregulated in b23 (b0b23_b23up; Figure 2) represent bio- b23 stages of IFTA (b1-b23 overlap; Figure 1B). The proteins

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Figure 2. (A and B) Hierarchical clustering outcome for the biologic function (A) and canonical pathway (B) annotations of differentially expressed proteins is shown. Protein identifications were split into 15 groups (data set key) that represent expression programs in different stages of CAN (b0 upregulated, green; b1 upregulated, yellow; b23 upregulated, red). Both functional categories and differential groups of proteins were clustered using Spearman rank average linkage metric. Each data point is colored according to the probability score (expressed as P value) of a functional category in a particular differentially expressed group of proteins. upregulated in b23 include PLG, AGT, hemopaxin, annexin 1, bronectin, mitogen-activated protein kinases (MAPK1 and complement factors 3 and H, ␤-2 microglobulin, and HSPG2. MAP2K1), Rac2, Ras (RHOA and RHOC), vasodilator-stimu- Thus, although proteins that belong to the acute-phase re- lated protein, complements 7 and 8, and complement factors B sponse signaling and complement system are upregulated in and I. We also identified tissue PLG exclusively in b23 samples. both b1 and b23, most are further upregulated in b23 com- PLG along with its inhibitor (plasminogen activator inhibitor pared with b1. These results further support their potential 1) have been linked to CAN/IFTA, in which plasminogen acti- mechanistic importance and the ongoing connection between vator inhibitor 1 upregulation is associated with renal fibrosis these pathways and progression of IFTA. The full list of 257 and thrombosis.39 The complete list of unique proteins is differentially expressed proteins is shown in Supplemental Ta- shown in Supplemental Table 5. ble 4. Correlation to Gene Expression Unique Proteins We have compared gene expression with protein expression There are also a significant number of unique proteins in each across the three stages of CAN for the subpopulation of pro- category of IFTA (Figure 1B, unique proteins). One of the teins we found to be differentially expressed across the b0, b1, dominant proteomes uniquely expressed in b23 samples was and b23 stages (184 proteins in Figure 1B, b0-b1-b23 overlap). the actin cytoskeleton pathway including multiple actins, fi- Using Pearson correlation coefficient, we determined that the

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Table 2. SRM validation of unique proteins identified via large-scale analysis Sample Targets Peptides Proteins (>2 Peptides) Average Coverage Average Intensity b23 b23 75/92 23/23(19) 0.94 10,478 b0 b0 39/96 17/21(12) 0.88 4780 b23 b0 20/96 13/23 (6) 0.81 4422 b0 b23 7/92 6/21 (1) 0.78 1226 average correlation between the gene and protein expression is tion is higher by 2 to 3 orders of magnitude40,41 than that of the 0.13 on the scale of Ϫ1 to 1. The low overall correlation be- large-scale method. Thus, it is not surprising that we discover tween the transcripts and the proteins can be explained by some of the “normal” b0 proteins in the b23 sample; however, considering the effects of posttranslational regulation and reg- the near absence of b23 markers in the b0 sample demonstrates ulatory degradation of gene products during IFTA. We list the that the unique b23 proteins discovered in the large-scale study individual correlations in Supplemental Table 6; however, in using MudPIT proteomics are highly correlated with IFTA as contrast, the transcript-to-protein correlations within the we have claimed. frameworks of specific molecular pathways that we have iden- tified during analysis are high (see the Discussion section). This high correlation at the pathway level emphasizes the value DISCUSSION of filtering unbiased genome-wide proteogenomic data sets during analysis by defined molecular networks with functional The clinicopathologic entity of CAN/IFTA represents an outcome significance on the basis of existing literature. reflecting a balance of many cellular processes, destructive and reparative, affecting the kidney transplant. It is evident from Fig- Validation of Identified Proteins ure 2 that overexpressed or unique proteins reveal IFTA as a shift- We have carried out a novel validation strategy for the proteins ing landscape of biologic functions from housekeeping to increas- unique to b0 and b23 stages of IFTA. We have selected 23 most ingly stress-related, immune/inflammatory, and tissue injury abundant unique b23 proteins and 21 most abundant unique functions. Figure 3 highlights these changes at the level of biologic b0 proteins for targeted validation using single-reaction ion functions (Figure 3A) and canonical pathways (Figure 3B). For monitoring (SRM) mass spectrometry (MS; see the Concise example, the percentage of differentially expressed proteins anno- Methods section). We were monitoring 96 peptides from b23 tated as cancer biology increases dramatically from 17 to 40% as a samples and 92 peptides from b0 samples. As part of the con- function of IFTA severity. Another example is the acute response- trol data sets, we also monitored b23 targets in b0 samples and signaling pathway represented in b1 and b23 by four and 32 iden- vice versa. Finally, we have acquired data sets in which we mon- tified proteins, respectively, and none in b0. The following path- itored b0 and b23 targets using a blank sample to establish the ways become upregulated during later stages of IFTA: Acute- intensity baseline threshold. The results are summarized in phase response signaling, actin cytoskeleton and chemokine Table 2. signaling, coagulation and complement systems, regulation of ac- We have confirmed 100% of the selected b23 protein targets tin-based motility by Rho, integrin signaling, hepatic fibrosis, and with 75 unique peptides and 19 proteins confirmed by two or PI3K/AKT signaling. more unique peptides (Supplemental Table 7). The average coverage of the peptide fragments was 0.94, and the average Complement Pathways intensity of the fragments was 10,478. We have confirmed 81% Figure 4 shows the components of the complement pathway and of the b0 proteins with 39 unique peptides and 12 proteins highlights proteins either overexpressed or unique to b23. Pro- confirmed by two or more unique peptides (Supplemental Ta- teins unique to b23 IFTA are highlighted in gray, whereas the ble 8). The average coverage of the peptide fragments was 0.88, differentially expressed proteins are colored in shades of red and and the average intensity of the fragments was 4780. We also labeled with their relative abundance (fold change relative to b0 attempted to find the b0 targets in b23 samples and vice versa to and b1). Here we also integrated mRNA expression levels from measure the selectivity of the large-scale analysis. When look- these same samples obtained by gene expression profiling. Thus, ing for the b0 targets in b23 samples, we did find 20 peptides identified proteins are also labeled with colored rectangular boxes and 13 proteins with only six proteins confirmed by multiple that show correlations between protein abundance and gene ex- peptides (Supplemental Table 9); however, when looking for pression across b0, b1, and b23. In these comparisons of comple- b23 targets in b0 samples, we could find only one protein con- ment pathway proteins, our results are consistently in agreement firmed by multiple peptides (Supplemental Table 10). Identi- with the gene expression results from parallel microarray analysis, fication of proteins with bottom-up MS is a concentration- and with the exception of C7 and C9, all have a strong positive dependent process whereby the most abundant proteins yield correlation with their mRNA transcript levels. the highest concentration of peptides, which are sampled more Some complement pathway proteins in kidney transplants frequently by the instrument and identified with higher confi- are expected.42,43 For example, C4d staining is one parameter dence scores. A key point is that the sensitivity of SRM valida- in the histologic Banff classification25; however, the number of

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Figure 3. (A and B) Top biologic functions (A) and canonical pathways (B) of differentially expressed and unique proteins among b0, b1, and b23 stages of CAN are shown. Each data series consists of proteins upregulated during b0 (black), b1 (red), and b23 (green) stages of CAN. Each enumerated annotation is assigned a probabilistic significance score represented as P value. The table lists enumerated annotations as well as the fractions of identified proteins that belong to that particular biologic function category (A) and the number of identified proteins that belong to a particular canonical pathway (B). upregulated complement system proteins in b23 stage biopsies as an amplifier circuit for low levels of donor- or tissue-specific emphasizes the importance of this pathway during IFTA. Al- antibodies or could represent a presently unknown, antibody- though it has been shown that the process of doing cadaveric, independent mechanism of complement activation linked to brain-dead donor transplants44,45 is a source of activated com- tissue injury and/or endothelial activation. Thus, we present plement components such as C3, these events are confined to direct proteomic evidence and describe correlative gene ex- the early days of the posttransplantation period. In contrast, pression evidence that complement activation is one of the key the ongoing upregulation of complement proteins docu- processes in graft injury and IFTA progression. mented in our studies from b0 to b23 identifies donor-inde- pendent upregulation of complement as a chronic progressive Actin Cytoskeleton and Lymphocyte/Macrophage Cell injury process happening over years after the transplantation Signaling surgery. Thus, we were able to identify and map a significant Two overlapping processes, —actin cytoskeleton signaling and number of the complement system members (12 total) and all regulation of actin-based motility by Rho—are also upregu- of the known members of the membrane attack complex. In lated in late IFTA compared with b0 and b1 (Figure 5). Among addition, proteins unique to b23 are complement factors B and the proteins exclusively expressed in b23 are RhoA (including I, C4BP, C7, C8, and C9. Our evidence suggests activation of ROCK-Rho–associated kinase), Rac, mitogen-activated ki- complement via both the classical (serpin peptidase inhibitor nases MEK and ERK, several isoforms of actinin, CD14 anti- and C4BP) and the alternative pathways (complement factors gen, myosin and myosin kinases, and several subunits of the B, D, H, I, and C3) but not the lectin pathway. Furthermore, we actin-related protein 2/3 complex, all of which are linked to observed overexpression of CD59 at b0 and b1 stages (Supple- macrophage and lymphocyte activation in immunity. Several mental Data) that is a known inhibitor of the complement of the identified differentially expressed proteins have also membrane attack complex.46 The activation of the classical been linked to disruption of podocyte structure in the glomer- complement system in late IFTA suggests ongoing antibody- ulus (␣-actinin-4,48 synaptopodin,49,50 CD2AP, CapZ, and mediated chronic rejection,47 despite the evidence that Ͻ10% RhoA51), consistent with the development of transplant glo- of these patients were C4d positive by histology (data not merulopathy as one element of IFTA. Also, in the glomerulus, shown). The activation of the alternative pathway could serve endothelial and mesangial cell proliferation via a Rho-depen-

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tiple processes involved in cell stress, tissue injury, immune responses, inflammation, signal transduction, and tissue re- modeling. The b1 stage is revealed here as a transition period in the progression of IFTA when upregulation of several immune rejection-associated processes such as PI3K/AKT signaling, ac- tin cytoskeleton/Rho kinase signaling, RAS, and the coagula- tion system begins. The b23 late stage of IFTA is highlighted by dramatic upregulation of proteins involved in distress path- ways such as the alternative complement pathway, actin cy- toskeleton signaling, Rho kinase signaling, and acute-phase re- sponses. A clinical challenge raised by our results is whether the many immune and inflammatory gene networks identified at the mRNA expression and protein levels here are under the control of the immunosuppressive drugs taken by all trans- plant patients. One possibility is that progressive tissue injury from other mechanisms results in a downstream common pathway of reactive and nonspecific immunity and inflamma- tion that is a secondary phenomenon. Alternatively, progres- sion of IFTA represents an ongoing donor-specific and/or tis- sue-specific immune response and represents a failure to maintain adequate levels of immunosuppression long term. If the latter is true, then a primary driver of IFTA is chronic rejection, a conclusion with significant clinical implications for therapy. These results demonstrate the success of shotgun pro- teomics to identify proteins that can be mapped to functionally significant molecular networks creating novel, testable, and clinically relevant insights into the mechanisms producing IFTA in kidney transplantation.

Figure 4. Complement activation pathway as represented by Ingenuity Pathway Analysis. Differentially expressed proteins are color coded as unique to b23 (gray), upregulated in b23 (shades CONCISE METHODS of red), and upregulated in b1 (yellow). The upregulated proteins are labeled with the abundance fold change relative to the CAN Clinical Samples stage with the lowest abundance. Colored rectangular boxes next Biologic samples consisted of kidney transplant biopsies obtained by to identified proteins represent correlation coefficient (from Ϫ1 protocol or “for cause” in transplant recipients treated with either [green] to ϩ1 [red]) between the protein and gene expression CNI-based immunosuppression (e.g., FK506, cyclosporine) or a de across the three stages of CAN. novo rapamycin therapy.53–55 Data set 1 represents 16 individual renal biopsies pooled according to histologic IFTA severity, whereas data dent actin mechanism52 alters glomerular architecture and fil- set 2 represents 17 individual biopsies, each with biopsy-documented tration function. Indeed, upregulation of actin cytoskeleton IFTA scores (Table 1). Severity was determined for both sets using the signaling as a function of progressively severe IFTA stages is Banff ’97 classification schema23 used originally for data set 1 so that also consistent with a progressive tissue remodeling and fibro- there was diagnostic uniformity. b0 represents no histologic evidence of sis, in effect suggesting one unifying mechanistic network. IFTA, b1 represents mild IFTA, and b2 and b3 grades are assigned to We have conducted the first large-scale, unbiased pro- grafts with advanced IFTA. Diagnosis was done first by local pathologists teomic profiling of kidney transplant biopsies from patients and reviewed in a blinded manner by Drs. Kim Solez (data set 1) and whose CAN/IFTA was diagnosed at various stages of increasing Lillian Gaber (data set 2). All of the research done at the Scripps Research severity. Our results support the notion that IFTA represents a Institute and the participating clinical centers were under institutional progression of multiple ongoing biologic processes character- review board–approved human subjects protocols. izing each stage of severity, some expected by the current knowledge in the literature and many novel and worthy of Sample Preparation and Data Acquisition further mechanistic investigations. The proteins identified Total protein (Trizol; Invitrogen) was denatured, alkylated, and tryp- and/or upregulated at b0 represent mainly metabolic and nor- sin-digested similar to as described previously.56 A total of 50 ␮gof mal regulatory pathways consistent with and defining the pro- digested protein sample (BCA; Pierce) was used for each experiment. teome of healthy, functioning kidney transplants. In contrast, Each clinical sample was analyzed in technical triplicates. Mass spec- the proteins upregulated in b1 and b23 biopsies belong to mul- trometry data were acquired using an LTQ LX linear ion trap mass

J Am Soc Nephrol 21: 362–373, 2010 Proteomics of Chronic Rejection 369 CLINICAL RESEARCH www.jasn.org

Figure 5. Actin cytoskeleton signaling pathway as represented by Ingenuity Pathway Analysis. Differentially expressed proteins are color coded as unique to b23 (gray), upregulated in b23 (shades of red), and upregulated in b1 (yellow). The upregulated proteins are labeled with the abundance fold change relative to the CAN stage with the lowest abundance. Colored rectangular boxes next to identified proteins represent correlation coefficient (from Ϫ1 [green] to ϩ1 [red]) between the protein and gene expression across the three stages of CAN. spectrometer (ThermoFisher Scientific) interfaced in-line with two- instrument, concentration-dependent nature of peptide fragmenta- dimensional HPLC. The chromatography was set up as MudPIT,57 tion, and presence of chemical noise. whereby discrete fractions from a front-end strong cation exchange column were loaded onto and eluted from a reverse-phase (RP) ana- Gene Expression Profiling lytical column. MudPIT is an implementation of orthogonal chro- Total RNA was extracted from graft biopsies, and biotinylated cRNA was matographic separation whereby columns with different properties prepared using Ambion MessageAmp Biotin II and hybridized to Af- (affinities toward the analyte molecules) are used in succession, fymetrix Human Genome U133 Plus 2.0 GeneChips according to stan- thereby improving resolving power of the separation. MudPIT was dard protocols (http://affymetrix.com/index.affx). Intensities of individ- implemented using strong cation exchange material as the first di- ual probe sets were quantile-normalized and log base 2–transformed.58 mension followed by RP column. Each experiment consisted of 14 Genes represented by more than one probe set were limited to the probe discrete strong cation exchange fractions followed by a 130-min linear set with the highest coefficient of variance across all categories of IFTA. RP gradient from 0 to 50% acetonitrile. Sample was introduced using Pair-wise comparison between differentially expressed proteomic and nanospray ESI at the flow rate of approximately 250 nl/min. Data sets genomic data were done using Pearson correlation whereby the normal- were acquired in a data-dependant tandem manner whereby the top ized protein expression across the b0, b1, and b23 stages was correlated to three peptide ion peaks from each full scan were fragmented via col- its gene expression across the same stages of IFTA. lision-induced dissociation. The full-scan data provide the mass-to- charge ratio of peptide ions, whereas the fragmentation pattern from Proteomic Data Analysis subsequent MS/MS scans provides the sequence information of that Raw data were searched against the human EBI database (December peptide ion. Only approximately 15% of the acquired MS/MS scans 1, 2006, release) supplemented with a decoy database in which each are identified as peptides as a result of the fast scanning rate of the entry of the original protein contains its reversed sequence. The data-

370 Journal of the American Society of Nephrology J Am Soc Nephrol 21: 362–373, 2010 www.jasn.org CLINICAL RESEARCH base search was carried out using a PBS parallelized version of SE- canonical pathways defined by identified proteins was measured in QUEST (v27).59 MS/MS search involves comparison of the observed two ways: (1) A ratio of the number of proteins from the data set that fragmentation patterns of unknown peptides from MS/MS scans to map to the pathway divided by the total number of molecules that the predicted patterns given the peptide sequences in annotated exist in the canonical pathway and (2)aP value (Fisher exact test) FASTA protein databases. The highest scoring known peptide se- determining the probability that the association between the proteins quence from the database gets assigned to the MS/MS scan. Search in the data set and the canonical pathway is explained by chance alone. outcomes were postprocessed and filtered using DTASelect60 2.0 (in preparation). DTASelect 2.0 uses a quadratic discriminant analysis to Validation of Identified Proteins adjust dynamically the XCorr and DeltaCN parameters to meet a SRM approach was carried out for validation using a triple-quadru- required false-positive rate (chance probability of 0.05). Postprocess- pole mass spectrometer (TSQ Ultra; ThermoScientific). Peptides pre- ing is required to establish statistical confidence in primary identifi- viously observed in large-scale experiments were selected as valida- cations and is usually done using a reversed or shuffled protein data- tion targets given the following conditions: A peptide was tryptic, a base that will yield false-positive identifications when applied to the peptide was observed with a charge state of higher than ϩ1, a peptide experimental data. Protein identifications were extracted, and a mea- did not contain either methionine or cysteine residue, and the maxi- sure of normalized amino acid coverage was used as label-free quan- mum m/z of a peptide was Ͻ1500. A series of unique fragmentation tification. The exact formula used to calculate relative protein abun- targets (three transitions per peptide) were generated for each pep- dance is as follows: tide, and the collision-induced dissociation energy was m/z depen- dent similar to that reported by Kuzyc et al.62 The first quadrupole ͸n (Q1) served as a lens programmed to acquire 3 amu wide, 0.075-s peptidei scans at the resolution of 0.7 around the m/z of each target precursor ϭ ϭ i 1 ion. The second quadrupole (Q2) served as a collision cell, and the Aprotein ͸k third quadrupole (Q3) was programmed to monitor the three frag- scanj ments of the precursor ion with the settings similar to that of Q1 ϭ j 1 except the resolution was set to 0.2. The instrument was operated in-line with a single-dimension RP column containing 100 ␮gof where Aprotein (protein abundance) is expressed as a ratio of the total redundant peptide identifications per protein to the total number of pooled b0 or pooled b23 sample. The target generation and data anal- scans identified in the experiment. Each protein identification was ysis were carried out with in-house software for SRM validation. The annotated by GO association61 (Revision 1.59; http://www.geneon- experiments were run in technical duplicates and included b0 valida- tology.org). Protein identifications across replicate experiments were tion; b23 validation; b0 validation with b23 sample (specificity mea- pooled to represent a union for each category of IFTA (b0, b1, and sure); b23 validation with b0 sample (specificity measure); and b0, b23). Relative protein abundance was compared across histologic cat- b23 validation with no sample (blank). The experimentally deter- egories of IFTA for proteins present in more than one category. One- mined threshold parameters were as follows: Minimum signal inten- way ANOVA (b0 versus b1 versus b23 comparison) and a two-tailed, sity, 100; mass accuracy of the fragment ion, unity; minimum number independent t test (pair-wise b0 versus b1 and b1 versus b23 compar- of unique targets observed per peptide, 2; minimum number of pep- isons) were used for hypothesis testing (P value cutoff of 0.05). Only tides per protein, 2. the significant differentially expressed proteins were considered for functional analysis. Proteins identified in more than one technical replicate in a single category and not in any other stage of IFTA were ACKNOWLEDGMENTS also considered for functional analysis as unique identifications. Funding was provided by National Institutes of Health grants U19 Clustering and Functional Annotations AI52349 and P41 RR011823, the Molly Baber Research Fund, and the Clustering of the relative expression profiles from the ANOVA set was Verna Harrah Research Fund. The funders had no role in study de- implemented with k-means algorithm, where n protein expression sign, data collection and analysis, decision to publish, or preparation profiles were partitioned into m categories (clusters) using Euclidian of the manuscript. distance as a metric. A protein’s expression profile represents its rel- A.N. and J.A.H. contributed equally to biopsy sample processing ative abundances across the three categories of IFTA. Hierarchical and collection of the proteomic data sets; A.N. took primary respon- clustering of the functional annotations (biologic function, canonical sibility for the writing of the manuscript with D.R.S.; D.R.S. and J.R.Y. pathway) was carried out using Spearman rank average linkage met- designed the original experiments and supervised the data acquisi- ric. A P value cutoff of 1.3 (chance probability of 0.05) was applied to tion, analysis, and writing; S.M.K., T.S.M., and S.R.H. supervised the functional profiles. Ingenuity Pathway Analysis tool (Ingenuity sample collections, pathology reviews, and gene expression data ac- Systems; http://www.ingenuity.com) was used to generate functional quisition; D.C. performed all gene expression profiling; and C.L.M. annotations of identified proteins in known molecular pathways. Fi- participated in sample collection, clinical data analysis, and manu- scher exact test was used to calculate a p value determining the prob- script writing. ability that each biologic function and/or disease process correlation We thank Conrad H. Lu, Tina Tan, and Donald L. Tschirhart (St. assigned to that data set is due to chance alone. The significance of the Vincent Medical Center); Frank Wesley Hall, David Bylund, and Ed-

J Am Soc Nephrol 21: 362–373, 2010 Proteomics of Chronic Rejection 371 CLINICAL RESEARCH www.jasn.org ward Kane, Jr. (Scripps Clinic); and Jonathan L. Myles (Cleveland Bieringer M, Breu V, Ganten D, Haller H, Luft FC: Cyclosporin A Clinic Foundation) for local pathology reviews from the participating protects against angiotensin II-induced end-organ damage in double transgenic rats harboring human renin and angiotensinogen genes. clinical centers and Dr. Lillian Gaber (Texas Medical Center, Hous- Hypertension 35: 360–366, 2000 ton) for the centralized reviews. We also acknowledge Joanna Sung 14. Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E, Ham- (Scripps Clinic), Barbara Mastroianni and Kathy Savas (Cleveland pich F, Fiebeler A, Ju X, Finckenberg P, Theuer J, Viedt C, Kreuzer J, Clinic), and Anjela Tsirunyan (St. Vincent Medical Center) for the Heidecke H, Haller H, Zenke M, Luft FC: Immunosuppressive treat- clinical coordination of this research study. ment protects against angiotensin II-induced renal damage. Am J Pathol 161: 1679–1693, 2002 15. Cao Z, Kelly DJ, Cox A, Casley D, Forbes JM, Martinello P, Dean R, Gilbert RE, Cooper ME: Angiotensin type 2 receptor is expressed in DISCLOSURES the adult rat kidney and promotes cellular proliferation and apoptosis. Kidney Int 58: 2437–2451, 2000 None. 16. Zhang S, Malmersjo S, Li J, Ando H, Aizman O, Uhlen P, Mikoshiba K, Aperia A: Distinct role of the N-terminal tail of the Na,K-ATPase catalytic subunit as a signal transducer. J Biol Chem 281: 21954–21962, 2006 17. 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J Am Soc Nephrol 21: 362–373, 2010 Proteomics of Chronic Rejection 373 Protein IPI Peptide Sequence Peptide Peptide Target1 Norm. Target2 Norm. Target3 Norm. Avg. Total Ion Charge m/z m/z Abundance m/z Abundance m/z Abundance Abundance Intensity IPI00021167.3 SDVQIHVPTFTFR 2 774.38 868 1 1005 1 1118 0 0.66666667 410.5 IPI00021167.3 SDVQIHVPTFTFR 2 774.38 868 1 1005 0 1118 1 0.66666667 411.3 IPI00029267.1 DALQGFK 1 778.88 479 1 592 1 663 1 1 994.1 IPI00029267.1 DALQGFK 1 778.88 479 1 592 1 663 1 1 2651.5 IPI00183508.3 YHFFLYK 1 1018.2 570 1 717 1 855 0 0.66666667 1421.7 IPI00183508.3 YHFFLYK 1 1018.2 570 1 717 1 855 0 0.66666667 793.9 IPI00384170.3 ILTPLTDQTVNLGK 2 757.39 759 1 875 1 976 0 0.66666667 684.6 IPI00384170.3 ILTPLTDQTVNLGK 2 757.39 759 1 875 1 976 1 1 682.9 IPI00787323.1 LEGLTDEINFLR 2 710.81 791 1 907 1 1008 0 0.66666667 765.8 IPI00787323.1 LEGLTDEINFLR 2 710.81 791 1 907 1 1008 1 1 2740.3 IPI00793862.1 GIELTLQIQSDTGVR 2 815.92 876 0 1004 1 1117 1 0.66666667 898.3 IPI00793862.1 GIELTLQIQSDTGVR 2 815.92 876 1 1004 1 1117 1 1 956.3 IPI00793862.1 VGLELIASENFASR 2 753.85 810 1 881 1 995 0 0.66666667 973.4 IPI00793862.1 VGLELIASENFASR 2 753.85 810 1 881 0 995 1 0.66666667 2784.1 ANOVA all ID b0 b1 b23 Hs.108080 0.00044 0.000579 0.001184 Hs.109752 0.000431 0.000389 0.000219 Hs.114172 0.000805 0.000575 0.000362 Hs.11729-S 0.000473 0.000623 0.000245 Hs.120165 0.000637 0.000287 0.000138 Hs.122523 0.000138 0.000584 0.000294 Hs.1227-AL 0.000577 0.000267 0.000203 Hs.1239-AN 0.001572 0.00155 0.000374 Hs.126265 0.000198 0.000454 0.000102 Hs.131711 0.001824 0.001208 0.000842 Hs.143250 0.000262 0.001516 0.001302 Hs.143436 0.0004 0.000318 0.000805 Hs.145384 0.001899 0.000898 0.000362 Hs.148559 0.001157 0.001245 0.000717 Hs.1498-H 0.000136 0.000176 0.000516 Hs.155097 0.002833 0.001142 0.001019 Hs.16355-M 0.001375 0.003875 0.00253 Hs.170622 0.001772 0.0012 0.002301 Hs.171280 0.000175 0.000323 0.000154 Hs.173381 0.00047 0.000953 0.000878 Hs.173724 0.000589 0.001369 0.000812 Hs.173878 0.001171 0.001183 0.000369 Hs.180346 0.000295 0.000497 0.000212 Hs.180414 0.001436 0.002468 0.002258 Hs.19383-A 0.000138 0.000195 0.000531 Hs.198003 0.000687 0.000297 0.000218 Hs.199368 0.000948 0.002073 0.00216 Hs.203717 0.000502 0.000793 0.001376 Hs.2257-SE 0.000192 0.000584 0.0005 Hs.232375 0.006654 0.00368 0.00304 Hs.237658 0.000549 0.000321 0.000927 Hs.246310 0.000738 0.000319 0.000149 Hs.2533-AL 0.000976 0.000789 0.000564 Hs.268488 0.000183 0.000348 0.000141 Hs.288959 0.002768 0.001331 0.000554 Hs.289271 0.000585 0.000654 0.000314 Hs.290404 0.001089 0.000849 0.00041 Hs.293970 0.003963 0.00447 0.001553 Hs.30345-T 0.000386 0.000302 0.000134 Hs.324746 0.001014 0.000927 0.002023 Hs.334707 0.008434 0.007334 0.002893 Hs.337295 0.000189 0.000626 0.000322 Hs.3439-ST 0.000693 0.000435 0.00018 Hs.350265 0.001248 0.000548 0.00025 Hs.356624 0.000574 0.001034 0.001434 Hs.368084 0.000439 0.001186 0.000436 Hs.368912 0.000328 0.000399 0.000192 Hs.369840 0.000382 0.001109 0.001035 Hs.370581 0.00039 0.001023 0.001031 Hs.371723 0.000222 0.000394 0.000145 Hs.371889 0.00158 0.002454 0.001433 Hs.390667 0.000355 0.000176 0.000136 Hs.396783 0.00114 0.001468 0.000471 Hs.4-ADH1 0.000477 0.001356 0.001699 Hs.406678 0.00042 0.000917 0.000378 Hs.406861 0.000514 0.00079 0.000422 Hs.409662 0.002151 0.003617 0.002255 Hs.413482 0.001208 0.000681 0.000547 Hs.418167 0.079535 0.053408 0.078113 Hs.419640 0.001131 0.000738 0.000776 Hs.424932 0.003541 0.001982 0.001063 Hs.427202 0.004842 0.003351 0.00826 Hs.429879 0.001686 0.00179 0.000753 Hs.433512 0.000225 0.000374 0.000752 Hs.434435 0.000601 0.001808 0.000692 Hs.437178 0.001441 0.001845 0.001085 Hs.439726 0.000152 0.000537 0.001241 Hs.440544 0.000989 0.000724 0.000383 Hs.444362 0.000307 0.000389 0.00066 Hs.444751 0.001069 0.001458 0.000565 Hs.445040 0.002499 0.001713 0.000511 Hs.460260 0.000479 0.000835 0.000399 Hs.464336 0.001092 0.001834 0.00149 Hs.465221 0.000264 0.000779 0.000317 Hs.470907 0.002668 0.000808 0.0005 Hs.471207 0.000742 0.001334 0.000534 Hs.474751 0.0044 0.009787 0.00749 Hs.476448 0.000485 0.00267 0.001614 Hs.481571 0.000301 0.000605 0.000171 Hs.481980 0.000347 0.000826 0.000364 Hs.482043 0.000333 0.000733 0.000398 Hs.483239 0.001655 0.001184 0.000695 Hs.489190 0.000531 0.000686 0.000314 Hs.491351 0.000711 0.003148 0.001718 Hs.494173 0.000526 0.001013 0.001287 Hs.500409 0.006915 0.004076 0.001196 Hs.502528 0.000296 0.000779 0.000239 Hs.509736 0.000726 0.002142 0.001102 Hs.513660 0.000966 0.001399 0.000655 Hs.515070 0.000749 0.002364 0.001817 Hs.516032 0.004172 0.003657 0.001545 Hs.517168 0.000852 0.001208 0.001621 Hs.518267 0.006563 0.006539 0.007724 Hs.518731 0.000171 0.000425 0.00025 Hs.520898 0.001364 0.001512 0.000639 Hs.522373 0.000861 0.001533 0.002156 Hs.523443 0.023072 0.011814 0.013221 Hs.524630 0.000221 0.000334 0.000132 Hs.525557 0.004543 0.006206 0.009982 Hs.525600 0.001088 0.002798 0.001627 Hs.533050 0.000266 0.000395 0.000203 Hs.533273 0.000953 0.002199 0.001712 Hs.534314 0.000262 0.000466 0.000517 Hs.534639 0.00221 0.00175 0.000908 Hs.534797 0.000546 0.001177 0.000408 Hs.546239 0.00047 0.000758 0.000969 Hs.546303 0.000127 0.000374 0.000181 Hs.558314 0.00067 0.001357 0.002242 Hs.567297 0.001313 0.000676 0.000234 Hs.567311 0.000964 0.000568 0.003158 Hs.572518 0.000302 0.000558 0.000208 Hs.573688 0.00213 0.001157 0.001008 Hs.591069 0.000437 0.000438 0.000225 Hs.592048 0.001059 0.001556 0.000942 Hs.592490 0.00232 0.001463 0.000769 Hs.592601 0.003171 0.001079 0.000506 Hs.595809 0.000202 0.00058 0.000194 Hs.604001 0.000284 0.000358 0.000549 Hs.604789 0.001151 0.000999 0.000468 Hs.633853 0.000248 0.000463 0.000172 Hs.63788-P 0.001419 0.000717 0.000526 Hs.642813 0.007828 0.009767 0.012309 Hs.645734 0.000247 0.000972 0.001045 Hs.647097 0.000257 0.000384 0.000165 Hs.650585 0.000209 0.000779 0.000586 Hs.654435 0.002466 0.001465 0.000906 Hs.654443 0.00011 0.000461 0.000936 Hs.654559 0.000315 0.000262 0.000559 Hs.654592 0.000531 0.000307 0.000231 Hs.654595 0.000348 0.000902 0.000344 Hs.655250 0.001825 0.001834 0.000683 Hs.657401 0.003908 0.002205 0.000766 Hs.658778 0.001491 0.00277 0.002413 Hs.659362 0.002062 0.004106 0.001983 Hs.676772 0.001187 0.002832 0.001621 Hs.696029 0.000191 0.000399 0.000172 Hs.699190 0.000558 0.000609 0.000866 Hs.700567 0.004184 0.004836 0.002602 Hs.74405-Y 0.000122 0.000272 0.000949 Hs.75069-S 0.000861 0.000491 0.000311 Hs.75318-T 0.002184 0.003368 0.002601 Hs.78183-A 0.000704 0.000995 0.0005 Hs.79387-P 0.000105 0.000312 0.000133 Hs.80756-B 0.005393 0.003188 0.001578 Hs.81934-A 0.001208 0.000957 0.000331 Hs.90093-H 0.000204 0.000643 0.000361 Hs.93659-P 0.000277 0.000735 0.000387 IPI0001998 0.000541 0.000327 0.000225 IPI0017952 0.000481 0.000856 0.0004 IPI0021613 0.000547 0.001209 0.002036 IPI0030571 0.000825 0.001824 0.000679 IPI0041372 0.003573 0.005216 0.003503 IPI0055099 0.000138 0.000607 0.001435 IPI0064477 0.006002 0.003823 0.0012 IPI0071908 0.002024 0.003354 0.006244 IPI0073979 0.005976 0.0036 0.001283 IPI0079653 0.001961 0.000981 0.000746 Hs.124696 0.001444 0.000622 0.000522 Hs.126688 0.000856 0.000664 0.000409 Hs.170107 0.00102 0.000622 0.000327 Hs.292493 0.00025 0.000423 0.00045 Hs.300774 0.000768 0.00176 0.002066 Hs.471381 0.00027 0.000452 0.000779 Hs.47649-M 0.000645 0.000497 0.000293 Hs.514934 0.000219 0.000182 0.00044 Hs.616909 0.002883 0.000317 0.000273 IPI0016872 0.001513 0.003869 0.002462 IPI0039813 0.000217 0.000314 0.000186 Hs.195464 0.002378 0.00407 0.006074 Hs.233240 0.003508 0.005449 0.011248 Hs.2795-LD 0.001029 0.001247 0.002285 Hs.381099 0.000425 0.00027 0.000903 Hs.430606 0.001159 0.000929 0.000592 Hs.437156 0.000241 0.000389 0.000812 Hs.513987 0.002541 0.001551 0.00095 Hs.594673 0.000533 0.000724 0.001281 Hs.609663 0.000324 0.000402 0.000703 Hs.654447 0.00081 0.000766 0.001448 Hs.654473 0.000823 0.000581 0.000329 Hs.655653 0.000748 0.00152 0.0009 Hs.695946 0.000174 0.000425 0.000389 Hs.699182 0.000394 0.000592 0.00036 Hs.75227-N 0.001661 0.000597 0.000396 Hs.89890-P 0.002219 0.001345 0.000916 cluster b0 ID b0 b1 b23 Hs.109752 0.000431 0.000389 0.000219 Hs.114172 0.000805 0.000575 0.000362 Hs.120165 0.000637 0.000287 0.000138 Hs.1227-AL 0.000577 0.000267 0.000203 Hs.1239-AN 0.001572 0.00155 0.000374 Hs.124696 0.001444 0.000622 0.000522 Hs.126688 0.000856 0.000664 0.000409 Hs.131711 0.001824 0.001208 0.000842 Hs.145384 0.001899 0.000898 0.000362 Hs.155097 0.002833 0.001142 0.001019 Hs.170107 0.00102 0.000622 0.000327 Hs.173878 0.001171 0.001183 0.000369 Hs.198003 0.000687 0.000297 0.000218 Hs.232375 0.006654 0.00368 0.00304 Hs.246310 0.000738 0.000319 0.000149 Hs.2533-AL 0.000976 0.000789 0.000564 Hs.288959 0.002768 0.001331 0.000554 Hs.290404 0.001089 0.000849 0.00041 Hs.30345-T 0.000386 0.000302 0.000134 Hs.334707 0.008434 0.007334 0.002893 Hs.3439-ST 0.000693 0.000435 0.00018 Hs.350265 0.001248 0.000548 0.00025 Hs.390667 0.000355 0.000176 0.000136 Hs.413482 0.001208 0.000681 0.000547 Hs.419640 0.001131 0.000738 0.000776 Hs.424932 0.003541 0.001982 0.001063 Hs.429879 0.001686 0.00179 0.000753 Hs.430606 0.001056 0.000674 0.000646 Hs.440544 0.000989 0.000724 0.000383 Hs.445040 0.002499 0.001713 0.000511 Hs.470907 0.002668 0.000808 0.0005 Hs.47649-M 0.000645 0.000497 0.000293 Hs.483239 0.001655 0.001184 0.000695 Hs.500409 0.006915 0.004076 0.001196 Hs.513987 0.002456 0.001434 0.000789 Hs.516032 0.004172 0.003657 0.001545 Hs.523443 0.023072 0.011814 0.013221 Hs.534639 0.00221 0.00175 0.000908 Hs.567297 0.001313 0.000676 0.000234 Hs.573688 0.00213 0.001157 0.001008 Hs.591069 0.000437 0.000438 0.000225 Hs.592490 0.00232 0.001463 0.000769 Hs.592601 0.003171 0.001079 0.000506 Hs.604789 0.001151 0.000999 0.000468 Hs.616909 0.002883 0.000317 0.000273 Hs.63788-P 0.001419 0.000717 0.000526 Hs.654435 0.002466 0.001465 0.000906 Hs.654473 0.000895 0.000641 0.000387 Hs.654592 0.000531 0.000307 0.000231 Hs.655250 0.001825 0.001834 0.000683 Hs.657401 0.003908 0.002205 0.000766 Hs.75069-S 0.000861 0.000491 0.000311 Hs.75227-N 0.001064 0.000502 0.000319 Hs.80756-B 0.005393 0.003188 0.001578 Hs.81934-A 0.001208 0.000957 0.000331 Hs.89890-P 0.002291 0.001723 0.000789 IPI0001998 0.000541 0.000327 0.000225 IPI0064477 0.006002 0.003823 0.0012 IPI0073979 0.005976 0.0036 0.001283 IPI0079653 0.001961 0.000981 0.000746 cluster b1 ID b0 b1 b23 Hs.11729-S 0.000473 0.000623 0.000245 Hs.122523 0.000138 0.000584 0.000294 Hs.126265 0.000198 0.000454 0.000102 Hs.143250 0.000262 0.001516 0.001302 Hs.148559 0.001157 0.001245 0.000717 Hs.16355-M 0.001375 0.003875 0.00253 Hs.171280 0.000175 0.000323 0.000154 Hs.173381 0.00047 0.000953 0.000878 Hs.173724 0.000589 0.001369 0.000812 Hs.180346 0.000295 0.000497 0.000212 Hs.180414 0.001436 0.002468 0.002258 Hs.2257-SE 0.000192 0.000584 0.0005 Hs.268488 0.000183 0.000348 0.000141 Hs.289271 0.000585 0.000654 0.000314 Hs.293970 0.003963 0.00447 0.001553 Hs.337295 0.000189 0.000626 0.000322 Hs.368084 0.000439 0.001186 0.000436 Hs.368912 0.000328 0.000399 0.000192 Hs.369840 0.000382 0.001109 0.001035 Hs.371723 0.000222 0.000394 0.000145 Hs.371889 0.00158 0.002454 0.001433 Hs.396783 0.00114 0.001468 0.000471 Hs.406678 0.00042 0.000917 0.000378 Hs.406861 0.000514 0.00079 0.000422 Hs.409662 0.002151 0.003617 0.002255 Hs.434435 0.000601 0.001808 0.000692 Hs.437178 0.001441 0.001845 0.001085 Hs.444751 0.001069 0.001458 0.000565 Hs.460260 0.000479 0.000835 0.000399 Hs.464336 0.001092 0.001834 0.00149 Hs.465221 0.000264 0.000779 0.000317 Hs.471207 0.000742 0.001334 0.000534 Hs.474751 0.0044 0.009787 0.00749 Hs.476448 0.000485 0.00267 0.001614 Hs.481571 0.000301 0.000605 0.000171 Hs.481980 0.000347 0.000826 0.000364 Hs.482043 0.000333 0.000733 0.000398 Hs.489190 0.000531 0.000686 0.000314 Hs.491351 0.000711 0.003148 0.001718 Hs.502528 0.000296 0.000779 0.000239 Hs.509736 0.000726 0.002142 0.001102 Hs.513660 0.000966 0.001399 0.000655 Hs.515070 0.000749 0.002364 0.001817 Hs.518731 0.000171 0.000425 0.00025 Hs.520898 0.001364 0.001512 0.000639 Hs.524630 0.000221 0.000334 0.000132 Hs.525600 0.001088 0.002798 0.001627 Hs.533050 0.000266 0.000395 0.000203 Hs.533273 0.000953 0.002199 0.001712 Hs.534797 0.000546 0.001177 0.000408 Hs.546303 0.000127 0.000374 0.000181 Hs.572518 0.000302 0.000558 0.000208 Hs.592048 0.001059 0.001556 0.000942 Hs.595809 0.000202 0.00058 0.000194 Hs.633853 0.000248 0.000463 0.000172 Hs.647097 0.000257 0.000384 0.000165 Hs.650585 0.000209 0.000779 0.000586 Hs.654595 0.000348 0.000902 0.000344 Hs.655653 0.001046 0.001418 0.000634 Hs.658778 0.001491 0.00277 0.002413 Hs.659362 0.002062 0.004106 0.001983 Hs.676772 0.001187 0.002832 0.001621 Hs.695946 0.00021 0.000464 0.000345 Hs.696029 0.000191 0.000399 0.000172 Hs.699182 0.000565 0.000616 0.000344 Hs.700567 0.004184 0.004836 0.002602 Hs.75318-T 0.002184 0.003368 0.002601 Hs.78183-A 0.000704 0.000995 0.0005 Hs.79387-P 0.000105 0.000312 0.000133 Hs.90093-H 0.000204 0.000643 0.000361 Hs.93659-P 0.000277 0.000735 0.000387 IPI0016872 0.001513 0.003869 0.002462 IPI0017952 0.000481 0.000856 0.0004 IPI0030571 0.000825 0.001824 0.000679 IPI0039813 0.000217 0.000314 0.000186 IPI0041372 0.003573 0.005216 0.003503 cluster b23 ID b0 b1 b23 Hs.108080 0.00044 0.000579 0.001184 Hs.143436 0.0004 0.000318 0.000805 Hs.1498-H 0.000136 0.000176 0.000516 Hs.170622 0.001772 0.0012 0.002301 Hs.19383-A 0.000138 0.000195 0.000531 Hs.195464 0.001718 0.006041 0.006727 Hs.199368 0.000948 0.002073 0.00216 Hs.203717 0.000502 0.000793 0.001376 Hs.233240 0.004373 0.007594 0.013144 Hs.237658 0.000549 0.000321 0.000927 Hs.2795-LD 0.000631 0.001076 0.00161 Hs.292493 0.00025 0.000423 0.00045 Hs.300774 0.000768 0.00176 0.002066 Hs.324746 0.001014 0.000927 0.002023 Hs.356624 0.000574 0.001034 0.001434 Hs.370581 0.00039 0.001023 0.001031 Hs.381099 0.000397 0.000484 0.001152 Hs.4-ADH1 0.000477 0.001356 0.001699 Hs.418167 0.079535 0.053408 0.078113 Hs.427202 0.004842 0.003351 0.00826 Hs.433512 0.000225 0.000374 0.000752 Hs.437156 0.000321 0.000573 0.000876 Hs.439726 0.000152 0.000537 0.001241 Hs.444362 0.000307 0.000389 0.00066 Hs.471381 0.00027 0.000452 0.000779 Hs.494173 0.000526 0.001013 0.001287 Hs.514934 0.000219 0.000182 0.00044 Hs.517168 0.000852 0.001208 0.001621 Hs.518267 0.006563 0.006539 0.007724 Hs.522373 0.000861 0.001533 0.002156 Hs.525557 0.004543 0.006206 0.009982 Hs.534314 0.000262 0.000466 0.000517 Hs.546239 0.00047 0.000758 0.000969 Hs.558314 0.00067 0.001357 0.002242 Hs.567311 0.000964 0.000568 0.003158 Hs.594673 0.00046 0.000831 0.001386 Hs.604001 0.000284 0.000358 0.000549 Hs.609663 0.000275 0.00067 0.000733 Hs.642813 0.007828 0.009767 0.012309 Hs.645734 0.000247 0.000972 0.001045 Hs.654443 0.00011 0.000461 0.000936 Hs.654447 0.001079 0.001172 0.001801 Hs.654559 0.000315 0.000262 0.000559 Hs.699190 0.000558 0.000609 0.000866 Hs.74405-Y 0.000122 0.000272 0.000949 IPI0021613 0.000547 0.001209 0.002036 IPI0055099 0.000138 0.000607 0.001435 IPI0071908 0.002024 0.003354 0.006244 b0 vs b1 ID b0 b1 Hs.120165 0.000637 0.000287 Hs.122523 0.000138 0.000584 Hs.1227-AL 0.000577 0.000267 Hs.126265 0.000198 0.000454 Hs.143250 0.000262 0.001516 Hs.144114 0.000127 0.000195 Hs.151220 0.000201 0.000108 Hs.16355-M 0.001375 0.003875 Hs.166463 0.000619 0.001116 Hs.171280 0.000175 0.000323 Hs.173381 0.00047 0.000953 Hs.173724 0.000589 0.001369 Hs.195464 0.001059 0.008012 Hs.198003 0.000687 0.000297 Hs.199368 0.000948 0.002073 Hs.233240 0.005238 0.009738 Hs.2420-SO0.000132 0.000699 Hs.2533-AL 0.000976 0.000789 Hs.268488 0.000183 0.000348 Hs.271135 0.000591 0.000456 Hs.271510 0.000306 0.000694 Hs.2795-LD 0.000233 0.000906 Hs.333786 0.000191 0.000131 Hs.337295 0.000189 0.000626 Hs.351593 0.000784 0.002028 Hs.369840 0.000382 0.001109 Hs.370581 0.00039 0.001023 Hs.371723 0.000222 0.000394 Hs.371889 0.00158 0.002454 Hs.390667 0.000355 0.000176 Hs.404321 0.000228 0.000379 Hs.406678 0.00042 0.000917 Hs.413482 0.001208 0.000681 Hs.415067 0.000191 0.000363 Hs.418167 0.079535 0.053408 Hs.419640 0.001131 0.000738 Hs.420269 0.001227 0.002605 Hs.430551 0.000278 0.000987 Hs.430606 0.000953 0.00042 Hs.433512 0.000225 0.000374 Hs.433615 0.008375 0.005559 Hs.434435 0.000601 0.001808 Hs.434937 0.000346 0.000743 Hs.435012 0.0008 0.000456 Hs.435832 0.000155 0.000369 Hs.436657 0.000394 0.000677 Hs.437156 0.000401 0.000757 Hs.439726 0.000152 0.000537 Hs.440544 0.000989 0.000724 Hs.460109 0.000663 0.003623 Hs.460260 0.000479 0.000835 Hs.464071 0.000382 0.000246 Hs.465413 0.000224 0.000425 Hs.470457 0.0001 0.000201 Hs.470907 0.002668 0.000808 Hs.474751 0.0044 0.009787 Hs.476448 0.000485 0.00267 Hs.481571 0.000301 0.000605 Hs.481980 0.000347 0.000826 Hs.482043 0.000333 0.000733 Hs.488181 0.00105 0.001494 Hs.491351 0.000711 0.003148 Hs.494691 0.000278 0.000743 Hs.499839 0.000103 0.000338 Hs.509736 0.000726 0.002142 Hs.513660 0.000966 0.001399 Hs.514535 0.000124 0.001068 Hs.515070 0.000749 0.002364 Hs.518731 0.000171 0.000425 Hs.522373 0.000861 0.001533 Hs.523443 0.023072 0.011814 Hs.524183 0.000103 0.00018 Hs.525600 0.001088 0.002798 Hs.530687 0.000421 0.00083 Hs.533273 0.000953 0.002199 Hs.534314 0.000262 0.000466 Hs.546255 0.000753 0.001452 Hs.546285 0.000218 0.000426 Hs.546303 0.000127 0.000374 Hs.567297 0.001313 0.000676 Hs.572518 0.000302 0.000558 Hs.573688 0.00213 0.001157 Hs.591996 0.000258 0.00059 Hs.592048 0.001059 0.001556 Hs.592601 0.003171 0.001079 Hs.594673 0.000387 0.000937 Hs.595809 0.000202 0.00058 Hs.602898 0.000535 0.000195 Hs.605502 0.00134 0.002201 Hs.609663 0.000226 0.000938 Hs.631742 0.000335 0.000692 Hs.632034 0.000124 0.000207 Hs.643451 0.000504 0.000398 Hs.645734 0.000247 0.000972 Hs.650585 0.000209 0.000779 Hs.651231 0.004734 0.005642 Hs.654434 0.000193 0.000725 Hs.655207 0.000213 0.000452 Hs.659362 0.002062 0.004106 Hs.696029 0.000191 0.000399 Hs.699250 0.001513 0.000511 Hs.700572 0.000336 0.000641 Hs.73722-A 0.000238 0.000384 Hs.74405-Y 0.000122 0.000272 Hs.75318-T 0.002184 0.003368 Hs.75812-P 0.009296 0.003635 Hs.78183-A 0.000704 0.000995 Hs.78771 0.007425 0.003406 Hs.79387-P 0.000105 0.000312 Hs.821-BG 0.001554 0.002246 Hs.878-SO 0.000452 0.001042 Hs.90093-H 0.000204 0.000643 Hs.93659-P 0.000277 0.000735 IPI0001957 0.00077 0.000426 IPI0017952 0.000481 0.000856 IPI0021613 0.000547 0.001209 IPI0030571 0.000825 0.001824 IPI0055099 0.000138 0.000607 IPI0073979 0.005976 0.0036 IPI0079653 0.001961 0.000981 Hs.11729-S 0.000183 0.000495 Hs.124696 0.001444 0.000622 Hs.203717 0.000536 0.000937 Hs.23118-C 0.000586 0.001237 Hs.254042 0.000406 0.000251 Hs.292493 0.00025 0.000423 Hs.406475 0.000456 0.001778 Hs.427202 0.005468 0.002549 Hs.433419 0.000245 0.000422 Hs.437594 0.000355 0.000631 Hs.440599 0.000254 0.000627 Hs.463074 9.15E-05 0.000154 Hs.465224 0.000121 0.000198 Hs.47649-M 0.000645 0.000497 Hs.487774 0.001205 0.002863 Hs.492212 0.000433 0.000919 Hs.502842 0.000107 0.000174 Hs.513987 0.002541 0.001551 Hs.517168 0.000878 0.002454 Hs.520974 0.000418 0.000669 Hs.533444 0.00043 0.000276 Hs.534309 0.000176 0.000403 Hs.584238 0.000156 0.000361 Hs.644646 0.000265 0.000392 Hs.651212 0.000407 0.000707 Hs.652390 0.00239 0.004552 Hs.654422 0.002356 0.004308 Hs.654614 0.000252 0.000929 Hs.654682 8.11E-05 0.000212 Hs.654720 8.77E-05 0.000135 Hs.665191 0.000179 9.51E-05 Hs.690634 0.000224 0.001328 Hs.699168 0.002338 0.005152 Hs.699181 0.000211 0.000506 Hs.700567 0.002891 0.005657 Hs.75227-N 0.001661 0.000597 Hs.78888-D 0.000246 0.000481 Hs.78989-A 0.000315 0.000703 Hs.80552-D 9.19E-05 0.000214 Hs.89890-P 0.002219 0.001345 IPI0016872 0.001513 0.003869 IPI0039813 0.000217 0.000314 IPI0047935 0.001392 0.002495 IPI0055064 0.001552 0.004099 IPI0064195 0.000143 0.000429 Hs.180414 0.001436 0.002468 Hs.300774 0.000824 0.001524 Hs.356624 0.000574 0.001034 Hs.464336 0.001092 0.001834 Hs.465221 0.000264 0.000779 Hs.471207 0.000742 0.001334 Hs.483305 0.000897 0.000292 Hs.502528 0.000296 0.000779 Hs.502756 0.000573 0.003577 Hs.513851 0.000274 0.000815 Hs.515162 0.00123 0.002157 Hs.654568 0.000403 0.001371 Hs.654595 0.000348 0.000902 Hs.658778 0.001491 0.00277 Hs.695946 0.000247 0.000503 Hs.89649-E 0.00023 0.000589 IPI0041372 0.003573 0.005216 b0 vs b23 ID b0 b23 Hs.109752 0.000431 0.000219 Hs.110837 0.006447 0.004462 Hs.11355-T 0.000103 0.000278 Hs.116448 0.002363 0.00062 Hs.11729-S 0.000473 0.000245 Hs.120759 0.000164 0.000494 Hs.1227-AL 0.000577 0.000203 Hs.131711 0.001824 0.000842 Hs.145384 0.001899 0.000362 Hs.148559 0.001157 0.000717 Hs.1498-H 0.000136 0.000516 Hs.155097 0.002833 0.001019 Hs.155742 0.001391 0.000593 Hs.16355-M 0.001375 0.00253 Hs.163893 0.000225 0.000339 Hs.166463 0.000619 0.000984 Hs.170622 0.001772 0.002301 Hs.173878 0.001171 0.000369 Hs.177766 0.000136 0.00027 Hs.191346 0.000155 0.000508 Hs.192374 0.00132 0.002802 Hs.19383-A 0.000138 0.000531 Hs.198003 0.000687 0.000218 Hs.198158 0.001744 0.000748 Hs.203637 0.000127 0.000211 Hs.212102 0.000734 0.001248 Hs.212838 0.001565 0.002524 Hs.224171 0.003193 0.005776 Hs.2257-SE 0.000192 0.0005 Hs.232375 0.006654 0.00304 Hs.237658 0.000549 0.000927 Hs.2420-SO0.000132 0.000471 Hs.2533-AL 0.000976 0.000564 Hs.259559 0.000475 0.000176 Hs.269944 0.000257 0.0001 Hs.282410 0.001408 0.000689 Hs.286226 0.000139 0.000299 Hs.288959 0.002768 0.000554 Hs.289271 0.000585 0.000314 Hs.290404 0.001089 0.00041 Hs.293970 0.003963 0.001553 Hs.295917 0.00106 0.000713 Hs.298280 0.008691 0.004117 Hs.299055 0.001305 0.000996 Hs.30345-T 0.000386 0.000134 Hs.309090 0.000155 0.000104 Hs.350265 0.001248 0.00025 Hs.351593 0.000784 0.002314 Hs.368525 0.000127 0.000357 Hs.370581 0.00039 0.001031 Hs.384598 0.000124 0.000247 Hs.388739 0.000485 0.000826 Hs.390667 0.000355 0.000136 Hs.396783 0.00114 0.000471 Hs.4-ADH1 0.000477 0.001699 Hs.413482 0.001208 0.000547 Hs.415067 0.000191 0.000571 Hs.424932 0.003541 0.001063 Hs.429879 0.001686 0.000753 Hs.433512 0.000225 0.000752 Hs.433615 0.008375 0.006255 Hs.435012 0.0008 0.000534 Hs.436657 0.000394 0.000882 Hs.437594 0.000276 0.000381 Hs.438289 0.002221 0.000904 Hs.439726 0.000152 0.001241 Hs.440544 0.000989 0.000383 Hs.444362 0.000307 0.00066 Hs.445040 0.002499 0.000511 Hs.460109 0.000663 0.002704 Hs.465808 0.000151 0.000313 Hs.465885 0.000139 0.000274 Hs.472213 0.000183 0.000351 Hs.473256 0.000185 0.001217 Hs.474751 0.0044 0.00749 Hs.481992 0.0001 0.000325 Hs.483239 0.001655 0.000695 Hs.485104 0.000183 0.001231 Hs.487774 0.001213 0.00164 Hs.489190 0.000531 0.000314 Hs.491351 0.000711 0.001718 Hs.493362 0.000265 0.000114 Hs.494691 0.000278 0.00086 Hs.499839 0.000103 0.000277 Hs.500409 0.006915 0.001196 Hs.500756 0.002192 0.00091 Hs.502914 0.0001 0.000152 Hs.511605 0.002427 0.003728 Hs.514303 0.000388 0.000221 Hs.514535 0.000124 0.000389 Hs.515070 0.000749 0.001817 Hs.516032 0.004172 0.001545 Hs.516155 0.000349 0.000545 Hs.516539 0.000259 0.000673 Hs.519659 0.000174 0.000358 Hs.522555 0.000103 8.02E-05 Hs.523443 0.023072 0.013221 Hs.524648 0.000193 0.00036 Hs.525600 0.001088 0.001627 Hs.530687 0.000421 0.000682 Hs.533273 0.000953 0.001712 Hs.534639 0.00221 0.000908 Hs.546239 0.00047 0.000969 Hs.546255 0.000753 0.002191 Hs.546271 0.000215 0.00063 Hs.556077 0.000195 0.000869 Hs.558314 0.00067 0.002242 Hs.567297 0.001313 0.000234 Hs.567311 0.000964 0.003158 Hs.567879 0.006337 0.001145 Hs.571037 0.00011 0.000149 Hs.571886 0.000222 0.000657 Hs.573688 0.00213 0.001008 Hs.586423 0.005293 0.002718 Hs.592490 0.00232 0.000769 Hs.592601 0.003171 0.000506 Hs.59486-H 0.000894 0.000335 Hs.602898 0.000535 0.00014 Hs.604001 0.000284 0.000549 Hs.62661-G 0.0001 0.000214 Hs.631554 0.000127 0.000414 Hs.632535 0.00011 0.000149 Hs.632828 0.000235 0.000448 Hs.643487 0.000866 0.000477 Hs.645734 0.000247 0.001045 Hs.654435 0.002466 0.000906 Hs.654443 0.00011 0.000936 Hs.654559 0.000315 0.000559 Hs.654568 0.000403 0.001684 Hs.655207 0.000213 0.000488 Hs.656685 0.000879 0.000282 Hs.657401 0.003908 0.000766 Hs.695918 0.000157 0.000279 Hs.699180 0.000858 0.001546 Hs.699182 0.000735 0.000327 Hs.699190 0.000558 0.000866 Hs.700071 0.000526 0.000352 Hs.74576-G 0.000848 0.000519 Hs.75069-S 0.000861 0.000311 Hs.75335-G 0.013087 0.00217 Hs.76394-E 0.005603 0.001864 Hs.77448-A 0.00773 0.001707 Hs.78183-A 0.000704 0.0005 Hs.80756-B 0.005393 0.001578 Hs.80828-K 0.000189 0.000967 Hs.81934-A 0.001208 0.000331 IPI0001998 0.000541 0.000225 IPI0002103 0.000631 0.002358 IPI0002498 0.000127 0.00021 IPI0021613 0.000547 0.002036 IPI0055099 0.000138 0.001435 IPI0064477 0.006002 0.0012 IPI0071908 0.002024 0.006244 IPI0073979 0.005976 0.001283 Hs.102798 0.000304 0.000132 Hs.12068-C 0.000211 0.000111 Hs.124696 0.001444 0.000522 Hs.17860-O 0.000842 0.000463 Hs.180909 0.002228 0.001061 Hs.189772 0.001016 0.000533 Hs.212088 0.000842 0.000513 Hs.254042 0.000406 0.000194 Hs.273621 0.000618 0.000334 Hs.277677 0.000547 0.000329 Hs.282244 9.92E-05 0.000171 Hs.3192-PC 0.000205 0.000148 Hs.331141 0.000304 0.000198 Hs.34494-A 0.000479 0.000327 Hs.359698 0.000788 0.000405 Hs.363396 0.000352 0.000827 Hs.368084 0.001214 0.000451 Hs.380929 0.000291 0.000143 Hs.405144 0.000319 0.000194 Hs.406475 0.000456 0.002154 Hs.409662 0.000345 0.001531 Hs.412117 0.000976 0.001325 Hs.430606 0.001159 0.000592 Hs.437366 0.00033 0.000116 Hs.443121 0.00028 0.000412 Hs.443914 0.002129 0.001224 Hs.445358 0.000612 0.001133 Hs.446309 0.00351 0.000893 Hs.466471 0.001255 0.000731 Hs.471381 0.00027 0.000779 Hs.474783 0.00178 0.000724 Hs.47649-M 0.000645 0.000293 Hs.483305 0.000438 0.000154 Hs.486520 0.000584 0.000225 Hs.487296 0.00025 0.000132 Hs.50223-R 0.001535 0.006144 Hs.511251 0.000552 0.000309 Hs.532699 0.000508 0.000228 Hs.593123 0.000142 0.000232 Hs.616909 0.002883 0.000273 Hs.622801 8.98E-05 0.000342 Hs.632177 0.000891 0.000519 Hs.643451 0.000274 0.000188 Hs.644953 0.000605 0.000217 Hs.651231 0.002067 0.00362 Hs.652390 0.00239 0.004003 Hs.655010 0.000479 0.000177 Hs.690634 0.000224 0.00072 Hs.695946 0.000174 0.000389 Hs.6980-AK 0.000557 0.000238 Hs.701075 0.00032 0.000541 Hs.73722-A 0.00012 0.000224 Hs.79322-Q 0.000392 0.000155 Hs.93659-P 0.000219 0.000496 IPI0001957 0.000567 0.000948 Hs.108080 0.00044 0.001184 Hs.114172 0.000805 0.000362 Hs.120165 0.000637 0.000138 Hs.126688 0.000689 0.000422 Hs.143250 0.000262 0.001302 Hs.143436 0.0004 0.000805 Hs.170107 0.0003 0.000132 Hs.173381 0.00047 0.000878 Hs.180414 0.001436 0.002258 Hs.183109 0.000615 0.000317 Hs.195464 0.001059 0.00738 Hs.199368 0.000948 0.00216 Hs.203717 0.000502 0.001376 Hs.233240 0.005238 0.015039 Hs.246310 0.000738 0.000149 Hs.247362 0.000382 0.000642 Hs.2795-LD 0.000233 0.000935 Hs.300774 0.000824 0.002886 Hs.324746 0.001014 0.002023 Hs.3439-ST 0.000693 0.00018 Hs.356624 0.000574 0.001434 Hs.369840 0.000382 0.001035 Hs.381099 0.000369 0.001401 Hs.420269 0.001227 0.002813 Hs.437156 0.000401 0.00094 Hs.449009 0.000196 0.000397 Hs.464336 0.001092 0.00149 Hs.470907 0.002668 0.0005 Hs.476448 0.000485 0.001614 Hs.481571 0.000301 0.000171 Hs.494173 0.000526 0.001287 Hs.494997 0.0001 0.000516 Hs.495219 0.000293 0.000131 Hs.502842 0.00018 0.000411 Hs.513851 0.000274 0.00094 Hs.513987 0.00237 0.000628 Hs.514934 0.00011 0.000194 Hs.517168 0.000852 0.001621 Hs.517949 0.000193 0.00031 Hs.518267 0.006563 0.007724 Hs.520974 0.000169 0.001023 Hs.522373 0.000861 0.002156 Hs.525557 0.004543 0.009982 Hs.529053 0.002676 0.005982 Hs.534314 0.000262 0.000517 Hs.546285 0.000218 0.000446 Hs.591069 0.000437 0.000225 Hs.594673 0.000387 0.00149 Hs.604789 0.001151 0.000468 Hs.609663 0.000226 0.000762 Hs.617193 0.00078 0.000293 Hs.632481 0.000797 0.001361 Hs.63788-P 0.001419 0.000526 Hs.642813 0.007828 0.012309 Hs.650585 0.000209 0.000586 Hs.651212 0.000291 0.001099 Hs.654447 0.001348 0.002153 Hs.654473 0.000966 0.000444 Hs.658778 0.001491 0.002413 Hs.690198 0.000465 0.000318 Hs.69293-H 0.000213 0.000383 Hs.694789 0.001336 0.002165 Hs.699155 0.001089 0.001438 Hs.73875-F 0.000653 0.000256 Hs.74405-Y 0.000122 0.000949 Hs.75227-N 0.000467 0.000241 Hs.75318-T 0.002184 0.002601 Hs.79110-N 0.000383 0.000616 Hs.89890-P 0.002363 0.000663 Hs.95990-P 0.000419 0.00023 IPI0064195 0.000164 0.00044 IPI0079653 0.001961 0.000746 b1 vs b23 ID b1 b23 Hs.10056-S 0.000588 0.000131 Hs.10136-B 0.000823 0.000331 Hs.109-DP 0.000946 0.000217 Hs.109752 0.000389 0.000219 Hs.114172 0.000575 0.000362 Hs.116448 0.000979 0.00062 Hs.119251 0.001851 0.000965 Hs.12013-A 0.000162 0.000101 Hs.122523 0.000584 0.000294 Hs.1239-AN 0.00155 0.000374 Hs.125113 0.00042 0.000219 Hs.126265 0.000454 0.000102 Hs.131711 0.001208 0.000842 Hs.133397 0.000355 0.000107 Hs.1342-CO0.000512 0.000286 Hs.143436 0.000318 0.000805 Hs.145384 0.000898 0.000362 Hs.148559 0.001245 0.000717 Hs.1498-H 0.000176 0.000516 Hs.15250-P 0.000917 0.000533 Hs.1600-CC0.000573 0.000299 Hs.170622 0.0012 0.002301 Hs.171280 0.000323 0.000154 Hs.180346 0.000497 0.000212 Hs.180946 0.000338 0.000264 Hs.184233 0.002456 0.00142 Hs.19383-A 0.000195 0.000531 Hs.2006-G 0.000298 0.000111 Hs.203717 0.000793 0.001376 Hs.213394 0.000317 0.000155 Hs.22242-E 0.000635 0.000361 Hs.237658 0.000321 0.000927 Hs.252549 0.000221 0.000118 Hs.2533-AL 0.000789 0.000564 Hs.255093 0.00083 0.000483 Hs.259559 0.000493 0.000176 Hs.268488 0.000348 0.000141 Hs.269944 0.000199 0.0001 Hs.282975 0.000579 0.000314 Hs.288959 0.001331 0.000554 Hs.289271 0.000654 0.000314 Hs.290404 0.000849 0.00041 Hs.293970 0.00447 0.001553 Hs.295917 0.001203 0.000713 Hs.300774 0.001524 0.002886 Hs.30345-T 0.000302 0.000134 Hs.333786 0.000131 0.000211 Hs.334707 0.007334 0.002893 Hs.337295 0.000626 0.000322 Hs.3439-ST 0.000435 0.00018 Hs.34494-A 0.00058 0.000316 Hs.350265 0.000548 0.00025 Hs.356624 0.001034 0.001434 Hs.36473-P 0.000819 0.000461 Hs.368084 0.001186 0.000436 Hs.368525 0.00018 0.000357 Hs.368912 0.000399 0.000192 Hs.370024 0.000292 0.000156 Hs.371723 0.000394 0.000145 Hs.371889 0.002454 0.001433 Hs.380774 0.000315 0.000195 Hs.381167 0.000185 0.000385 Hs.396783 0.001468 0.000471 Hs.401903 0.001256 0.000659 Hs.406678 0.000917 0.000378 Hs.406861 0.00079 0.000422 Hs.415067 0.000363 0.000571 Hs.415846 0.000518 0.000227 Hs.418167 0.053408 0.078113 Hs.424932 0.001982 0.001063 Hs.426485 0.0022 0.002649 Hs.427202 0.003351 0.00826 Hs.429879 0.00179 0.000753 Hs.432648 0.001067 0.00049 Hs.433512 0.000374 0.000752 Hs.434435 0.001808 0.000692 Hs.435369 0.000193 0.001482 Hs.437178 0.001845 0.001085 Hs.439152 0.000579 0.000337 Hs.440475 0.001484 0.00077 Hs.440544 0.000724 0.000383 Hs.444751 0.001458 0.000565 Hs.445358 0.002086 0.003156 Hs.446628 0.000267 0.000452 Hs.460260 0.000835 0.000399 Hs.465221 0.000779 0.000317 Hs.465413 0.000425 0.000255 Hs.465929 0.000369 0.000807 Hs.471207 0.001334 0.000534 Hs.474783 0.00063 0.000366 Hs.481571 0.000605 0.000171 Hs.481980 0.000826 0.000364 Hs.483239 0.001184 0.000695 Hs.483305 0.000292 0.000493 Hs.488181 0.001494 0.00086 Hs.489142 0.000261 0.000631 Hs.489190 0.000686 0.000314 Hs.491351 0.003148 0.001718 Hs.494496 0.001898 0.001236 Hs.500409 0.004076 0.001196 Hs.50223-R 0.002028 0.013602 Hs.502302 0.001659 0.001272 Hs.507076 0.000361 0.000191 Hs.508343 0.000529 0.000271 Hs.509414 0.000312 0.000216 Hs.509736 0.002142 0.001102 Hs.513490 0.001946 0.007411 Hs.513660 0.001399 0.000655 Hs.513987 0.001317 0.000628 Hs.514303 0.000324 0.000221 Hs.516032 0.003657 0.001545 Hs.518267 0.006539 0.007724 Hs.520898 0.001512 0.000639 Hs.520967 0.002429 0.001363 Hs.522373 0.001533 0.002156 Hs.524630 0.000334 0.000132 Hs.525459 0.00058 0.000269 Hs.525557 0.006206 0.009982 Hs.529053 0.003815 0.006337 Hs.529989 0.000348 0.000194 Hs.530331 0.000601 0.000286 Hs.533050 0.000395 0.000203 Hs.534797 0.001177 0.000408 Hs.544577 0.00907 0.014546 Hs.546239 0.000758 0.000969 Hs.546303 0.000374 0.000181 Hs.555866 0.000421 0.000251 Hs.556077 0.000368 0.000869 Hs.567297 0.000676 0.000234 Hs.567311 0.000568 0.003158 Hs.572518 0.000558 0.000208 Hs.591069 0.000438 0.000225 Hs.591940 0.001554 0.002268 Hs.592490 0.001463 0.000769 Hs.592601 0.001079 0.000506 Hs.595071 0.0011 0.000784 Hs.596461 0.002412 0.001339 Hs.605502 0.002201 0.001428 Hs.631602 0.000352 0.000141 Hs.632034 0.000207 0.000146 Hs.632133 0.000369 0.000215 Hs.632733 0.003238 0.001829 Hs.633853 0.000463 0.000172 Hs.642813 0.009767 0.012309 Hs.643610 0.004687 0.002676 Hs.644953 0.000537 0.000273 Hs.647097 0.000384 0.000165 Hs.653685 0.000131 9.42E-05 Hs.654435 0.001465 0.000906 Hs.654443 0.000461 0.000936 Hs.654553 0.000471 0.000168 Hs.654559 0.000262 0.000559 Hs.654614 0.000682 0.000367 Hs.654957 0.000703 0.000356 Hs.655196 0.001639 0.002106 Hs.655250 0.001834 0.000683 Hs.655519 0.000131 0.000508 Hs.657401 0.002205 0.000766 Hs.661916 0.001383 0.000628 Hs.663430 0.001199 0.000547 Hs.664670 0.000431 0.000273 Hs.665191 0.000153 0.000245 Hs.676772 0.002832 0.001621 Hs.68714-S 0.000185 0.000114 Hs.695946 0.000503 0.0003 Hs.695950 0.000185 0.00014 Hs.696029 0.000399 0.000172 Hs.6980-AK 0.000868 0.000268 Hs.699181 0.000354 0.000157 Hs.699190 0.000609 0.000866 Hs.699191 0.001479 0.000885 Hs.699250 0.000511 0.001226 Hs.700567 0.004836 0.002602 Hs.700643 0.001002 0.000362 Hs.700749 0.002848 0.001167 Hs.73875-F 0.000466 0.000256 Hs.74405-Y 0.000272 0.000949 Hs.75160-P 0.000199 0.000432 Hs.75318-T 0.003368 0.002601 Hs.75335-G 0.005112 0.00217 Hs.75438-Q 0.000251 0.000119 Hs.76394-E 0.002823 0.001864 Hs.78183-A 0.000995 0.0005 Hs.78989-A 0.000568 0.000329 Hs.79322-Q 0.000292 0.000167 Hs.79387-P 0.000312 0.000133 Hs.80741-P 0.001039 0.000757 Hs.81934-A 0.000957 0.000331 Hs.88778-C 0.000995 0.000799 Hs.89890-P 0.0021 0.000663 Hs.95990-P 0.00101 0.00023 IPI0000153 0.007824 0.002908 IPI0017952 0.000856 0.0004 IPI0030571 0.001824 0.000679 IPI0041372 0.005216 0.003503 IPI0042654 0.0015 0.000683 IPI0045196 0.000868 0.000347 IPI0045347 0.000932 0.001196 IPI0055099 0.000607 0.001435 IPI0064477 0.003823 0.0012 IPI0071908 0.003354 0.006244 IPI0073979 0.0036 0.001283 Hs.153961 0.000447 0.000256 Hs.172928 0.000311 0.000536 Hs.178551 0.000223 0.000139 Hs.183109 0.000557 0.000253 Hs.2795-LD 0.001247 0.002285 Hs.28988-G 0.001579 0.000889 Hs.298280 0.012023 0.006037 Hs.407966 0.000463 0.000233 Hs.437156 0.000389 0.000812 Hs.437191 0.000214 0.000426 Hs.47649-M 0.000497 0.000293 Hs.494173 0.000934 0.001662 Hs.520048 0.000194 0.000302 Hs.546271 0.000183 0.000264 Hs.567583 0.000638 0.000312 Hs.594673 0.000724 0.001281 Hs.620557 0.000154 7.78E-05 Hs.631618 0.001824 0.001133 Hs.651231 0.002364 0.00362 Hs.655010 0.000402 0.000177 Hs.75841-E 0.000699 0.000398 Hs.8360-C 0.000709 0.001246 Hs.89643-T 0.001045 0.000662 IPI0002463 0.000135 0.000208 IPI0016872 0.003869 0.002462 IPI0039813 0.000314 0.000186 Hs.108080 0.000579 0.001184 Hs.11729-S 0.000623 0.000245 Hs.12068-C 0.000207 0.000121 Hs.210995 0.000292 0.000177 Hs.233240 0.009738 0.015039 Hs.307734 0.000526 0.000177 Hs.324746 0.000927 0.002023 Hs.363396 0.000569 0.001138 Hs.370703 0.00049 0.000209 Hs.381099 0.000699 0.001401 Hs.445040 0.001713 0.000511 Hs.464137 0.000855 0.000231 Hs.488189 0.000851 0.00211 Hs.493362 0.000255 0.000114 Hs.500756 0.001225 0.00091 Hs.502528 0.000779 0.000239 Hs.522555 0.000153 8.02E-05 Hs.558314 0.001357 0.002242 Hs.592048 0.001556 0.000942 Hs.595809 0.00058 0.000194 Hs.604789 0.000999 0.000468 Hs.644646 0.000207 0.000138 Hs.654447 0.001577 0.002153 Hs.654473 0.000702 0.000444 Hs.654595 0.000902 0.000344 Hs.655653 0.001316 0.000369 Hs.694881 0.000545 0.000312 Hs.699182 0.000639 0.000327 Hs.77448-A 0.003592 0.001707 uniq b0 ID Hs.520026-VARS IPI00003438 Hs.50382-TJP2 IPI00003933 Hs.23262-RNASE6 Hs.283749-ANG Hs.50727-NAGLU Hs.368805-HAAO Hs.368855-GMPR2 Hs.7739-HDHD3 Hs.380135-FABP1 IPI00010397 Hs.406515-NQO1 Hs.581614-MRPS22 Hs.5158-ILK Hs.654543-TUBB2A Hs.465849-PIN1 Hs.208765-GPHN Hs.256034-L2HGDH Hs.118725-SEPHS2 Hs.211929-TXN2 Hs.606807 Hs.699361-AGK Hs.728-RNASE2 Hs.696154 Hs.515104-LOC554363;STXBP2 Hs.699233 Hs.631971-MRPS36 Hs.632704-TSFM Hs.189716 Hs.584881-C3orf28 Hs.76152-AQP1 Hs.695948 Hs.516700-CYP27A1 Hs.248174-HIST1H2AB Hs.69745-FDXR Hs.471441-PSMB2 Hs.370895-RPN2 Hs.98791-ACTR1B Hs.204041-AHSA1 Hs.19904-CTH Hs.71040-AP1M1 Hs.406739-HIST1H2AA Hs.657617-LYPLAL1 Hs.8360-C11orf54 Hs.546407-CAND1 Hs.518355-GFM1 Hs.461727-ACSF3 Hs.105685-LRRC24;MGC70857 Hs.535639-D2HGDH Hs.647045-ABHD11 Hs.459779-DNAJA3 Hs.128316-BAIAP2 Hs.126550-VPS4B Hs.296422-COASY Hs.701937 Hs.654438-ANK1 Hs.417303-SPTB Hs.528300-PITRM1 Hs.498732-PHYH Hs.699746 Hs.365286-FAM21A Hs.350899-CAPN2 Hs.18069-LGMN Hs.410388-LACTB Hs.436062-GBE1 IPI00299026 Hs.114412-TXNL1 Hs.508716-COL4A2 Hs.696180 Hs.546387-FAHD2A;FAHD2B Hs.659311-CBR4 Hs.128420-VPS4A Hs.24763-RANBP1 Hs.590956-TIMM50 Hs.274416-NDUFA6 IPI00419307 Hs.513632-COQ9 Hs.334832-CYB5R1 Hs.696394-HSP90AB1 Hs.516402 Hs.193491-TUBB6 Hs.137400-TUBA8 Hs.580547-A26C1A Hs.558782-LOC653269 Hs.595053-HSPD1 uniq b1 ID Hs.643130-PAWR Hs.461787-NENF Hs.2178-HIST2H2BE Hs.132513-HSD17B12;LOC390110 Hs.181368-PRPF8 Hs.632034-PDLIM2 Hs.476092-CLEC3B IPI00010951 Hs.26915-SPTBN2 Hs.627414-RP5-1033B10.18;RPS18 Hs.434248-PLEC1 Hs.137594-HIST1H2BL Hs.490415-ZYX Hs.407580-PKP4 Hs.659985-XYLB IPI00021157 Hs.699367 Hs.429180-EIF2S2 Hs.645283-RTN4 Hs.437422-EPB41L1 Hs.480042-ANXA3 Hs.388654-ATP6V1G1 Hs.83190-FASN Hs.655995-FHIT Hs.523215-NDUFB8 Hs.77897-SF3A3 Hs.466165-PGLS Hs.59486-HSDL2 Hs.156738-AASS Hs.144468-CHID1 Hs.568075-DHTKD1 Hs.655728-ACMSD IPI00140827 Hs.662342-AKR7A3 Hs.190384-COPS4 Hs.655653-DMGDH Hs.143873-S100A10 Hs.131555-ENTPD5 IPI00216134 Hs.133892-TPM1 Hs.103502-GPT Hs.248133-HIST1H1E Hs.593620-SPAG9 Hs.654433-ADH1C Hs.36992-ATP4A Hs.610975-TLN2 Hs.519909-MARCKS Hs.534453-NDUFA13 Hs.632015-ASL Hs.119825-SPTA1 Hs.699408-CLINT1 Hs.586161-ADH6 Hs.192233-PPL Hs.148989-CGNL1 Hs.309849-C14orf159 Hs.499725-ANK3 Hs.700676 Hs.567380-FUBP1 Hs.700635 Hs.148340-RPL10A Hs.436338-LOC554235 IPI00429358 IPI00430820 Hs.8752-CNPY2 Hs.9857-DCXR IPI00448800 Hs.333427-NDUFA7 Hs.493164-NAPRT1 Hs.282417-PYGL Hs.654634-CDC42BPB Hs.127011-TINAG Hs.149387-MYO6 Hs.486589-HEBP2 uniq b23 ID Hs.473788-OTUB1 Hs.180062-PSMB8 Hs.509343-FERMT2 Hs.674833 Hs.193725-PSMD5 Hs.3745-MFGE8 Hs.50889-MYLPF Hs.631827-ANXA7 Hs.530904-CSRP2 Hs.467306-ISOC2 Hs.431850-MAPK1 Hs.151787-EFTUD2 Hs.7486-ETHE1 Hs.198241-AOC3 Hs.497589-PIGR Hs.592205-CRKL Hs.591897-NIPSNAP3A Hs.654907-RARS Hs.288487-SMS Hs.489284-ARPC1B Hs.524741-ARPC3 Hs.75117-ILF2 Hs.67201-NT5C Hs.26530-SDPR Hs.534457-C14orf166 Hs.416073-S100A8 Hs.513954-HDGFRP3 Hs.510334-SERPINA5 Hs.458272-MPO Hs.124490-ACIN1 IPI00007634 Hs.529495-DYNC1LI1 IPI00007856 Hs.436564-PREP Hs.643267-RAD23A Hs.483408-PPP2CA Hs.149387-MYO6 Hs.699176 Hs.525419-LIMA1 Hs.126938-NAPA Hs.133135-UTRN Hs.278839-C20orf77 Hs.26010-PFKP Hs.695930-VCAN Hs.374477-EWSR1 Hs.99936-KRT10 Hs.654848-EIF6 Hs.406300-RPL23;SNORA21 Hs.558865-CES1 Hs.517601-RAC2 Hs.570065-COL4A3 Hs.699163-ME2 Hs.528222-NDUFS4 Hs.546286-RPS3;SNORD15B Hs.527105-BMX;HNRPDL Hs.436123-SULT1C2 Hs.50098-NDUFA4 IPI00011891 Hs.83383-PRDX4 Hs.512676-RPS25 Hs.699274-HNRPUL1 Hs.656176-TMEM137 Hs.446429-PTGDS Hs.56729-LSP1 IPI00013769 Hs.699337-HNRPH3 Hs.300772-TPM2 Hs.3100-KARS Hs.435765-ENPEP Hs.517216-PEA15 Hs.307835-PGM5 Hs.505676-DNAJC14 Hs.50425-PTGES3 Hs.80691-CKMT2 Hs.651923-CNN2 Hs.97887-RCN1 Hs.351875-COX6C Hs.486470-EPB41L2 Hs.644809-RAB7A Hs.643072-RAB10 Hs.479808-IGFBP7 Hs.567328-RAB5B Hs.498143-TBCE Hs.489615-PBEF1 Hs.607144-PARVA Hs.647064-RARRES2 Hs.435255-UBXD1 Hs.654569-KRT9 Hs.444319-TPMT Hs.1321-F12 Hs.83634-HCFC1 Hs.695957-DEK Hs.402752-TAF15 Hs.655278-FER1L3 Hs.632540-PRKRA Hs.707-KRT2 Hs.368808-EHD3 Hs.347270-HLA-DPA1 Hs.1012-C4BPA Hs.280342-PRKAR1A Hs.24557-RAB11FIP5 Hs.533017-SEPT8 Hs.632729-FAM62A Hs.247700-FOXP3 Hs.526464-PML Hs.507080-APCS Hs.505059-PIPSL;PSMD4 Hs.296049-MFAP4 Hs.246506-SLC25A4 Hs.333388-EEF1D Hs.533040-PDLIM7 Hs.644024-MLLT4 Hs.146406-NIT1 Hs.695185-NAP1L1 Hs.191734-MGST3 Hs.301404-RBM3 Hs.418668-ATP5D Hs.12341-ADAR Hs.129673-EIF4A1 Hs.458747-ANP32A IPI00025880 Hs.14601-HCLS1 Hs.432760-CAPZB IPI00026197 Hs.465295-LMAN1 Hs.654404-HLA-B Hs.696282 Hs.162877-ARFGAP3;RPL5 Hs.435228-SYNPO Hs.658289-RHOC Hs.179986-FLOT1 Hs.112405-S100A9 Hs.275243-S100A6 Hs.334347-CKM Hs.657976-RHOA Hs.604479-HEXA Hs.74137-TMED10;TMED10P Hs.421724-CTSG Hs.658434-PSIP1 Hs.591450-GBP2;GBP7 Hs.274313-IGFBP6 Hs.163867-CD14 Hs.79088-RCN2 Hs.528952-TRIM25 Hs.76224-EFEMP1 Hs.12102-SNX3 Hs.159509-SERPINF2 Hs.42151-HNMT IPI00030205 Hs.699271 Hs.513984-FLII Hs.528007-U2AF2 IPI00032064 Hs.654432-ACTN3 Hs.104879-SERPINB9 Hs.654444-S100A4 Hs.77741-KNG1 Hs.302903-UBE2I Hs.36587-PPP1R7 Hs.520070-CUTA Hs.693617-KCTD12 Hs.521924-PUF60 Hs.436687-SET IPI00074489 Hs.436500-DBNL IPI00102821 Hs.655396-PSMD11 Hs.303116-SDF2L1 Hs.642618-HEBP1 Hs.567482-ACAD9 Hs.297814-ENPP6 Hs.491242-PEBP4 Hs.369168-SCFD1 Hs.699620-ALDH1A2 Hs.165195 Hs.279696-SUMF2 Hs.421608-EEF1B2;hCG_1983058 Hs.700610-IGJ Hs.49582-PPP1R12A Hs.527295-ENPP1 Hs.193163-BIN1 Hs.496984-MPP1 Hs.70327-CRIP1 Hs.77741-KNG1 Hs.157351-OLA1 Hs.496666-SEPT6 Hs.529353-ACSS1 Hs.82129-CA3 Hs.77269-GNAI2 Hs.412707-HPRT1 Hs.527193-RPS23 Hs.28914-APRT Hs.36927-HSPH1 Hs.279837-GSTM1;GSTM2 Hs.1869-PGM1 Hs.145442-MAP2K1 Hs.523836-GSTP1 Hs.122785-MGAM Hs.504687-MYL9 Hs.433750-EIF4G1 Hs.531176-SARS Hs.514819-AP2B1 Hs.370504-RPS15A Hs.397609-RPS16 Hs.433427-RPS17 Hs.229641-SUB1 Hs.556600-MYLK Hs.101302-COL12A1 IPI00239405 Hs.512815-AP3D1 Hs.529059-EIF3G Hs.464572-NDUFV2 Hs.350927-SLC25A6 Hs.312485-CFI Hs.420257-ITIH1 Hs.592212-ECGF1 Hs.431400-RAI14 Hs.31053-TBCB Hs.391835-C8B Hs.504895-STRAP Hs.655583-PAPLN Hs.580681-SAMHD1 Hs.622998-ASPH Hs.409034-COL15A1 Hs.162121-COPA Hs.164226-THBS1 Hs.640064-LOC442122 Hs.593123-FBLN1 Hs.78065-C7 Hs.523145-DDOST Hs.148641-CTSH Hs.335513-F13A1 Hs.695351 Hs.33642-ARCN1 IPI00298860 Hs.181301-CTSS Hs.204238-LCN2 Hs.3887-PSMD1 Hs.513484-QPRT;SPN Hs.514435-SF3B3 Hs.515469 Hs.233389-CPVL Hs.126941-FAM49B Hs.699781-RBMX Hs.433951-GPX4 Hs.655202-GNA11 Hs.591600-ROCK2 Hs.211426-THBS4 Hs.159628-SERPINA4 Hs.654572-LAMA4 Hs.438236-ABLIM1 Hs.498397-SCCPDH IPI00332493 Hs.124126-ARPC1A Hs.248746-HNRPAB Hs.467142-MYH14 Hs.656870-SLC25A24 Hs.439620-MYO1B IPI00376429 Hs.388664-RPL11 Hs.535581-TPM3 Hs.151220-PALLD Hs.591572-PCYOX1 Hs.288981-NUBPL Hs.418167-ALB Hs.371001-EIF3B Hs.513530-TGFB1I1 Hs.443687-FHL2 IPI00397701 IPI00398435 Hs.530892-LOC387867;LOC388707;LOC389141;LOC644464;LOC653162 Hs.664318-POSTN Hs.493164-NAPRT1 Hs.651219-NDUFA5 Hs.485518-CD2AP Hs.374588-RPL17;hCG_39912 IPI00414283 IPI00423463 Hs.136905-HUWE1 IPI00465032 Hs.132854-HIST1H3I Hs.410817-RPL13 Hs.306769-RUFY1 Hs.654404-HLA-B Hs.654404-HLA-B Hs.654404-HLA-B Hs.654404-HLA-B IPI00472610 Hs.499725-ANK3 IPI00477090 Hs.655361-HPR IPI00478540 IPI00480016 Hs.518609-ARPC5 Hs.436439-TWF2 Hs.514174-JUP Hs.696144 Hs.406013-KRT18;PCDH11X;PCDH11Y Hs.323342-TTLL3 Hs.446522-IGL@;IGLC1;IGLJ3;IGLV2-14;IGLV3-21;IGLV3-25;IGLV4-3;IGLV@;IL8;LOC96610;NTN2L;RPL14 Hs.418497-GC IPI00556589 Hs.370581-CAP1 Hs.69771-CFB IPI00642032 IPI00645363 IPI00645452 IPI00719373 IPI00738024 Hs.654406 IPI00742127 Hs.546292-RPS27A Hs.286226-MYO1C Hs.406238-AOX1 Hs.497599-WARS Hs.438678-TALDO1 Hs.529161-A1BG;ZNF497 Hs.94107-GSTA2;GSTA5 Hs.654406 IPI00747752 Hs.695991-SFRP1 Hs.529053-C3 Hs.471014-TLN1 Hs.440932-SEPT9 IPI00784985 IPI00785200 IPI00790207 IPI00792115 IPI00792850 Hs.422986-ANXA4 IPI00795980 IPI00796708 IPI00807413 Hs.155742 1 Hs.212088 1 Hs.3192 1 Hs.359698 1 Hs.433615 1 Hs.435012 1 Hs.438289 1 Hs.486520 1 Hs.495219 1 Hs.643451 1 Hs.293970 0.999997909 Hs.290404 0.999990167 Hs.494173 0.999988992 Hs.47649 0.999964544 Hs.520898 0.999854377 Hs.50727 0.999716504 Hs.470907 0.999681096 Hs.654473 0.996592189 Hs.126688 0.995396056 Hs.444751 0.990084497 Hs.424932 0.983576538 Hs.695946 0.982643772 Hs.430606 0.976052089 Hs.128316 0.97577942 Hs.81934 0.971933422 Hs.558314 0.969092004 Hs.429879 0.957391139 Hs.232375 0.953003067 Hs.513987 0.952985912 Hs.246506 0.946350745 Hs.390667 0.944452581 Hs.75812 0.939736308 Hs.446628 0.923506018 Hs.350265 0.922216125 Hs.513632 0.917557011 Hs.114172 0.89107015 Hs.7739 0.889233598 Hs.433427 0.865964795 Hs.567297 0.846549277 Hs.421724 0.846440618 Hs.520974 0.845141597 Hs.518267 0.831695668 Hs.288959 0.825057181 Hs.396783 0.808177129 Hs.70327 0.80294873 Hs.592601 0.791891264 Hs.30345 0.779787854 Hs.655250 0.778000633 Hs.211929 0.775113596 Hs.654682 0.749115017 Hs.546387 0.709563616 Hs.654434 0.697086282 Hs.655653 0.66211253 Hs.695930 0.659210949 Hs.229641 0.655162142 Hs.289271 0.649803736 Hs.3745 0.63045207 Hs.878 0.60925296 Hs.371723 0.60036899 Hs.76224 0.596927783 Hs.631742 0.556044276 Hs.459779 0.521676623 Hs.144114 0.52056611 Hs.75335 0.479485082 Hs.433512 0.443963635 Hs.104879 0.439426209 Hs.517216 0.422671674 Hs.654595 0.42253385 Hs.647045 0.41580165 Hs.89649 0.376440816 Hs.126265 0.374664729 Hs.133892 0.362050258 Hs.659311 0.35711065 Hs.656870 0.333533676 Hs.131555 0.305589621 Hs.307734 0.303878716 Hs.526464 0.302108876 Hs.655728 0.294326685 Hs.479808 0.269429313 Hs.213394 0.267680331 Hs.148989 0.229000356 Hs.481980 0.207945848 Hs.654433 0.116605499 Hs.203717 0.049858946 Hs.116448 0.033631884 Hs.654422 0.028919801 Hs.350927 0.016774125 Hs.8360 0.00302717 Hs.529353 -0.028919925 Hs.356624 -0.07387511 Hs.434435 -0.081183847 Hs.370703 -0.163401827 Hs.280342 -0.185189036 Hs.435255 -0.20801431 Hs.73875 -0.282500195 Hs.528007 -0.286990257 Hs.23118 -0.299120072 Hs.295917 -0.302638984 Hs.75438 -0.316689278 Hs.415846 -0.323530756 Hs.6980 -0.325110391 Hs.36473 -0.341892062 Hs.76394 -0.352106003 Hs.309849 -0.364582202 Hs.10136 -0.370480596 Hs.77448 -0.396876624 Hs.467306 -0.399849672 Hs.529495 -0.401178711 Hs.643610 -0.414244701 Hs.282975 -0.475502094 Hs.513660 -0.497077748 Hs.184233 -0.49857017 Hs.556600 -0.562658731 Hs.371889 -0.592153387 Hs.95990 -0.611151802 Hs.620557 -0.632987653 Hs.530331 -0.635692882 Hs.651219 -0.638842495 Hs.544577 -0.64076839 Hs.445358 -0.650116344 Hs.248746 -0.671383861 Hs.136905 -0.681123234 Hs.500756 -0.69759479 Hs.24557 -0.719865707 Hs.440475 -0.737941442 Hs.488181 -0.770480122 Hs.525459 -0.792359562 Hs.496984 -0.800197295 Hs.436123 -0.813713108 Hs.146406 -0.829350482 Hs.546239 -0.842484056 Hs.15250 -0.843216826 Hs.433750 -0.85150805 Hs.435765 -0.864687632 Hs.162121 -0.866534581 Hs.124490 -0.872077253 Hs.210995 -0.875289234 Hs.278839 -0.88889886 Hs.119251 -0.899843245 Hs.255093 -0.925842954 Hs.527295 -0.931924926 Hs.499725 -0.944072672 Hs.193163 -0.970691919 Hs.514303 -0.971466568 Hs.143436 -0.978041164 Hs.144468 -0.98433832 Hs.75841 -0.987748796 Hs.19383 -0.989781657 Hs.476448 -0.994634359 Hs.193491 -0.995248603 Hs.122785 -0.999647011 Hs.309090 -1 Hs.690198 -1 Protein IPI Peptide Sequence Peptide Peptide Target1 Norm. Target2 Norm. Target3 Norm. Avg. Total Ion Charge m/z m/z Abundance m/z Abundance m/z Abundance Abundance Intensity IPI00009480.1 GILEQGWQADSTTR 2 781.84 965 1 1022 1 1150 1 1.00 2459 IPI00009480.1 GILEQGWQADSTTR 2 781.84 965 1 1022 1 1150 1 1.00 6792 IPI00009480.1 KPVAGALDVSFNK 2 673.79 709 1 822 1 894 0 0.67 2062.3 IPI00009480.1 KPVAGALDVSFNK 2 673.79 709 1 822 1 894 1 1.00 7403 IPI00009480.1 SANSELGGIWSVGQR 2 781.35 846 1 903 1 960 1 1.00 5847.1 IPI00009480.1 SANSELGGIWSVGQR 2 781.35 846 1 903 1 960 1 1.00 4064.7 IPI00010244.4 FSIYPPIPGEESSLR 2 846.96 874 1 988 1 1085 1 1.00 1869.6 IPI00010244.4 FSIYPPIPGEESSLR 2 846.96 874 1 988 0 1085 1 0.67 3957.2 IPI00010244.4 GTGIAAQTAGIAAAAR 2 700.79 802 1 930 1 1001 1 1.00 3951.6 IPI00010244.4 GTGIAAQTAGIAAAAR 2 700.79 802 1 930 1 1001 1 1.00 8814.6 IPI00018768.1 GFHLDVEDYLSGVLILASELSR 2 1217.88 1101 1 1158 0 1245 1 0.67 536.3 IPI00018768.1 GFHLDVEDYLSGVLILASELSR 2 1217.88 1101 1 1158 0 1245 1 0.67 1487.9 IPI00019345.1 INVNEIFYDLVR 2 748.36 812 1 926 1 1055 0 0.67 6162.3 IPI00019345.1 INVNEIFYDLVR 2 748.36 812 1 926 1 1055 1 1.00 34143.6 IPI00019345.1 LVVLGSGGVGK 2 493.6 504 1 561 1 674 1 1.00 8652.1 IPI00019345.1 LVVLGSGGVGK 2 493.6 504 1 561 1 674 1 1.00 2054.9 IPI00019345.1 SALTVQFVQGIFVEK 2 833.98 920 1 1067 1 1195 1 1.00 4499.2 IPI00019345.1 SALTVQFVQGIFVEK 2 833.98 920 1 1067 1 1195 1 1.00 10736.3 IPI00019345.1 YDPTIEDSYR 2 630.16 669 1 782 1 883 1 1.00 1448.5 IPI00019345.1 YDPTIEDSYR 2 630.16 669 1 782 1 883 1 1.00 7522.3 IPI00019385.3 FFDEESYSLLR 2 703.77 738 1 868 1 997 1 1.00 12081.7 IPI00019385.3 FFDEESYSLLR 2 703.77 738 1 868 1 997 0 0.67 9919.2 IPI00019385.3 NNEDISIIPPLFTVSVDHR 2 1084.22 1171 1 1268 1 1381 1 1.00 619.8 IPI00019385.3 NNEDISIIPPLFTVSVDHR 2 1084.22 1171 1 1268 1 1381 1 1.00 989.3 IPI00019385.3 SAHAGTYEVR 2 546.09 566 1 667 1 724 1 1.00 1426.4 IPI00019385.3 SAHAGTYEVR 2 546.09 566 1 667 1 724 1 1.00 5752.1 IPI00022421.2 LTSDSTVYDYAGK 2 710.76 716 1 815 1 916 1 1.00 28893.2 IPI00022421.2 LTSDSTVYDYAGK 2 710.76 716 1 815 1 916 1 1.00 28626.5 IPI00023004.6 EDGQEYAQVIK 2 640.69 721 1 851 1 979 1 1.00 2266 IPI00023004.6 EDGQEYAQVIK 2 640.69 721 1 851 1 979 1 1.00 2026.2 IPI00023004.6 VWINTSDIILVGLR 2 800.46 899 1 986 1 1087 1 1.00 1289 IPI00023004.6 VWINTSDIILVGLR 2 800.46 899 1 986 1 1087 1 1.00 6003.8 IPI00175096.1 AGVAFFHLQDYDQAR 2 869.95 895 1 1009 1 1146 0 0.67 528.2 IPI00175096.1 AGVAFFHLQDYDQAR 2 869.95 895 1 1009 1 1146 1 1.00 2242.5 IPI00175096.1 YLQLTQSELSSYHR 2 863.45 891 1 979 1 1107 1 1.00 9110.4 IPI00175096.1 YLQLTQSELSSYHR 2 863.45 891 1 979 1 1107 1 1.00 7609.2 IPI00182293.5 ATDLRPIYISVQPPSLHVLEQR 3 845.32 1176 1 1304 0 1403 1 0.67 1238.4 IPI00182293.5 ATDLRPIYISVQPPSLHVLEQR 3 845.32 1176 1 1304 1 1403 1 1.00 714.4 IPI00182293.5 LLQEHSGIFGFSVSHTTR 2 1009.13 1139 1 1252 0 1309 1 0.67 425.5 IPI00182293.5 LLQEHSGIFGFSVSHTTR 2 1009.13 1139 1 1252 1 1309 1 1.00 2429.9 IPI00294193.4 AGFSWIEVTFK 2 643.25 736 1 923 1 1010 1 1.00 5077.7 IPI00294193.4 AGFSWIEVTFK 2 643.25 736 1 923 1 1010 1 1.00 8730.1 IPI00294193.4 FAHTVVTSR 2 509.58 561 1 662 1 799 1 1.00 1955 IPI00294193.4 FAHTVVTSR 2 509.58 561 1 662 1 799 1 1.00 3245.7 IPI00294193.4 GPDVLTATVSGK 2 573.15 663 1 777 1 876 1 1.00 14313.9 IPI00294193.4 GPDVLTATVSGK 2 573.15 663 1 777 1 876 1 1.00 2028.7 IPI00294193.4 ITFELVYEELLK 2 749.39 794 1 894 1 1007 1 1.00 48878.1 IPI00294193.4 ITFELVYEELLK 2 749.39 794 1 894 1 1007 1 1.00 19112.3 IPI00294193.4 LGVYELLLK 2 524.66 615 1 779 1 878 1 1.00 1902.2 IPI00294193.4 LGVYELLLK 2 524.66 615 1 779 1 878 1 1.00 6612.3 IPI00294193.4 LWAYLTIQQLLEQTVSASDADQQ 3 988.44 1162 1 1261 1 1362 1 1.00 1494.6 IPI00294193.4 LWAYLTIQQLLEQTVSASDADQQ 3 988.44 1162 1 1261 1 1362 1 1.00 2843.7 IPI00294193.4 NGIDIYSLTVDSR 2 727.3 777 1 941 1 1054 1 1.00 3819.9 IPI00294193.4 NGIDIYSLTVDSR 2 727.3 777 1 941 1 1054 1 1.00 3739.3 IPI00294193.4 NVHSGSTFFK 2 562.62 629 1 686 1 773 1 1.00 7797.9 IPI00294193.4 NVHSGSTFFK 2 562.62 629 1 686 1 773 1 1.00 5773.5 IPI00294193.4 NVVFVIDK 1 934.12 474 1 621 1 720 1 1.00 15844.3 IPI00294193.4 NVVFVIDK 1 934.12 474 1 621 1 720 1 1.00 25866.1 IPI00294193.4 SPEQQETVLDGNLIIR 2 907.01 914 1 1013 0 1114 1 0.67 1017.2 IPI00294193.4 SPEQQETVLDGNLIIR 2 907.01 914 1 1013 1 1114 1 1.00 4643.8 IPI00383531.1 ESALEPGPVPEAPAGGPVHAVTV 2 1433.65 1210 1 1309 1 1406 1 1.00 1334.3 IPI00383531.1 ESALEPGPVPEAPAGGPVHAVTV 2 1433.65 1210 1 1309 1 1406 0 0.67 741.2 IPI00383531.1 SHDTTSNTLAQLLAK 2 800.89 858 1 972 1 1059 1 1.00 4388.9 IPI00383531.1 SHDTTSNTLAQLLAK 2 800.89 858 1 972 1 1059 1 1.00 6738.7 IPI00384170.3 DEEEVSPPSALPPGLGSR 2 919.49 955 1 1052 1 1149 1 1.00 2484.8 IPI00384170.3 DEEEVSPPSALPPGLGSR 2 919.49 955 1 1052 1 1149 1 1.00 2736.1 IPI00384170.3 FTITGLPTDAK 2 582.68 644 1 701 1 802 1 1.00 2921.4 IPI00384170.3 FTITGLPTDAK 2 582.68 644 1 701 1 802 1 1.00 8025.2 IPI00384170.3 IAFQYGITDLR 2 649.25 674 1 838 1 966 1 1.00 7797.4 IPI00384170.3 IAFQYGITDLR 2 649.25 674 1 838 1 966 1 1.00 14095.6 IPI00384170.3 IILDGLDADNTVTVIAGNK 2 972.11 1017 1 1132 1 1203 1 1.00 1211.5 IPI00384170.3 IILDGLDADNTVTVIAGNK 2 972.11 1017 1 1132 1 1203 1 1.00 2672.6 IPI00384170.3 ILTPLTDQTVNLGK 2 757.39 759 1 875 1 976 1 1.00 9754.7 IPI00384170.3 ILTPLTDQTVNLGK 2 757.39 759 1 875 1 976 1 1.00 9713.3 IPI00384170.3 QQEEEPQVDVWELLK 2 936.03 1002 1 1130 0 1227 1 0.67 327.7 IPI00384170.3 QQEEEPQVDVWELLK 2 936.03 1002 1 1130 1 1227 1 1.00 1424.2 IPI00384170.3 SGEGQEDAGELDFSGLLK 2 926.98 1022 1 1079 1 1150 0 0.67 1832.6 IPI00384170.3 SGEGQEDAGELDFSGLLK 2 926.98 1022 1 1079 1 1150 1 1.00 3645.5 IPI00384170.3 VGEAVNLVIPFQGKPRPELTWK 2 1240.47 1155 1 1212 1 1340 0 0.67 321.3 IPI00384170.3 VGEAVNLVIPFQGKPRPELTWK 2 1240.47 1155 1 1212 1 1340 1 1.00 1908 IPI00384170.3 VGEDITFIAK 2 547.14 579 1 692 1 808 1 1.00 3439.7 IPI00384170.3 VGEDITFIAK 2 547.14 579 1 692 1 808 1 1.00 65803 IPI00384646.7 LAALTNYLQPQLDWQAR 2 1001.64 1014 1 1142 1 1255 0 0.67 1050.6 IPI00384646.7 LAALTNYLQPQLDWQAR 2 1001.64 1014 1 1142 1 1255 0 0.67 910.9 IPI00397860.3 FLEEHPGGEEVLR 2 756.84 759 1 857 1 994 1 1.00 9614.5 IPI00397860.3 FLEEHPGGEEVLR 2 756.84 759 1 857 1 994 1 1.00 13840.3 IPI00397860.3 STWLILHHK 2 568.18 647 1 761 1 947 1 1.00 20162.7 IPI00397860.3 STWLILHHK 2 568.18 647 1 761 1 947 1 1.00 3800 IPI00397860.3 TFIIGELHPDDRPK 2 819.94 864 1 978 1 1107 1 1.00 3082.3 IPI00397860.3 TFIIGELHPDDRPK 2 819.94 864 1 978 1 1107 1 1.00 3778.5 IPI00397860.3 YYTLEEIQK 2 594.17 646 1 759 1 861 1 1.00 8633.5 IPI00397860.3 YYTLEEIQK 2 594.17 646 1 759 1 861 1 1.00 9109.4 IPI00472130.1 APWIEQEGPEYWDR 2 888.96 922 1 1052 1 1180 1 1.00 3209.5 IPI00472130.1 APWIEQEGPEYWDR 2 888.96 922 1 1052 1 1180 1 1.00 1930.8 IPI00472130.1 FISVGYVDDTQFVR 2 823.92 880 1 980 1 1143 0 0.67 3301.5 IPI00472130.1 FISVGYVDDTQFVR 2 823.92 880 1 980 1 1143 0 0.67 14628.9 IPI00472130.1 WAAVVVPSGEEQR 2 714.8 802 1 901 1 1001 1 1.00 11959.5 IPI00472130.1 WAAVVVPSGEEQR 2 714.8 802 1 901 1 1001 1 1.00 3825.6 IPI00479018.2 DSTGHVGFIFK 2 604.68 611 1 710 1 848 1 1.00 14436.9 IPI00479018.2 DSTGHVGFIFK 2 604.68 611 1 710 1 848 1 1.00 5008.4 IPI00550451.1 AHQVVEDGYEFFAK 2 820.9 861 1 976 1 1106 1 1.00 2488.5 IPI00550451.1 AHQVVEDGYEFFAK 2 820.9 861 1 976 1 1106 1 1.00 13605.2 IPI00550451.1 EIFLSQPILLELEAPLK 2 977.68 1026 1 1139 1 1236 0 0.67 2859.5 IPI00550451.1 EIFLSQPILLELEAPLK 2 977.68 1026 1 1139 1 1236 1 1.00 9290.3 IPI00550451.1 LLEVQGSRPGK 2 592.69 601 1 729 1 829 1 1.00 6698.2 IPI00550451.1 LLEVQGSRPGK 2 592.69 601 1 729 1 829 1 1.00 13816.2 IPI00550451.1 YPENFFLLR 2 600.2 695 1 810 1 939 1 1.00 68291.5 IPI00550451.1 YPENFFLLR 2 600.2 695 1 810 1 939 1 1.00 48200.9 IPI00556276.2 IGSEGQGFLIAVR 2 674.28 719 1 776 1 904 1 1.00 8899.4 IPI00556276.2 IGSEGQGFLIAVR 2 674.28 719 1 776 1 904 1 1.00 19682 IPI00556276.2 VAFDFAAR 2 449.01 464 1 579 1 726 1 1.00 7779.3 IPI00556276.2 VAFDFAAR 2 449.01 464 1 579 1 726 1 1.00 2374.9 IPI00645201.1 ISSLLEEQFQQGK 2 754.35 864 1 994 1 1107 1 1.00 3307.5 IPI00645201.1 ISSLLEEQFQQGK 2 754.35 864 1 994 1 1107 1 1.00 25027.7 IPI00738107.4 GHSGLQPTGFLS 2 601.17 621 1 749 1 863 1 1.00 4287.1 IPI00738107.4 GHSGLQPTGFLS 2 601.17 621 1 749 1 863 1 1.00 10769.4 IPI00738107.4 HNYGVGESFTVQR 2 747.81 866 1 924 1 1023 1 1.00 16842.4 IPI00738107.4 HNYGVGESFTVQR 2 747.81 866 1 924 1 1023 1 1.00 7471 IPI00738107.4 VTVYPSK 1 793.94 494 1 593 1 694 1 1.00 13566.2 IPI00738107.4 VTVYPSK 1 793.94 494 1 593 1 694 1 1.00 16321.4 IPI00787323.1 ASLEAAIADAEQR 2 673.23 689 1 802 1 873 1 1.00 72720.8 IPI00787323.1 ASLEAAIADAEQR 2 673.23 689 1 802 1 873 1 1.00 16146.3 IPI00787323.1 LEGLTDEINFLR 2 710.81 791 1 907 1 1008 1 1.00 144436.5 IPI00787323.1 LEGLTDEINFLR 2 710.81 791 1 907 1 1008 1 1.00 18553.4 IPI00787323.1 LSELEAALQR 2 565.65 687 1 801 1 930 1 1.00 18093.9 IPI00787323.1 LSELEAALQR 2 565.65 687 1 801 1 930 1 1.00 22630.9 IPI00787323.1 LVSESSDILPK 2 594.69 672 1 759 1 889 1 1.00 10911 IPI00787323.1 LVSESSDILPK 2 594.69 672 1 759 1 889 1 1.00 1802.3 IPI00787323.1 QLETLGQEK 1 1046.17 574 1 675 1 804 1 1.00 6660.8 IPI00787323.1 QLETLGQEK 1 1046.17 574 1 675 1 804 1 1.00 15622.8 IPI00787323.1 WSLLQQQK 2 516.1 531 1 644 1 758 0 0.67 3517 IPI00787323.1 WSLLQQQK 2 516.1 531 1 644 1 758 1 1.00 2329.9 IPI00787323.1 YEELQSLAGK 2 569.64 603 1 716 1 846 1 1.00 14632 IPI00787323.1 YEELQSLAGK 2 569.64 603 1 716 1 846 0 0.67 3950.2 IPI00790949.1 GLIVSVGPPR 2 498.11 525 1 612 1 711 0 0.67 1262.2 IPI00790949.1 GLIVSVGPPR 2 498.11 525 1 612 1 711 1 1.00 10716.8 IPI00790949.1 TLPETLDPAEYNISPETR 2 1024.12 1109 1 1180 1 1277 1 1.00 1481.4 IPI00790949.1 TLPETLDPAEYNISPETR 2 1024.12 1109 1 1180 1 1277 0 0.67 1644.6 IPI00793862.1 ALSEALTELGYK 2 648.24 710 1 824 1 895 1 1.00 49441.1 IPI00793862.1 ALSEALTELGYK 2 648.24 710 1 824 1 895 1 1.00 16663.5 IPI00793862.1 DADLWSSHDK 2 587.61 759 1 872 1 988 1 1.00 9498.9 IPI00793862.1 DADLWSSHDK 2 587.61 759 1 872 1 988 1 1.00 4797.3 IPI00793862.1 DSDVEVYNIIK 2 648.22 650 1 750 1 879 1 1.00 20527.1 IPI00793862.1 DSDVEVYNIIK 2 648.22 650 1 750 1 879 1 1.00 6310.4 IPI00793862.1 GIELTLQIQSDTGVR 2 815.92 876 1 1004 0 1117 1 0.67 1438.8 IPI00793862.1 GIELTLQIQSDTGVR 2 815.92 876 1 1004 1 1117 1 1.00 11610.8 IPI00793862.1 IVTGGSDNHLILVDLR 2 862 979 1 1093 1 1208 1 1.00 1732.4 IPI00793862.1 IVTGGSDNHLILVDLR 2 862 979 1 1093 1 1208 1 1.00 1145.2 IPI00793862.1 VGLELIASENFASR 2 753.85 810 1 881 1 995 1 1.00 12786.2 IPI00793862.1 VGLELIASENFASR 2 753.85 810 1 881 1 995 1 1.00 48030.5 Protein IPI Peptide Sequence Peptide Peptide Target1 Norm. Target2 Norm. Target3 Norm. Avg. Total Ion Charge m/z m/z Abundance m/z Abundance m/z Abundance Abundance Intensity IPI00216027.2 VNNSSLIGVGYTQTLRPGVK 2 1052.71 1163 0 1220 1 1319 1 0.66666667 779.7 IPI00216027.2 VNNSSLIGVGYTQTLRPGVK 2 1052.71 1163 1 1220 0 1319 1 0.66666667 1704.2 IPI00298406.3 TFESLVDFSK 2 587.16 595 1 708 1 795 0 0.66666667 660.8 IPI00298406.3 TFESLVDFSK 2 587.16 595 1 708 1 795 1 1 1937.1 IPI00298406.3 TGEGFYK 1 801.87 457 1 514 1 643 1 1 11151.6 IPI00298406.3 TGEGFYK 1 801.87 457 1 514 1 643 1 1 27180.2 IPI00298406.3 TLSTIATSTDAASVVHSTDLVVEAIVENLK 3 1029.49 1114 1 1227 1 1342 1 1 1694.9 IPI00298406.3 TLSTIATSTDAASVVHSTDLVVEAIVENLK 3 1029.49 1114 1 1227 1 1342 0 0.66666667 1035.8 IPI00374975.2 YADLTEDQLPSYESPK 2 928.99 1049 1 1164 1 1293 1 1 5387.8 IPI00374975.2 YADLTEDQLPSYESPK 2 928.99 1049 1 1164 1 1293 1 1 2306.7 IPI00399054.1 DSSTSPGDYVLSVSENSR 2 950.98 991 1 1154 1 1269 0 0.66666667 528.7 IPI00399054.1 DSSTSPGDYVLSVSENSR 2 950.98 991 1 1154 1 1269 1 1 1545.9 IPI00399054.1 IHYLDTTTLIEPVSR 2 880.01 915 1 1016 1 1117 1 1 875.3 IPI00399054.1 IHYLDTTTLIEPVSR 2 880.01 915 1 1016 1 1117 0 0.66666667 1292.5 IPI00399054.1 TALALEVGELVK 2 622.25 644 1 773 1 887 0 0.66666667 14996 IPI00399054.1 TALALEVGELVK 2 622.25 644 1 773 1 887 1 1 11488.6 IPI00418418.4 AIVQVFEGTSGIDAR 2 782.38 905 1 1053 1 1152 0 0.66666667 1555.6 IPI00418418.4 AIVQVFEGTSGIDAR 2 782.38 905 1 1053 1 1152 1 1 3882.2 IPI00418418.4 EGALQDLAPDTAL 1 1314.44 700 1 815 1 944 1 1 4981.5 IPI00418418.4 EGALQDLAPDTAL 1 1314.44 700 1 815 1 944 0 0.66666667 2797.8 IPI00418418.4 IPQAVIDEFYSR 2 719.82 816 1 929 1 1029 1 1 1405.3 IPI00418418.4 IPQAVIDEFYSR 2 719.82 816 1 929 1 1029 1 1 7815.2 IPI00418418.4 SVFESLDLGWK 2 641.23 731 0 818 1 948 1 0.66666667 2285.1 IPI00418418.4 SVFESLDLGWK 2 641.23 731 1 818 0 948 1 0.66666667 11514.3 IPI00465363.2 QVHPDTGISSK 1 1169.28 592 1 707 1 804 1 1 8133.6 IPI00465363.2 QVHPDTGISSK 1 1169.28 592 1 707 1 804 1 1 4884.3 IPI00478493.3 TEGDGVYTLNNEK 2 720.76 881 1 981 1 1038 1 1 1711.2 IPI00478493.3 TEGDGVYTLNNEK 2 720.76 881 1 981 1 1038 1 1 2216.1 IPI00478493.3 VGYVSGWGR 1 981.1 562 1 661 1 824 1 1 6540.4 IPI00478493.3 VGYVSGWGR 1 981.1 562 1 661 1 824 1 1 6677.7 IPI00478493.3 VVLHPNYSQVDIGLIK 2 898.56 973 1 1136 1 1250 0 0.66666667 1133.4 IPI00478493.3 VVLHPNYSQVDIGLIK 2 898.56 973 1 1136 1 1250 1 1 2218.9 IPI00549725.5 ALPFWNEEIVPQIK 2 842.99 956 1 1070 0 1256 1 0.66666667 2027.1 IPI00549725.5 ALPFWNEEIVPQIK 2 842.99 956 1 1070 1 1256 0 0.66666667 1505 IPI00549725.5 HGESAWNLENR 2 657.19 831 1 903 1 990 0 0.66666667 1772.8 IPI00549725.5 HGESAWNLENR 2 657.19 831 1 903 1 990 1 1 2478 IPI00549725.5 HYGGLTGLNK 1 1060.2 532 1 645 1 702 1 1 13637.9 IPI00549725.5 HYGGLTGLNK 1 1060.2 532 1 645 1 702 1 1 8138.8 IPI00553164.3 AIVAIENPADVSVISSR 2 871.5 934 1 1031 1 1145 0 0.66666667 1447.5 IPI00553164.3 AIVAIENPADVSVISSR 2 871.5 934 1 1031 1 1145 1 1 2364.8 IPI00553164.3 FAAATGATPIAGR 2 602.69 614 0 675 1 685 0 0.66666667 1684.4 IPI00553164.3 FAAATGATPIAGR 2 602.69 614 1 675 1 685 1 0.666 7081.4 IPI00553164.3 FTPGTFTNQIQAAFR 2 850.46 948 1 1049 1 1196 1 1 2706.6 IPI00553164.3 FTPGTFTNQIQAAFR 2 850.46 948 1 1049 1 1196 1 1 1983.2 IPI00556507.1 VAAGLPPILVHTDAAQALGK 2 972.15 1012 1 1111 1 1224 0 0.66666667 1153.1 IPI00556507.1 VAAGLPPILVHTDAAQALGK 2 972.15 1012 1 1111 1 1224 1 1 2695.1 IPI00556507.1 VSGQTEVDDILAAVRPTTR 2 1015.13 1098 1 1213 1 1328 0 0.66666667 2932.5 IPI00556507.1 VSGQTEVDDILAAVRPTTR 2 1015.13 1098 1 1213 1 1328 1 1 1707.4 IPI00647704.1 QEPSQGTTTFAVTSILR 2 919.02 1008 1 1109 1 1210 1 1 2743.9 IPI00647704.1 QEPSQGTTTFAVTSILR 2 919.02 1008 1 1109 1 1210 0 0.66666667 1170.7 IPI00647704.1 WLQGSQELPR 2 607.69 642 1 729 1 786 1 1 5220.2 IPI00647704.1 WLQGSQELPR 2 607.69 642 1 729 0 786 1 0.66666667 14453.4 IPI00719084.3 ESYSVYVYK 1 1138.26 572 1 671 1 758 1 1 13265.2 IPI00719084.3 ESYSVYVYK 1 1138.26 572 1 671 1 758 1 1 13811.1 IPI00744627.1 ELLELGSNVVIASR 2 750.87 759 1 846 1 903 1 1 3607.5 IPI00744627.1 ELLELGSNVVIASR 2 750.87 759 1 846 1 903 1 1 4600.5 IPI00746221.1 FIYEAWQGVER 2 699.78 774 1 845 0 975 1 0.66666667 760.4 IPI00746221.1 FIYEAWQGVER 2 699.78 774 1 845 1 975 1 1 2727.8 IPI00746221.1 TFKPIDLSDLK 2 639.26 690 1 804 1 901 0 0.66666667 538.4 IPI00746221.1 TFKPIDLSDLK 2 639.26 690 1 804 1 901 1 1 1936.7 IPI00784865.1 DSTYSLSSTLTLSK 2 752.33 837 1 950 1 1037 1 1 11086.7 IPI00784865.1 DSTYSLSSTLTLSK 2 752.33 837 1 950 1 1037 1 1 7871.6 IPI00784865.1 TVAAPSVFIFPPSDEQLK 2 974.12 1061 1 1174 1 1321 1 1 1864.7 IPI00784865.1 TVAAPSVFIFPPSDEQLK 2 974.12 1061 1 1174 0 1321 1 0.66666667 4331.7 IPI00787680.1 HVFGESDELIGQK 2 730.3 802 1 890 1 1019 1 1 3383.1 IPI00787680.1 HVFGESDELIGQK 2 730.3 802 1 890 1 1019 1 1 4835.1 IPI00787680.1 SNVSDAVAQSTR 2 618.15 661 1 732 1 847 1 1 986.6 IPI00787680.1 SNVSDAVAQSTR 2 618.15 661 1 732 1 847 0 0.66666667 1622.9 IPI00787680.1 VVFEQTK 1 850.99 505 1 652 1 751 1 1 14726.6 IPI00787680.1 VVFEQTK 1 850.99 505 1 652 1 751 1 1 18317.2 IPI00792207.1 ANNSTYGLAAAVFTK 2 764.86 821 1 878 1 1041 1 1 4891.7 IPI00792207.1 ANNSTYGLAAAVFTK 2 764.86 821 1 878 1 1041 1 1 4446 IPI00792207.1 EAGFPPGVVNIVPGFGPTAGAAIASHEDVDK 3 1007.79 1156 1 1213 1 1284 1 1 1162.9 IPI00792207.1 EAGFPPGVVNIVPGFGPTAGAAIASHEDVDK 3 1007.79 1156 1 1213 1 1284 1 1 1591 IPI00792207.1 TEQGPQVDETQFK 2 754.3 767 1 866 1 995 1 1 7536.7 IPI00792207.1 TEQGPQVDETQFK 2 754.3 767 1 866 1 995 1 1 5894.4 IPI00792207.1 TFVQEDIYDEFVER 2 895.97 957 1 1071 1 1186 0 0.66666667 1772.9 IPI00792207.1 TFVQEDIYDEFVER 2 895.97 957 1 1071 1 1186 1 1 2093.1 Protein IPI Peptide Sequence Peptide Peptide Target1 Norm. Target2 Norm. Target3 Norm. Avg. Total Ion Charge m/z m/z Abundance m/z Abundance m/z Abundance Abundance Intensity IPI00216027.2 YQLDPTASISAK 2 647.73 677 1 774 1 890 1 1 2253.3 IPI00216027.2 YQLDPTASISAK 2 647.73 677 1 774 0 890 1 0.66666667 899.9 IPI00298406.3 AGDEFVEK 2 447.98 522 1 651 0 766 1 0.66666667 472 IPI00298406.3 AGDEFVEK 2 447.98 522 1 651 0 766 1 0.66666667 5290.9 IPI00298406.3 TFESLVDFSK 2 587.16 595 1 708 1 795 1 1 1832.2 IPI00298406.3 TFESLVDFSK 2 587.16 595 1 708 0 795 1 0.66666667 328.6 IPI00298406.3 TGEGFYK 1 801.87 457 1 514 1 643 1 1 10721.9 IPI00298406.3 TGEGFYK 1 801.87 457 1 514 1 643 0 0.66666667 1479.6 IPI00399054.1 QEAVALLQGQR 2 607.19 714 1 786 1 885 1 1 2088.1 IPI00399054.1 QEAVALLQGQR 2 607.19 714 1 786 1 885 0 0.66666667 2376.8 IPI00399054.1 TALALEVGELVK 2 622.25 644 1 773 1 887 0 0.66666667 15241.5 IPI00399054.1 TALALEVGELVK 2 622.25 644 1 773 1 887 1 1 2594.7 IPI00418418.4 IPQAVIDEFYSR 2 719.82 816 1 929 1 1029 1 1 3857.5 IPI00418418.4 IPQAVIDEFYSR 2 719.82 816 1 929 0 1029 1 0.66666667 1364.6 IPI00465363.2 QVHPDTGISSK 1 1169.28 592 1 707 1 804 1 1 4502.8 IPI00465363.2 QVHPDTGISSK 1 1169.28 592 1 707 1 804 0 0.66666667 1989.1 IPI00478493.3 VGYVSGWGR 1 981.1 562 1 661 1 824 1 1 22245.1 IPI00478493.3 VGYVSGWGR 1 981.1 562 1 661 1 824 1 1 2906.6 IPI00549725.5 ALPFWNEEIVPQIK 2 842.99 956 1 1070 1 1256 1 1 3040.4 IPI00549725.5 ALPFWNEEIVPQIK 2 842.99 956 1 1070 0 1256 1 0.66666667 316.9 IPI00549725.5 HYGGLTGLNK 1 1060.2 532 1 645 1 702 1 1 4647.1 IPI00549725.5 HYGGLTGLNK 1 1060.2 532 1 645 1 702 1 1 2935 IPI00553164.3 AIVAIENPADVSVISSR 2 871.5 934 1 1031 1 1145 0 0.66666667 6537.9 IPI00553164.3 AIVAIENPADVSVISSR 2 871.5 934 0 1031 1 1145 1 0.66666667 306.6 IPI00553164.3 FAAATGATPIAGR 2 602.69 614 1 675 1 685 1 0.666 14027.6 IPI00553164.3 FAAATGATPIAGR 2 602.69 614 1 675 1 685 1 0.6666 2212.3 IPI00719084.3 ESYSVYVYK 1 1138.26 572 1 671 1 758 1 1 8968.1 IPI00719084.3 ESYSVYVYK 1 1138.26 572 1 671 1 758 0 0.66666667 2163.8 IPI00746221.1 TFKPIDLSDLK 2 639.26 690 1 804 0 901 1 0.66666667 2386 IPI00746221.1 TFKPIDLSDLK 2 639.26 690 1 804 0 901 1 0.66666667 3910.9 IPI00784865.1 DSTYSLSSTLTLSK 2 752.33 837 1 950 1 1037 1 1 17572.5 IPI00784865.1 DSTYSLSSTLTLSK 2 752.33 837 1 950 1 1037 1 1 6406.9 IPI00787680.1 SNVSDAVAQSTR 2 618.15 661 1 732 1 847 0 0.66666667 1369.8 IPI00787680.1 SNVSDAVAQSTR 2 618.15 661 1 732 1 847 0 0.66666667 444.5 IPI00787680.1 VVFEQTK 1 850.99 505 1 652 1 751 1 1 9843.9 IPI00787680.1 VVFEQTK 1 850.99 505 1 652 1 751 0 0.66666667 3014.5 IPI00792207.1 EAGFPPGVVNIVPGFGPTAGAAIASHEDVDK 3 1007.79 1156 1 1213 1 1284 1 1 1502.7 IPI00792207.1 EAGFPPGVVNIVPGFGPTAGAAIASHEDVDK 3 1007.79 1156 1 1213 1 1284 0 0.66666667 606.5 IPI00792207.1 ILGYINTGK 2 490.09 532 0 695 1 752 1 0.66666667 509.9 IPI00792207.1 ILGYINTGK 2 490.09 532 1 695 0 752 1 0.66666667 1747.3