CORD-19-Sentences  

CORD-19:01e3b313e78a352593be2ff64927192af66619b5 JSONTXT 8 Projects

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Id Subject Object Predicate Lexical cue
TextSentencer_T1 0-6 Sentence denotes Title:
TextSentencer_T1 0-6 Sentence denotes Title:
TextSentencer_T2 7-69 Sentence denotes Viruses are a dominant driver of protein adaptation in mammals
TextSentencer_T2 7-69 Sentence denotes Viruses are a dominant driver of protein adaptation in mammals
TextSentencer_T3 71-79 Sentence denotes Abstract
TextSentencer_T3 71-79 Sentence denotes Abstract
TextSentencer_T4 80-254 Sentence denotes Viruses interact with hundreds to thousands of proteins in mammals, yet adaptation 6 against viruses has only been studied in a few proteins specialized in antiviral defense.
TextSentencer_T4 80-254 Sentence denotes Viruses interact with hundreds to thousands of proteins in mammals, yet adaptation 6 against viruses has only been studied in a few proteins specialized in antiviral defense.
TextSentencer_T5 255-390 Sentence denotes Whether adaptation to viruses typically involves only specialized antiviral proteins or 8 affects a broad array of proteins is unknown.
TextSentencer_T5 255-390 Sentence denotes Whether adaptation to viruses typically involves only specialized antiviral proteins or 8 affects a broad array of proteins is unknown.
TextSentencer_T6 391-532 Sentence denotes Here, we analyze adaptation in ~1,300 9 virus-interacting proteins manually curated from a set of 9,900 proteins conserved 10 across mammals.
TextSentencer_T6 391-532 Sentence denotes Here, we analyze adaptation in ~1,300 9 virus-interacting proteins manually curated from a set of 9,900 proteins conserved 10 across mammals.
TextSentencer_T7 533-811 Sentence denotes We show that viruses (i) use the more evolutionarily constrained 11 proteins from the cellular functions they hijack and that (ii) despite this high constraint, 12 virus-interacting proteins account for a high proportion of all protein adaptation in 13 humans and other mammals.
TextSentencer_T7 533-811 Sentence denotes We show that viruses (i) use the more evolutionarily constrained 11 proteins from the cellular functions they hijack and that (ii) despite this high constraint, 12 virus-interacting proteins account for a high proportion of all protein adaptation in 13 humans and other mammals.
TextSentencer_T8 812-949 Sentence denotes Adaptation is elevated in virus-interacting proteins across 14 all functional categories, including both immune and non-immune functions.
TextSentencer_T8 812-949 Sentence denotes Adaptation is elevated in virus-interacting proteins across 14 all functional categories, including both immune and non-immune functions.
TextSentencer_T9 950-1090 Sentence denotes Our results 15 demonstrate that viruses are one of the most dominant drivers of evolutionary change 16 across mammalian and human proteomes.
TextSentencer_T9 950-1090 Sentence denotes Our results 15 demonstrate that viruses are one of the most dominant drivers of evolutionary change 16 across mammalian and human proteomes.
TextSentencer_T10 1091-1093 Sentence denotes 17
TextSentencer_T10 1091-1093 Sentence denotes 17
TextSentencer_T11 1095-1185 Sentence denotes The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T11 1095-1185 Sentence denotes The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T12 1186-1326 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint specialized in antiviral defense, and do not even have any known role in immunity.
TextSentencer_T12 1186-1326 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint specialized in antiviral defense, and do not even have any known role in immunity.
TextSentencer_T13 1327-1521 Sentence denotes Many 1 VIPs instead have key functions in basic cellular processes subverted by viruses, and 2 viruses tend to interact with proteins that are functionally important hubs in the protein- 2015) .
TextSentencer_T13 1327-1521 Sentence denotes Many 1 VIPs instead have key functions in basic cellular processes subverted by viruses, and 2 viruses tend to interact with proteins that are functionally important hubs in the protein- 2015) .
TextSentencer_T14 1522-1615 Sentence denotes It is plausible that many VIPs might evolve to limit the impact of the viruses on the 5 host.
TextSentencer_T14 1522-1615 Sentence denotes It is plausible that many VIPs might evolve to limit the impact of the viruses on the 5 host.
TextSentencer_T15 1616-1808 Sentence denotes However, it is unknown whether the war against viruses is fought by a 6 "professional" army of specifically antiviral proteins, or whether it is a global war fought 7 by a broad range of VIPs.
TextSentencer_T15 1616-1808 Sentence denotes However, it is unknown whether the war against viruses is fought by a 6 "professional" army of specifically antiviral proteins, or whether it is a global war fought 7 by a broad range of VIPs.
TextSentencer_T16 1809-2083 Sentence denotes One reason to believe that the war against viruses might not affect evolution of a broad 9 array of VIPs is that, contrary to the pattern observed for specifically antiviral proteins, The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T16 1809-2083 Sentence denotes One reason to believe that the war against viruses might not affect evolution of a broad 9 array of VIPs is that, contrary to the pattern observed for specifically antiviral proteins, The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T17 2084-2337 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint viruses have driven a substantial proportion of all adaptations across the human and 1 mammalian proteomes, establishing that the war against viruses does indeed affect the 2 proteome as a whole.
TextSentencer_T17 2084-2337 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint viruses have driven a substantial proportion of all adaptations across the human and 1 mammalian proteomes, establishing that the war against viruses does indeed affect the 2 proteome as a whole.
TextSentencer_T18 2338-2592 Sentence denotes We finally showcase the power of our global scan for adaptation in VIPs by studying the 4 case of aminopeptidase N, a well-known multifunctional enzyme (Mina-Osorio, 2008) 5 used by coronaviruses as a receptor (Delmas et al., 1992; Yeager et al., 1992) .
TextSentencer_T18 2338-2592 Sentence denotes We finally showcase the power of our global scan for adaptation in VIPs by studying the 4 case of aminopeptidase N, a well-known multifunctional enzyme (Mina-Osorio, 2008) 5 used by coronaviruses as a receptor (Delmas et al., 1992; Yeager et al., 1992) .
TextSentencer_T19 2593-2766 Sentence denotes Using 6 our approach we reach an amino-acid level understanding of parallel adaptive evolution 7 in aminopeptidase N in response to coronaviruses in a wide range of mammals.
TextSentencer_T19 2593-2766 Sentence denotes Using 6 our approach we reach an amino-acid level understanding of parallel adaptive evolution 7 in aminopeptidase N in response to coronaviruses in a wide range of mammals.
TextSentencer_T20 2767-2768 Sentence denotes 8
TextSentencer_T20 2767-2768 Sentence denotes 8
TextSentencer_T21 2769-3005 Sentence denotes Here we analyze patterns of both adaptive evolution and evolutionary 10 constraint/purifying selection in a large set of 1,256 manually curated VIPs from the low-11 throughput virology literature (Methods and Table S1 available online).
TextSentencer_T21 2769-3005 Sentence denotes Here we analyze patterns of both adaptive evolution and evolutionary 10 constraint/purifying selection in a large set of 1,256 manually curated VIPs from the low-11 throughput virology literature (Methods and Table S1 available online).
TextSentencer_T22 3006-3039 Sentence denotes We exclude Table S2 and Methods).
TextSentencer_T22 3006-3039 Sentence denotes We exclude Table S2 and Methods).
TextSentencer_T23 3040-3117 Sentence denotes VIPs in our dataset interact with viral 16 proteins, viral RNA, or viral DNA.
TextSentencer_T23 3040-3117 Sentence denotes VIPs in our dataset interact with viral 16 proteins, viral RNA, or viral DNA.
TextSentencer_T24 3118-3234 Sentence denotes Most of them (95%) correspond to an interaction 17 between a human protein and a virus infecting humans (Table S1 ).
TextSentencer_T24 3118-3234 Sentence denotes Most of them (95%) correspond to an interaction 17 between a human protein and a virus infecting humans (Table S1 ).
TextSentencer_T25 3235-3240 Sentence denotes Human
TextSentencer_T25 3235-3240 Sentence denotes Human
TextSentencer_T26 3241-3387 Sentence denotes Immunodeficiency Virus type 1 (HIV-1) is the best-represented virus with 240 VIPs, with 19 nine other viruses having at least 50 VIPs (Table S1 ).
TextSentencer_T26 3241-3387 Sentence denotes Immunodeficiency Virus type 1 (HIV-1) is the best-represented virus with 240 VIPs, with 19 nine other viruses having at least 50 VIPs (Table S1 ).
TextSentencer_T27 3388-3508 Sentence denotes This dataset represents the largest, most up-to-date set of VIPs backed up by individual 21 low-throughput publications.
TextSentencer_T27 3388-3508 Sentence denotes This dataset represents the largest, most up-to-date set of VIPs backed up by individual 21 low-throughput publications.
TextSentencer_T28 3509-3588 Sentence denotes Nonetheless, given that many VIPs were discovered only (Methods and Table S4 ).
TextSentencer_T28 3509-3588 Sentence denotes Nonetheless, given that many VIPs were discovered only (Methods and Table S4 ).
TextSentencer_T29 3589-3693 Sentence denotes These 241 immune VIPs include the VIPs 2 classified as antiviral (Table S4 ) throughout this manuscript.
TextSentencer_T29 3589-3693 Sentence denotes These 241 immune VIPs include the VIPs 2 classified as antiviral (Table S4 ) throughout this manuscript.
TextSentencer_T30 3694-3797 Sentence denotes In total, 162 overlapping GO 3 cellular and supracellular processes have more than 50 VIPs (Table S3) .
TextSentencer_T30 3694-3797 Sentence denotes In total, 162 overlapping GO 3 cellular and supracellular processes have more than 50 VIPs (Table S3) .
TextSentencer_T31 3798-3918 Sentence denotes These 4 observations confirm that viruses interact with proteins involved in the majority of basic 5 cellular processes.
TextSentencer_T31 3798-3918 Sentence denotes These 4 observations confirm that viruses interact with proteins involved in the majority of basic 5 cellular processes.
TextSentencer_T32 3920-4162 Sentence denotes To disentangle whether the slower evolution of VIPs is due to stronger purifying 14 selection or to a lower rate of adaptation, we use the ratio of non-synonymous 15 polymorphisms to synonymous polymorphisms pN/pS rather than the dN/dS ratio.
TextSentencer_T32 3920-4162 Sentence denotes To disentangle whether the slower evolution of VIPs is due to stronger purifying 14 selection or to a lower rate of adaptation, we use the ratio of non-synonymous 15 polymorphisms to synonymous polymorphisms pN/pS rather than the dN/dS ratio.
TextSentencer_T33 4163-4392 Sentence denotes Unlike 16 dN/dS that is strongly influenced by both the effects of purifying selection and 17 adaptation, pN/pS is primarily determined by the efficiency of purifying selection in 18 removing deleterious non-synonymous mutations.
TextSentencer_T33 4163-4392 Sentence denotes Unlike 16 dN/dS that is strongly influenced by both the effects of purifying selection and 17 adaptation, pN/pS is primarily determined by the efficiency of purifying selection in 18 removing deleterious non-synonymous mutations.
TextSentencer_T34 4393-4643 Sentence denotes Genome-wide polymorphisms required to measure pN/pS at the scale of the proteome 20 have become available for humans (Abecasis et al., 2012) (1,000 Genomes Project) 21 (Table S5) , and chimpanzee, gorilla, and orangutans (Prado-Martinez et al., 2013)
TextSentencer_T34 4393-4643 Sentence denotes Genome-wide polymorphisms required to measure pN/pS at the scale of the proteome 20 have become available for humans (Abecasis et al., 2012) (1,000 Genomes Project) 21 (Table S5) , and chimpanzee, gorilla, and orangutans (Prado-Martinez et al., 2013)
TextSentencer_T35 4644-4685 Sentence denotes (Great Apes Genome Project) ( Table S6 ).
TextSentencer_T35 4644-4685 Sentence denotes (Great Apes Genome Project) ( Table S6 ).
TextSentencer_T36 4686-4816 Sentence denotes The 1,000 Genomes Project and the Great The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T36 4686-4816 Sentence denotes The 1,000 Genomes Project and the Great The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T37 4817-4952 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint suited for the estimation of the pN/pS ratio in as many proteins as possible.
TextSentencer_T37 4817-4952 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint suited for the estimation of the pN/pS ratio in as many proteins as possible.
TextSentencer_T38 4953-5230 Sentence denotes Specifically, 1 we measure pN/pS as the average across non-human great apes (or as the average in 2 the 1,000 Genomes African populations; Supplemental Methods) using the data from the 3 largest chimpanzee, gorilla, and orangutan populations in order to further limit the noise
TextSentencer_T38 4953-5230 Sentence denotes Specifically, 1 we measure pN/pS as the average across non-human great apes (or as the average in 2 the 1,000 Genomes African populations; Supplemental Methods) using the data from the 3 largest chimpanzee, gorilla, and orangutan populations in order to further limit the noise
TextSentencer_T39 5232-5374 Sentence denotes In line with this, VIPs also show an excess of low frequency (≤10%) deleterious non-12 synonymous variants compared to non-VIPs ( Figure S3 ).
TextSentencer_T39 5232-5374 Sentence denotes In line with this, VIPs also show an excess of low frequency (≤10%) deleterious non-12 synonymous variants compared to non-VIPs ( Figure S3 ).
TextSentencer_T40 5375-5401 Sentence denotes In great apes, the average
TextSentencer_T40 5375-5401 Sentence denotes In great apes, the average
TextSentencer_T41 5403-5667 Sentence denotes The higher level of purifying selection in VIPs might be due to the fact that VIPs 22 participate in the more constrained host functions, or, alternatively, because within each 23 specific host function, viruses tend to interact with the more constrained proteins.
TextSentencer_T41 5403-5667 Sentence denotes The higher level of purifying selection in VIPs might be due to the fact that VIPs 22 participate in the more constrained host functions, or, alternatively, because within each 23 specific host function, viruses tend to interact with the more constrained proteins.
TextSentencer_T42 5668-5903 Sentence denotes In 24 order to assess these two non-mutually exclusive scenarios we generated 10 4 control 25 sets of non-VIPs chosen to be in the same 162 Gene Ontology processes as VIPs (GO 26 processes with more than 50 VIPs; Table S3 and Methods).
TextSentencer_T42 5668-5903 Sentence denotes In 24 order to assess these two non-mutually exclusive scenarios we generated 10 4 control 25 sets of non-VIPs chosen to be in the same 162 Gene Ontology processes as VIPs (GO 26 processes with more than 50 VIPs; Table S3 and Methods).
TextSentencer_T43 5904-6165 Sentence denotes In great apes, GO-matched non-VIPs still have a much higher pN/pS ratio compared to 28 VIPs, suggesting that VIPs tend to be more conserved than non-VIPs from the same GO The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T43 5904-6165 Sentence denotes In great apes, GO-matched non-VIPs still have a much higher pN/pS ratio compared to 28 VIPs, suggesting that VIPs tend to be more conserved than non-VIPs from the same GO The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T44 6166-6270 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint 6 permutation test P=0 after 10 9 iterations).
TextSentencer_T44 6166-6270 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint 6 permutation test P=0 after 10 9 iterations).
TextSentencer_T45 6271-6355 Sentence denotes The stronger purifying selection acting on VIPs 1 is apparent within most functions.
TextSentencer_T45 6271-6355 Sentence denotes The stronger purifying selection acting on VIPs 1 is apparent within most functions.
TextSentencer_T46 6356-6457 Sentence denotes Figure 1C shows stronger purifying selection in the 20 2 high level GO categories with the most VIPs.
TextSentencer_T46 6356-6457 Sentence denotes Figure 1C shows stronger purifying selection in the 20 2 high level GO categories with the most VIPs.
TextSentencer_T47 6458-6604 Sentence denotes In all the 20 GO categories pN/pS is lower 3 in VIPs than in non-VIPs, and the difference is significant for 17 of these categories 4 (Table S3 ).
TextSentencer_T47 6458-6604 Sentence denotes In all the 20 GO categories pN/pS is lower 3 in VIPs than in non-VIPs, and the difference is significant for 17 of these categories 4 (Table S3 ).
TextSentencer_T48 6605-6713 Sentence denotes This shows that within a wide range of host functions, viruses tend to target 5 the most conserved proteins.
TextSentencer_T48 6605-6713 Sentence denotes This shows that within a wide range of host functions, viruses tend to target 5 the most conserved proteins.
TextSentencer_T49 6714-6934 Sentence denotes Interestingly, even immune VIPs (Table S4 ) have a significantly reduced pN/pS ratio 7 compared to immune non-VIPs ( Figure 1C ), which suggests that immune proteins in 8 direct contact with viruses are more constrained.
TextSentencer_T49 6714-6934 Sentence denotes Interestingly, even immune VIPs (Table S4 ) have a significantly reduced pN/pS ratio 7 compared to immune non-VIPs ( Figure 1C ), which suggests that immune proteins in 8 direct contact with viruses are more constrained.
TextSentencer_T50 6935-7119 Sentence denotes The reduction in pN/pS in non-immune 9 VIPs (no antiviral or any other immune function, Table S4 ) is very similar to the reduction 10 observed in the entire set of VIPs ( Figure 1C ).
TextSentencer_T50 6935-7119 Sentence denotes The reduction in pN/pS in non-immune 9 VIPs (no antiviral or any other immune function, Table S4 ) is very similar to the reduction 10 observed in the entire set of VIPs ( Figure 1C ).
TextSentencer_T51 7120-7140 Sentence denotes Table S3 Table S5 ).
TextSentencer_T51 7120-7140 Sentence denotes Table S3 Table S5 ).
TextSentencer_T52 7141-7387 Sentence denotes Since VIPs are more 23 constrained than non-VIPs and tend to have more non-synonymous deleterious low 24 frequency variants than non-VIPs (Figures 1 and S3 The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T52 7141-7387 Sentence denotes Since VIPs are more 23 constrained than non-VIPs and tend to have more non-synonymous deleterious low 24 frequency variants than non-VIPs (Figures 1 and S3 The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T53 7388-7447 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint 7
TextSentencer_T53 7388-7447 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint 7
TextSentencer_T54 7448-7681 Sentence denotes The classic MK test is known to be biased downward by the presence of slightly 1 deleterious non-synonymous variants and this bias is difficult to eliminate fully even by 2 excluding low frequency variants (Messer and Petrov, 2013) .
TextSentencer_T54 7448-7681 Sentence denotes The classic MK test is known to be biased downward by the presence of slightly 1 deleterious non-synonymous variants and this bias is difficult to eliminate fully even by 2 excluding low frequency variants (Messer and Petrov, 2013) .
TextSentencer_T55 7682-8090 Sentence denotes Note that our application 3 of the classic MK test to discover the higher rate of adaptation in VIPs compared to non-4 VIPs is conservative given that the VIPs have a higher proportion of slightly deleterious We therefore apply an asymptotic modification of the MK test known to provide 10 estimates of α without a downward bias in the presence of slightly deleterious variants 11 (Messer and Petrov, 2013) .
TextSentencer_T55 7682-8090 Sentence denotes Note that our application 3 of the classic MK test to discover the higher rate of adaptation in VIPs compared to non-4 VIPs is conservative given that the VIPs have a higher proportion of slightly deleterious We therefore apply an asymptotic modification of the MK test known to provide 10 estimates of α without a downward bias in the presence of slightly deleterious variants 11 (Messer and Petrov, 2013) .
TextSentencer_T56 8091-8310 Sentence denotes To further validate the asymptotic MK test we carry out 12 extensive population simulations (Messer, 2013) to show that this test is indeed robust to 13 a number of potential biases (Supplemental Methods and Table S8 ).
TextSentencer_T56 8091-8310 Sentence denotes To further validate the asymptotic MK test we carry out 12 extensive population simulations (Messer, 2013) to show that this test is indeed robust to 13 a number of potential biases (Supplemental Methods and Table S8 ).
TextSentencer_T57 8311-8467 Sentence denotes 14 Using the asymptotic MK test we estimate that in VIPs, ~27% of the 1,897 amino acid 15 substitutions along the human lineage were adaptive ( Figure 1D ).
TextSentencer_T57 8311-8467 Sentence denotes 14 Using the asymptotic MK test we estimate that in VIPs, ~27% of the 1,897 amino acid 15 substitutions along the human lineage were adaptive ( Figure 1D ).
TextSentencer_T58 8468-8572 Sentence denotes This proportion is 16 three times higher than the estimated proportion of ~9% in non-VIPs ( Figure 1D ).
TextSentencer_T58 8468-8572 Sentence denotes This proportion is 16 three times higher than the estimated proportion of ~9% in non-VIPs ( Figure 1D ).
TextSentencer_T59 8573-8578 Sentence denotes Thus,
TextSentencer_T59 8573-8578 Sentence denotes Thus,
TextSentencer_T60 8579-8747 Sentence denotes although VIPs represent only 13% of the orthologs in our dataset, we estimate that in 18 human evolution they account for almost 30% of all adaptive amino-acid changes.
TextSentencer_T60 8579-8747 Sentence denotes although VIPs represent only 13% of the orthologs in our dataset, we estimate that in 18 human evolution they account for almost 30% of all adaptive amino-acid changes.
TextSentencer_T61 8748-8752 Sentence denotes Note
TextSentencer_T61 8748-8752 Sentence denotes Note
TextSentencer_T62 8754-8905 Sentence denotes The high α in VIPs is not explained by higher rates of adaptation in the host GO 22 processes where VIPs are well represented ( Figure S4 and Methods).
TextSentencer_T62 8754-8905 Sentence denotes The high α in VIPs is not explained by higher rates of adaptation in the host GO 22 processes where VIPs are well represented ( Figure S4 and Methods).
TextSentencer_T63 8906-9133 Sentence denotes Furthermore, the 23 large difference in α observed between VIPs and non-VIPs is robust to a number of 24 potentially confounding factors such as recombination, GC content or gene length (Table 25 S9 and Supplemental Methods).
TextSentencer_T63 8906-9133 Sentence denotes Furthermore, the 23 large difference in α observed between VIPs and non-VIPs is robust to a number of 24 potentially confounding factors such as recombination, GC content or gene length (Table 25 S9 and Supplemental Methods).
TextSentencer_T64 9134-9212 Sentence denotes The lower pN/pS in VIPs does not explain their higher α 26 either (Table S9 ).
TextSentencer_T64 9134-9212 Sentence denotes The lower pN/pS in VIPs does not explain their higher α 26 either (Table S9 ).
TextSentencer_T65 9213-9445 Sentence denotes We further use the classic MK test (excluding variants below 10%) to investigate the 28 excess of adaptation for the specific VIPs of ten human viruses and in the 20 high level 29 GO categories with the most VIPs ( Figure 1E and F).
TextSentencer_T65 9213-9445 Sentence denotes We further use the classic MK test (excluding variants below 10%) to investigate the 28 excess of adaptation for the specific VIPs of ten human viruses and in the 20 high level 29 GO categories with the most VIPs ( Figure 1E and F).
TextSentencer_T66 9446-9477 Sentence denotes We do not use the asymptotic MK
TextSentencer_T66 9446-9477 Sentence denotes We do not use the asymptotic MK
TextSentencer_T67 9479-9878 Sentence denotes Finally and importantly, the 80% of VIPs with no known antiviral or broader immune 6 function (Table S4 ) have a strongly increased rate of adaptation according to both the 7 classic MK test (α=0.26 in VIPs versus -0.02 in non-VIPs, permutation test P=3x10 -7 ; 8 Figure 1F ) and the asymptotic MK test, with the latter estimating α=38% in non-immune 9 VIPs against only 11% for non-immune non-VIPs.
TextSentencer_T67 9479-9878 Sentence denotes Finally and importantly, the 80% of VIPs with no known antiviral or broader immune 6 function (Table S4 ) have a strongly increased rate of adaptation according to both the 7 classic MK test (α=0.26 in VIPs versus -0.02 in non-VIPs, permutation test P=3x10 -7 ; 8 Figure 1F ) and the asymptotic MK test, with the latter estimating α=38% in non-immune 9 VIPs against only 11% for non-immune non-VIPs.
TextSentencer_T68 9879-10092 Sentence denotes Intriguingly, unlike for non-immune 10 VIPs or all VIPs considered together (top of Figure 1F ), immune VIPs, including antiviral 11 VIPs (Table S4) , do not show any increase of adaptation compared to immune non-
TextSentencer_T68 9879-10092 Sentence denotes Intriguingly, unlike for non-immune 10 VIPs or all VIPs considered together (top of Figure 1F ), immune VIPs, including antiviral 11 VIPs (Table S4) , do not show any increase of adaptation compared to immune non-
TextSentencer_T69 10093-10098 Sentence denotes VIPs.
TextSentencer_T69 10093-10098 Sentence denotes VIPs.
TextSentencer_T70 10099-10386 Sentence denotes We speculate that this pattern might reflect the masking effect of balancing The increased rate of adaptation in VIPs in the human lineage strongly suggests that 20 VIPs in our dataset, 95% of which interact with modern viruses (Table S1 ), were also 21 VIPs during past human evolution.
TextSentencer_T70 10099-10386 Sentence denotes We speculate that this pattern might reflect the masking effect of balancing The increased rate of adaptation in VIPs in the human lineage strongly suggests that 20 VIPs in our dataset, 95% of which interact with modern viruses (Table S1 ), were also 21 VIPs during past human evolution.
TextSentencer_T71 10387-10535 Sentence denotes It is also plausible that a substantial proportion of the The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T71 10387-10535 Sentence denotes It is also plausible that a substantial proportion of the The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T72 10536-10643 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint 1 mammalian tree used for the analysis (Methods).
TextSentencer_T72 10536-10643 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint 1 mammalian tree used for the analysis (Methods).
TextSentencer_T73 10644-10885 Sentence denotes For a specific coding sequence, the 2 BS-REL test estimates the proportion of codons where the rate of non-synonymous 3 substitutions is higher than the rate of synonymous substitutions (dN/dS>1), which is a 4 hallmark of adaptive evolution.
TextSentencer_T73 10644-10885 Sentence denotes For a specific coding sequence, the 2 BS-REL test estimates the proportion of codons where the rate of non-synonymous 3 substitutions is higher than the rate of synonymous substitutions (dN/dS>1), which is a 4 hallmark of adaptive evolution.
TextSentencer_T74 10886-11079 Sentence denotes The BS-REL test then compares two competing models 5 of evolution, one with adaptive substitutions and one without adaptive substitutions, and 6 decides which of the two models is the best fit.
TextSentencer_T74 10886-11079 Sentence denotes The BS-REL test then compares two competing models 5 of evolution, one with adaptive substitutions and one without adaptive substitutions, and 6 decides which of the two models is the best fit.
TextSentencer_T75 11080-11226 Sentence denotes For each branch of the tree, the BS-REL 7 test provides a P-value that corresponds to the probability that no adaptation occurred in 8 the branch.
TextSentencer_T75 11080-11226 Sentence denotes For each branch of the tree, the BS-REL 7 test provides a P-value that corresponds to the probability that no adaptation occurred in 8 the branch.
TextSentencer_T76 11227-11397 Sentence denotes The product of P-values across all branches in the tree then gives the 9 probability that no adaptation occurred anywhere along the entire tree (Supplemental 10 Methods).
TextSentencer_T76 11227-11397 Sentence denotes The product of P-values across all branches in the tree then gives the 9 probability that no adaptation occurred anywhere along the entire tree (Supplemental 10 Methods).
TextSentencer_T77 11398-11481 Sentence denotes The product of P-values is a good measure of whether a specific protein experienced
TextSentencer_T77 11398-11481 Sentence denotes The product of P-values is a good measure of whether a specific protein experienced
TextSentencer_T78 11483-11632 Sentence denotes The purifying selection-wise permutation test shows that adaptation has been much 29 more common in VIPs than in non-VIPs across mammals (Figure 2 ).
TextSentencer_T78 11483-11632 Sentence denotes The purifying selection-wise permutation test shows that adaptation has been much 29 more common in VIPs than in non-VIPs across mammals (Figure 2 ).
TextSentencer_T79 11633-11649 Sentence denotes We estimate that
TextSentencer_T79 11633-11649 Sentence denotes We estimate that
TextSentencer_T80 11650-11726 Sentence denotes VIPs have experienced 77% more adaptation compared to non-VIPs (Figure 2A) .
TextSentencer_T80 11650-11726 Sentence denotes VIPs have experienced 77% more adaptation compared to non-VIPs (Figure 2A) .
TextSentencer_T81 11727-11821 Sentence denotes In 31 total, this represents ~76,000 more adaptive amino acid changes in VIPs compared to 32 .
TextSentencer_T81 11727-11821 Sentence denotes In 31 total, this represents ~76,000 more adaptive amino acid changes in VIPs compared to 32 .
TextSentencer_T82 11822-11970 Sentence denotes CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T82 11822-11970 Sentence denotes CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T83 11971-12038 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint non-VIPs.
TextSentencer_T83 11971-12038 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint non-VIPs.
TextSentencer_T84 12039-12281 Sentence denotes We further use an increasingly strict level of evidence for the presence of 1 adaptation, by including only proteins with increasingly low products of P-values; that is, 2 increasingly low probability that no adaptation occurred (Figure 2A ).
TextSentencer_T84 12039-12281 Sentence denotes We further use an increasingly strict level of evidence for the presence of 1 adaptation, by including only proteins with increasingly low products of P-values; that is, 2 increasingly low probability that no adaptation occurred (Figure 2A ).
TextSentencer_T85 12282-12288 Sentence denotes Figure
TextSentencer_T85 12282-12288 Sentence denotes Figure
TextSentencer_T86 12290-12553 Sentence denotes GO processes with a strong excess of adaptation include cellular processes such as 17 transcription, signal transduction, apoptosis, or post-translational protein modification, 18 but also supracellular processes related to development ( Figure 2C and Table S3 ).
TextSentencer_T86 12290-12553 Sentence denotes GO processes with a strong excess of adaptation include cellular processes such as 17 transcription, signal transduction, apoptosis, or post-translational protein modification, 18 but also supracellular processes related to development ( Figure 2C and Table S3 ).
TextSentencer_T87 12554-12612 Sentence denotes Importantly, VIPs with no known immune function (Table S4)
TextSentencer_T87 12554-12612 Sentence denotes Importantly, VIPs with no known immune function (Table S4)
TextSentencer_T88 12614-12870 Sentence denotes Since 95% of the VIPs were discovered for viruses infecting humans, it is possible that 24 the observed excess of adaptation in VIPs in mammals is due to higher rates of 25 adaptation exclusively in the primate branches of the mammalian tree ( Figure S1 ).
TextSentencer_T88 12614-12870 Sentence denotes Since 95% of the VIPs were discovered for viruses infecting humans, it is possible that 24 the observed excess of adaptation in VIPs in mammals is due to higher rates of 25 adaptation exclusively in the primate branches of the mammalian tree ( Figure S1 ).
TextSentencer_T89 12871-12974 Sentence denotes However, all mammalian clades in the tree show a similar excess of adaptation in VIPs 27 ( Figure 2D ).
TextSentencer_T89 12871-12974 Sentence denotes However, all mammalian clades in the tree show a similar excess of adaptation in VIPs 27 ( Figure 2D ).
TextSentencer_T90 12975-13129 Sentence denotes Primates stand out due to their low overall proportions of positively selected 28 codons compared to the other mammalian clades in the tree ( Figure 2D ).
TextSentencer_T90 12975-13129 Sentence denotes Primates stand out due to their low overall proportions of positively selected 28 codons compared to the other mammalian clades in the tree ( Figure 2D ).
TextSentencer_T91 13130-13233 Sentence denotes This is most The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T91 13130-13233 Sentence denotes This is most The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T92 13234-13504 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint well-known antiviral VIPs ( Figure 3A) , antiviral VIPs where adaptation was previously 1 unknown ( Figure 3B) , and non-antiviral VIPs with diverse, well-studied functions in the 2 mammalian hosts ( Figure 3C ).
TextSentencer_T92 13234-13504 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint well-known antiviral VIPs ( Figure 3A) , antiviral VIPs where adaptation was previously 1 unknown ( Figure 3B) , and non-antiviral VIPs with diverse, well-studied functions in the 2 mammalian hosts ( Figure 3C ).
TextSentencer_T93 13505-13643 Sentence denotes This phylogenetically widespread excess of adaptation 3 implies that many of the VIPs annotated in humans were also VIPs for a substantial
TextSentencer_T93 13505-13643 Sentence denotes This phylogenetically widespread excess of adaptation 3 implies that many of the VIPs annotated in humans were also VIPs for a substantial
TextSentencer_T94 13645-13909 Sentence denotes To identify a new non-antiviral protein we first exclude all VIPs with a well-known 16 antiviral activity (Table S4 ) and then select all remaining VIPs with strong overall 17 evidence of adaptation (Table S10 ) and at least 10 branches with signals of adaptation.
TextSentencer_T94 13645-13909 Sentence denotes To identify a new non-antiviral protein we first exclude all VIPs with a well-known 16 antiviral activity (Table S4 ) and then select all remaining VIPs with strong overall 17 evidence of adaptation (Table S10 ) and at least 10 branches with signals of adaptation.
TextSentencer_T95 13910-14157 Sentence denotes Because we want to understand how adaptation to viruses proceeded, we then select 19 proteins with i) at least one available tertiary structure, ii) amino acid level resolution of 20 the interaction with one or more viruses, and iii) host tropism.
TextSentencer_T95 13910-14157 Sentence denotes Because we want to understand how adaptation to viruses proceeded, we then select 19 proteins with i) at least one available tertiary structure, ii) amino acid level resolution of 20 the interaction with one or more viruses, and iii) host tropism.
TextSentencer_T96 14158-14257 Sentence denotes The most positively selected non-antiviral VIP that fulfills all these requirements is Figure 4D ).
TextSentencer_T96 14158-14257 Sentence denotes The most positively selected non-antiviral VIP that fulfills all these requirements is Figure 4D ).
TextSentencer_T97 14258-14328 Sentence denotes The consensus was regained only two times after loss 28 ( Figure 4D ).
TextSentencer_T97 14258-14328 Sentence denotes The consensus was regained only two times after loss 28 ( Figure 4D ).
TextSentencer_T98 14329-14402 Sentence denotes This means that the signals of adaptation detected at the first and third
TextSentencer_T98 14329-14402 Sentence denotes This means that the signals of adaptation detected at the first and third
TextSentencer_T99 14404-14583 Sentence denotes Although we already find a strong signal of increased adaptation, the amount of adaptive 18 evolution that can be attributed to viruses is probably underestimated by our analysis.
TextSentencer_T99 14404-14583 Sentence denotes Although we already find a strong signal of increased adaptation, the amount of adaptive 18 evolution that can be attributed to viruses is probably underestimated by our analysis.
TextSentencer_T100 14584-14633 Sentence denotes First, there may still be many undiscovered VIPs.
TextSentencer_T100 14584-14633 Sentence denotes First, there may still be many undiscovered VIPs.
TextSentencer_T101 14634-14759 Sentence denotes Within the past few years, there has 20 been no sign that the pace of discovery of new VIPs is slowing down ( Figure S2 host?
TextSentencer_T101 14634-14759 Sentence denotes Within the past few years, there has 20 been no sign that the pace of discovery of new VIPs is slowing down ( Figure S2 host?
TextSentencer_T102 14760-14925 Sentence denotes We show that there has been so much adaptation in VIPs that it is very hard to 23 imagine that none of these adaptive events had any consequences on host phenotypes.
TextSentencer_T102 14760-14925 Sentence denotes We show that there has been so much adaptation in VIPs that it is very hard to 23 imagine that none of these adaptive events had any consequences on host phenotypes.
TextSentencer_T103 14926-14982 Sentence denotes Interestingly, VIPs tend to be multifunctional proteins.
TextSentencer_T103 14926-14982 Sentence denotes Interestingly, VIPs tend to be multifunctional proteins.
TextSentencer_T104 14983-15180 Sentence denotes Indeed they represent 13% of all 25 the orthologs in the analysis, 33% of the orthologs with 60 or more annotated GO 26 processes, and 40% of orthologs with 100 or more GO processes ( Figure S8A ).
TextSentencer_T104 14983-15180 Sentence denotes Indeed they represent 13% of all 25 the orthologs in the analysis, 33% of the orthologs with 60 or more annotated GO 26 processes, and 40% of orthologs with 100 or more GO processes ( Figure S8A ).
TextSentencer_T105 15181-15427 Sentence denotes Pleiotropy is more likely in proteins with many functions (He and Zhang, 2006), and the 28 subset of VIPs with many annotated GO processes has an excess of adaptation that is 29 very similar to the one observed when using all VIPs ( Figure S8B ).
TextSentencer_T105 15181-15427 Sentence denotes Pleiotropy is more likely in proteins with many functions (He and Zhang, 2006), and the 28 subset of VIPs with many annotated GO processes has an excess of adaptation that is 29 very similar to the one observed when using all VIPs ( Figure S8B ).
TextSentencer_T106 15428-15530 Sentence denotes Adaptation to viruses 30 could thus have affected the evolution of host phenotypes in unexpected ways.
TextSentencer_T106 15428-15530 Sentence denotes Adaptation to viruses 30 could thus have affected the evolution of host phenotypes in unexpected ways.
TextSentencer_T107 15531-15718 Sentence denotes In this 31 respect, it is particularly intriguing that VIPs have experienced highly increased rates of 32 adaptation within host functions such as development or neurogenesis (Table S3) .
TextSentencer_T107 15531-15718 Sentence denotes In this 31 respect, it is particularly intriguing that VIPs have experienced highly increased rates of 32 adaptation within host functions such as development or neurogenesis (Table S3) .
TextSentencer_T108 15719-15720 Sentence denotes .
TextSentencer_T108 15719-15720 Sentence denotes .
TextSentencer_T109 15721-15869 Sentence denotes CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T109 15721-15869 Sentence denotes CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T110 15870-15927 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint
TextSentencer_T110 15870-15927 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint
TextSentencer_T111 15929-16097 Sentence denotes We identified 1,256 VIPs out of a total of 9,861 proteins with orthologs in the genomes of 16 the 24 mammals included in the analysis ( Figure S1 and Tables S1 and S2).
TextSentencer_T111 15929-16097 Sentence denotes We identified 1,256 VIPs out of a total of 9,861 proteins with orthologs in the genomes of 16 the 24 mammals included in the analysis ( Figure S1 and Tables S1 and S2).
TextSentencer_T112 16098-16108 Sentence denotes Annotation
TextSentencer_T112 16098-16108 Sentence denotes Annotation
TextSentencer_T113 16110-16167 Sentence denotes The pN/pS-based purifying selection-wise permutation test
TextSentencer_T113 16110-16167 Sentence denotes The pN/pS-based purifying selection-wise permutation test
TextSentencer_T114 16168-16277 Sentence denotes We created a permutation test that compares VIPs and non-VIPs with the same amount 12 of purifying selection.
TextSentencer_T114 16168-16277 Sentence denotes We created a permutation test that compares VIPs and non-VIPs with the same amount 12 of purifying selection.
TextSentencer_T115 16278-16487 Sentence denotes This is achieved by using the pN/pS ratio as a proxy for purifying 14 Retrieving of ANPEP mammalian coding sequences 15 We analyzed patterns of adaptation in ANPEP in a tree of mammals including 84 16 species.
TextSentencer_T115 16278-16487 Sentence denotes This is achieved by using the pN/pS ratio as a proxy for purifying 14 Retrieving of ANPEP mammalian coding sequences 15 We analyzed patterns of adaptation in ANPEP in a tree of mammals including 84 16 species.
TextSentencer_T116 16488-16604 Sentence denotes These species are the ones with annotated, known or predicted mRNAs ( Table 17 S11 for their Genbank identifiers).
TextSentencer_T116 16488-16604 Sentence denotes These species are the ones with annotated, known or predicted mRNAs ( Table 17 S11 for their Genbank identifiers).
TextSentencer_T117 16605-16682 Sentence denotes The coding sequences were extracted from the 18 mRNAs and aligned with PRANK.
TextSentencer_T117 16605-16682 Sentence denotes The coding sequences were extracted from the 18 mRNAs and aligned with PRANK.
TextSentencer_T118 16683-16894 Sentence denotes Gene Ontology-matching control samples 20 We created a permutation scheme that compares VIPs with random samples of non- The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T118 16683-16894 Sentence denotes Gene Ontology-matching control samples 20 We created a permutation scheme that compares VIPs with random samples of non- The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T119 16895-16997 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint 1 processes with the highest number of VIPs.
TextSentencer_T119 16895-16997 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint 1 processes with the highest number of VIPs.
TextSentencer_T120 16998-17122 Sentence denotes The full GO process name for "protein 2 modification" as written in the figure is "post-translational protein modification".
TextSentencer_T120 16998-17122 Sentence denotes The full GO process name for "protein 2 modification" as written in the figure is "post-translational protein modification".
TextSentencer_T121 17123-17125 Sentence denotes D)
TextSentencer_T121 17123-17125 Sentence denotes D)
TextSentencer_T122 17126-17294 Sentence denotes Asymptotic MK test (Supplemental Methods) for the proportion of adaptive amino acid 4 substitutions (α) in VIPs (blue dots and curve) and non-VIPs (red dots and curve).
TextSentencer_T122 17126-17294 Sentence denotes Asymptotic MK test (Supplemental Methods) for the proportion of adaptive amino acid 4 substitutions (α) in VIPs (blue dots and curve) and non-VIPs (red dots and curve).
TextSentencer_T123 17295-17474 Sentence denotes Pink 5 area: superposition of fitted logarithmic curves for 5,000 random sets of 1,256 non-VIPs 6 (as many as VIPs) where the estimated α falls within α's 95% confidence interval.
TextSentencer_T123 17295-17474 Sentence denotes Pink 5 area: superposition of fitted logarithmic curves for 5,000 random sets of 1,256 non-VIPs 6 (as many as VIPs) where the estimated α falls within α's 95% confidence interval.
TextSentencer_T124 17475-17633 Sentence denotes E) 7 Classic MK test (Supplemental Methods) for VIPs (blue dot) and non-VIPs (red dot and 8 95% confidence interval) for the ten viruses with 50 or more VIPs.
TextSentencer_T124 17475-17633 Sentence denotes E) 7 Classic MK test (Supplemental Methods) for VIPs (blue dot) and non-VIPs (red dot and 8 95% confidence interval) for the ten viruses with 50 or more VIPs.
TextSentencer_T125 17634-17740 Sentence denotes F) Same as E) but for 9 the 20 top high level GO processes with the most VIPs below the dotted black line.
TextSentencer_T125 17634-17740 Sentence denotes F) Same as E) but for 9 the 20 top high level GO processes with the most VIPs below the dotted black line.
TextSentencer_T126 17741-17859 Sentence denotes Above the dotted black line: the classic MK test for all VIPs, for non-immune VIPs and 11 for immune VIPs (Table S4 ).
TextSentencer_T126 17741-17859 Sentence denotes Above the dotted black line: the classic MK test for all VIPs, for non-immune VIPs and 11 for immune VIPs (Table S4 ).
TextSentencer_T127 17860-18053 Sentence denotes See also Tables S3, S4, S5, S6, S7, S8 and S9 and VIPs (blue dot) and non-VIPs (red dot and 95% confidence interval) in the mammalian 12 clades represented by more than one species in the tree.
TextSentencer_T127 17860-18053 Sentence denotes See also Tables S3, S4, S5, S6, S7, S8 and S9 and VIPs (blue dot) and non-VIPs (red dot and 95% confidence interval) in the mammalian 12 clades represented by more than one species in the tree.
TextSentencer_T128 18054-18071 Sentence denotes All: entire tree.
TextSentencer_T128 18054-18071 Sentence denotes All: entire tree.
TextSentencer_T129 18072-18080 Sentence denotes Primata:
TextSentencer_T129 18072-18080 Sentence denotes Primata:
TextSentencer_T130 18081-18082 Sentence denotes .
TextSentencer_T130 18081-18082 Sentence denotes .
TextSentencer_T131 18083-18231 Sentence denotes CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T131 18083-18231 Sentence denotes CC-BY 4.0 International license is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the author/funder.
TextSentencer_T132 18232-18289 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint
TextSentencer_T132 18232-18289 Sentence denotes It . https://doi.org/10.1101/029397 doi: bioRxiv preprint