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Id Subject Object Predicate Lexical cue
T1 0-115 Sentence denotes Comparative genetic analysis of the novel coronavirus (2019-nCoV/SARS-CoV-2) receptor ACE2 in different populations
T2 117-129 Sentence denotes Dear Editor,
T3 130-314 Sentence denotes The ACE2 gene encodes the angiotensin-converting enzyme-2, which has been proved to be the receptor for both the SARS-coronavirus (SARS-CoV) and the human respiratory coronavirus NL63.
T4 315-439 Sentence denotes Recent studies and analyses indicate that ACE2 could be the host receptor for the novel coronavirus 2019-nCoV/SARS-CoV-21,2.
T5 440-556 Sentence denotes Previous studies demonstrated the positive correlation of ACE2 expression and the infection of SARS-CoV in vitro3,4.
T6 557-660 Sentence denotes A number of ACE2 variants could reduce the association between ACE2 and S-protein in SARS-CoV or NL635.
T7 661-849 Sentence denotes Therefore, the expression level and expression pattern of human ACE2 in different tissues might be critical for the susceptibility, symptoms, and outcome of 2019-nCoV/SARS-CoV-2 infection.
T8 850-968 Sentence denotes A recent single-cell RNA-sequencing (RNA-seq) analysis indicated that Asian males may have higher expression of ACE26.
T9 969-1094 Sentence denotes Currently, the clinical reports of 2019-nCoV/SARS-CoV-2 infection from non-Asian populations for comparison are very limited.
T10 1095-1210 Sentence denotes A study from Munich reported four German cases, all of which showed mild clinical symptoms without severe illness7.
T11 1211-1320 Sentence denotes However, the genetic basis of ACE2 expression and function in different populations is still largely unknown.
T12 1321-1595 Sentence denotes Therefore, genetic analysis of expression quantitative trait loci (eQTLs)8 and potential functional coding variants in ACE2 among populations are required for further epidemiological investigations of 2019-nCoV/SARS-CoV-2 spreading in East Asian (EAS) and other populations.
T13 1596-1931 Sentence denotes To systematically investigate the candidate functional coding variants in ACE2 and the allele frequency (AF) differences between populations, we analyzed all the 1700 variants (Supplementary Table S1) in ACE2 gene region from the ChinaMAP (China Metabolic Analytics Project, under reviewing) and 1KGP (1000 Genomes Project)9 databases.
T14 1932-2092 Sentence denotes The AFs of 62 variants located in the coding regions of ACE2 in ChinaMAP, 1KGP, and other large-scale genome databases were summarized (Supplementary Table S2).
T15 2093-2204 Sentence denotes All of the 32 variants potentially affecting the amino acid sequence of ACE2 in databases were shown (Fig. 1a).
T16 2205-2371 Sentence denotes Previous study showed that the residues near lysine 31, and tyrosine 41, 82–84, and 353–357 in human ACE2 were important for the binding of S-protein in coronavirus5.
T17 2372-2457 Sentence denotes The mutations in these residues were not found in different populations in our study.
T18 2458-2553 Sentence denotes Only a singleton truncating variant of ACE2 (Gln300X) was identified in the ChinaMAP (Fig. 1a).
T19 2554-2677 Sentence denotes These data suggested that there was a lack of natural resistant mutations for coronavirus S-protein binding in populations.
T20 2678-2792 Sentence denotes The effects of low-frequency missense variants in populations for S-protein binding could be further investigated.
T21 2793-2974 Sentence denotes The distributions of seven hotspot variants (Lys26Arg, Ile468Val, Ala627Val, Asn638Ser, Ser692Pro, Asn720Asp, and Leu731Ile/Leu731Phe) in different populations were shown (Fig. 1b).
T22 2975-3191 Sentence denotes Six low-frequency loci (rs200180615, rs140473595, rs199951323, rs147311723, rs149039346, and rs73635825) were found to be specific in 1KGP database, the AFs of which were also low in the gnomAD and TopMed10 database.
T23 3192-3330 Sentence denotes Only two of these six variants (rs200180615 and rs140473595) could be found in CHB (Han Chinese in Beijing) population with the AF < 0.01.
T24 3331-3594 Sentence denotes Interestingly, the SNP rs2285666 with the highest AF in the 62 variants exhibited much higher AF in the ChinaMAP (0.556) and CHS (Han Chinese South, 0.557) populations compared to others (AMR, Ad Mixed American, 0.336; AFR, African, 0.2114; EUR, European, 0.235).
T25 3595-3742 Sentence denotes In addition, the homozygous mutation rate in males (0.550) was much higher than females (0.310) in the Chinese population (Supplementary Table S2).
T26 3743-3921 Sentence denotes Taken together, the differences in AFs of ACE2 coding variants among different populations suggested that the diverse genetic basis might affect ACE2 functions among populations.
T27 3922-4019 Sentence denotes Fig. 1 The coding-region variants and eQTL variants for ACE2 in East Asian and other populations.
T28 4020-4109 Sentence denotes a Schematics of 32 coding variants in ACE2 identified in the ChinaMAP and 1KGP databases.
T29 4110-4191 Sentence denotes Yellow stars indicate the nonsense variants; dots indicate the missense variants.
T30 4192-4330 Sentence denotes The number of samples with hotspot variants was marked. b The distribution of hotspot missense mutations of ACE2 in different populations.
T31 4331-4486 Sentence denotes The colors indicate different populations. c The distribution and the allele frequencies of representative eQTL variants for ACE2 in different populations.
T32 4487-4582 Sentence denotes Pie charts depict the allele frequencies of an intron variant of ACE2 (rs4646127) in the world.
T33 4583-4684 Sentence denotes Orange color denotes the frequency of alteration allele, and blue color denotes the reference allele.
T34 4685-4754 Sentence denotes The allele frequencies of 15 eQTLs for ACE2 gene are shown in tables.
T35 4755-4838 Sentence denotes The color gradient from blue to red indicates the increasing of allele frequencies.
T36 4839-4929 Sentence denotes The allele frequencies of INDEL variant rs200781818 were annotated by the gnomAD database.
T37 4930-5017 Sentence denotes EAS, East Asian; EUR, European; AFR, African; SAS, South Asian; AMR, Ad Mixed American.
T38 5018-5163 Sentence denotes To analyze the distribution of eQTLs for ACE2, we used the Genotype Tissue Expression (GTEx) database (https://www.gtexportal.org/home/datasets).
T39 5164-5461 Sentence denotes We found 15 unique eQTL variants (14 SNPs and 1 INDELs) for ACE2 with q value ≤ 0.05 in 20 tissues from the GTEx database (rs112171234, rs12010448, rs143695310, rs1996225, rs200781818, rs2158082, rs4060, rs4646127, rs4830974, rs4830983, rs5936011, rs5936029, rs6629110, rs6632704, and rs75979613).
T40 5462-5536 Sentence denotes The AFs of the 15 eQTL variants were compared among different populations.
T41 5537-5728 Sentence denotes Notably, our results showed most of the 15 eQTL variants had much higher AFs in the ChinaMAP dataset and EAS populations compared to European populations (Fig. 1c and Supplementary Table S3).
T42 5729-5962 Sentence denotes The AFs of the top 6 common variants (rs4646127, rs2158082, rs5936011, rs6629110, rs4830983, and rs5936029) were higher than 95% in EAS populations, whereas the AFs of these variants in European populations were much lower (52%–65%).
T43 5963-6134 Sentence denotes All of the 11 common variants (AF > 0.05) and 1 rare variant (rs143695310) in the 15 eQTLs are associated with high expression of ACE2 in tissues (Supplementary Table S3).
T44 6135-6333 Sentence denotes For instance, the eQTL variant rs4646127 (log allelic fold change = 0.314), which locates in the intron of ACE2 gene, has the highest AFs in both of the ChinaMAP (0.997) and EAS (0.994) populations.
T45 6334-6428 Sentence denotes Comparatively, the AFs of rs4646127 in EUR (0.651) and AMR (0.754) populations are much lower.
T46 6429-6563 Sentence denotes These findings suggested the genotypes of ACE2 gene polymorphism may be associated higher expression levels of ACE2 in EAS population.
T47 6564-6688 Sentence denotes Recent reports of the ACE2 expression analysis in lung tissues from Asian and Caucasian populations are still controversial.
T48 6689-6835 Sentence denotes The single-cell RNA-seq analysis reported that the Asian donor had much higher ACE2 expression cell ratio than white and African-American donors6.
T49 6836-7044 Sentence denotes In contrast, the ACE2 expression analysis using the RNA-seq and microarray datasets from control lung tissues indicated there were no significant differences between Asian and Caucasian, or male and female11.
T50 7045-7119 Sentence denotes The ACE2-expressing cells are a very small part of cells in lung tissues6.
T51 7120-7230 Sentence denotes The sample size and the purity of ACE2-positive cells in the selected samples would influence the conclusions.
T52 7231-7427 Sentence denotes Our analysis showed the differences in distribution and AFs of eQTLs for ACE2 in different populations, indicating the diversity of ACE2 expression pattern in populations (Supplementary Table S3).
T53 7428-7582 Sentence denotes Large-scale and multiple tissue-level analysis of single-cell RNA-seq would be more accurate for the expression analysis of ACE2 in different populations.
T54 7583-7795 Sentence denotes In addition, our data showed the moderate difference in AFs of eQTLs between South Asian and EAS, which suggests the potential difference of ACE2 expression in different populations and ethnics in Asia (Fig. 1c).
T55 7796-8028 Sentence denotes In summary, we systematically analyzed coding-region variants in ACE2 and the eQTL variants, which may affect the expression of ACE2 using the GTEx database to compare the genomic characteristics of ACE2 among different populations.
T56 8029-8219 Sentence denotes Our findings indicated that no direct evidence was identified genetically supporting the existence of coronavirus S-protein binding-resistant ACE2 mutants in different populations (Fig. 1a).
T57 8220-8376 Sentence denotes The data of variant distribution and AFs may contribute to the further investigations of ACE2, including its roles in acute lung injury and lung function12.
T58 8377-8642 Sentence denotes The East Asian populations have much higher AFs in the eQTL variants associated with higher ACE2 expression in tissues (Fig. 1c), which may suggest different susceptibility or response to 2019-nCoV/SARS-CoV-2 from different populations under the similar conditions.
T59 8644-8669 Sentence denotes Supplementary information
T60 8671-8693 Sentence denotes Supplementary Table S1
T61 8694-8716 Sentence denotes Supplementary Table S2
T62 8717-8739 Sentence denotes Supplementary Table S3
T63 8741-8876 Sentence denotes Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
T64 8877-8911 Sentence denotes These authors contributed equally:
T65 8912-8929 Sentence denotes Yanan Cao, Lin Li
T66 8931-8956 Sentence denotes Supplementary information
T67 8957-9036 Sentence denotes Supplementary Information accompanies the paper at (10.1038/s41421-020-0147-1).
T68 9038-9054 Sentence denotes Acknowledgements
T69 9055-9225 Sentence denotes This work is supported by the National Basic Research Program of China (973 Program, 2015CB553601); the National Natural Science Foundation of China (81530020, 81522032).
T70 9227-9247 Sentence denotes Author contributions
T71 9248-9371 Sentence denotes Y.C. and W.W. conceived the study; L.L., Z.F, S.W., P.H., X.S., F.W., X.H., and Y.C. performed the bioinformatics analysis.
T72 9372-9422 Sentence denotes G.N. contributed to the discussion of the results.
T73 9423-9496 Sentence denotes Y.C. and L.L. wrote the manuscript; Y.C. and W.W. revised the manuscript.
T74 9498-9518 Sentence denotes Conflict of interest
T75 9519-9578 Sentence denotes The authors declare that they have no conflict of interest.