Population transcriptomics: a novel tool for studying genetic diversity in human populations under normal and pathological

   Genetic mechanisms regulating gene expression encompass complex processes such as transcription, translation, epigenetic modifications, and interactions of regulatory elements. These mechanisms play a crucial role in shaping phenotypic diversity in humans. High-throughput technologies, such as expression microarrays and next-generation sequencing (NGS), have enabled precise analysis of transcripts for thousands of genes genome-wide. These methods have enabled researchers to measure gene expression levels in various tissues and cells and to gain deeper insights into previously inaccessible biological processes. Numerous studies show that gene expression varies significantly among individuals. However, there are also notable differences between populations from different continental groups, driven by genetic, epigenetic, environmental factors, and natural selection. Furthermore, disease states represent an important factor influencing gene activity, as they can significantly alter the transcriptomic profiles of individual cells. In this context, comparative population genetic studies help uncover the molecular mechanisms underlying complex phenotypic traits and identify population-specific features of transcriptomic profiles in both health and disease. However, despite significant progress in this field, many aspects remain underexplored. Specifically, the distribution of gene expression variability among populations, the degree of research coverage for specific ethnic groups, the spectrum of biological materials used, and the contribution of population affiliation to observed differences in gene expression during pathological conditions require further investigation. This review presents an overview of contemporary research focused on analyzing variability in expression profiles across different human populations. It summarizes findings from individual studies, outlines the advantages and limitations of the methods employed, highlights key research directions in population transcriptomics, and discusses potential practical applications of the data obtained.

1. 1000 Genomes Project Consortium; Abecasis G.R., Auton A., Brooks L.D., DePristo M.A., Durbin R.M., Handsaker R.E., Kang H.M., Marth G.T., McVean G.A. An integrated map of genetic variation from 1,092 human genomes. Nature. 2012;491(7422): 56-65. doi: 10.1038/nature11632

2. Akulenko L.V., Sakvarelidze N.Yu., Mackevich V.A., Tsakhilova S.G. Genotype markers predispositions for preeclampsia. Problemy Reproduktsii = Russ J Hum Reprod. 2020;26(6):26-33. doi: 10.17116/repro20202606126 (in Russian)

3. Allard J.E., Chandramouli G.V., Stagliano K., Hood B.L., Litzi T., Shoji Y., Boyd J., Berchuck A., Conrads T.P., Maxwell G.L., Risinger J.I. Analysis of PSPHL as a candidate gene influencing the racial disparity in endometrial cancer. Front Oncol. 2012;2:65. doi: 10.3389/fonc.2012.00065

4. Babovskaya A.A., Trifonova E.A., Stepanov V.A. Population transcriptomics of preeclampsia. In: Bioinformatics of Genome Regulation and Structure / Systems Biology: Fourteenth International Multiconference: Abstracts, Russia, Novosibirsk, 5–10 August, 2024. Novosibirsk, 2024;762-763. doi: 10.18699/bgrs2024-4.2-02

5. Baust J.M., Buehring G.C., Campbell L., Elmore E., Harbell J.W., Nims R.W., Price P., Reid Y.A., Simione F. Best practices in cell culture : an overview. In Vitro Cell Dev Biol Anim. 2017;53(8):669-672. doi: 10.1007/s11626-017-0177-7

6. Beretta L., Barturen G., Vigone B., Bellocchi C., Hunzelmann N., De Langhe E., Cervera R., … Kerick M., Alarcón-Riquelme M.E., Martin J.; PRECISESADS SSc substudy group; PRECISESADS Flow Cytometry study group. Genome-wide whole blood transcriptome profiling in a large European cohort of systemic sclerosis patients. Ann Rheum Dis. 2020;79(9):1218-1226. doi: 10.1136/annrheumdis-2020-217116

7. Daca-Roszak P., Zietkiewicz E. Transcriptome variation in human populations and its potential application in forensics. J Appl Genet. 2019;60(3-4):319-328. doi: 10.1007/s13353-019-00510-1

8. Dixon A.L., Liang L., Moffatt M.F., Chen W., Heath S., Wong K.C., Taylor J., Burnett E., Gut I., Farrall M., Lathrop G.M., Abecasis G.R., Cookson W.O. A genome-wide association study of global gene expression. Nat Genet. 2007;39(10):1202-1207. doi: 10.1038/ng2109

9. Fan H.P.Y., Di Liao C., Fu B.Y., Lam L.C., Tang N.L. Interindividual and interethnic variation in genome-wide gene expression: insights into the biological variation of gene expression and clinical implications. Clin Chem. 2009;55(4):774-785. doi: 10.1373/clinchem.2008.119107

10. Fellenberg K., Busold C.H., Witt O., Bauer A., Beckmann B., Hauser N.C., Frohme M., Winter S., Dippon J., Hoheisel J.D. Systematic interpretation of microarray data using experiment annotations. BMC Genomics. 2006;7:319. doi: 10.1186/1471-2164-7-319

11. Ferreira P.G., Muñoz-Aguirre M., Reverter F., Sá Godinho C.P., Sousa A., Amadoz A., Sodaei R., … Oliveira C., Dopazo J., Sammeth M., Ardlie K.G., Guigó R. The effects of death and post-mortem cold ischemia on human tissue transcriptomes. Nat Commun. 2018;9(1):490. doi: 10.1038/s41467-017-02772-x

12. Field L.A., Love B., Deyarmin B., Hooke J.A., Shriver C.D., Ellsworth R.E. Identification of differentially expressed genes in breast tumors from African American compared with Caucasian women. Cancer. 2012;118(5):1334-1344. doi: 10.1002/cncr.26405

13. Ghosh G., Grewal J., Männistö T., Mendola P., Chen Z., Xie Y., Laughon S.K. Racial/ethnic differences in pregnancy-related hypertensive disease in nulliparous women. Ethn Dis. 2014;24(3):283-289

14. González-Herrera L., Valenzuela A., Marchal J.A., Lorente J.A., Villanueva E. Studies on RNA integrity and gene expression in human myocardial tissue, pericardial fluid and blood, and its postmortem stability. Forensic Sci Int. 2013;232(1-3):218-228. doi: 10.1016/j.forsciint.2013.08.001

15. Göring H.H.H., Curran J.E., Johnson M.P., Dyer T.D., Charlesworth J., Cole S.A., Jowett J.B., … MacCluer J.W., Kissebah A.H., Collier G.R., Moses E.K., Blangero J. Discovery of expression QTLs using large-scale transcriptional profiling in human lymphocytes. Nat Genet. 2007;39(10):1208-1216. doi: 10.1038/ng2119

16. Gurdasani D., Barroso I., Zeggini E., Sandhu M.S. Genomics of disease risk in globally diverse populations. Nat Rev Genet. 2019;20(9): 520-535. doi: 10.1038/s41576-019-0144-0

17. Hodgson J.A., Mulligan C.J., Al-Meeri A., Raaum R.L. Early back-to-Africa migration into the Horn of Africa. PLoS Genet. 2014;10(6): e1004393. doi: 10.1371/journal.pgen.1004393

18. Hoffjan S. Dissecting the genetic background of multifactorial diseases and traits – a major challenge for genetic research. Mol Cell Probes. 2016;30(6):345. doi: 10.1016/j.mcp.2016.11.003

19. Hrdlickova R., Toloue M., Tian B. RNA-Seq methods for transcriptome analysis. Wiley Interdiscip Rev RNA. 2017;8(1):e1364. doi: 10.1002/wrna.1364

20. Hughes D.A., Kircher M., He Z., Guo S., Fairbrother G.L., Moreno C.S., Khaitovich P., Stoneking M. Evaluating intra- and inter-individual variation in the human placental transcriptome. Genome Biol. 2015;16:54. doi: 10.1186/s13059-015-0627-z

21. Idaghdour Y., Czika W., Shianna K.V., Lee S.H., Visscher P.M., Martin H.C., Miclaus K., Jadallah S.J., Goldstein D.B., Wolfinger R.D., Gibson G. Geographical genomics of human leukocyte gene expression variation in southern Morocco. Nat Genet. 2010;42(1):62-67. doi: 10.1038/ng.495

22. International HapMap Consortium. The International HapMap Project. Nature. 2003;426(6968):789-796. doi: 10.1038/nature02168

23. Johnson W.E., Li C., Rabinovic A. Adjusting batch effects in microarray expression data using empirical Bayes methods. Biostatistics. 2007;8(1):118-127. doi: 10.1093/biostatistics/kxj037

24. Kelley-Hedgepeth A., Lloyd-Jones D.M., Colvin A., Matthews K.A., Johnston J., Sowers M.R., Sternfeld B., Pasternak R.C., Chae C.U.; SWAN Investigators. Ethnic differences in C-reactive protein concentrations. Clin Chem. 2008;54(6):1027-1037. doi: 10.1373/clinchem.2007.098996

25. Kelly D.E., Hansen M.E.B., Tishkoff S.A. Global variation in gene expression and the value of diverse sampling. Curr Opin Syst Biol. 2017;1:102-108. doi: 10.1016/j.coisb.2016.12.018

26. Kinseth M.A., Jia Z., Rahmatpanah F., Sawyers A., Sutton M., Wang-Rodriguez J., Mercola D., McGuire K.L. Expression differences between African American and Caucasian prostate cancer tissue reveals that stroma is the site of aggressive changes. Int J Cancer. 2014;134(1):81-91. doi: 10.1002/ijc.28326

27. Kukurba K.R., Montgomery S.B. RNA sequencing and analysis. Cold Spring Harb Protoc. 2015;2015(11):951-969. doi: 10.1101/pdb.top084970

28. Lappalainen T., Sammeth M., Friedländer M.R., ‘t Hoen P.A., Monlong J., Rivas M.A., Gonzàlez-Porta M., … Rosenstiel P., Guigó R., Gut I.G., Estivill X., Dermitzakis E.T. Transcriptome and genome sequencing uncovers functional variation in humans. Nature. 2013; 501(7468):506-511. doi: 10.1038/nature12531

29. Li J.W., Lai K.P., Ching A.K., Chan T.F. Transcriptome sequencing of Chinese and Caucasian population identifies ethnic-associated differential transcript abundance of heterogeneous nuclear ribonucleo-protein K (hnRNPK). Genomics. 2014;103(1):56-64. doi: 10.1016/j.ygeno.2013.12.005

30. Martin A.R., Costa H.A., Lappalainen T., Henn B.M., Kidd J.M., Yee M.C., Grubert F., Cann H.M., Snyder M., Montgomery S.B., Bustamante C.D. Transcriptome sequencing from diverse human populations reveals differentiated regulatory architecture. PLoS Genet. 2014;10(8):e1004549. doi: 10.1371/journal.pgen.1004549

31. Martin D.N., Boersma B.J., Yi M., Reimers M., Howe T.M., Yfantis H.G., Tsai Y.C., Williams E.H., Lee D.H., Stephens R.M., Weissman A.M., Ambs S. Differences in the tumor microenvironment between African-American and European-American breast cancer patients. PLoS One. 2009;4(2):e4531. doi: 10.1371/journal.pone.0004531

32. Melé M., Ferreira P.G., Reverter F., DeLuca D.S., Monlong J., Sammeth M., Young T.R., … Calvo M., Getz G., Dermitzakis E.T., Ard lie K.G., Guigó R. Human genomics. The human transcriptome across tissues and individuals. Science. 2015;348(6235):660-665. doi: 10.1126/science.aaa0355

33. Mitchell K.A., Zingone A., Toulabi L., Boeckelman J., Ryan B.M. Comparative transcriptome profiling reveals coding and noncoding RNA differences in NSCLC from African Americans and European Americans. Clin Cancer Res. 2017;23(23):7412-7425. doi: 10.1158/1078-0432.CCR-17-0527

34. Nédélec Y., Sanz J., Baharian G., Szpiech Z.A., Pacis A., Dumaine A., Grenier J.C., … Hernandez R.D., Pique-Regi R., Tung J., Yotova V., Barreiro L.B. Genetic ancestry and natural selection drive population differences in immune responses to pathogens. Cell. 2016; 167(3):657-669.e21. doi: 10.1016/j.cell.2016.09.025

35. Ness R.B., Haggerty C.L., Harger G., Ferrell R. Differential distribution of allelic variants in cytokine genes among African Americans and White Americans. Am J Epidemiol. 2004;160(11):1033-1038. doi: 10.1093/aje/kwh325

36. Price A.L., Butler J., Patterson N., Capelli C., Pascali V.L., Scarnicci F., Ruiz-Linares A., … Nemesh J., Arbeitman L., Goldstein D.B., Reich D., Hirschhorn J.N. Discerning the ancestry of European Americans in genetic association studies. PLoS Genetics. 2008;4(1):e236. doi: 10.1371/journal.pgen.0030236

37. Quach H., Rotival M., Pothlichet J., Loh Y.E., Dannemann M., Zidane N., Laval G., … Boland A., Deleuze J.F., Kelso J., Albert M.L., Quintana-Murci L. Genetic adaptation and Neandertal admixture shaped the immune system of human populations. Cell. 2016; 167(3):643-656.e17. doi: 10.1016/j.cell.2016.09.024

38. Raj T., Rothamel K., Mostafavi S., Ye C., Lee M.N., Replogle J.M., Feng T., … Hacohen N., Mathis D., Benoist C., Stranger B.E., De Jager P.L. Polarization of the effects of autoimmune and neurodegenerative risk alleles in leukocytes. Science. 2014;344(6183): 519-523. doi: 10.1126/science.1249547

39. Rana S., Burke S.D., Karumanchi S.A. Imbalances in circulating angiogenic factors in the pathophysiology of preeclampsia and related disorders. Am J Obstet Gynecol. 2022;226(2S):S1019-S1034. doi: 10.1016/j.ajog.2020.10.022

40. Sirugo G., Williams S.M., Tishkoff S.A. The missing diversity in human genetic studies. Cell. 2019;177(1):26-31. doi: 10.1016/j.cell.2019.04.032

41. Spielman R.S., Bastone L.A., Burdick J.T., Morley M., Ewens W.J., Cheung V.G. Common genetic variants account for differences in gene expression among ethnic groups. Nat Genet. 2007;39(2):226-231. doi: 10.1038/ng1955

42. Steinberg K.M., Antonacci F., Sudmant P.H., Kidd J.M., Campbell C.D., Vives L., Malig M., … Froment A., Donnelly M.P., Kidd K.K., Tishkoff S.A., Eichler E.E. Structural diversity and African origin of the 17q21.31 inversion polymorphism. Nat Genet. 2012;44(8):872-880. doi: 10.1038/ng.2335

43. Stepanov V.A. Evolution of genetic diversity and human diseases. Russ J Genet. 2016;52(7):746-756. doi: 10.1134/S1022795416070103

44. Storey J.D., Madeoy J., Strout J.L., Wurfel M., Ronald J., Akey J.M. Gene-expression variation within and among human populations. Am J Hum Genet. 2007;80(3):502-509. doi: 10.1086/512017

45. Stranger B.E., Nica A.C., Forrest M.S., Dimas A., Bird C.P., Beazley C., Ingle C.E., Dunning M., Flicek P., Koller D., Montgomery S., Tavaré S., Deloukas P., Dermitzakis E.T. Population genomics of human gene expression. Nat Genet. 2007;39(10):1217-1224. doi: 10.1038/ng2142

46. Stranger B.E., Montgomery S.B., Dimas A.S., Parts L., Stegle O., Ingle C.E., Sekowska M., Gutierrez-Arcelus M., Nisbett J., Nica A.C., Beazley C., Durbin R. Patterns of cis regulatory variation in diverse human populations. PLoS Genet. 2012;8(4):e1002639. doi: 10.1371/journal.pgen.1002639

47. Thames A.D., Irwin M.R., Breen E.C., Cole S.W. Experienced discrimination and racial differences in leukocyte gene expression. Psycho neuroendocrinology. 2019;106:277-283. doi: 10.1016/j.psyneuen.2019.04.016

48. Torchin H., Ancel P.Y., Jarreau P.H., Goffinet F. Epidemiology of pre-term birth: prevalence, recent trends, short- and long-term outcomes. J Gynecol Obstet Biol Reprod (Paris). 2015;44(8):723-731. doi: 10.1016/j.jgyn.2015.06.010

49. Trifonova E., Babovskaya A., Zarubin A., Markov A., Stepanov V. Placental tissue co-expression networks across Russians and Yakuts identify key genes and pathways for preeclampsia. Eur J Hum Genet. 2022;30:108-109. doi: 10.1038/s41431-021-01026-1

50. Wallace T.A., Prueitt R.L., Yi M., Howe T.M., Gillespie J.W., Yfantis H.G., Stephens R.M., Caporaso N.E., Loffredo C.A., Ambs S. Tumor immunobiological differences in prostate cancer between African-American and European-American men. Cancer Res. 2008; 68(3):927-936. doi: 10.1158/0008-5472.CAN-07-2608

51. Way G.P., Rudd J., Wang C., Hamidi H., Fridley B.L., Konecny G.E., Goode E.L., Greene C.S., Doherty J.A. Comprehensive cross-population analysis of high-grade serous ovarian cancer supports no more than three subtypes. G3 (Bethesda). 2016;6(12):4097-4103. doi: 10.1534/g3.116.033514

52. Wei P., Milbauer L.C., Enenstein J., Nguyen J., Pan W., Hebbel R.P. Differential endothelial cell gene expression by African Americans versus Caucasian Americans: a possible contribution to health disparity in vascular disease and cancer. BMC Med. 2011;9:2. doi: 10.1186/1741-7015-9-2

53. Westen A.A., Matai A.S., Laros J.F., Meiland H.C., Jasper M., de Leeuw W.J., de Knijff P., Sijen T. Tri-allelic SNP markers enable analysis of mixed and degraded DNA samples. Forensic Sci Int Genet. 2009;3(4):233-241. doi: 10.1016/j.fsigen.2009.02.003

54. Whitney A.R., Diehn M., Popper S.J., Alizadeh A.A., Boldrick J.C., Relman D.A., Brown P.O. Individuality and variation in gene expression patterns in human blood. Proc Natl Acad Sci USA. 2003; 100(4):1896-1901. doi: 10.1073/pnas.252784499

55. Wolf M., Hubel C.A., Lam C., Sampson M., Ecker J.L., Ness R.B., Rajakumar A., Daftary A., Shakir A.S., Seely E.W., Roberts J.M., Sukhatme V.P., Karumanchi S.A., Thadhani R. Preeclampsia and future cardiovascular disease: potential role of altered angiogenesis and insulin resistance. J Clin Endocrinol Metab. 2004;89(12): 6239-6243. doi: 10.1210/jc.2004-0548

56. Yang H.C., Lin C.W., Chen C.W., Chen J.J. Applying genome-wide gene-based expression quantitative trait locus mapping to study population ancestry and pharmacogenetics. BMC Genomics. 2014; 15:319. doi: 10.1186/1471-2164-15-319

57. Yin L., Coelho S.G., Ebsen D., Smuda C., Mahns A., Miller S.A., Beer J.Z., Kolbe L., Hearing V.J. Epidermal gene expression and ethnic pigmentation variations among individuals of Asian, European and African ancestry. Exp Dermatol. 2014;23(10):731-735. doi: 10.1111/exd.12518

58. Zhang W., Duan S., Kistner E.O., Bleibel W.K., Huang R.S., Clark T.A., Chen T.X., Schweitzer A.C., Blume J.E., Cox N.J., Dolan M.E. Evaluation of genetic variation contributing to differences in gene expression between populations. Am J Hum Genet. 2008;82(3): 631-640. doi: 10.1016/j.ajhg.2007.12.015