Impact of natural selection on global patterns of genetic variation, and association with clinical phenotypes, at genes involved in SARS-CoV-2 infection

  1. Chao Zhang
  2. Anurag Verma
  3. Yuanqing Feng
  4. Marcelo C. R. Melo
  5. Michael McQuillan
  6. Matthew Hansen
  7. Anastasia Lucas
  8. Joseph Park
  9. Alessia Ranciaro
  10. Simon Thompson
  11. Meghan A. Rubel
  12. Michael C. Campbell
  13. William Beggs
  14. Jibril Hirbo
  15. Sununguko Wata Mpoloka
  16. Gaonyadiwe George Mokone
  17. Regeneron Genetic Center
  18. Thomas Nyambo
  19. Dawit Wolde Meskel
  20. Gurja Belay
  21. Charles Fokunang
  22. Alfred K. Njamnshi
  23. Sabah A. Omar
  24. Scott M. Williams
  25. Daniel Rader
  26. Marylyn D. Ritchie
  27. Cesar de la Fuente Nunez
  28. Giorgio Sirugo
  29. Sarah Tishkoff
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Abstract

We investigated global patterns of genetic variation and signatures of natural selection at host genes relevant to SARS-CoV-2 infection (ACE2, TMPRSS2, DPP4,andLY6E). We analyzed novel data from 2,012 ethnically diverse Africans and 15,997 individuals of European and African ancestry with electronic health records, and integrated with global data from the 1000GP. AtACE2,we identified 41 non-synonymous variants that were rare in most populations, several of which impact protein function. However, three non-synonymous variants were common among Central African hunter-gatherers from Cameroon and are on haplotypes that exhibit signatures of positive selection. We identify strong signatures of selection impacting variation at regulatory regions influencingACE2expression in multiple African populations. AtTMPRSS2, we identified 13 amino acid changes that are adaptive and specific to the human lineage. Genetic variants that are targets of natural selection are associated with clinical phenotypes common in patients with COVID-19.

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