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Open accessJournal ArticleDOI: 10.1073/PNAS.2026309118

A genomic region associated with protection against severe COVID-19 is inherited from Neandertals.

02 Mar 2021-Proceedings of the National Academy of Sciences of the United States of America (National Academy of Sciences)-Vol. 118, Iss: 9
Abstract: It was recently shown that the major genetic risk factor associated with becoming severely ill with COVID-19 when infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is inherited from Neandertals. New, larger genetic association studies now allow additional genetic risk factors to be discovered. Using data from the Genetics of Mortality in Critical Care (GenOMICC) consortium, we show that a haplotype at a region on chromosome 12 associated with requiring intensive care when infected with the virus is inherited from Neandertals. This region encodes proteins that activate enzymes that are important during infections with RNA viruses. In contrast to the previously described Neandertal haplotype that increases the risk for severe COVID-19, this Neandertal haplotype is protective against severe disease. It also differs from the risk haplotype in that it has a more moderate effect and occurs at substantial frequencies in all regions of the world outside Africa. Among ancient human genomes in western Eurasia, the frequency of the protective Neandertal haplotype may have increased between 20,000 and 10,000 y ago and again during the past 1,000 y.

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Topics: Haplotype (55%), Intensive care (54%)
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40 results found


Open accessJournal ArticleDOI: 10.1038/S41591-021-01281-1
25 Feb 2021-Nature Medicine
Abstract: To identify circulating proteins influencing Coronavirus Disease 2019 (COVID-19) susceptibility and severity, we undertook a two-sample Mendelian randomization (MR) study, rapidly scanning hundreds of circulating proteins while reducing bias due to reverse causation and confounding. In up to 14,134 cases and 1.2 million controls, we found that an s.d. increase in OAS1 levels was associated with reduced COVID-19 death or ventilation (odds ratio (OR) = 0.54, P = 7 × 10−8), hospitalization (OR = 0.61, P = 8 × 10−8) and susceptibility (OR = 0.78, P = 8 × 10−6). Measuring OAS1 levels in 504 individuals, we found that higher plasma OAS1 levels in a non-infectious state were associated with reduced COVID-19 susceptibility and severity. Further analyses suggested that a Neanderthal isoform of OAS1 in individuals of European ancestry affords this protection. Thus, evidence from MR and a case–control study support a protective role for OAS1 in COVID-19 adverse outcomes. Available pharmacological agents that increase OAS1 levels could be prioritized for drug development. A variant of the OAS1 gene, which encodes an enzyme that is critical for the innate immune response to viral infections, is associated with decreased risk of death in patients with COVID-19.

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Topics: Mendelian randomization (53%), Case-control study (51%), Odds ratio (51%)

40 Citations


Open accessJournal ArticleDOI: 10.1186/S40246-021-00326-3
10 May 2021-Human Genomics
Abstract: COVID-19 has engulfed the world and it will accompany us all for some time to come. Here, we review the current state at the milestone of 1 year into the pandemic, as declared by the WHO (World Health Organization). We review several aspects of the on-going pandemic, focusing first on two major topics: viral variants and the human genetic susceptibility to disease severity. We then consider recent and exciting new developments in therapeutics, such as monoclonal antibodies, and in prevention strategies, such as vaccines. We also briefly discuss how advances in basic science and in biotechnology, under the threat of a worldwide emergency, have accelerated to an unprecedented degree of the transition from the laboratory to clinical applications. While every day we acquire more and more tools to deal with the on-going pandemic, we are aware that the path will be arduous and it will require all of us being community-minded. In this respect, we lament past delays in timely full investigations, and we call for bypassing local politics in the interest of humankind on all continents.

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Topics: Pandemic (52%)

13 Citations


Open accessPosted ContentDOI: 10.1101/2021.02.21.21252137
23 Feb 2021-medRxiv
Abstract: BackgroundSARS-CoV-2 is continuously spreading worldwide at an unprecedented scale and evolved into seven clades according to GISAID where four (G, GH, GR and GV) are globally prevalent in 2020. These major predominant clades of SARS-CoV- 2 are continuously increasing COVID-19 cases worldwide; however, after an early rise in 2020, the death-case ratio has been decreasing to a plateau. G clade viruses contain four co- occurring mutations in their genome (C241T+C3037T+C14408T: RdRp.P323L+A23403G:spike.D614G). GR, GH, and GV strains are defined by the presence of these four mutations in addition to the clade-featured mutation in GGG28881- 28883AAC:N. RG203-204KR, G25563T:ORF3a.Q57H, and C22227T:spike.A222V+C28932T-N.A220V+G29645T, respectively. The research works are broadly focused on the spike protein mutations that have direct roles in receptor binding, antigenicity, thus viral transmission and replication fitness. However, mutations in other proteins might also have effects on viral pathogenicity and transmissibility. How the clade- featured mutations are linked with viral evolution in this pandemic through gearing their fitness and virulence is the main question of this study. MethodologyWe thus proposed a hypothetical model, combining a statistical and structural bioinformatics approach, endeavors to explain this infection paradox by describing the epistatic effects of the clade-featured co-occurring mutations on viral fitness and virulence. Results and DiscussionThe G and GR/GV clade strains represent a significant positive and negative association, respectively, with the death-case ratio (incidence rate ratio or IRR = 1.03, p <0.001 and IRR= 0.99/0.97, p < 0.001), whereas GH clade strains showed no association with the Docking analysis showed the higher infectiousness of a spike mutant through more favorable binding of G614 with the elastase-2. RdRp mutation p.P323L significantly increased genome-wide mutations (p<0.0001) since more expandable RdRp (mutant)-NSP8 interaction may accelerate replication. Superior RNA stability and structural variation at NSP3:C241T might impact upon protein or RNA interactions. Another silent 5UTR:C241T mutation might affect translational efficiency and viral packaging. These G- featured co-occurring mutations might increase the viral load, alter immune responses in host and hence can modulate intra-host genomic plasticity. An additional viroporin ORF3a:p.Q57H mutation, forming GH-clade, prevents ion permeability by cysteine (C81)- histidine (H57) inter-transmembrane-domain interaction mediated tighter constriction of the channel pore and possibly reduces viral release and immune response. GR strains, four G clade mutations and N:p.RG203-204KR, would have stabilized RNA interaction by more flexible and hypo-phosphorylated SR-rich region. GV strains seemingly gained the evolutionary advantage of superspreading event through confounder factors; nevertheless, N:p.A220V might affect RNA binding. ConclusionThese hypotheses need further retrospective and prospective studies to understand detailed molecular and evolutionary events featuring the fitness and virulence of SARS-CoV-2. HighlightsO_LIWe speculated an association of particular SARS-CoV-2 clade with death rate. C_LIO_LIThe polymerase mutant virus can speed up replication that corresponds to higher mutations. C_LIO_LIThe impact on viral epistasis by evolving mutations in SARS-CoV-2. C_LIO_LIHow the virus changes its genotype and circulate with other types given the overall dynamics of the epidemics? C_LIO_LIHuman intervention seems to work well to control the viral virulence. This hygiene practice will control the overall severity of the pandemic situation as recommended by the WHO. Our work has given the same message but explain with the dominant co-occurring mutations. C_LI

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Topics: Viral evolution (56%), Mutation (54%), Viral load (51%) ... show more

6 Citations


Open accessJournal ArticleDOI: 10.1093/GENETICS/IYAB052
Sivan Yair1, Kristin M. Lee2, Graham Coop1Institutions (2)
17 May 2021-Genetics
Abstract: Admixture has the potential to facilitate adaptation by providing alleles that are immediately adaptive in a new environment or by simply increasing the long-term reservoir of genetic diversity for future adaptation. A growing number of cases of adaptive introgression are being identified in species across the tree of life, however the timing of selection, and therefore the importance of the different evolutionary roles of admixture, is typically unknown. Here, we investigate the spatio-temporal history of selection favoring Neanderthal-introgressed alleles in modern human populations. Using both ancient and present-day samples of modern humans, we integrate the known demographic history of populations, namely population divergence and migration, with tests for selection. We model how a sweep placed along different branches of an admixture graph acts to modify the variance and covariance in neutral allele frequencies among populations at linked loci. Using a method based on this model of allele frequencies, we study previously identified cases of adaptive Neanderthal introgression. From these, we identify cases in which Neanderthal-introgressed alleles were quickly beneficial and other cases in which they persisted at low frequency for some time. For some of the alleles that persisted at low frequency, we show that selection likely independently favored them later on in geographically separated populations. Our work highlights how admixture with ancient hominins has contributed to modern human adaptation and contextualizes observed levels of Neanderthal ancestry in present-day and ancient samples.

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Topics: Genetic hitchhiking (56%), Population (52%), Introgression (50%) ... show more

5 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.ABJ3624
Arthur Wickenhagen1, Elena Sugrue1, Spyros Lytras1, Srikeerthana Kuchi1  +49 moreInstitutions (11)
28 Sep 2021-Science
Abstract: Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response.

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3 Citations


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45 results found


Open accessJournal ArticleDOI: 10.1038/NATURE15393
Adam Auton1, Gonçalo R. Abecasis2, David Altshuler3, Richard Durbin4  +514 moreInstitutions (90)
01 Oct 2015-Nature
Abstract: The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies.

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Topics: 1000 Genomes Project (62%), Exome sequencing (59%), Genome-wide association study (59%) ... show more

9,821 Citations


Journal ArticleDOI: 10.1038/NG917
10 Jun 2002-Nature Genetics
Abstract: Determination of recombination rates across the human genome has been constrained by the limited resolution and accuracy of existing genetic maps and the draft genome sequence. We have genotyped 5,136 microsatellite markers for 146 families, with a total of 1,257 meiotic events, to build a high-resolution genetic map meant to: (i) improve the genetic order of polymorphic markers; (ii) improve the precision of estimates of genetic distances; (iii) correct portions of the sequence assembly and SNP map of the human genome; and (iv) build a map of recombination rates. Recombination rates are significantly correlated with both cytogenetic structures (staining intensity of G bands) and sequence (GC content, CpG motifs and poly(A)/poly(T) stretches). Maternal and paternal chromosomes show many differences in locations of recombination maxima. We detected systematic differences in recombination rates between mothers and between gametes from the same mother, suggesting that there is some underlying component determined by both genetic and environmental factors that affects maternal recombination rates.

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Topics: Gene mapping (54%), Genome (53%), Genetic marker (52%) ... show more

1,702 Citations


Open accessJournal ArticleDOI: 10.1126/SCIENCE.1224344
Matthias Meyer1, Martin Kircher1, Marie Theres Gansauge1, Heng Li2  +37 moreInstitutions (11)
12 Oct 2012-Science
Abstract: We present a DNA library preparation method that has allowed us to reconstruct a high-coverage (30×) genome sequence of a Denisovan, an extinct relative of Neandertals. The quality of this genome allows a direct estimation of Denisovan heterozygosity indicating that genetic diversity in these archaic hominins was extremely low. It also allows tentative dating of the specimen on the basis of “missing evolution” in its genome, detailed measurements of Denisovan and Neandertal admixture into present-day human populations, and the generation of a near-complete catalog of genetic changes that swept to high frequency in modern humans since their divergence from Denisovans.

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Topics: Denisovan (57%), Anatomically modern human (54%), Neanderthal genome project (53%) ... show more

1,492 Citations


Open accessJournal ArticleDOI: 10.1038/NATURE12886
Kay Prüfer1, Fernando Racimo2, Nick Patterson3, Flora Jay2  +41 moreInstitutions (13)
02 Jan 2014-Nature
Abstract: We present a high-quality genome sequence of a Neanderthal woman from Siberia. We show that her parents were related at the level of half-siblings and that mating among close relatives was common among her recent ancestors. We also sequenced the genome of a Neanderthal from the Caucasus to low coverage. An analysis of the relationships and population history of available archaic genomes and 25 present-day human genomes shows that several gene flow events occurred among Neanderthals, Denisovans and early modern humans, possibly including gene flow into Denisovans from an unknown archaic group. Thus, interbreeding, albeit of low magnitude, occurred among many hominin groups in the Late Pleistocene. In addition, the high-quality Neanderthal genome allows us to establish a definitive list of substitutions that became fixed in modern humans after their separation from the ancestors of Neanderthals and Denisovans.

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Topics: Neanderthal genome project (74%), Neanderthal (64%), Denisovan (61%) ... show more

1,459 Citations


Open accessJournal ArticleDOI: 10.1056/NEJMOA2020283
David Ellinghaus1, Frauke Degenhardt1, Luis Bujanda1, Maria Buti1  +142 moreInstitutions (1)
Abstract: Background There is considerable variation in disease behavior among patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (Covid-19) Genomewide association analysis may allow for the identification of potential genetic factors involved in the development of Covid-19 Methods We conducted a genomewide association study involving 1980 patients with Covid-19 and severe disease (defined as respiratory failure) at seven hospitals in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe After quality control and the exclusion of population outliers, 835 patients and 1255 control participants from Italy and 775 patients and 950 control participants from Spain were included in the final analysis In total, we analyzed 8,582,968 single-nucleotide polymorphisms and conducted a meta-analysis of the two case-control panels Results We detected cross-replicating associations with rs11385942 at locus 3p2131 and with rs657152 at locus 9q342, which were significant at the genomewide level (P Conclusions We identified a 3p2131 gene cluster as a genetic susceptibility locus in patients with Covid-19 with respiratory failure and confirmed a potential involvement of the ABO blood-group system (Funded by Stein Erik Hagen and others)

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970 Citations


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