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Post by Admin on Jan 22, 2021 7:32:16 GMT
Materials and Methods Evidence for Introgression The V660L polymorphism sits on a 56.2-kb-long haplotype (r2>0.8 in all 1000G individuals) defined by 28 private SNPs on the Neandertal lineage (i.e., the Neandertal allele is missing in 108 Yoruba individuals) with coordinates chr11:100877202–100933412 (hg19). Inserting this length into the formula derived by Huerta-Sánchez et al. (2018) yields a probability of P = 0.02 for incomplete ancestral lineage sorting (ILS), using a generation time of 25 years, the local recombination rate of 0.87 cM/Mb (deCODE; Kong et al. 2010), and a branch length of 200 ky for the modern human branch, and 100 ka for the Neandertal branch. We use a conservative lower estimate of the branch lengths because the formula underestimates the probability of ILS if the branch lengths are overestimated. Previous genome-wide analyses (Sankararaman et al. 2014; Danneman and Kelso 2017; Li et al. 2018) have similarly indicated this locus as carrying introgressed Neandertal haplotypes.
Detecting Mobile Elements in Archaic Genomes If an insertion is not present in the reference genome, the read depth should drop (to zero if homozygous) in a symmetrical fashion around the position of insertion. This pattern is observed for the Chagyrskaya Neandertal genome. A smaller drop is seen for the Altai Neandertal genome. We realigned the sequenced fragments to a reference sequence containing the Alu insertion. A sequence 11 bp upstream to the Alu insertion and 11 bp into the Alu insertion (that is unique in the entire NCBI database) was used to identify junction fragments.
A Neandertal PGR without the Alu Element We find that V660L is not in particularly high linkage disequilibrium with the Alu insertion (r2 = 0.72). To rule out sequencing error, we verified this in two of the 24 high-coverage 1000G genomes, which carried V660L but not the Alu insertion (NA19625 and HG01500). Linkage disequilibrium between V660L and the Alu element for all 1000G subpopulations is given supplementary table S1, Supplementary Material online.
Phenotypic Consequences We investigated phenotypic associations in the UK Biobank using the GeneAtlas tool (Canela-Xandri et al. 2018). In brief, the Gene ATLAS provides 778 associations based on Mixed Linear Models using 452,264 Britons with European descent. As fixed effects, the model includes sex, array batch, UK Biobank Assessment Center, age, and 20 genomic principal components. Population structure was captured as a random effect. Both V660L (rs1042838) and S344T (rs3740753) are included in UK Biobank SNP array, so no imputation was needed for these. However, the Alu insertion is not genotyped and our analyses are thus limited to the missense variants of the haplotype. P-values were adjusted for multiple comparisons by controlling for the family-wise error rate (supplementary table S3, Supplementary Material online). Confidence intervals for the odds ratios were calculated using the method described in Altman and Bland (2011). Of the 778 association in the GeneAtlas, 22 where classified as belonging to ICD chapter XV (Pregnancy, childbirth, and the puerperium, supplementary table S3, Supplementary Material online). In addition, we identified 53 traits, which we considered to be related to the female reproductive system. For V660L we found negative correlations with “hemorrhage in early pregnancy” (P = 0.002), miscarriage (P = 0.01), and positive correlation with more sisters (P = 0.0036). This result was replicated for S344T (P = 0.0006, P = 0.028, and P = 0.00097, respectively). P-values and odds ratios for V660L are shown in figure 3 and supplementary table S3, Supplementary Material online.
We analyzed the age of menarche and menopause using the Biobank Japan (Horikoshi et al. 2018). Among 43,861 Japanese women, the Neandertal haplotype is associated with a somewhat earlier menopause (rs585447, 0.19 years per allele, P = 0.048) whereas there is no effect on menarche. P-values and effect sizes were taken directly from Biobank Japan.
We analyzed the effect of V660L (rs1042838) on PGR mRNA expression levels using the version eigth release of the Genotype-Tissues Expression (GTEx) project. Tissues which were predicted to show an effect were selected based on a posterior probability (i.e., m-value) >0.9. The effect across tissues was estimated using Han and Eskin’s Random Effects model (RE2; Han and Eskin 2012).
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Post by Admin on Feb 18, 2021 4:07:21 GMT
Researchers have discovered a possible genetic link between Neanderthal DNA and a lower risk of developing a severe case of the coronavirus. A new study, conducted by Hugo Zeberg and Svante Pääbo at the Max Planck Institute for Evolutionary Anthropology in Germany, followed up on recent research that suggested Neanderthal DNA was actually linked to higher risk of severe illness. They found that a certain haplogroup, a population that shares common DNA, was roughly 22 percent less likely to develop a severe case of COVID-19. The common DNA is believed to have been inherited from Neanderthals. The haplogroup is common in populations outside of Africa, the study notes, as Neanderthal evolved off the continent. The Neanderthal DNA believed to protect against illness was found on the 12th chromosome, while the DNA discovered in a previous study that researchers theorized increased the chances of severe illness was found on the third chromosome. The researchers said that Neanderthals and their Asian sister group the Denisovans became extinct tens of thousands of years ago, but their genetic impact still lingers today. "Some of these contributions may reflect adaptations to environments outside Africa where Neanderthals lived over several hundred thousands of years. During this time, they are likely to have adapted to infectious diseases, which are known to be strong selective factors that may, at least partly, have differed between sub-Saharan Africa and Eurasia," they wrote. The study suggested that the Neanderthal DNA that protects against severe illness may have occurred due to past epidemics that were caused by RNA viruses, a category that includes the coronavirus. A genomic region associated with protection against severe COVID-19 is inherited from Neandertals Hugo Zeberg and Svante Pääbo PNAS March 2, 2021 118 (9) e2026309118; doi.org/10.1073/pnas.2026309118Significance We show that a haplotype on chromosome 12, which is associated with a ∼22% reduction in relative risk of becoming severely ill with COVID-19 when infected by SARS-CoV-2, is inherited from Neandertals. This haplotype is present at substantial frequencies in all regions of the world outside Africa. The genomic region where this haplotype occurs encodes proteins that are important during infections with RNA viruses. 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. Neandertals evolved in western Eurasia about half a million years ago and subsequently lived largely separated from the ancestors of modern humans in Africa (1), although limited gene flow from Africa is likely to have occurred (2⇓⇓–5). Neandertals as well as Denisovans, their Asian sister group, then became extinct about 40,000 y ago (6). However, they continue to have a biological impact on human physiology today through genetic contributions to modern human populations that occurred during the last tens of thousands of years of their existence (e.g., refs. 7⇓⇓–10). Some of these contributions may reflect adaptations to environments outside Africa where Neandertals lived over several hundred thousands of years (11). During this time, they are likely to have adapted to infectious diseases, which are known to be strong selective factors that may, at least partly, have differed between sub-Saharan Africa and Eurasia (12). Indeed, several genetic variants contributed by archaic hominins to modern humans have been shown to affect genes involved in immunity (e.g., refs. 7, 8, 13, 14). In particular, variants at several loci containing genes involved in innate immunity come from Neandertals and Denisovans (15), for example, toll-like receptor gene variants which decrease the susceptibility to Helicobacter pylori infections and the risk for allergies (16). Furthermore, proteins interacting with RNA viruses have been shown to be encoded by DNA regions introgressed from Neandertals more often than expected (17), and RNA viruses might have driven many adaptive events in humans (18). Recently, it was shown that a haplotype in a region on chromosome 3 is associated with becoming critically ill upon infection with the novel severe acute respiratory coronavirus 2 (SARS-CoV-2) (19) and was contributed to modern humans by Neandertals (20). Each copy of this haplotype approximately doubles the risk of its carriers requiring intensive care when infected by SARS-CoV-2. It reaches carrier frequencies of up to ∼65% in South Asia and ∼16% in Europe, whereas it is almost absent in East Asia. Thus, although this haplotype is detrimental for its carriers during the current pandemic, it may have been beneficial in earlier times in South Asia (21), perhaps by conferring protection against other pathogens, whereas it may have been eliminated in East Asia by negative selection. A new study from the Genetic of Mortality in Critical Care (GenOMICC) consortium, which includes 2,244 critically ill COVID-19 patients and controls (22), recently became available. In addition to the risk locus on chromosome 3, it identifies seven loci with genome-wide significant effects located on chromosomes 6, 12, 19, and 21. Here, we show that, at one of these loci, a haplotype associated with reduced risk of becoming severely ill upon SARS-CoV-2 infection is derived from Neandertals.
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Post by Admin on Feb 18, 2021 21:16:17 GMT
Results and Discussion A Neandertal Haplotype on Chromosome 12. We investigated whether the index single-nucleotide polymorphisms (SNPs), that is, the SNPs with the strongest association (Materials and Methods), at the seven loci associated with risk of requiring intensive care upon SARS-CoV-2 infection on chromosomes 6, 12, 19, and 21 (22) harbor Neandertal-like alleles. To this end, we required that one of the alleles of the index SNPs should match all three high-quality Neandertals genomes, while being absent in the genomes of 108 African Yoruba individuals [r2 > 0.80; the 1000 Genomes Project (23)]. None of the index SNPs for the loci on chromosomes 6, 19, and 21 fulfilled these criteria, whereas the locus on chromosome 12 did. To further investigate this locus, we used data from the COVID-19 Host Genetics Initiative [HGI; round 4 (24)]. We find that the SNPs in the chromosome 12 locus associated with COVID-19 hospitalization (P < 1.0e-5; Fig. 1) are in linkage disequilibrium (LD) (r2 ≥ 0.8) in Europeans and form a haplotype of ∼75 kb (chr12: 113,350,796 to 113,425,679; hg19). LD to the index SNP of the GenOMICC study is given in SI Appendix, Table S1. Haplotypes of this length carrying alleles absent in Yoruba but present in Neandertals are likely to have been introduced into the gene pool of modern humans due to interbreeding with Neandertals (25). Fig. 1. Genetic variants associated with COVID-19 hospitalization at the OAS locus. Variants marked in red have P values less than 1e-5. In Europeans, they are in LD with the index variant (r2 ≥ 0.8), forming a haplotype (black bar) with the genomic coordinates chr12: 113,350,796 to 113,425,679. P values are from the HGI (24), excluding the 23andMe data for which only sparse SNP data are available. The x axis gives hg19 coordinates; genes in the region are indicated below. The three OAS genes are transcribed from left to right. Yellow dots indicate rs10735079 (right, the GenOMICC index SNP) and rs1156361 (left, typed by the Human Origins Array). To test whether the 75-kb haplotype is the result of gene flow from Neandertals, we analyzed its relationship to present-day and archaic genomes. To do this, we used the haplotypes seen more than 10 times among the individuals in the 1000 Genomes Project (23) and the genome sequences of a ∼70,000-y-old Neandertal from Chagyrskaya Cave in southern Siberia (26), a ∼50,000-y-old Neandertal from Vindija Cave in Croatia (27), a ∼120,000-y-old Neandertal from Denisova Cave in southern Siberia (1), and a ∼80,000-y-old Denisovan individual from the same site (28). Fig. 2 shows a phylogenetic tree estimating the relationships among these haplotypes. Among the 64 modern human haplotypes, eight form a monophyletic group with the three Neandertal sequences. Fig. 2. Phylogeny relating DNA sequences associated with COVID-19 severity on chromosome 12. Haplotypes from three Neandertal genomes, the Denisovan genome, and haplotypes seen more than 20 times in individuals in the 1000 Genomes Project are included. The colored area indicates haplotypes that carry the protective allele at rs1156361. The tree is rooted with the inferred ancestral sequence from Ensembl (46). Six heterozygous positions in the archaic genomes were excluded. Haplotypes XXIX and XXX are partially made up of Neandertal-like DNA sequences due to recombination events. Genomic segments with similarity to Neandertal genomes may either derive from common ancestors of the two groups that lived about half a million years ago or be contributed by Neandertals to modern humans by mixing between the two groups when they met less than 100,000 y ago (25). To test whether a segment of 75 kb may have survived in this region of the genome since the common ancestor of the groups without being broken down by recombination that affects chromosomes in each generation, we use a published equation (29), a generation time of 29 y (30), a regional recombination rate of 0.80 cM/Mb (31), and a split time between Neandertals and modern humans of 550,000 y (1) followed by interbreeding ∼50,000 y ago. Under these assumptions, in this region, segments of length 16.3 kb or longer are not expected to derive from the population ancestral to Neandertals and modern humans (P = 0.05), making it highly unlikely that a 75-kb haplotype does so (P = 8.2e-9). We thus conclude that the haplotype entered the human gene pool from Neandertals. In agreement with this, a previous study (32) has described gene flow from Neandertals in this genomic region.
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Post by Admin on Feb 19, 2021 7:49:00 GMT
COVID-19 Protection and Geographic Distribution. We find that the index variant of the protective haplotype in the GenOMICC study (rs10735079, P = 1.7e-8) matches all three Neandertal genomes available. The relative risk of needing intensive care is reduced by ∼22% per copy of the Neandertal haplotype (under the rare disease assumption, odds ratio [OR] = 0.78, 95% CI 0.71 to 0.85). As expected given the phylogeny (Fig. 2), almost all of the alleles cosegregating with the protective allele of the index SNP are found in the Neandertal genomes (34 of 35 called SNPs; see SI Appendix, Table S2, which, in contrast to Fig. 1, includes data contributed by 23andMe to HGI). Today, the haplotype is almost completely absent in African populations south of the Sahara but exists at frequencies of ∼25 to 30% in most populations in Eurasia (Fig. 3). In the Americas, it occurs in lower frequencies in some populations of African ancestry, presumably due to gene flow from populations of European or Native American ancestry (33). Fig. 3. Geographic distribution of the allele indicative of the Neandertal haplotype protective against severe COVID-19. Pie charts indicate minor allele frequency in red at rs1156361. Frequency data are from the 1000 Genomes Project (23). Map source data are from OpenStreetMap. Putative Functional Variants. The Neandertal haplotype protective against severe COVID-19 on chromosome 12 contains parts or all of the three genes OAS1, OAS2, and OAS3, which encode oligoadenylate synthetases. These enzymes are induced by interferons and activated by double-stranded RNA. They produce short-chain polyadenylates, which, in turn, activate ribonuclease L, an enzyme that degrades intracellular double-stranded RNA and activates other antiviral mechanisms in cells infected by viruses (reviewed by ref. 34). To investigate which of these genes might be involved in protection against severe COVID-19, we plot the genomic location of the OAS genes below the P values for the SNPs associated with severe COVID-19 (Fig. 1). While the association (P < 1.0e-5) overlaps all three OAS genes, the SNPs with the most significant associations (P < 5.0e-8) are in OAS3. However, the high level of LD and stochasticity in the associations make any conclusion regarding causality based on P values tenuous. Nevertheless, there are alleles on the Neandertal haplotype which stand out as potentially functionally important. One SNP (rs10774671) has been described as affecting a splice acceptor site in OAS1 (35). The derived allele at this SNP, which is the most frequent allele in present-day humans, alters splicing of OAS1 transcript such that several protein isoforms are produced instead of the ancestral isoform which is preserved in Neandertals (p46) (36). The latter, Neandertal-like isoform has higher enzymatic activity than the derived isoforms common in modern humans (37). Outside Africa, the ancestral allele is present only in the context of the Neandertal haplotype, whereas, in Africa, it exists independently of this haplotype, presumably as a genetic variant inherited from the common ancestors of modern humans and Neandertals that was lost in modern human populations that left Africa (35). In addition to the splice acceptor site, the Neandertal haplotype contains a missense variant (rs2660) in OAS1, a missense variant (rs1859330) and two synonymous variants (rs1859329 and rs2285932) in OAS3, and a missense variant in OAS2 (rs1293767). Three of these Neandertal-like variants are ancestral and occur in Africa (rs2660, rs1859330, and rs1859329), whereas two are derived in Neandertals (rs2285932 and rs1293767). Several SNPs on the chromosome 12 haplotype have previously been studied with respect to their effects on other viral infections. The Neandertal-like splice acceptor variant has been associated with protection against West Nile Virus (rs10774671, OR = 0.63, 95% CI 0.5–0.83) (38), and the Neandertal-like haplotype has been associated with increased resistance to hepatitis C infections (39). Notably, the Neandertal missense variant in OAS1 (rs2660) (or variants in LD with this variant) has been shown to be associated with moderate to strong protection against SARS-CoV [OR = 0.42, 95% CI: 0.20 to 0.89 (40)], although this study was limited in numbers of cases and controls. The SARS-CoV is closely related to SARS-CoV-2, emerged in 2003, and caused a mortality rate of ∼9% among infected individuals of all ages, and much higher rates of fatalities in older individuals (41). Finally, the Neandertal versions of the OAS genes are expressed differently in response to different viral infections in cells in tissue culture in terms of both expression levels and splice forms (35)
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Post by Admin on Feb 19, 2021 19:34:08 GMT
Haplotype Frequencies across Time. During the past few years, genome-wide data from thousands of prehistoric humans have been generated and compiled (42). This makes it possible to begin to directly gauge how frequencies of genetic variants have changed over time. Although this approach is still limited by the relatively small numbers of individuals and geographic regions for which data are available, we apply it here for the two Neandertal-derived haplotypes that affect the clinical outcomes upon infection with SARS-CoV-2. To tag the Neandertal OAS haplotype on chromosome 12, we use an SNP (rs1156361) that carries a derived Neandertal-like allele, is associated with the index variant of the GenOMICC study (r2 = 0.99 in Eurasia), and is typed by the Affymetrix Human Origins array used to study the majority of ancient human genomes used here (42). Although this analysis is limited in that it tracks a single tag SNP, the fact that it is derived on the Neandertal lineage and in LD with the Neandertal haplotype makes this analysis feasible. We restrict the analysis to Eurasia and divide the data into five time windows that vary between 20,000 and 2,000 y in length, to balance the number of genomes available while still allowing potential differences in frequency to be discerned. Fig. 4A shows that the Neandertal OAS haplotype seems to have occurred at frequencies below 10% prior to 20,000 y ago. Between 20,000 and 10,000 y ago, the allele frequency was in the order of 15%. Subsequently, it seems to have been present at frequencies at or slightly below 20% until 3,000 y to 1,000 y ago. Intriguingly, the current allele frequency in Eurasia is ∼30%, suggesting that the Neandertal OAS haplotype may have increased in frequency relatively recently. Fig. 4. Frequencies across time of two Neandertal haplotypes associated with COVID-19 severity. Frequencies for rs1156361 at the OAS locus on chromosome 12 (A) and rs10490770 at the chromosome 3 locus (B). Error bars indicate SE (Wilson scores). Time periods are indicated in years before present (bp). Ancient data are from a compiled dataset (42), and present-day data are from the 1000 Genomes Project (23). To similarly estimate the frequency of the Neandertal risk haplotype on chromosome 3 (20), we use the SNP rs10490770 that fulfills the criteria applied above for the chromosome 12 haplotype (Fig. 4B). Prior to 20,000 y ago, we find no carrier of the risk haplotype among 16 genomes available. Among individuals who lived between 20,000 and 10,000 y ago and later, the haplotype is present in ∼10% until today, when it occurs at a frequency of ∼12.5%. Thus, similar to the OAS locus, the Neandertal chromosome 3 locus, the frequency seems to be lower in the period prior to 20,000 y ago than in the later periods. However, the data are still scarce, making this observation preliminary. In contrast to the OAS locus, there is no indication of any increase in the frequency of the Neandertal haplotype on chromosome 3 in historical times. We caution that the prehistoric data available are heavily biased toward western Eurasia and are still sparse, particularly for older periods. However, additional data from ancient human remains are rapidly being generated, making us confident that it will soon be possible to identify loci that may have been the targets of positive and negative selection, by studying allele frequencies over time in certain geographical regions while correcting for migration events that caused genome-wide shifts in allele frequencies. Despite theses caveats, it is interesting that the Neandertal-derived OAS locus has recently increased in frequency in Eurasia. This is compatible with previous work on the variation among present-day populations (32, 35, 43) suggesting that this locus has been positively selected. It is also compatible with Denisovans having contributed a version of this locus, which carries ancestral variants, for example, at the slice acceptor site (rs10774671), to people in Oceania, where it occurs at substantial frequencies today (44).
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