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Aberdeen New India Investment Trust PLC GBP — Aberdeen New India Investment Trust — Technical Presentation (April 2022)
48 slides from Aberdeen New India Investment Trust PLC GBP's technical presentation, Apr 20, 2022
Slide 1: Exploring evolutionary immunogenomics: Lessons from our ancestors and past pandemics
Science Exploring evolutionary immunogenomics: Lessons from our ancestors and past pandemics 20 Apr 2022 Participating expert: Luis Barreiro, Ph.D. University of Chicago Chicago, IL Sponsored by 10x Science GENOMICS Brought to you by the Science/AAAS Custom Publishing Office AVAAAS
Slide 2: Instructions for viewers
Science Instructions for viewers ¢ Toshare webinar via social media [a oO in | ce | ¢ To share webinar via email: G ¢ To see speaker biographies, click: View Bio under speaker name ¢ To ask a question, click the Ask A Question tab to the right Sponsored by 10x Science GENOMICS Brought to you by the
Slide 3: Exploring evolutionary immunogenomics: Lessons from our ancestors and past pandemics
Exploring evolutionary immunogenomics: Lessons from our ancestors and past pandemics. Luis Barreiro University of Chicago email: |barreiro@uchicago.edu VW @LB Barreiro
Slide 4: Pathogens have been the strongest selective pressure through human evolution
Pathogens have been the strongest selective pressure through human evolution Alexander Fleming Survival (%) 1928: Discover of penicillin, the first natural antibiotic. Louis Pasteur 1885: rabies vaccine. Vaccines against diphtheria, tetanus, anthrax, cholera, plague, typhoid, tuberculosis, and more
Slide 5: The molecular traces of natural selection in the human genome
The molecular traces of natural selection in the human genome Time (# of generations) neutrality positive selection Neutrality tests
Slide 6: Natural selection on the immune system
Natural selection on the immune system Inter-species level Within human populations Kosiol et al. (2008) PLoS Genetics Barreiro & Quintana-Murci (2009) Nature Reviews Genetics Barreiro et al (2008) Nature Genetics
Slide 7: Our approach to study selection on immune-related processes
Our approach to study selection on immune-related processes a = ee
Slide 8: Outline
Outline a ae |. Ancestry-associated differences in immune responses . Variation in immune responses to bacterial pathogens . Single cell resolution map of immune variation to flu infection . The impact of past pandemics to the evolution of immune responses EAT ET
Slide 9: African origin of modern humans
AFRICAN ORIGIN OF MODERN HUMANS 20 kya humans arrive to North Asia 40 kya humans enter Europe ~15 kya humans arrive to the Americas Homo sapiens ~200 kya 60 kya the first humans leave Africa 50 kya they reach Australia
Slide 10: Genetic Ancestry Drives Population Differences in Immune Responses to Pathogens
Genetic Ancestry Drives Population Differences in Immune Responses to Pathogens Over 20% of genes responding to either infection show a significant difference in the intensity of the response between European and African individuals. Increased African ancestry is associated with a stronger transcrip
Slide 11: Natural Selection Contributed to Ancestry-Associated Differences in Immune response
Natural Selection Contributed to Ancestry-Associated Differences in Immune response CEU o 1 liHS| value : po rh ay f it ey a pi! pF fe $ 7 34 ae és o , liH'S| value
Slide 12: I. Ancestry-associated differences in immune responses
I. Ancestry-associated differences in immune responses . Single cell resolution map of immune variation to flu infection tA
Slide 13: Ancestry differences in immune regulation at single cell resolution
Ancestry differences in immune regulation at single cell resolution Haley Randolph 90 individuals REAR DAD Bi iiicorancesay” single-cell RNAseq 236,993 cells mock and IAV culture PBMCs infect with i} HATH influenza A/Cal/04/09 180 samples, paired mock-exposed and IAV-infected (MOI = 0.5) samples fro
Slide 14: Clustering separates cells into five major populations
Clustering separates cells into five major populations Dataset: 235,161 high-quality RNA-seq profiles retained after filtering CD4*T 5 10 15
Slide 15: Monocytes are the most responsive to IAV infection
RESULTS | Monocytes are the most responsive to IAV infection •38% of the monocyte transcriptome changes in response to IAV infection
Slide 16: Differences in immune response between African- and European-ancestry individuals
RESULTS | Differences in immune response between African- and European-ancestry individuals _ — * Collected low-pass (4X) whole-genome sequencing for the 90 individuals in the study. - After imputation we obtained genotypes across >60 million SNPs per individual. proportion genetic ancestry
Slide 17: Differences in immune response between African- and European-ancestry individuals
RESULTS | Differences in immune response between African- and European-ancestry individuals Population Differently Expressed genes Population Differently Responsive genes pop-DE genes pop-DR genes log2 fold change Gene expression
Slide 18: Most genetic ancestry effects are cell-type specific
RESULTS | Most genetic ancestry effects are cell-type specific ~52% of popDE genes identified in only one or two cell types
Slide 19: Interferon pathways exhibit higher expression in individuals with increased European ancestry
RESULTS | Interferon pathways exhibit higher expression in individuals with increased European ancestry mock IAV
Slide 20: Interferon pathways exhibit higher expression in individuals with increased European ancestry
RESULTS | Interferon pathways exhibit higher expression in individuals with increased European ancestry Mean Pearson’s r across Pearson’s Mean cell types = r-0.005 across cell types = -0.26 Fisher’s meta-p = 0.75 Fisher’s meta-p = 2.9x10-6 European-ancestry individuals engage a stronger interferon r
Slide 21: An early stronger interferon response is associated with better viral clearance
RESULTS | An early stronger interferon response is associated with better viral clearance at later time points Individuals better able to mount type I IFN responses shortly after infection are also better able to limit viral replication at later time points.
Slide 22: Genetic drivers of population differences in immune response
RESULTS | Genetic drivers of population differences in immune response eGenes were 3.2 to 6.5 X more We identified 2,234 genes (eGenes) that are likely be classified as popDE than Cis eQTL associated with at least one cis-eQTL expected by chance TLR4 TLR4
Slide 23: Genetic drivers of population differences in immune response
RESULTS | Genetic drivers of population differences in immune response Among popDE genes in which we identify at least one cis-eQTL across cell types and conditions, we estimate that, on average, cis-eQTLs explain approximately 53% of the variance in the observed population differences
Slide 24: Do ancestry-associated immune differences underlie variation in COVID-19 susceptibility?
Do genetic ancestry-associated differences in immune responses partially underlie some of the observed variation in COVID-19 susceptibility? • Association with age, sex, race/ethnicity, and underlying comorbidities and risk of COVID-19 hospitalization • CDC estimates a 79% higher rate of influenza-r
Slide 25: Can ancestry-associated differences in immune response explain COVID-19 health disparities?
RESULTS | Can ancestry-associated differences in immune response to viruses explain health disparities in COVID-19 outcomes? • COVID-19 patients with scRNA-seq data on PBMCs collected shortly after initial diagnosis •n = 127 patients, 505,616 cells total •Disease severity measured by WHO ordinal sca
Slide 26: Some take home messages
Some take home messages: + Genetic ancestry effects on the immune response to IAV are common but highly cell type specific. + Increased European ancestry is associated with a stronger type | IFN response shortly after influenza infection, which in turn predicts reduced viral titers at later time poi
Slide 27: II. The impact of past pandemics to the evolution of immune responses
Il. Ancestry-associated differences in immune responses . The impact of past pandemics to the evolution of immune responses
Slide 28: COVID-19 susceptibility and past selective events
COVID-19 susceptibility and past selective events Article The major genetic risk factor for severe COVID-19 is inherited from Neanderthals medicine se ARTICIES Bee wr sone A Neanderthal OAS1 isoform protects individuals of European ancestry against COVID-19 susceptibility and severity
Slide 29: Black Death (1346-1353 CE)
Black Death (1346-1353 CE), which was caused by¥ Europe, killing 30-50% of the ~~ 2
Slide 30: Hypothesis
Hypothesis @ Neutral variant Allele Frequency ----- Pre-BD BD Post-BD Present
Slide 31: Hypothesis
Hypothesis @ Neutral variant @ Advantageous variant Allele Frequency ----- Pre-BD BD Post-BD Present
Slide 32: Slide 32
Slide 33: Study-design
Study-design: Studied genetic variation around immune-related genes from 321 ancient DNA samples from two European populations directly before, during, and after the Black Death Targeted enrichment for: Exons: exons from 356 immune- related genes. Neutral loci: 200 regions of 1.5kb. GWAS loci: 446 S
Slide 34: Immune loci are strongly enriched for highly differentiated sites
Immune loci are strongly enriched for highly differentiated sites For variants with a MAF>30% highly-differentiated sites are found at 3.9x the rate expected by chance (binomial test p = 1.16x10-14)
Slide 35: Immune loci are strongly enriched for highly differentiated sites
Immune loci are strongly enriched for highly differentiated sites We identified 245 variants that are highly differentiated within London
Slide 36: Functional impact of putatively selected loci
Functional impact of putatively selected loci pests a @8 / ND 2 SS vector / = unstimulated 24h IO) cells bulk sequencing of macrophages single-cell sequencing of PBMCs Mari Cobb & Anne Dumaine
Slide 37: Functional impact of putatively selected loci
Functional impact of putatively selected loci Macrophages from 30 individuals infected with Y. Pestis locus 1 locus 2 locus 3 locus 4 (tag SNP: rs2549794) (1817473484) (rs1052025) (rs11571319) > expression following infection (log2 fold-change) o fl ERAP1 ERAP2 LNPEP TICAM2 TMED7 Icos CTLA4
Slide 38: The protective allele is associated with increased levels of ERAP2
The protective allele is associated with increased levels of ERAP2 normalized expression Se nce ERAP2 Not-Infected Infected Tr #TiC = ClC TT TiC Clic 182549794 genotype - aA ON @
Slide 39: The protective allele is associated with increased levels of ERAP2
The protective allele is associated with increased levels of ERAP2 PBMCs using single-cell RNA sequencing, on a panel of 10 individuals, 5 of which were homozygous for the protective rs2549794 C allele and 5 of which are homozygous for the T allele 15 B cells Monocytes a CD4+ T cells 5 10 A | ee -10
Slide 40: The protective allele is associated with increased levels of ERAP2
The protective allele is associated with increased levels of ERAP2 ERAP2 Expression relative expression UMAP_1 0 025 05 075 1
Slide 41: The protective allele is associated with increased levels of ERAP2
The protective allele is associated with increased levels of ERAP2 Andres et al. 2010 (PLoS Genetics)
Slide 42: Increased ERAP2 seems to have been protective during Black Death
Increased ERAP2 seems to have been protective during Black Death ERAP1 and ERAP2 are aminopeptidases that work synergistically to trim peptides so that they can be presented to CD8+ T cells by MHC class I Lorente, et al. (2020) Bergman, et al. (2009)
Slide 43: Functional depiction of ERAP2 protective allele
Functional depiction of ERAP2 protective allele Is the ERAP2 genotype was associated with variation in the cytokine response to Y. pestis infection? What we did: we infected MDMs from 25 individuals with virulent Y. pestis and measured the protein levels of 10 cytokines involved in various aspects o
Slide 44: Some take home messages
Some take home messages: Black Death was an important selective force that shaped genetic diversity around some immune loci. We speculate that the selective advantage provided by the ERAP2 variant stems from an increased ability to present Yersinia-derived antigens to CD8* T cells and/or variation i
Slide 45: Thanks to those who actually did the work
Thanks to those who actually did the work… Research Assistants Key Collaborators: Flu project Ryan Langlois (U Minnesota) Pestis Hendrik Poinar (McMaster U) Anne Dumaine Vania Yotova Renata Sindeaux Mari Cobb Saideep Gonna Javier Pizarro-Cerda (Pasteur) Lab Manager Lab Manager R. Assistant R. Assist
Slide 46: Exploring evolutionary immunogenomics: Lessons from our ancestors and past pandemics
Science Exploring evolutionary immunogenomics: Lessons from our ancestors and past pandemics Sponsored by 10x GENOMICS the Ask a Question tab on the right Q & To ask a question, click Luis Barreiro, Ph.D. University of Chicago Chicago, IL Brought to you by the Science/AAAS Custom Publishing Office 2
Slide 47: Look out for more webinars in the series
Science Exploring evolutionary immunogenomics: Lessons from our ancestors and past pandemics 20 Apr 2022 Look out for more webinars in the series at: science.org/webinars To provide feedback on this webinar, please email your comments to webinar @aaas.org Sponsored by 10x Science GENOMICS Brought to
Slide 48: On-demand version being prepared
Science Exploring evolutionary immunogenomics: Lessons from our ancestors and past pandemics ; " ‘ . 20 Apr 2022 The on-demand version of this webinar is currently being prepared. You will receive an email notification when the archive is ready for viewing. Thank you for your patience. Sponsored by
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