Idiopathic collapsing glomerulopathy is associated with APOL1 high-risk genotypes or Mendelian variants in most affected individuals in a highly admixed population.

Collapsing glomerulopathy (CG) is most often associated with fast progression to kidney failure with an incidence apparently higher in Brazil than in other countries. However, the reason for this occurrence is unknown. To better understand this, we performed an integrated analysis of clinical, histological, therapeutic, causative genetic and genetic ancestry data in a highly genetically admixed cohort of 70 children and adult patients with idiopathic CG (ICG). The disease onset occurred at 23 (interquartile range: 17-31) years and approximately half of patients progressed to chronic kidney disease requiring kidney replacement therapy (CKD-KRT) 36 months after diagnosis. Causative genetic bases, assessed by targeted-gene panel or whole-exome sequencing, were identified in 58.6% of patients. Among these cases, 80.5% harbored APOL1 high-risk genotypes (HRG) and 19.5% causative Mendelian variants (MV). Self-reported non-White patients more frequently had HRG. MV was an independent risk factor for progression to CKD-KRT by 36 months and the end of follow-up, while remission was an independent protective factor. All patients with HRG manifested CG at 9-44 years of age, whereas in those with APOL1 low-risk genotype, the disease arose throughout life. HRGs were associated with higher proportion of African genetic ancestry. Novel causative MVs were identified in COL4A5, COQ2 and PLCE1 and previously described causative MVs were identified in MYH9, TRPC6, COQ2, COL4A3 and TTC21B. Three patients displayed HRG combined with a variant of uncertain significance (ITGB4, LAMA5 or PTPRO). MVs were associated with worse kidney prognosis. Thus, our data reveal that the genetic status plays a major role in ICG pathogenesis, accounting for more than half of cases in a highly admixed Brazilian population.

Population Histories and Genomic Diversity of South American Natives.

South America is home to one of the most culturally diverse present-day native populations. However, the dispersion pattern, genetic substructure, and demographic complexity within South America are still poorly understood. Based on genome-wide data of 58 native populations, we provide a comprehensive scenario of South American indigenous groups considering the genomic, environmental, and linguistic data. Clear patterns of genetic structure were inferred among the South American natives, presenting at least four primary genetic clusters in the Amazonian and savanna regions and three clusters in the Andes and Pacific coast. We detected a cline of genetic variation along a west-east axis, contradicting a hard Andes-Amazon divide. This longitudinal genetic variation seemed to have been shaped by both serial population bottlenecks and isolation by distance. Results indicated that present-day South American substructures recapitulate ancient macroregional ancestries and western Amazonia groups show genetic evidence of cultural exchanges that led to language replacement in precontact times. Finally, demographic inferences pointed to a higher resilience of the western South American groups regarding population collapses caused by the European invasion and indicated precontact population reductions and demic expansions in South America.

Genomic insight into the origins and dispersal of the Brazilian coastal natives.

In the 15th century, ∼900,000 Native Americans, mostly Tupí speakers, lived on the Brazilian coast. By the end of the 18th century, the coastal native populations were declared extinct. The Tupí arrived on the east coast after leaving the Amazonian basin ∼2,000 y before present; however, there is no consensus on how this migration occurred: toward the northern Amazon and then directly to the Atlantic coast, or heading south into the continent and then migrating to the coast. Here we leveraged genomic data from one of the last remaining putative representatives of the Tupí coastal branch, a small, admixed, self-reported Tupiniquim community, as well as data of a Guaraní Mbyá native population from Southern Brazil and of three other native populations from the Amazonian region. We demonstrated that the Tupiniquim Native American ancestry is not related to any extant Brazilian Native American population already studied, and thus they could be considered the only living representatives of the extinct Tupí branch that used to settle the Atlantic Coast of Brazil. Furthermore, these data show evidence of a direct migration from Amazon to the Northeast Coast in pre-Columbian time, giving rise to the Tupí Coastal populations, and a single distinct migration southward that originated the Guaraní people from Brazil and Paraguay. This study elucidates the population dynamics and diversification of the Brazilian natives at a genomic level, which was made possible by recovering data from the Brazilian coastal population through the genomes of mestizo individuals.

The oldest unvaccinated Covid-19 survivors in South America.

BACKGROUND: Although older adults are at a high risk of severe or critical Covid-19, there are many cases of unvaccinated centenarians who had a silent infection or recovered from mild or moderate Covid-19. We studied three Brazilian supercentenarians, older than 110 years, who survived Covid-19 in 2020 before being vaccinated. RESULTS: Despite their advanced age, humoral immune response analysis showed that these individuals displayed robust levels of IgG and neutralizing antibodies (NAbs) against SARS-CoV-2. Enrichment of plasma proteins and metabolites related to innate immune response and host defense was also observed. None presented autoantibodies (auto-Abs) to type I interferon (IFN). Furthermore, these supercentenarians do not carry rare variants in genes underlying the known inborn errors of immunity, including particular inborn errors of type I IFN. CONCLUSION: These observations suggest that their Covid-19 resilience might be a combination of their genetic background and their innate and adaptive immunity.

Genetic signatures of gene flow and malaria-driven natural selection in sub-Saharan populations of the "endemic Burkitt Lymphoma belt".

Populations in sub-Saharan Africa have historically been exposed to intense selection from chronic infection with falciparum malaria. Interestingly, populations with the highest malaria intensity can be identified by the increased occurrence of endemic Burkitt Lymphoma (eBL), a pediatric cancer that affects populations with intense malaria exposure, in the so called "eBL belt" in sub-Saharan Africa. However, the effects of intense malaria exposure and sub-Saharan populations' genetic histories remain poorly explored. To determine if historical migrations and intense malaria exposure have shaped the genetic composition of the eBL belt populations, we genotyped ~4.3 million SNPs in 1,708 individuals from Ghana and Northern Uganda, located on opposite sides of eBL belt and with ≥ 7 months/year of intense malaria exposure and published evidence of high incidence of BL. Among 35 Ghanaian tribes, we showed a predominantly West-Central African ancestry and genomic footprints of gene flow from Gambian and East African populations. In Uganda, the North West population showed a predominantly Nilotic ancestry, and the North Central population was a mixture of Nilotic and Southern Bantu ancestry, while the Southwest Ugandan population showed a predominant Southern Bantu ancestry. Our results support the hypothesis of diverse ancestral origins of the Ugandan, Kenyan and Tanzanian Great Lakes African populations, reflecting a confluence of Nilotic, Cushitic and Bantu migrations in the last 3000 years. Natural selection analyses suggest, for the first time, a strong positive selection signal in the ATP2B4 gene (rs10900588) in Northern Ugandan populations. These findings provide important baseline genomic data to facilitate disease association studies, including of eBL, in eBL belt populations.

Biased pathogenic assertions of loss of function variants challenge molecular diagnosis of admixed individuals.

Diagnosis of individuals affected by monogenic disorders was significantly improved by next-generation sequencing targeting clinically relevant genes. Whole exomes yield a large number of variants that require several filtering steps, prioritization, and pathogenicity classification. Among the criteria recommended by ACMG, those that rely on population databases critically affect analyses of individuals with underrepresented ancestries. Population-specific allelic frequencies need consideration when characterizing potential deleteriousness of variants. An orthogonal input for classification is annotation of variants previously classified as pathogenic as a criterion that provide supporting evidence widely sourced at ClinVar. We used a whole-genome dataset from a census-based cohort of 1,171 elderly individuals from São Paulo, Brazil, highly admixed, and unaffected by severe monogenic disorders, to investigate if pathogenic assertions in ClinVar are enriched with higher proportions of European ancestry, indicating bias. Potential loss of function (pLOF) variants were filtered from 4,250 genes associated with Mendelian disorders and annotated with ClinVar assertions. Over 1,800 single nucleotide pLOF variants were included, 381 had non-benign assertions. Among carriers (N = 463), average European ancestry was significantly higher than noncarriers (N = 708; p = .011). pLOFs in genomic contexts of non-European local ancestries were nearly three times less likely to have any ClinVar entry (OR = 0.353; p <.0001). Independent pathogenicity assertions are useful for variant classification in molecular diagnosis. However, European overrepresentation of assertions can promote distortions when classifying variants in non-European individuals, even in admixed samples with a relatively high proportion of European ancestry. The investigation and deposit of clinically relevant findings of diverse populations is fundamental improve this scenario.

An immunogenetic view of COVID-19.

Meeting the challenges brought by the COVID-19 pandemic requires an interdisciplinary approach. In this context, integrating knowledge of immune function with an understanding of how genetic variation influences the nature of immunity is a key challenge. Immunogenetics can help explain the heterogeneity of susceptibility and protection to the viral infection and disease progression. Here, we review the knowledge developed so far, discussing fundamental genes for triggering the innate and adaptive immune responses associated with a viral infection, especially with the SARS-CoV-2 mechanisms. We emphasize the role of the HLA and KIR genes, discussing what has been uncovered about their role in COVID-19 and addressing methodological challenges of studying these genes. Finally, we comment on questions that arise when studying admixed populations, highlighting the case of Brazil. We argue that the interplay between immunology and an understanding of genetic associations can provide an important contribution to our knowledge of COVID-19.

Genetic signature of natural selection in first Americans.

When humans moved from Asia toward the Americas over 18,000 y ago and eventually peopled the New World they encountered a new environment with extreme climate conditions and distinct dietary resources. These environmental and dietary pressures may have led to instances of genetic adaptation with the potential to influence the phenotypic variation in extant Native American populations. An example of such an event is the evolution of the fatty acid desaturases (FADS) genes, which have been claimed to harbor signals of positive selection in Inuit populations due to adaptation to the cold Greenland Arctic climate and to a protein-rich diet. Because there was evidence of intercontinental variation in this genetic region, with indications of positive selection for its variants, we decided to compare the Inuit findings with other Native American data. Here, we use several lines of evidence to show that the signal of FADS-positive selection is not restricted to the Arctic but instead is broadly observed throughout the Americas. The shared signature of selection among populations living in such a diverse range of environments is likely due to a single and strong instance of local adaptation that took place in the common ancestral population before their entrance into the New World. These first Americans peopled the whole continent and spread this adaptive variant across a diverse set of environments.

Dietary inclusion of dehydrated bocaiuva pulp increases the antioxidant potential of quail eggs.

The aim of this study was to evaluate dietary supplementation of different levels of dehydrated bocaiuva pulp (DBP) on the productive performance of laying quails, and on lipid oxidation, and quality in their eggs. A total of 120 quails were distributed in a completely randomized design with six treatments (0%, 0.1%, 0.2%, 0.3%, 0.4% and 0.5% of DBP), five replicates and four birds per experimental unit. To evaluate lipid oxidation, the eggs were collected on five consecutive days at the end of the trial and distributed in a completely randomized experimental design in a 6 × 5 factorial scheme (eggs from quails fed different levels of DBP × evaluated fresh and after 7, 14, 21 and 28 days). The antioxidant potential of diets was improved (p < 0.05) when the DBP was added estimated as 2,2'-azinobis-3-ethylbenzothiazolin-6-sulfonic acid (ABTS) free radical scavenging capacity. No effect (p > 0.05) was observed on feed intake, hen-day egg production and feed conversion (kg/kg and kg/dz). There were no changes (p > 0.05) in the egg weight, Haugh unit, yolk index or eggshell percentage. Although no difference was observed (p > 0.05), when comparing each level with the control, a negative linear effect (p < 0.05) on specific gravity was observed. In addition, only the treatment with 0.5% pulp exhibited lower (p < 0.05) eggshell thickness compared with the control (0%). Thiobarbituric acid reactive substances (TBARS) analysis showed that as the dietary pulp level was increased, malondialdehyde content decreased linearly (p < 0.05) in the egg yolks, regardless of the storage period. Inclusion of DBP in the diets had no effect (p > 0.05) on the concentration of conjugated dienes in the eggs. The diets containing DBP showed a potential antioxidant effect, reducing the degree of lipid oxidation in egg yolk. However, no beneficial effects were observed on performance and egg quality.

A genomic perspective on HLA evolution.

Several decades of research have convincingly shown that classical human leukocyte antigen (HLA) loci bear signatures of natural selection. Despite this conclusion, many questions remain regarding the type of selective regime acting on these loci, the time frame at which selection acts, and the functional connections between genetic variability and natural selection. In this review, we argue that genomic datasets, in particular those generated by next-generation sequencing (NGS) at the population scale, are transforming our understanding of HLA evolution. We show that genomewide data can be used to perform robust and powerful tests for selection, capable of identifying both positive and balancing selection at HLA genes. Importantly, these tests have shown that natural selection can be identified at both recent and ancient timescales. We discuss how findings from genomewide association studies impact the evolutionary study of HLA genes, and how genomic data can be used to survey adaptive change involving interaction at multiple loci. We discuss the methodological developments which are necessary to correctly interpret genomic analyses involving the HLA region. These developments include adapting the NGS analysis framework so as to deal with the highly polymorphic HLA data, as well as developing tools and theory to search for signatures of selection, quantify differentiation, and measure admixture within the HLA region. Finally, we show that high throughput analysis of molecular phenotypes for HLA genes-namely transcription levels-is now a feasible approach and can add another dimension to the study of genetic variation.

Inferring paternal history of rural African-derived Brazilian populations from Y chromosomes.

OBJECTIVES: Quilombo remnants are relics of communities founded by runaway or abandoned African slaves, but often with subsequent extensive and complex admixture patterns with European and Native Americans. We combine a genetic study of Y-chromosome markers with anthropological surveys in order to obtain a portrait of quilombo structure and history in the region that has the largest number of quilombo remnants in the state of São Paulo. METHODS: Samples from 289 individuals from quilombo remnants were genotyped using a set of 17 microsatellites on the Y chromosome (AmpFlSTR-Yfiler). A subset of 82 samples was also genotyped using SNPs array (Axiom Human Origins-Affymetrix). We estimated haplotype and haplogroup frequencies, haplotype diversity and sharing, and pairwise genetic distances through FST and RST indexes. RESULTS: We identified 95 Y chromosome haplotypes, classified into 15 haplogroups. About 63% are European, 32% are African, and 6% Native American. The most common were: R1b (European, 34.2%), E1b1a (African, 32.3%), J1 (European, 6.9%), and Q (Native American, 6.2%). Genetic differentiation among communities was low (FST = 0.0171; RST = 0.0161), and haplotype sharing was extensive. Genetic, genealogical and oral surveys allowed us to detect five main founder haplotypes, which explained a total of 27.7% of the Y chromosome lineages. CONCLUSIONS: Our results showed a high European patrilineal genetic contribution among the founders of quilombos, high amounts of gene flow, and a recent common origin of these populations. Common haplotypes and genealogical data indicate the origin of quilombos from a few male individuals. Our study reinforces the importance of a dual approach, involving the analysis of both anthropological and genetic data.

Estimation of inbreeding and substructure levels in African-derived Brazilian quilombo populations.

This article deals with the estimation of inbreeding and substructure levels in a set of 10 (later regrouped as eight) African-derived quilombo communities from the Ribeira River Valley in the southern portion of the state of São Paulo, Brazil. Inbreeding levels were assessed through F-values estimated from the direct analysis of genealogical data and from the statistical analysis of a large set of 30 molecular markers. The levels of population substructure found were modest, as was the degree of inbreeding: in the set of all communities considered together, F-values were 0.00136 and 0.00248 when using raw and corrected data from their complete genealogical structures, respectively, and 0.022 and 0.036 when using the information taken from the statistical analysis of all 30 loci and of 14 single-nucleotide polymorphic loci, respectively. The overall frequency of consanguineous marriages in the set of all communities considered together was ∼ 2%. Although modest, the values of the estimated parameters are much larger than those obtained for the overall Brazilian population and in general much smaller than the ones recorded for other Brazilian isolates. To circumvent problems related to heterogeneous sampling and virtual absence of reliable records of biological relationships, we had to develop or adapt several methods for making valid estimates of the prescribed parameters.

Genomic Exploration of Essential Hypertension in African-Brazilian Quilombo Populations: A Comprehensive Approach with Pedigree Analysis and Family-Based Association Studies.

Essential Hypertension (EH) is a major global health concern, causing about 9.4 million deaths annually. Its prevalence varies across different regions, affecting 17% of the population in the Americas, 19.2% in the Western Pacific, 23.2% in Europe, 25.1% in Southeast Asia, 26.3% in the Eastern Mediterranean, and 27.2% in Africa. EH is a multifactorial disease influenced by both genetic and environmental factors. While genetic factors contribute 30-60% to blood pressure variation, the genetic complexity of EH remains largely unexplained due to limited knowledge of candidate genes and population-specific differences. Various methods, including candidate gene studies, genome-wide linkage analysis (GWLA), and genome-wide association studies (GWAS), have been employed to identify genetic factors, yet much of the heritability of EH is still unknown. This study aimed to investigate the genetic basis of EH by mapping regions of interest (ROIs) and identifying candidate genes and variants influencing EH in African-derived individuals from partially isolated populations of quilombo remnants in Vale do Ribeira, São Paulo, Brazil. Samples from 431 individuals (167 affected, 261 unaffected, 3 with unknown phenotype) from eight quilombo remnant populations were genotyped using a 650k SNP array. The global ancestry proportions were estimated at 47% African, 36% European, and 16% Native American. Genealogical information from 673 individuals was used to construct six pedigrees comprising 1104 individuals. The mapping strategy consisted of a multi-level computational approach. We constructed pedigrees based on interviews and kinship coefficient, pruned the dataset to obtain three non-overlapping markers subpanels, phased the haplotype and performed local ancestry to account for admixture. We performed GWLA and dense linkage analyses using markers subpanels and performed fine-mapping using family-based association studies (FBAS) based on population and pedigree imputed data, investigating EH-related genes and variants. The linkage analysis identified 22 ROIs with LOD scores 1.45-3.03, containing markers co-segregating with the phenotype. These ROIs encompassed 2363 genes. Fine-mapping identified 60 EH-related candidate genes and 118 suggestive or significant variants (FBAS). Among these, 14 genes, including PHGDH, S100A10, MFN2, and RYR2, were highlighted with strong evidence of association with hypertension. These genes, harboring 29 SNPs, were implicated in regulating blood pressure, sodium and potassium levels, and the aldosterone pathway. This study revealed, through a complementary approach - combining admixture-adjusted genome-wide linkage analysis based on Markov chain Monte Carlo (MCMC) methods, association studies on imputed data, and in silico investigations - genetic regions, variants and candidate genes that shed light on the genetic basis of essential hypertension, with significant potential to explain the genetic etiology in quilombo remnant populations.

Indigenous people from Amazon show genetic signatures of pathogen-driven selection.

Ecological conditions in the Amazon rainforests are historically favorable for the transmission of numerous tropical diseases, especially vector-borne diseases. The high diversity of pathogens likely contributes to the strong selective pressures for human survival and reproduction in this region. However, the genetic basis of human adaptation to this complex ecosystem remains unclear. This study investigates the possible footprints of genetic adaptation to the Amazon rainforest environment by analyzing the genomic data of 19 native populations. The results based on genomic and functional analysis showed an intense signal of natural selection in a set of genes related to Trypanosoma cruzi infection, which is the pathogen responsible for Chagas disease, a neglected tropical parasitic disease native to the Americas that is currently spreading worldwide.

Immunological evaluation of young unvaccinated patients with Turner syndrome after COVID-19.

OBJECTIVES: The X-chromosome contains the largest number of immune-related genes, which play a major role in COVID-19 symptomatology and susceptibility. Here, we had a unique opportunity to investigate, for the first time, COVID-19 outcomes in six unvaccinated young Brazilian patients with Turner syndrome (TS; 45, X0), including one case of critical illness in a child aged 10 years, to evaluate their immune response according to their genetic profile. METHODS: A serological analysis of humoral immune response against SARS-CoV-2, phenotypic characterization of antiviral responses in peripheral blood mononuclear cells after stimuli, and the production of cytotoxic cytokines of T lymphocytes and natural killer cells were performed in blood samples collected from the patients with TS during the convalescence period. Whole exome sequencing was also performed. RESULTS: Our volunteers with TS showed a delayed or insufficient humoral immune response to SARS-CoV-2 (particularly immunoglobulin G) and a decrease in interferon-γ production by cluster of differentiation (CD)4+ and CD8+ T lymphocytes after stimulation with toll-like receptors 7/8 agonists. In contrast, we observed a higher cytotoxic activity in the volunteers with TS than the volunteers without TS after phorbol myristate acetate/ionomycin stimulation, particularly granzyme B and perforin by CD8+ and natural killer cells. Interestingly, two volunteers with TS carry rare genetic variants in genes that regulate type I and III interferon immunity. CONCLUSION: Following previous reports in the literature for other conditions, our data showed that patients with TS may have an impaired immune response against SARS-CoV-2. Furthermore, other medical conditions associated with TS could make them more vulnerable to COVID-19.

Challenges in selecting admixture models and marker sets to infer genetic ancestry in a Brazilian admixed population.

The inference of genetic ancestry plays an increasingly prominent role in clinical, population, and forensic genetics studies. Several genotyping strategies and analytical methodologies have been developed over the last few decades to assign individuals to specific biogeographic regions. However, despite these efforts, ancestry inference in populations with a recent history of admixture, such as those in Brazil, remains a challenge. In admixed populations, proportion and components of genetic ancestry vary on different levels: (i) between populations; (ii) between individuals of the same population, and (iii) throughout the individual's genome. The present study evaluated 1171 admixed Brazilian samples to compare the genetic ancestry inferred by tri-/tetra-hybrid admixture models and evaluated different marker sets from those with small numbers of ancestry informative markers panels (AIMs), to high-density SNPs (HDSNP) and whole-genome-sequence (WGS) data. Analyses revealed greater variation in the correlation coefficient of ancestry components within and between admixed populations, especially for minority ancestral components. We also observed positive correlation between the number of markers in the AIMs panel and HDSNP/WGS. Furthermore, the greater the number of markers, the more accurate the tri-/tetra-hybrid admixture models.

How HLA diversity is apportioned: influence of selection and relevance to transplantation.

In his 1972 paper 'The apportionment of human diversity', Lewontin showed that, when averaged over loci, genetic diversity is predominantly attributable to differences among individuals within populations. However, selection can alter the apportionment of diversity of specific genes or genomic regions. We examine genetic diversity at the human leucocyte antigen (HLA) loci, located within the major histocompatibility complex (MHC) region. HLA genes code for proteins that are critical to adaptive immunity and are well-documented targets of balancing selection. The single-nucleotide polymorphisms (SNPs) within HLA genes show strong signatures of balancing selection on large timescales and are broadly shared among populations, displaying low FST values. However, when we analyse haplotypes defined by these SNPs (which define 'HLA alleles'), we find marked differences in frequencies between geographic regions. These differences are not reflected in the FST values because of the extreme polymorphism at HLA loci, illustrating challenges in interpreting FST. Differences in the frequency of HLA alleles among geographic regions are relevant to bone-marrow transplantation, which requires genetic identity at HLA loci between patient and donor. We discuss the case of Brazil's bone marrow registry, where a deficit of enrolled volunteers with African ancestry reduces the chance of finding donors for individuals with an MHC region of African ancestry. This article is part of the theme issue 'Celebrating 50 years since Lewontin's apportionment of human diversity'.

Frequency and origin of the c.2090T>G p.(Leu697Trp) MYO3A variant associated with autosomal dominant hearing loss.

We recently described a novel missense variant [c.2090T>G:p.(Leu697Trp)] in the MYO3A gene, found in two Brazilian families with late-onset autosomal dominant nonsyndromic hearing loss (ADNSHL). Since then, with the objective of evaluating its contribution to ADNSHL in Brazil, the variant was screened in additional 101 pedigrees with probable ADNSHL without conclusive molecular diagnosis. The variant was found in three additional families, explaining 3/101 (~3%) of cases with ADNSHL in our Brazilian pedigree collection. In order to identify the origin of the variant, 21 individuals from the five families were genotyped with a high-density SNP array (~600 K SNPs- Axiom Human Origins; ThermoFisher). The identity by descent (IBD) approach revealed that many pairs of individuals from the different families have a kinship coefficient equivalent to that of second cousins, and all share a minimum haplotype of ~607 kb which includes the c.2090T>G variant suggesting it probably arose in a common ancestor. We inferred that the mutation occurred in a chromosomal segment of European ancestry and the time since the most common ancestor was estimated in 1100 years (CI = 775-1425). This variant was also reported in a Dutch family, which shares a 87,121 bp haplotype with the Brazilian samples, suggesting that Dutch colonists may have brought it to Northeastern Brazil in the 17th century. Therefore, the present study opens new avenues to investigate this variant not only in Brazilians but also in European families with ADNSHL.

MUC22, HLA-A, and HLA-DOB variants and COVID-19 in resilient super-agers from Brazil.

Background: Although aging correlates with a worse prognosis for Covid-19, super elderly still unvaccinated individuals presenting mild or no symptoms have been reported worldwide. Most of the reported genetic variants responsible for increased disease susceptibility are associated with immune response, involving type I IFN immunity and modulation; HLA cluster genes; inflammasome activation; genes of interleukins; and chemokines receptors. On the other hand, little is known about the resistance mechanisms against SARS-CoV-2 infection. Here, we addressed polymorphisms in the MHC region associated with Covid-19 outcome in super elderly resilient patients as compared to younger patients with a severe outcome. Methods: SARS-CoV-2 infection was confirmed by RT-PCR test. Aiming to identify candidate genes associated with host resistance, we investigated 87 individuals older than 90 years who recovered from Covid-19 with mild symptoms or who remained asymptomatic following positive test for SARS-CoV-2 as compared to 55 individuals younger than 60 years who had a severe disease or died due to Covid-19, as well as to the general elderly population from the same city. Whole-exome sequencing and an in-depth analysis of the MHC region was performed. All samples were collected in early 2020 and before the local vaccination programs started. Results: We found that the resilient super elderly group displayed a higher frequency of some missense variants in the MUC22 gene (a member of the mucins' family) as one of the strongest signals in the MHC region as compared to the severe Covid-19 group and the general elderly control population. For example, the missense variant rs62399430 at MUC22 is two times more frequent among the resilient super elderly (p = 0.00002, OR = 2.24). Conclusion: Since the pro-inflammatory basal state in the elderly may enhance the susceptibility to severe Covid-19, we hypothesized that MUC22 might play an important protective role against severe Covid-19, by reducing overactive immune responses in the senior population.