Origin and dynamics of admixture in Brazilians and its effect on the pattern of deleterious mutations

While South Americans are underrepresented in human genomic diversity studies, Brazil has been a classical model for population genetics studies on admixture. We present the results of the EPIGEN Brazil Initiative, the most comprehensive up-to-date genomic analysis of any Latin-American population. A population-based genome-wide analysis of 6,487 individuals was performed in the context of worldwide genomic diversity to elucidate how ancestry, kinship, and inbreeding interact in three populations with different histories from the Northeast (African ancestry: 50%), Southeast, and South (both with European ancestry >70%) of Brazil. We showed that ancestry-positive assortative mating permeated Brazilian history. We traced European ancestry in the Southeast/South to a wider European/Middle Eastern region with respect to the Northeast, where ancestry seems restricted to Iberia. By developing an approximate Bayesian computation framework, we infer more recent European immigration to the Southeast/South than to the Northeast. Also, the observed low Native-American ancestry (6–8%) was mostly introduced in different regions of Brazil soon after the European Conquest. We broadened our understanding of the African diaspora, the major destination of which was Brazil, by revealing that Brazilians display two within-Africa ancestry components: one associated with non-Bantu/western Africans (more evident in the Northeast and African Americans) and one associated with Bantu/eastern Africans (more present in the Southeast/South). Furthermore, the whole-genome analysis of 30 individuals (42-fold deep coverage) shows that continental admixture rather than local post-Columbian history is the main and complex determinant of the individual amount of deleterious genotypes.

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Genomic, Ancestral and Networking Analyses of a High-Altitude Native American Ecuadorian Patient with Congenital Insensitivity to Pain with Anhidrosis

10.1101/529263 ◽

2019 ◽

Author(s):

Andrés López-Cortés ◽

Ana Karina Zambrano ◽

Patricia Guevara-Ramírez ◽

Byron Albuja Echeverría ◽

Santiago Guerrero ◽

...

Keyword(s):

Native American ◽

High Altitude ◽

African Ancestry ◽

Genomic Analysis ◽

European Ancestry ◽

Tyrosine Kinase Receptor ◽

Pain Matrix ◽

Congenital Insensitivity ◽

Congenital Insensitivity To Pain ◽

Insensitivity To Pain

ABSTRACTCongenital insensitivity to pain with anhidrosis (CIPA) is an extremely rare autosomal recessive disorder characterized by insensitivity to pain, inability to sweat and intellectual disability. CIPA is caused by mutations in the neurotrophic tyrosine kinase receptor type 1 gene (NTRK1) that encodes the high-affinity receptor of nerve growth factor (NGF). Patients with CIPA lack the primary afferents and sympathetic postganglionic neurons leading to lack of pain sensation and the presence of anhidrosis, respectively. Herein, we conducted a genomic analysis of 4,811 genes and 18,933 variants, including 54 mutations of NTRK1 in a high-altitude indigenous Ecuadorian patient with CIPA. As results, the patient presented 87.8% of Native American ancestry, 6.6% of African ancestry and 5.6% of European ancestry. The mutational analysis of the kinase domain of NTRK1 showed two pathogenic mutations, rs80356677 (Asp674Tyr) and rs763758904 (Arg602*). The genomic analysis showed 68 pathogenic and/or likely pathogenic variants in 45 genes, and two variants of uncertain significance in CACNA2D1 (rs370103843) and TRPC4 (rs80164537) genes involved in the pain matrix. The GO enrichment analysis showed 28 genes with relevant mutations involved in several biological processes, cellular components and molecular functions. In addition, the protein-protein interaction (PPi) networking analysis showed that NTRK1, SPTBN2 and GRM6 interact with several proteins of the pain matrix. In conclusion, this is the first time that a study associates genomic, ancestral and networking data in a high-altitude Native American Ecuadorian patient with consanguinity background in order to better understand CIPA pathogenesis.

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Genetic admixture patterns in Argentinian Patagonia

10.1101/586610 ◽

2019 ◽

Author(s):

María Laura Parolin ◽

Ulises F Toscanini ◽

Irina F Velázquez ◽

Cintia Llull ◽

Gabriela L Berardi ◽

...

Keyword(s):

Native American ◽

Latin American ◽

African Ancestry ◽

Geographic Origin ◽

Sub Saharan Africa ◽

European Ancestry ◽

Genetic Admixture ◽

The North ◽

Sub Saharan ◽

Different Origins

AbstractAs for other Latin American populations, Argentinians are the result of the admixture amongst different continental groups, mainly from America and Europe, and to a lesser extent from Sub-Saharan Africa. However, it is known that the admixture processes did not occur homogeneously throughout the country. Therefore, considering the importance for anthropological, medical and forensic researches, this study aimed to investigate the population genetic structure of the Argentinian Patagonia, through the analysis of 46 ancestry informative markers, in 433 individuals from five different localities. Overall, in the Patagonian sample, the average individual ancestry was estimated as 35.8% Native American (95% CI: 32.2-39.4%), 62.1% European (58.5-65.7%) and 2.1% African (1.7-2.4%). Comparing the five localities studied, statistically significant differences were observed for the Native American and European contributions, but not for the African ancestry. The admixture results combined with the genealogical information revealed intra-regional variations that are consistent with the different geographic origin of the participants and their ancestors. As expected, a high European ancestry was observed for donors with four grandparents born in Europe (96.8%) or in the Central region of Argentina (85%). In contrast, the Native American ancestry increased when the four grandparents were born in the North (71%) or in the South (61.9%) regions of the country, or even in Chile (60.5%). In summary, our results showed that differences on continental ancestry contribution have different origins in each region in Patagonia, and even in each locality, highlighting the importance of knowing the origin of the participants and their ancestors for the correct interpretation and contextualization of the genetic information.

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Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

10.1101/2020.10.28.359240 ◽

2020 ◽

Author(s):

Naser Ansari-Pour ◽

Yonglan Zheng ◽

Jason J. Pitt ◽

Stefan Dentro ◽

Toshio F. Yoshimatsu ◽

...

Keyword(s):

Breast Cancer ◽

Black Women ◽

White Women ◽

African Ancestry ◽

Clinical Intervention ◽

The Cancer Genome Atlas ◽

European Ancestry ◽

Precision Oncology ◽

Whole Genome Analysis ◽

Somatic Evolution

AbstractBlack women of African ancestry experience more aggressive breast cancer with higher mortality rates than White women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast tumors, with RNA-seq in a subset, from indigenous African patients in Nigeria in comparison to The Cancer Genome Atlas (n=76) revealed a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations and a 10.5-year younger age at diagnosis. We also found evidence for non-coding mutations in two novel drivers (ZNF217 and SYPL1) and a novel INDEL signature strongly associated with African ancestry proportion. This comprehensive analysis of an understudied population underscores the need to incorporate diversity of genomes as a key parameter in fundamental research with potential to tailor clinical intervention and promote equity in precision oncology care.

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Whole-genome analysis of Nigerian patients with breast cancer reveals ethnic-driven somatic evolution and distinct genomic subtypes

Nature Communications ◽

10.1038/s41467-021-27079-w ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Naser Ansari-Pour ◽

Yonglan Zheng ◽

Toshio F. Yoshimatsu ◽

Ayodele Sanni ◽

Mustapha Ajani ◽

...

Keyword(s):

Breast Cancer ◽

Black Women ◽

White Women ◽

African Ancestry ◽

The Cancer Genome Atlas ◽

European Ancestry ◽

Breast Cancers ◽

Whole Genome Analysis ◽

Somatic Evolution ◽

Germline Variation

AbstractBlack women across the African diaspora experience more aggressive breast cancer with higher mortality rates than white women of European ancestry. Although inter-ethnic germline variation is known, differential somatic evolution has not been investigated in detail. Analysis of deep whole genomes of 97 breast cancers, with RNA-seq in a subset, from women in Nigeria in comparison with The Cancer Genome Atlas (n = 76) reveal a higher rate of genomic instability and increased intra-tumoral heterogeneity as well as a unique genomic subtype defined by early clonal GATA3 mutations with a 10.5-year younger age at diagnosis. We also find non-coding mutations in bona fide drivers (ZNF217 and SYPL1) and a previously unreported INDEL signature strongly associated with African ancestry proportion, underscoring the need to expand inclusion of diverse populations in biomedical research. Finally, we demonstrate that characterizing tumors for homologous recombination deficiency has significant clinical relevance in stratifying patients for potentially life-saving therapies.

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Ancestry-Specific Predisposing Germline Variants in Cancer

10.1101/2020.04.14.032557 ◽

2020 ◽

Author(s):

Ninad Oak ◽

Andrew D. Cherniack ◽

R. Jay Mashl ◽

Fred R. Hirsch ◽

Li Ding ◽

...

Keyword(s):

Gene Expression ◽

Cell Carcinoma ◽

Latin American ◽

Genetic Predisposition ◽

African Ancestry ◽

East Asian ◽

Lung Squamous Cell Carcinoma ◽

European Ancestry ◽

Pathogenic Variants ◽

Cancer Types

AbstractBackgroundCancer risk differs across ancestries and these differences may result from differing prevalence of inherited genetic predisposition. Yet, most germline genomic studies performed to date have focused on individuals of European ancestry. Ancestry-specific analyses of germline genomes are required to inform cancer genetic risk and prognosis for each ancestral group. Here, we investigate potentially germline pathogenic variants in cancer predisposition genes (CPG) and their somatic effects in patients across diverse ancestral backgrounds.MethodsWe performed a retrospective analysis of germline genomic data of 9,899 patients from 33 cancer types generated by The Cancer Genome Atlas (TCGA) project along with matching somatic genomic and transcriptomic data. By collapsing pathogenic and likely pathogenic variants to the gene level, we analyzed the association between variants in CPGs and cancer types within each ancestry. We also identified ancestry- specific predisposing variants and their associated somatic two-hit events and gene expression levels.ResultsRecent genetic ancestry analysis classified the cohort of 9,899 cancer cases into individuals of primarily European, (N = 8,184, 82.7%), African (N = 966, 9.8%), East Asian (N = 649, 6.6%), South Asian (N=48, 0.5%), Native/Latin American (N=41, 0.4%), and admixed (N=11, 0.1%) ancestries. In the African ancestry, we discovered a potentially novel association of BRCA2 in lung squamous cell carcinoma (OR = 41.4 [95% CI, 6.1-275.6]; FDR = 0.002) along with the previously identified association of BRCA2 in ovarian serous cystadenocarcinoma (OR=8.5 [95% CI, 1.5-47.4]; FDR=0.045). Similarly, in the East Asian ancestry, we discovered one previously known association of BRIP1 in stomach adenocarcinoma (OR=12.8 [95% CI, 1.8-90.84]; FDR=0.038). Rare variant burden analysis further identified 7 suggestive associations for cancer-gene pairs in African ancestry individuals previously well described in European ancestry including SDHB in pheochromocytoma and paraganglioma, ATM in prostate adenocarcinoma, VHL in kidney renal clear cell carcinoma, FH in kidney renal papillary cell carcinoma, and PTEN in uterine corpus endometrial carcinoma. Loss of heterozygosity was identified for 7 out of the 15 African ancestry carriers of predisposing variants. Further, tumors from the SDHB or BRCA2 carriers showed simultaneous allelic specific expression and low gene expression of their respective affected genes; and FH splice-site variant carriers showed mis-splicing of FH.ConclusionWhile several predisposing genes are shared across patients, many pathogenic variants are found to be ancestry-specific and trigger somatic effects. Analysis of larger diverse ancestries genomic cohorts are required to pinpoint ancestry- specific genetic predisposition to inform personalized diagnosis and screening strategies.

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Imputation Performance in Latin American Populations: Improving Rare Variants Representation With the Inclusion of Native American Genomes

Frontiers in Genetics ◽

10.3389/fgene.2021.719791 ◽

2022 ◽

Vol 12 ◽

Author(s):

Andrés Jiménez-Kaufmann ◽

Amanda Y. Chong ◽

Adrián Cortés ◽

Consuelo D. Quinto-Cortés ◽

Selene L. Fernandez-Valverde ◽

...

Keyword(s):

Native American ◽

Latin American ◽

Statistical Power ◽

Association Studies ◽

Demographic History ◽

Genotype Imputation ◽

Genomic Research ◽

European Ancestry ◽

Local Source ◽

Genome Wide Association Studies

Current Genome-Wide Association Studies (GWAS) rely on genotype imputation to increase statistical power, improve fine-mapping of association signals, and facilitate meta-analyses. Due to the complex demographic history of Latin America and the lack of balanced representation of Native American genomes in current imputation panels, the discovery of locally relevant disease variants is likely to be missed, limiting the scope and impact of biomedical research in these populations. Therefore, the necessity of better diversity representation in genomic databases is a scientific imperative. Here, we expand the 1,000 Genomes reference panel (1KGP) with 134 Native American genomes (1KGP + NAT) to assess imputation performance in Latin American individuals of mixed ancestry. Our panel increased the number of SNPs above the GWAS quality threshold, thus improving statistical power for association studies in the region. It also increased imputation accuracy, particularly in low-frequency variants segregating in Native American ancestry tracts. The improvement is subtle but consistent across countries and proportional to the number of genomes added from local source populations. To project the potential improvement with a higher number of reference genomes, we performed simulations and found that at least 3,000 Native American genomes are needed to equal the imputation performance of variants in European ancestry tracts. This reflects the concerning imbalance of diversity in current references and highlights the contribution of our work to reducing it while complementing efforts to improve global equity in genomic research.

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Abstract P152: Do Self-reported Race, Socioeconomic Status And Genetic Ancestry Influence Fasting Glucose? Preliminary Results From the Ongoing Bach Prediabetes Study

Circulation ◽

10.1161/circ.125.suppl_10.ap152 ◽

2012 ◽

Vol 125 (suppl_10) ◽

Author(s):

James B Meigs ◽

Gavin Miyasoto ◽

Bianca Porneala ◽

Lisa Marceau ◽

John B McKinlay

Keyword(s):

Socioeconomic Status ◽

Native American ◽

Fasting Glucose ◽

African Ancestry ◽

Ethnic Disparities ◽

Community Dwelling ◽

Genetic Ancestry ◽

European Ancestry ◽

Epidemiologic Survey ◽

Race Ethnicity

Background: Race/ethnic disparities in type 2 diabetes (T2D) may have both biophysical and social determinants that likely arise before T2D diagnosis. We examined the association of self-reported (SR) race/ethnicity, socioeconomic status (SES) and genetic ancestry with levels of fasting glucose (FG) in individuals not known to have T2D. Methods: The Boston Area Community Health (BACH) Prediabetes study is an ongoing epidemiologic survey of community-dwelling residents of inner-city Boston. A stratified random sample of 3,300 subjects are being drawn from the parent BACH cohort study, recruiting approximately equal numbers in pre-specified age (30–79 years), sex and race/ethnicity groups. Fasting blood is collected, including FG, other health and SES information, during an early AM in-home interview. SES is measured as a standardized composite score of income and education. Genetic ancestry informative markers (AIMs, n=63) that discriminate European, African and Native American continental ancestry are currently available on a random subset. We compared FG levels across groups using ANOVA, testing independent associations of SR race/ethnicity SES using multiple linear regression with significant P=< 0.05. Results: Of 2,933 participants recruited, 63% were women and 70% were older than 50 years. Black, Hispanic and white SR race/ethnicity comprised 32%, 33% and 35% of the sample, respectively. The majority had low SES (57%), 35% had moderate SES and 8% had high SES. FG varied significantly by SR race/ethnicity (mean±SD, mg/dL): 113±37 for white, 119±46 for Hispanic and 121±49 for black subjects (P<0.001). FG was inversely associated with SES (low 122±49, medium 113±39, high 106±23, P<0.001). In joint SR race/ethnicity and SES models adjusting for age and sex, both main effects were attenuated but remained associated with FG (SR race/ethnicity P=0.01; SES P<0.001). For the subsample with AIMs data (n=373), predominant AIMs ancestry, defined as the ancestry most likely as predicted by AIMs, was closely linked to SR race/ethnicity. European ancestry was predominant in 100% of 110 SR white respondents, while African ancestry was predominant in 95% of 129 SR black respondents. In 134 SR Hispanics, 43% were predominantly European, 41% African and 16% Native American. FG varied with predominant AIMs ancestry (European 115±45 mg/dL, African 121±53 and Native American 127±67), although not significantly so (P=0.33), likely due to the limited sample size. Conclusions: Both self-reported race/ethnicity and SES are associated with FG in community-based individuals without known T2D, and they share explanatory information reflecting a common effect. A larger sample with AIMs will help disentangle the degree to which FG variation is socially patterned in the community versus a biophysical phenomenon determined in part by genetic ancestry.

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Assortative mating on ancestry-variant traits in admixed Latin American populations

10.1101/177634 ◽

2017 ◽

Cited By ~ 2

Author(s):

Emily T. Norris ◽

Lavanya Rishishwar ◽

Lu Wang ◽

Andrew B. Conley ◽

Aroon T. Chande ◽

...

Keyword(s):

Native American ◽

Assortative Mating ◽

Latin American ◽

African Ancestry ◽

Ethnically Diverse ◽

Continental Population Groups ◽

Continental Population ◽

Novel Approach ◽

Genome Wide ◽

Facial Development

AbstractBackgroundAssortative mating is a universal feature of human societies, and individuals from ethnically diverse populations are known to mate assortatively based on similarities in genetic ancestry. However, little is currently known regarding the exact phenotypic cues, or their underlying genetic architecture, which inform ancestry-based assortative mating.ResultsWe developed a novel approach, using genome-wide analysis of ancestry-specific haplotypes, to evaluate ancestry-based assortative mating on traits whose expression varies among the three continental population groups – African, European, and Native American – that admixed to form modern Latin American populations. Application of this method to genome sequences sampled from Colombia, Mexico, Peru, and Puerto Rico revealed widespread ancestry-based assortative mating. We discovered a number of anthropometric traits (body mass, height, facial development and waist-hip ratio) and neurological attributes (educational attainment and schizophrenia) that serve as phenotypic cues for ancestry-based assortative mating. Major histocompatibility complex (MHC) loci show population-specific patterns of both assortative and disassortative mating in Latin America. Ancestry-based assortative mating in the populations analyzed here appears to be driven primarily by African ancestry.ConclusionsThis study serves as an example of how population genomic analyses can yield novel insights into human behavior.

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Genomics of an endemic cystic fibrosis Burkholderia multivorans strain reveals low within-patient evolution but high between-patient diversity

PLoS Pathogens ◽

10.1371/journal.ppat.1009418 ◽

2021 ◽

Vol 17 (3) ◽

pp. e1009418

Author(s):

Cédric Lood ◽

Charlotte Peeters ◽

Quentin Lamy-Besnier ◽

Jeroen Wagemans ◽

Daniel De Vos ◽

...

Keyword(s):

Cystic Fibrosis ◽

Burkholderia Cepacia ◽

Genomic Analysis ◽

Genomic Diversity ◽

Epidemiological Surveillance ◽

Nucleotide Polymorphisms ◽

Whole Genome Analysis ◽

Structural Genomic ◽

Burkholderia Multivorans ◽

Sequencing Technologies

Burkholderia multivorans is a member of the Burkholderia cepacia complex (Bcc), notorious for its pathogenicity in persons with cystic fibrosis. Epidemiological surveillance suggests that patients predominantly acquire B. multivorans from environmental sources, with rare cases of patient-to-patient transmission. Here we report on the genomic analysis of thirteen isolates from an endemic B. multivorans strain infecting four cystic fibrosis patients treated in different pediatric cystic fibrosis centers in Belgium, with no evidence of cross-infection. All isolates share an identical sequence type (ST-742) but whole genome analysis shows that they exhibit peculiar patterns of genomic diversity between patients. By combining short and long reads sequencing technologies, we highlight key differences in terms of small nucleotide polymorphisms indicative of low rates of adaptive evolution within patient, and well-defined, hundred Kbps-long segments of high enrichment in mutations between patients. In addition, we observed large structural genomic variations amongst the isolates which revealed different plasmid contents, active roles for transposase IS3 and IS5 in the deactivation of genes, and mobile prophage elements. Our study shows limited within-patient B. multivorans evolution and high between-patient strain diversity, indicating that an environmental microdiverse reservoir must be present for this endemic strain, in which active diversification is taking place. Furthermore, our analysis also reveals a set of 30 parallel adaptations across multiple patients, indicating that the specific genomic background of a given strain may dictate the route of adaptation within the cystic fibrosis lung.

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Implementing genomic screening in diverse populations

Genome Medicine ◽

10.1186/s13073-021-00832-y ◽

2021 ◽

Vol 13 (1) ◽

Cited By ~ 2

Author(s):

Noura S. Abul-Husn ◽

Emily R. Soper ◽

Giovanna T. Braganza ◽

Jessica E. Rodriguez ◽

Natasha Zeid ◽

...

Keyword(s):

Screening Program ◽

African Ancestry ◽

Genomic Medicine ◽

European Ancestry ◽

Transthyretin Amyloidosis ◽

Medicine Research ◽

Screening Programs ◽

Genomic Screening ◽

Genomic Results ◽

To Receive

Abstract Background Population-based genomic screening has the predicted ability to reduce morbidity and mortality associated with medically actionable conditions. However, much research is needed to develop standards for genomic screening and to understand the perspectives of people offered this new testing modality. This is particularly true for non-European ancestry populations who are vastly underrepresented in genomic medicine research. Therefore, we implemented a pilot genomic screening program in the BioMe Biobank in New York City, where the majority of participants are of non-European ancestry. Methods We initiated genomic screening for well-established genes associated with hereditary breast and ovarian cancer syndrome (HBOC), Lynch syndrome (LS), and familial hypercholesterolemia (FH). We evaluated and included an additional gene (TTR) associated with hereditary transthyretin amyloidosis (hATTR), which has a common founder variant in African ancestry populations. We evaluated the characteristics of 74 participants who received results associated with these conditions. We also assessed the preferences of 7461 newly enrolled BioMe participants to receive genomic results. Results In the pilot genomic screening program, 74 consented participants received results related to HBOC (N = 26), LS (N = 6), FH (N = 8), and hATTR (N = 34). Thirty-three of 34 (97.1%) participants who received a result related to hATTR were self-reported African American/African (AA) or Hispanic/Latinx (HL), compared to 14 of 40 (35.0%) participants who received a result related to HBOC, LS, or FH. Among the 7461 participants enrolled after the BioMe protocol modification to allow the return of genomic results, 93.4% indicated that they would want to receive results. Younger participants, women, and HL participants were more likely to opt to receive results. Conclusions The addition of TTR to a pilot genomic screening program meant that we returned results to a higher proportion of AA and HL participants, in comparison with genes traditionally included in genomic screening programs in the USA. We found that the majority of participants in a multi-ethnic biobank are interested in receiving genomic results for medically actionable conditions. These findings increase knowledge about the perspectives of diverse research participants on receiving genomic results and inform the broader implementation of genomic medicine in underrepresented patient populations.

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