Biology subjects

O'Connor, T. D.

Publications and source records attributed to O'Connor, T. D..

16 recordsLinked to original sources

bioRxiv2025

Peruvian Population Genomics: Unraveling the Genetic Landscape and Admixture Dynamics of Urban Populations

Latin American populations exhibit high genetic and phenotypic diversity shaped by complex admixture histories, yet remain underrepresented in genomic research. Here, we analyze genome-wide data from 432 urban individuals across 13 regions of Peru, including 346 newly genotyped from the Peruvian Genome Project. We revealed fine-scale population structure and demographic patterns shaped by both ancient and recent events. Indigenous American ancestries in urban individuals trace back to ancient north-south interactions consisted with archaeological records, while admixture events occurring within the last 8-10 generations involved sources already admixed between distinct ancestral lineages. Identity-by-descent analyses reveal sustained gene flow in southern Peru, while effective population size trends highlight demographic stability in Lima over the past 25 generations. Sex-biased admixture patterns suggest Indigenous ancestry contribution preferentially mediated by females. These findings offer a comprehensive view of Perus genetic heritage, advancing our understanding of human genetic diversity and historical demographic processes in Latin America.

genetics↗

bioRxiv2025

Subcontinental Genetic Diversity in the All of Us Research Program: Implications for Biomedical Research

The All of Us Research Program (All of Us) seeks to accelerate biomedical research and address the underrepresentation of minorities by recruiting over one million ethnically diverse participants across the United States. A key question is how self-identification with discrete, predefined race and ethnicity categories compares to genetic diversity at continental and subcontinental levels. To contextualize the genetic diversity in All of Us, we analyzed [~]2 million common variants from 230,016 unrelated whole genomes using classical population genetics methods, alongside reference panels such as the 1000 Genomes Project, Human Genome Diversity Project, and Simons Genome Diversity Project. Our analysis reveals that participants within self-identified race and ethnicity groups exhibit a gradient of genetic diversity rather than discrete clusters. The distributions of continental and subcontinental ancestries show considerable variation within race and ethnicity, both nationally and across states, reflecting the historical impacts of U.S. colonization, the transatlantic slave trade, and recent migrations. All of Us samples filled most gaps along the top five principal components of genetic diversity in current global reference panels. Notably, "Hispanic or Latino" participants spanned much of the three-way (African, Native American, and European) admixture spectrum. Ancestry was significantly associated with body mass index (BMI) and height, even after adjusting for socio-environmental covariates. In particular, West-Central and East African ancestries showed opposite associations with BMI. This study emphasizes the importance of assessing subcontinental ancestries, as the continental approach is insufficient to control for confounding in genetic association studies.

genomics↗

bioRxiv2024

ClOneHORT: Approaches for Improved Fidelity in Generative Models of Synthetic Genomes

MotivationDeep generative models have the potential to overcome difficulties in sharing individual-level genomic data by producing synthetic genomes that preserve the genomic associations specific to a cohort while not violating the privacy of any individual cohort member. However, there is significant room for improvement in the fidelity and usability of existing synthetic genome approaches. ResultsWe demonstrate that when combined with plentiful data and with population-specific selection criteria, deep generative models can produce synthetic genomes and cohorts that closely model the original populations. Our methods improve fidelity in the site-frequency spectra and linkage disequilibrium decay and yield synthetic genomes that can be substituted in downstream local ancestry inference analysis, recreating results with .91 to .94 accuracy. AvailabilityThe model described in this paper is freely available at github.com/rlaboulaye/clonehort.

genomics↗

bioRxiv2024

Variation in spatial population structure in the Anopheles gambiae species complex

Anopheles gambiae, Anopheles coluzzii, and Anopheles arabiensis are three of the most widespread vectors of malaria parasites, with geographical ranges stretching across wide swaths of Africa. Understanding the population structure of these closely related species, including the extent to which populations are connected by gene flow, is essential for understanding how vector control implemented in one location might indirectly affect vector populations in other locations. Here, we assessed the population structure of each species based on a combined data set of publicly available and newly processed whole-genome sequences. The data set included single nucleotide polymorphisms from whole genomes of 2,410 individual mosquitoes sampled from 128 locations across 19 African countries. We found that A. gambiae sampled from several countries in West and Central Africa showed low genetic differentiation from each other according to principal components analysis (PCA) and ADMIXTURE modeling. Using Estimated Effective Migration Surfaces (EEMS), we showed that this low genetic differentiation indicates high effective migration rates for A. gambiae across this region. Outside of this region, we found eight groups of sampling locations from Central, East, and Southern Africa for which A. gambiae showed higher genetic differentiation, and lower effective migration rates, between each other and the West/Central Africa group. These results indicate that the barriers to and corridors for migration between populations of A. gambiae differ across the geographical range of this malaria vector species. Using the same methods, we found higher genetic differentiation and lower migration rates between populations of A. coluzzii in West and Central Africa than for A. gambiae in the same region. In contrast, we found lower genetic differentiation and higher migration rates between populations of A. arabiensis in Tanzania, compared to A. gambiae in the same region. These differences between A. gambiae, A. coluzzii, and A. arabiensis indicate that migration barriers and corridors may vary, even between very closely related species. Overall, our results demonstrate that migration rates vary both within and between species of Anopheles mosquitoes, presumably based on species-specific responses to the ecological or environmental conditions that may impede or facilitate migration, and the geographical patterns of these conditions across the landscape. Together with previous findings, this study provides robust evidence that migration rates between populations of malaria vectors depend on the ecological context, which should be considered when planning surveillance of vector populations, monitoring for insecticide resistance, and evaluating interventions.

ecology↗

bioRxiv2024

Benchmarking and Optimization of Methods for the Detection of Identity-By-Descent in Plasmodium falciparum

Genomic surveillance is crucial for identifying at-risk populations for targeted malaria control and elimination. Identity-by-descent (IBD) is increasingly being used in Plasmodium population genomics to estimate genetic relatedness, effective population size (Ne), population structure, and signals of positive selection. Despite its potential, a thorough evaluation of IBD segment detection tools for species with high recombination rates, such as P. falciparum, remains absent. Here, we perform comprehensive benchmarking of IBD callers - probabilistic (hmmIBD, isoRelate), identity-by-state-based (hap-IBD, phased IBD) and others (Refined IBD) - using population genetic simulations tailored for high recombination, and IBD quality metrics at both the IBD segment level and the IBD-based downstream inference level. Our results demonstrate that low marker density per genetic unit, related to high recombination relative to mutation, significantly compromises the accuracy of detected IBD segments. In genomes with high recombination rates resembling P. falciparum, most IBD callers exhibit high false negative rates for shorter IBD segments, which can be partially mitigated through optimization of IBD caller parameters, especially those related to marker density. Notably, IBD detected with optimized parameters allows for more accurate capture of selection signals and population structure; IBD-based Ne inference is very sensitive to IBD detection errors, with IBD called from hmmIBD uniquely providing less biased estimates of Ne in this context. Validation with empirical data from the MalariaGEN Pf 7 database, representing different transmission settings, corroborates these findings. We conclude that context-specific evaluation and parameter optimization are essential for accurate IBD detection in high-recombining species and recommend hmmIBD for Plasmodium species, especially for quality-sensitive analyses, such as estimation of Ne. Our optimization and high-level benchmarking methods not only improve IBD segment detection in high-recombining genomes but also enhance overall genomic analysis, paving the way for more accurate genomic surveillance and targeted intervention strategies for malaria.

evolutionary biology↗

bioRxiv2024

Comparing the effect of imputation reference panel composition in four distinct Latin American cohorts

Genome-wide association studies have been useful in identifying genetic risk factors for various phenotypes. These studies rely on imputation and many existing panels are largely composed of individuals of European ancestry, resulting in lower levels of imputation quality in underrepresented populations. We aim to analyze how the composition of imputation reference panels affects imputation quality in four target Latin American cohorts. We compared imputation quality for chromosomes 7 and X when altering the imputation reference panel by: 1) increasing the number of Latin American individuals; 2) excluding either Latin American, African, or European individuals, or 3) increasing the Indigenous American (IA) admixture proportions of included Latin Americans. We found that increasing the number of Latin Americans in the reference panel improved imputation quality in the four populations; however, there were differences between chromosomes 7 and X in some cohorts. Excluding Latin Americans from analysis resulted in worse imputation quality in every cohort, while differential effects were seen when excluding Europeans and Africans between and within cohorts and between chromosomes 7 and X. Finally, increasing IA-like admixture proportions in the reference panel increased imputation quality at different levels in different populations. The difference in results between populations and chromosomes suggests that existing and future reference panels containing Latin American individuals are likely to perform differently in different Latin American populations.

genomics↗

bioRxiv2023

The relationships between genetic ancestry, somatic mutation frequency, and histologic subtypes in high-grade endometrial cancer

High-grade endometrial cancer, like numerous other cancer types, exhibits clear racial disparities in the United States for both the incidence and outcomes of the disease. While institutional factors are likely the primary contributor to these disparities, other underlying causes cannot be ignored (i.e., molecular, genetic, and histopathologic factors). This study seeks to interrogate the role that germline genetic influences, specifically genetic ancestry, may play in contributing to characteristics of high-grade endometrial cancer. This is mainly accomplished by examining the relationship between local ancestry inferences and somatic mutation frequency as well as histologic subtypes. An association between clinical characteristics and patient survival was also interrogated, and while global ancestry was seen to have no significant effect, tumor mutation burden (TMB) did impact patient survival. Here, we identify associations between local ancestry segments on chromosomes 1 and 14 and an increased TMB in self-described (SD) Black patients. We also highlight a complex relationship between heterozygous ancestry combinations within genomic regions (i.e., [European/African] vs. [African/African]) and an increase in local somatic mutation frequency. Furthermore, we explore the relationship between local ancestry and histologic subtype. We identify one region (chr9q32) wherein the African/European local ancestry diplotype was associated with a higher incidence of serous carcinoma. We also underline a difference in somatic mutation frequency between endometrioid and serous carcinoma. While highly exploratory, these findings begin to characterize the complex relationship between genetic ancestry and characteristics of high-grade endometrial cancer, which may impact patient survival.

genomics↗

bioRxiv2023

Strong Positive Selection Biases Identity-By-Descent-Based Inferences of Recent Demography and Population Structure in Plasmodium falciparum

Malaria genomic surveillance often estimates parasite genetic relatedness using metrics such as Identity-By-Decent (IBD). Yet, strong positive selection stemming from antimalarial drug resistance or other interventions may bias IBD-based estimates. In this study, we utilized simulations, a true IBD inference algorithm, and empirical datasets from different malaria transmission settings to investigate the extent of such bias and explore potential correction strategies. We analyzed whole genome sequence data generated from 640 new and 4,026 publicly available Plasmodium falciparum clinical isolates. Our findings demonstrated that positive selection distorts IBD distributions, leading to underestimated effective population size and blurred population structure. Additionally, we discovered that the removal of IBD peak regions partially restored the accuracy of IBD-based inferences, with this effect contingent on the populations background genetic relatedness. Consequently, we advocate for selection correction for parasite populations undergoing strong, recent positive selection, particularly in high malaria transmission settings.

evolutionary biology↗

bioRxiv2020

Peptide Ancestry Informative Markers in Uterine Neoplasms from Women of European, African and Asian Ancestry

Characterization of ancestry-linked peptide variants in disease-relevant patient tissues represents a foundational step to connect patient ancestry with molecular disease pathogenesis. Nonsynonymous single nucleotide polymorphisms (SNPs) encoding missense substitutions within tryptic peptides exhibiting high allele frequencies in European, African, and East Asian populations, termed peptide ancestry informative markers (pAIMs), were prioritized from 1000 genomes. In silico analysis shows that as few as 20 pAIMs can determine ancestry proportions similarly to >260K SNPs (R2=0.9905). Multiplexed proteomic analysis of >100 human endometrial cancer cell lines and uterine leiomyoma tissues resulted in the quantitation of 62 pAIMs that correlate with self-described race and genotype-confirmed patient ancestry. Candidates include a D451E substitution in GC vitamin D-binding protein previously associated with altered vitamin D levels in African and European populations. These efforts describe a generalized set of markers for proteoancestry assessment that will further support studies investigating the impact of ancestry on the human proteome and how this relates to the pathogenesis of uterine neoplasms.

cancer biology↗

bioRxiv2020

Rare variant enriched identity-by-descent enables the detection of distant relatedness and older divergence between populations

MotivationThe global human population has experienced an explosive growth from a few million to roughly 7 billion people in the last 10,000 years. Accompanying this growth has been the accumulation of rare variants that can inform our understanding of human evolutionary history. Common variants have primarily been used to infer the structure of the human population and relatedness between two individuals. However, with the increasing abundance of rare variants observed in large-scale projects, such as Trans-Omics for Precision Medicine (TOPMed), the use of rare variants to decipher cryptic relatedness and fine-scale population structure can be beneficial to the study of population demographics and association studies. Identity-by-descent (IBD) is an important framework used for identifying these relationships. IBD segments are broken down by recombination over time, such that longer shared haplotypes give strong evidence of recent relatedness while shorter shared haplotypes are indicative of more distant relationships. Current methods to identify IBD accurately detect only long segments (> 2cM) found in related individuals. AlgorithmWe describe a metric that leverages rare-variants shared between individuals to improve the detection of short IBD segments. We computed IBD segments using existing methods implemented in Refined IBD where we enrich the signal using our metric that facilitates the detection of short IBD segments (<2cM) by explicitly incorporating rare variants. ResultsTo test our new metric, we simulated datasets involving populations with varying divergent time-scales. We show that rare-variant IBD identifies shorter segments with greater confidence and enables the detection of older divergence between populations. As an example, we applied our metric to the Old-Order Amish cohort with known genealogies dating 14 generations back to validate its ability to detect genetic relatedness between distant relatives. This analysis shows that our method increases the accuracy of identifying shorter segments that in turn capture distant relationships. ConclusionsWe describe a method to enrich the detection of short IBD segments using rare-variant sharing within IBD segments. Leveraging rare-variant sharing improves the information content of short IBD segments better than common variants alone. We validated the method in both simulated and empirical datasets. This method can benefit association analyses, IBD mapping analyses, and demographic inferences.

genomics↗

bioRxiv2020

The genetic structure and adaptation of Andean highlanders and Amazonian dwellers is influenced by the interplay between geography and culture

Western South America was one of the worldwide cradles of civilization. The well known Inca Empire was the tip of the iceberg of a cultural and biological evolutionary process that started 14-11 thousand years ago. Genetic data from 18 Peruvian populations reveal that: (1) The between-population homogenization of the central-southern Andes and its differentiation with respect to Amazonian populations of similar latitudes do not extend northward. Instead, longitudinal gene flow between the northern coast of Peru, Andes and Amazonia accompanied cultural and socioeconomic interactions revealed by archeological studies. This pattern recapitulates the environmental and cultural differentiation between the fertile north, where altitudes are lower; and the arid south, where the Andes are higher, acting as a genetic barrier between the sharply different environments of the Andes and Amazonia (2). The genetic homogenization between the populations of the arid Andes is not only due to migration during the Inca Empire or the subsequent colonial period. It started at least during the earlier expansion of the pre-Inca Wari Empire (600-1000 YBP) (3) This demographic history allowed for cases of positive natural selection in the high and arid Andes vs. the low Amazon tropical forest: in the Andes, HAND2-AS1 (heart and neural crest derivatives expressed 2 antisense RNA1, related with cardiovascular function) and DUOX2 (dual oxidase 2, related to thyroid function and innate immunity) genes; in the Amazon, the gene encoding for the CD45 protein, essential for antigen recognition by T/B lymphocytes in viral-host interaction, consistent with the host-virus arms race hypothesis.

evolutionary biology↗

bioRxiv2019

Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass- and fat mass-indexes

Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely under-represented in genomic studies. Leveraging admixture in Brazilians, whose chromosomes are mosaics of fragments of Native American, European and African origins, we used genome-wide data to perform admixture mapping/fine-mapping of Body Mass Index (BMI) in three population-based cohorts from Northeast (Salvador), Southeast (Bambui) and South (Pelotas) of the country. We found significant associations with African-associated alleles in children from Salvador (PALD1 and ZMIZ1 genes), and in young adults from Pelotas (NOD2 and MTUS2 genes). More importantly, in Pelotas, rs114066381, mapped in a potential regulatory region, is significantly associated only in females (p= 2.76 e-06). This variant is very rare in Europeans but with frequencies of ~3% in West Africa, and has a strong female-specific effect (95%CI: 2.32-5.65 kg/m2 per each A allele). We confirmed this sex-specific association and replicated its strong effect for an adjusted fat-mass index in the same Pelotas cohort, and for BMI in another Brazilian cohort from Sao Paulo (Southeast Brazil). A meta-analysis confirmed the significant association. Remarkably, we observed that while the frequency of rs114066381-A allele ranges from 0.8 to 2.1% in the studied populations, it attains ~9% among morbidly obese women from Pelotas, Sao Paulo, and Bambui. The effect size of rs114066381 is at least five-times the effect size of the FTO SNPs rs9939609 and rs1558902, already emblematic for their high effects, and for which we replicated associations in Pelotas. We demonstrate how, after a decade of GWAS mostly performed in European-ancestry populations, non-European and admixed populations are a source of new relevant phenotype-associated genetic variants.

genetics↗

bioRxiv2019

De novo mutations across 1,465 diverse genomes reveal novel mutational insights and reductions in the Amish founder population.

de novo Mutations (DNMs), or mutations that appear in an individual despite not being seen in their parents, are an important source of genetic variation whose impact is relevant to studies of human evolution, genetics, and disease. Utilizing high-coverage whole genome sequencing data as part of the Trans-Omics for Precision Medicine (TOPMed) program, we directly estimate and analyze DNM counts, rates, and spectra from 1,465 trios across an array of diverse human populations. Using the resulting call set of 86,865 single nucleotide DNMs, we find a significant positive correlation between local recombination rate and local DNM rate, which together can explain up to 35.5% of the genome-wide variation in population level rare genetic variation from 41K unrelated TOPMed samples. While genome-wide heterozygosity does correlate weakly with DNM count, we do not find significant differences in DNM rate between individuals of European, African, and Latino ancestry, nor across ancestrally distinct segments within admixed individuals. However, interestingly, we do find significantly fewer DNMs in Amish individuals compared with other Europeans, even after accounting for parental age and sequencing center. Specifically, we find significant reductions in the number of T[->]C mutations in the Amish, which seems to underpin their overall reduction in DNMs. Finally, we calculate near-zero estimates of narrow sense heritability (h2), which suggest that variation in DNM rate is significantly shaped by non-additive genetic effects and/or the environment, and that a less mutagenic environment may be responsible for the reduced DNM rate in the Amish. SignificanceHere we provide one of the largest and most diverse human de novo mutation (DNM) call sets to date, and use it to quantify the genome-wide relationship between local mutation rate and population-level rare genetic variation. While we demonstrate that the human single nucleotide mutation rate is similar across numerous human ancestries and populations, we also discover a reduced mutation rate in the Amish founder population, which shows that mutation rates can shift rapidly. Finally, we find that variation in mutation rates is not heritable, which suggests that the environment may influence mutation rates more significantly than previously realized.

genetics↗

bioRxiv2017

The Evolutionary Genomic Dynamics of Peruvians Before, During, and After the Inca Empire

Native Americans from the Amazon, Andes, and coast regions of South America have a rich cultural heritage, but have been genetically understudied leading to gaps in our knowledge of their genomic architecture and demographic history. Here, we sequenced 150 high-coverage and genotyped 130 genomes from Native American and mestizo populations in Peru. A majority of our samples possess greater than 90% Native American ancestry and demographic modeling reveals, consistent with a rapid peopling model of the Americas, that most of Peru was peopled approximately 12,000 years ago. While the Native American populations possessed distinct ancestral divisions, the mestizo groups were admixtures of multiple Native American communities which occurred before and during the Inca Empire. The mestizo communities also show Spanish introgression only after Peruvian Independence. Thus, we present a detailed model of the evolutionary dynamics which impacted the genomes of modern day Peruvians.

genomics↗

bioRxiv2017

Genome-wide association study of asthma in individuals of African ancestry reveals novel asthma susceptibility loci

BACKGROUNDAsthma is a complex disease with striking disparities across racial and ethnic groups, which may be partly attributable to genetic factors. One of the main goals of the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to discover genes conferring risk to asthma in populations of African descent.\n\nMETHODSWe performed a genome-wide meta-analysis of asthma across 11 CAAPA datasets (4,827 asthma cases and 5,397 controls), genotyped on the African Diaspora Power Chip (ADPC) and including existing GWAS array data. The genotype data were imputed up to a whole genome sequence reference panel from n=880 African ancestry individuals for a total of 61,904,576 SNPs. Statistical models appropriate to each study design were used to test for association, and results were combined using the weighted Z-score method. We also used admixture mapping as a complementary approach to identify loci involved in asthma pathogenesis in subjects of African ancestry.\n\nRESULTSSNPs rs787160 and rs17834780 on chromosome 2q22.3 were significantly associated with asthma (p=6.57 x 10-9 and 2.97 x 10-8, respectively). These SNPs lie in the intergenic region between the Rho GTPase Activating Protein 15 (ARHGAP15) and Glycosyltransferase Like Domain Containing 1 (GTDC1) genes. Four low frequency variants on chromosome 1q21.3, which may be involved in the \"atopic march\" and which are not polymorphic in Europeans, also showed evidence for association with asthma (1.18 x10-6 [≤] p [≤] 3.06 x10-6). SNP rs11264909 on chromosome 1q23.1, close to a region previously identified by the EVE asthma meta-analysis as having a putative African ancestry specific effect, only showed differences in counts in subjects homozygous for alleles of African ancestry. Admixture mapping also identified a significantly associated region on chromosome 6q23.2, which includes the Transcription Factor 21 (TCF21) gene, previously shown to be differentially expressed in bronchial tissues of asthmatics and non-asthmatics.\n\nCONCLUSIONSWe have identified a number of novel asthma association signals warranting further investigation.

bioinformatics↗

bioRxiv2017

Identifying tagging SNPs for African specific genetic variation from the African Diaspora Genome

A primary goal of The Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA) is to develop an African Diaspora Power Chip (ADPC), a genotyping array consisting of tagging SNPs, useful in comprehensively identifying African specific genetic variation. This array is designed based on the novel variation identified in 642 CAAPA samples of African ancestry with high coverage whole genome sequence data (~30x depth). This novel variation extends the pattern of variation catalogued in the 1000 Genomes and Exome Sequencing Projects to a spectrum of populations representing the wide range of West African genomic diversity. These individuals from CAAPA also comprise a large swath of the African Diaspora population and incorporate historical genetic diversity covering nearly the entire Atlantic coast of the Americas. Here we show the results of designing and producing such a microchip array. This novel array covers African specific variation far better than other commercially available arrays, and will enable better GWAS analyses for researchers with individuals of African descent in their study populations. A recent study1 cataloging variation in continental African populations suggests this type of African-specific genotyping array is both necessary and valuable for facilitating large-scale GWAS in populations of African ancestry.

genomics↗