Biology subjects

Uren, C.

Publications and source records attributed to Uren, C..

9 recordsLinked to original sources

bioRxiv2025

Mitochondrial DNA Imputation Accuracy and Its Application in a Southern African Mitochondrial Genome-wide Association Study

Southern African populations harbor exceptional mitochondrial genetic diversity and include the earliest diverging mitochondrial haplogroups. Yet, they remain significantly underrepresented in genetic studies and reference databases. This underrepresentation raises concerns about the performance and generalizability of mitochondrial imputation tools in populations with complex demographic histories. In this study, we conducted a comprehensive evaluation of the publicly available MitoImpute reference panel to assess its accuracy and suitability for use in southern African cohorts. We examined imputation performance for mitochondrial DNA (mtDNA), the impact of imputation on haplogroup assignment, and the extent to which population-specific variants were recovered by the panel. As a proof-of-principle application, we used the MitoImpute reference panel and imputation workflow to merge five southern African tuberculosis (TB) case-control mtDNA datasets and perform a mitochondrial genome-wide association study (miWAS) of TB susceptibility. Although MitoImpute performed well in predicting mitochondrial haplogroups and accurately imputing a subset of mtDNA variants, substantial population-specific variation was not captured. No significant associations with TB susceptibility were identified, highlighting key limitations of array-based mtDNA genotyping and imputation in highly diverse populations. Together, these findings underscore the need for improved reference panels enriched for African mitochondrial diversity and provide practical guidelines for mitochondrial data harmonization and analysis in multi-ancestry cohorts.

genetics↗

bioRxiv2025

Recovering the pre-colonial population structure of Khoe-San descendant populations

San populations from Botswana and Namibia retain exceptional linguistic, cultural and genetic diversity, but few Khoisan-speaking groups remain south of the Kalahari Desert. However, historically, far southern Africa was home to many San and Khoekhoe groups. Popular opinion often implies that such populations do not contribute to the ancestry of contemporary South Africans. Here, we characterize the genetic ancestry of self-identified South African Coloured groups and reconstruct pre- and colonial population structure from 620 newly sampled individuals. These groups retain majority Khoe-San genetic ancestry (>48%), suggesting the persistence of Khoe-San ancestry to the present day. By isolating the Khoe-San ancestry component, we show that it is intermediate between the =Khomani San and Nama, and distinct from Kalahari Khoe-San populations. We also find that signatures of the Indian Ocean slave trade can be traced to Indonesian islands such as Sulawesi, Java, and Flores, while the South Asian ancestry is regionally non-specific. TeaserLarge-scale genomic study uncovers enduring indigenous ancestry in South African populations, exposing a complex past.

evolutionary biology↗

bioRxiv2024

Polymorphic tandem repeats shape single-cell gene expression across the immune landscape

Tandem repeats (TRs) - highly polymorphic, repetitive sequences across the human genome - are important regulators of gene expression but remain underexplored due to challenges in accurate genotyping and analysis1. Here, we generate new whole genome and single-cell RNA sequencing from >5.4 million blood-derived cells across 1,925 individuals in two cohorts [Cuomo et al., accompanying manuscript], and perform meta-analysis to characterize the impact of variation in >1.7 million TR loci on immune cell type-specific gene expression. We identify >69,000 single-cell expression TR loci (sc-eTRs), 30.7% of which are specific to one of 28 immune cell types, and reveal dynamic regulatory effects using cell-state inference. Matched single-cell ATAC sequencing profiles from >3.4 million nuclei in 922 individuals [Xue et al., accompanying manuscript]. uncover chromatin accessibility QTLs for nearly one-third of expression-associated TRs, supporting coordinated effects on cis-regulatory architecture. Fine-mapping implicates 1,490 TRs as candidate causal drivers of gene expression in 6.1% of tested genes, and colocalization analyses highlight >200 genes in which TRs likely mediate genetic associations with immune and hematological traits. Together, these results provide a genome-wide, multiomic view of TR-mediated regulation in the human immune system, establishing TRs as key contributors to cell type-specific regulatory variation and complex trait architecture.

genomics↗

bioRxiv2023

Slave Trade and Colonial Expansion Resulted in Strong Sex-Biased Admixture in South Africa

The colonial-period arrival of Europeans in southern Africa is associated with strong sex-biased migration by which male settlers displaced indigenous Khoekhoe and San men. Simultaneously, the importation of South Asian, Indonesian and Eastern African slaves may have contributed female-biased migration to Cape Town and surrounding areas. We examine the spatial and temporal spread of sex-biased migration from the Cape northward into Namaqualand and the southern Kalahari using genetic data from more than 1,400 individuals. In all regions, admixture patterns were sex-biased, with evidence of a greater male contribution of European ancestry and greater female contribution of Khoe-San ancestry. While admixture among Khoe-San, European, equatorial African, and Asian groups has likely been continuous from the founding of Cape Town to present-day, we find that Khoe-San groups further north experienced a single pulse of European admixture 6-8 generations ago. European admixture was followed by additional Khoe-San gene flow, potentially reflecting an aggregation of indigenous groups due to disruption by colonial interlopers. Male migration into the northern frontier territories was not a homogenous group of expanding Afrikaners and slaves. The Nama show evidence of distinct founder effects and derive 15% of their male lineages from Asian men, a pattern absent in the =Khomani San. Khoe-San ancestry from the paternal line is greatly diminished in populations from Cape Town, the Cederberg Mountains and Upington, but remains more frequent in self-identified ethnically indigenous groups. Strikingly, we estimate that Khoe-San Y-chromosomes were experiencing unprecedented population growth at the time of European arrival. Our findings shed light on the patterns of admixture and the population history of South Africa as the colonial frontier expanded.

genetics↗

bioRxiv2022

cis-eQTL mapping of TB-T2D comorbidity elucidates the involvement of African ancestry in TB susceptibility

The validation of genome-wide association signals for tuberculosis (TB) susceptibility and the development of type 2 diabetes (T2D) across diverse populations remain problematic. The ancestry-specific variants (coding and non-coding) that contribute to previously identified differentially expressed genes (DEG) in patients with TB, T2D and comorbid TB-T2D, remain unknown. Identifying ancestry-specific expression quantitative trait loci (eQTLs) can aid in distinguishing the most probable disease-causing variants for population-specific therapeutic interventions. Therefore, this study conducted cis-eQTL mapping in TB, T2D and TB-T2D patients to identify variants associated with DEG. Both genotyping (Infinium H3A array with [~]2.3 M markers) and RNA sequencing data of 96 complex multi-way admixed South Africans were used for this purpose. Importantly, both global-and local ancestry adjustment were included in statistical analysis to account for complex admixture. Unique gene-variant pairs were associated with TB-T2D on chromosome 7p22 whilst adjusting for Bantu-speaking African ancestry (PRKAR1B:rs4464850; P=7.68e-07) and Khoe-San ancestry (PRKAR1B:rs117842122; P=3.66e-07). In addition, IFITM3 (a biomarker for the development of TB) was associated with three SNPs (rs11025530, rs3808990, and rs10896664) on chromosome 11p15 while adjusting for Khoe-San ancestry. Our results also indicated that the upregulation of the NLRP6 inflammasome is strongly associated with people with TB-T2D while adjusting for Khoe-San ancestry. Three African-specific eGenes (NLRP6, IFITM3 and PRKAR1B) would have been missed if local ancestry adjustment was not conducted. This study determined a list of ancestry-specific eQTLs in TB-T2D patients that could potentially guide the search for new therapeutic targets for TB-T2D in African populations. Author SummaryThe limitation of genome-wide association study (GWAS) is that the particular biological pathway impacted by a variant might not be evident. eQTL mapping can be conducted to determine the impact that a genetic variant might have on the expression of a specific gene in a biological pathway. In this study the use of cis-eQTL mapping was explored to elucidate the underlying genetic variants that regulate gene expression between TB-T2D and T2D patients, and between TB patients and healthy controls with multi-way genetic admixture from South Africa. Using RNA sequencing data and newly genotyped dataset of 96 individuals (Illumina Infinium H3Africa array with [~]2.5 M markers), we were able to identify ancestry-specific eQTLs. eQTLs of indigenous Khoe-San ancestral origin were identified in genetic regions previously implicated in TB and T2D in African populations. If local ancestry was not incorporated in the cis-eQTL mapping analysis these important African-specific eQTLs would have been missed. Our results provide a list of possible ancestry-specific causal variants associated with TB-T2 comorbidity that could guide the search for new therapeutic targets for African-specific populations. Including populations with complex ancestry and admixture in genetic studies is necessary to improve the quality of genetic research in sub-Saharan African groups.

genetics↗

bioRxiv2022

GWAS in the Southern African context

Researchers would generally adjust for the possible confounding effect of population structure by considering global ancestry proportions or top principle components. Alternatively, researchers would conduct admixture mapping to increase the power to detect variants with an ancestry effect. This is sufficient in simple admixture scenarios, however, populations from southern Africa can be complex multi-way admixed populations. Duan et al. (2018) first described local ancestry adjusted allelic (LAAA) analysis as a robust method for discovering association signals, while producing minimal false-positives. Their simulation study, however, was limited to a two-way admixed population. Realizing that their findings might not translate to other admixture scenarios, we simulated a three- and five-way admixed population to compare the LAAA model to other models commonly used in GWAS. We found that, given our admixture scenarios, the LAAA model identifies the most causal variants in most of the phenotypes we tested across both the three-way and five-way admixed populations. The LAAA model also produced a high number of false-positives which was potentially caused by the ancestry effect size that we assumed. Considering the extent to which the various models tested differed in their results and considering that the source of a given association is unknown, we recommend that researchers use multiple GWAS models when analysing populations with complex ancestry.

genetics↗

bioRxiv2021

The Recombination Landscape of the Khoe-San - the Upper Limits of Recombination Divergence in Humans

Recombination maps are important resources for epidemiological and evolutionary analyses, however, there are currently no recombination maps representing any African population outside of those with West African ancestry. We inferred the demographic history for the Nama, an indigenous Khoe-San population of southern Africa, and derived a novel, population-specific recombination map from the whole genome sequencing of 54 Nama individuals. We hypothesized that there are no publicly available recombination maps representative of the Nama, considering the deep population divergence and subsequent isolation of the Khoe-San from other African groups. We showed that the recombination landscape of the Nama does not cluster with any continental groups with publicly available representative recombination maps. Finally, we used selection scans as an example of how fine-scale differences between the Nama recombination map and the combined Phase II HapMap recombination map can impact the outcome of selection scans.

bioinformatics↗

bioRxiv2019

Putting RFMix and ADMIXTURE to the test in a complex admixed population

Global and local ancestry inference in admixed human populations can be performed using computational tools implementing distinct algorithms, such as RFMix and ADMIXTURE. The accuracy of these tools has been tested largely on populations with relatively straightforward admixture histories but little is known about how well they perform in more complex admixture scenarios. Using simulations, we show that RFMix outperforms ADMIXTURE in determining global ancestry proportions in a complex 5-way admixed population. In addition, RFMix correctly assigns local ancestry with an accuracy of 89%. The increase in reported local ancestry inference accuracy in this population (as compared to previous studies) can largely be attributed to the recent availability of large-scale genotyping data for more representative reference populations. The ability of RFMix to determine global and local ancestry to a high degree of accuracy, allows for more reliable population structure analysis, scans for natural selection, admixture mapping and case-control association studies. This study highlights the utility of the extension of computational tools to become more relevant to genetically structured populations, as seen with RFMix. This is particularly noteworthy as modern-day societies are becoming increasingly genetically complex and some genetic tools are therefore less appropriate. We therefore suggest that RFMix be used for both global and local ancestry estimation in complex admixture scenarios.

genomics↗

bioRxiv2017

Fine-scale human population structure in southern Africa reflects ecogeographic boundaries

Recent genetic studies have established that the KhoeSan populations of southern Africa are distinct from all other African populations and have remained largely isolated during human prehistory until about 2,000 years ago. Dozens of different KhoeSan groups exist, belonging to three different language families, but very little is known about their population history. We examine new genome-wide polymorphism data and whole mitochondrial genomes for more than one hundred South Africans from the =Khomani San and Nama populations of the Northern Cape, analyzed in conjunction with 19 additional southern African populations. Our analyses reveal fine-scale population structure in and around the Kalahari Desert. Surprisingly, this structure does not always correspond to linguistic or subsistence categories as previously suggested, but rather reflects the role of geographic barriers and the ecology of the greater Kalahari Basin. Regardless of subsistence strategy, the indigenous Khoe-speaking Nama pastoralists and the N|u-speaking =Khomani (formerly hunter-gatherers) share ancestry with other Khoe-speaking forager populations that form a rim around the Kalahari Desert. We reconstruct earlier migration patterns and estimate that the southern Kalahari populations were among the last to experience gene flow from Bantu-speakers, approximately 14 generations ago. We conclude that local adoption of pastoralism, at least by the Nama, appears to have been primarily a cultural process with limited genetic impact from eastern Africa.\n\nData depositionData files are freely available on the Henn Lab website: http://ecoevo.stonybrook.edu/hennlab/data-software/\n\nSummaryDistinct, spatially organized ancestries demonstrate fine-scale population structure in southern Africa, implying a more complex history of the KhoeSan than previously thought. Southern KhoeSan ancestry in the Nama and =Khomani is shared in a rim around the Kalahari Desert. We hypothesize that there was recent migration of pastoralists from East Africa into southern Africa, independent of the Bantu-expansion, but the spread of pastoralism within southern Africa occurred largely by cultural diffusion.

genetics↗