Biology subjects

Henn, B. M.

Publications and source records attributed to Henn, B. M..

17 recordsLinked to original sources

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↗

bioRxiv2025

No evidence for disassortative mating based on HLA genotype in a natural fertility population

Studies dating back several decades have suggested that humans prefer potential mates with dissimilar HLA genotypes. Evidence for actualized disassortative mating based on the human-specific MHC remains inconclusive. For instance, cosmopolitan populations have often exhibited the opposite trend whereby assortative mating at the MHC is observed, indicating that social stratification may overwhelm potential biological mate preferences. However, small-scale, endogamous populations-whose social structures more closely resemble those throughout most of human evolution-have been largely overlooked. Here, we assess HLA dissimilarity among Himba pastoralists from Namibia, where socially accepted concurrency allows individuals to maintain both arranged marital and self-selected ("love match") partnerships. This provides a rare opportunity to directly test HLA similarity across contrasting partnership types (arranged vs chosen) within the same social system (n = 249 observed partnerships). We find no difference in HLA dissimilarity (neither at the genotype nor protein divergence level) between partnership types, nor in their fitness benefits to potential offspring as assessed via computationally predicted pathogen binding affinities. The effects of the partnership types likewise do not differ from a random, background distribution of 18,487 possible unrelated pairings. Finally, we detect extensive haplotype sharing across the HLA region, suggesting that episodes of fluctuating positive selection may be a stronger force maintaining HLA polymorphism than disassortative mating, even in an evolutionarily relevant social context.

evolutionary biology↗

bioRxiv2024

Improving GWAS performance in underrepresented groups by appropriate modeling of genetics, environment, and sociocultural factors

Genome-wide association studies (GWAS) and polygenic score (PGS) development are typically constrained by the data available in biobank repositories in which European cohorts are vastly overrepresented. Here, we increase the utility of non-European participant data within the UK Biobank (UKB) by characterizing the genetic affinities of UKB participants who self-identify as Bangladeshi, Indian, Pakistani, "White and Asian" (WA), and "Any Other Asian" (AOA), towards creating a more robust South Asian sample size for future genetic analyses. We assess the relationships between genetic structure and self-selected ethnic identities and use consistent patterns of clustering in the dataset to train a support vector machine (SVM). The SVM was utilized to reassign n = 1,853 AOA and WA participants at the subcontinental level, and increase the sample size of the UKB South Asian group by 1,381 additional participants. We further leverage these samples to assess GWAS performance and PGS development. We include environmental covariates in the height GWAS by implementing a rigorous covariate selection procedure, and compare the outputs of two GWAS models: GWASnull and GWASenv. We show that PGS performance derived from both GWAS models yield comparable prediction to PGS models developed with an order of magnitude larger training, and environmentally-adjusted PGS models reduce the sex-bias in predictive performance. In summary, we demonstrate how GWAS performance can be improved by leveraging ambiguous ethnicity codes, ancestry matched imputation panels, and including environmental covariates.

genetics↗

bioRxiv2024

Common DNA sequence variation influences epigenetic aging in African populations

Aging is associated with genome-wide changes in DNA methylation in humans, facilitating the development of epigenetic age prediction models. However, most of these models have been trained primarily on European-ancestry individuals, and none account for the impact of methylation quantitative trait loci (meQTL). To address these gaps, we analyzed the relationships between age, genotype, and CpG methylation in 3 understudied populations: central African Baka (n = 35), southern African {ddagger}Khomani San (n = 52), and southern African Himba (n = 51). We find that published prediction methods yield higher mean errors in these cohorts compared to European-ancestry individuals, and find that unaccounted-for DNA sequence variation may be a significant factor underlying this loss of accuracy. We leverage information about the associations between DNA genotype and CpG methylation to develop an age predictor that is minimally influenced by meQTL, and show that this model remains accurate across a broad range of genetic backgrounds. Intriguingly, we also find that the older individuals and those exhibiting relatively lower epigenetic age acceleration in our cohorts tend to carry more epigenetic age-reducing genetic variants, suggesting a novel mechanism by which heritable factors can influence longevity.

genetics↗

bioRxiv2023

Transcriptomics and chromatin accessibility in multiple African population samples

Mapping the functional human genome and impact of genetic variants is often limited to European-descendent population samples. To aid in overcoming this limitation, we measured gene expression using RNA sequencing in lymphoblastoid cell lines (LCLs) from 599 individuals from six African populations to identify novel transcripts including those not represented in the hg38 reference genome. We used whole genomes from the 1000 Genomes Project and 164 Maasai individuals to identify 8,881 expression and 6,949 splicing quantitative trait loci (eQTLs/sQTLs), and 2,611 structural variants associated with gene expression (SV-eQTLs). We further profiled chromatin accessibility using ATAC-Seq in a subset of 100 representative individuals, to identity chromatin accessibility quantitative trait loci (caQTLs) and allele-specific chromatin accessibility, and provide predictions for the functional effect of 78.9 million variants on chromatin accessibility. Using this map of eQTLs and caQTLs we fine-mapped GWAS signals for a range of complex diseases. Combined, this work expands global functional genomic data to identify novel transcripts, functional elements and variants, understand population genetic history of molecular quantitative trait loci, and further resolve the genetic basis of multiple human traits and disease.

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↗

bioRxiv2023

Impact of cross-ancestry genetic architecture on GWAS in admixed populations

Genome-wide association studies (GWAS) have identified thousands of variants for disease risk. These studies have predominantly been conducted in individuals of European ancestries, which raises questions about their transferability to individuals of other ancestries. Of particular interest are admixed populations, usually defined as populations with recent ancestry from two or more continental sources. Admixed genomes contain segments of distinct ancestries that vary in composition across individuals in the population, allowing for the same allele to induce risk for disease on different ancestral backgrounds. This mosaicism raises unique challenges for GWAS in admixed populations, such as the need to correctly adjust for population stratification to balance type I error with statistical power. In this work we quantify the impact of differences in estimated allelic effect sizes for risk variants between ancestry backgrounds on association statistics. Specifically, while the possibility of estimated allelic effect-size heterogeneity by ancestry (HetLanc) can be modeled when performing GWAS in admixed populations, the extent of HetLanc needed to overcome the penalty from an additional degree of freedom in the association statistic has not been thoroughly quantified. Using extensive simulations of admixed genotypes and phenotypes we find that modeling HetLanc in its absence reduces statistical power by up to 72%. This finding is especially pronounced in the presence of allele frequency differentiation. We replicate simulation results using 4,327 African-European admixed genomes from the UK Biobank for 12 traits to find that for most significant SNPs HetLanc is not large enough for GWAS to benefit from modeling heterogeneity.

bioinformatics↗

bioRxiv2022

Increased homozygosity due to endogamy results in fitness consequences in a human population

Recessive alleles have been shown to directly affect both human Mendelian disease phenotypes and complex traits like height. Pedigree studies also suggest that consanguinity results in increased childhood mortality and adverse health phenotypes, presumably through penetrance of recessive mutations. Here, we test whether the accumulation of homozygous, recessive alleles decreases reproductive success in a human population. We address this question among the Namibian Himba, an endogamous agro-pastoralist population, who until very recently practiced natural fertility. Using a sample of 681 individuals, we show that Himba exhibit elevated levels of "inbreeding", calculated as the fraction of the genome in runs of homozygosity (FROH). Many individuals contain multiple long segments of ROH in their genomes, indicating that their parents had high kinship coefficients. However, we did not find evidence that this is explained by first-cousin consanguinity, despite a reported social preference for cross-cousin marriages. Rather, we show that elevated haplotype sharing in the Himba is due to a bottleneck, likely in the past 60 generations. We test whether increased recessive mutation load results in observed fitness consequences by assessing the effects of FROH on completed fertility in a cohort of post-reproductive women (n=69). We find that higher FROH is significantly associated with lower fertility among women who have had at least one child (p<0.006). Our data suggest a multi-locus genetic effect on fitness driven by the expression of deleterious recessive alleles, especially those in long ROH. However, these effects are not the result of consanguinity but rather elevated background identity by descent.

genetics↗

bioRxiv2022

Predicting environmental and ecological drivers of human population structure

Landscape, climate, and culture can all structure human populations, but few methods are designed to disentangle the importance of these many variables. We developed a machine learning method for identifying the variables which best explain migration rates, as measured by the coalescent-based program MAPS that uses shared identical by descent tracts to infer and extrapolate spatial migration across a region of interest. We applied our method to 30 human populations in eastern Africa with high density SNP array data. The remarkable diversity of ethnicities, languages, and environments in this region offers a unique opportunity to explore the variables that shape migration and genetic structure in humans. We explored more than twenty spatial variables relating to landscape, climate, and presence of tsetse flies (an important regional disease vector). The full model explained ~40% of variance in migration rate over the past 56 generations. Precipitation, minimum temperature of the coldest month, and altitude were the most important variables. Among the three groups of tsetse flies, the most important was the fusca group which is a vector for livestock trypanosomiasis. We also performed a selection scan on a subgroup of the populations who live in Ethiopia at relatively high altitudes. We did not identify well-known high-altitude genes, but we did find signatures of positive selection related to metabolism and disease. We conclude that environment has notably shaped the migration and adaptation of human populations in eastern Africa; the remaining variance in structure is likely due to cultural factors not captured in our model.

evolutionary biology↗

bioRxiv2022

A weakly structured stem for human origins in Africa

While it is now broadly accepted that Homo sapiens originated within Africa, considerable uncertainty surrounds specific models of divergence and migration across the continent. Progress is hampered by a paucity of fossil and genomic data, as well as variability in prior divergence time estimates. Here we use linkage disequilibrium and diversity-based statistics, optimized for rapid, complex demographic inference to discriminate among such models. We infer detailed demographic models for populations across Africa, including representatives from eastern and western groups, as well as 44 newly whole-genome sequenced individuals from the Nama (Khoe-San). Despite the complexity of African population history, contemporary population structure dates back to Marine Isotope Stage (MIS) 5. The earliest population divergence among contemporary populations occurs 120-135ka, between the Khoe-San and other groups. Prior to the divergence of contemporary African groups, we infer long-lasting structure between two or more weakly differentiated ancestral Homo populations connected by gene flow over hundreds of thousands of years (i.e. a weakly structured stem). We find that weakly structured stem models provide more likely explanations of polymorphism that had previously been attributed to contributions from archaic hominins in Africa. In contrast to models with archaic introgression, we predict that fossil remains from coexisting ancestral populations should be morphologically similar. Despite genetic similarity between these populations, an inferred 1-4% of genetic differentiation among contemporary human populations can be attributed to genetic drift between stem populations. We show that model misspecification explains variation in previous divergence time estimates and argue that studying a suite of models is key to robust inferences about deep history.

genomics↗

bioRxiv2021

Admixed Populations Improve Power for Variant Discovery and Portability in Genome-wide Association Studies

Genome-wide association studies (GWAS) are primarily conducted in single-ancestry settings. The low transferability of results has limited our understanding of human genetic architecture across a range of complex traits. In contrast to homogeneous populations, admixed populations provide an opportunity to capture genetic architecture contributed from multiple source populations and thus improve statistical power. Here, we provide a mechanistic simulation framework to investigate the statistical power and transferability of GWAS under directional polygenic selection or varying divergence. We focus on a two-way admixed population and show that GWAS in admixed populations can be enriched for power in discovery by up to 2-fold compared to the ancestral populations under similar sample size. Moreover, higher accuracy of cross-population polygenic score estimates is also observed if variants and weights are trained in the admixed group rather than in the ancestral groups. Common variant associations are also more likely to replicate if first discovered in the admixed group and then transferred to an ancestral population, than the other way around (across 50 iterations with 1,000 causal SNPs, training on 10,000 individuals, testing on 1,000 in each population, p=3.78e-6, 6.19e-101, ~0 for FST = 0.2, 0.5, 0.8, respectively). While some of these FST values may appear extreme, we demonstrate that they are found across the entire phenome in the GWAS catalog. This framework demonstrates that investigation of admixed populations harbors significant advantages over GWAS in single-ancestry cohorts for uncovering the genetic architecture of traits and will improve downstream applications such as personalized medicine across diverse populations.

genetics↗

bioRxiv2020

A rapid, accurate approach to inferring pedigrees in endogamous populations

Accurate reconstruction of pedigrees from genetic data remains a challenging problem. Pedigree inference algorithms are often trained only on European-descent families in urban locations. Many relationship categories can be difficult to distinguish (e.g. half-sibships versus avuncular) without external information. Furthermore, existing methods perform poorly in endogamous populations for which there may be reticulations within the pedigrees and elevated haplotype sharing. We present a simple, rapid algorithm which initially uses only high-confidence first-degree relationships to seed a machine learning step based on summary statistics of identity-by-descent (IBD) sharing. One of these statistics, our "haplotype score", is novel and can be used to: (1) distinguish half-sibling pairs from avuncular or grandparent-grandchildren pairs; and (2) assign individuals to ancestor versus descendant generation. We test our approach in a sample of 700 individuals from northern Namibia, sampled from an endogamous population called the Himba. Due to a culture of concurrent relationships in the Himba, there is a high proportion of half-sibships. We accurately identify first through fourth-degree relationships and distinguish between various second-degree relationships: half-sibships, avuncular pairs, and grandparent-grandchildren. We further validate our approach in a second diverse African-descent dataset, the Barbados Asthma Genetics Study (BAGS). Accurate reconstruction of pedigrees holds promise for tracing allele frequency trajectories, improved phasing and other population genomic questions.

bioinformatics↗

bioRxiv2019

DNA methylation-based forensic age estimation in human bone

DNA methylation is an epigenetic modification of cytosine nucleotides that represents a promising suite of aging markers with broad potential applications. In particular, determining an individuals age from their skeletal remains is an enduring problem in the field of forensic anthropology, and one that epigenetic markers are particularly well-suited to address. However, all DNA methylation-based age prediction methods published so far focus on tissues other than bone. While high accuracy has been achieved for saliva, blood and sperm, which are easily accessible in living individuals, the highly tissue-specific nature of DNA methylation patterns means that age prediction models trained on these particular tissues may not be directly applicable to other tissues. Bone is a prime target for the development of DNA methylation-based forensic identification tools as skeletal remains are often recoverable for years post-mortem, and well after soft tissues have decomposed. In this study, we generate genome-wide DNA methylation data from 32 individual bone samples. We analyze this new dataset alongside published data from 133 additional bone donors, both living and deceased. We perform an epigenome-wide association study on this combined dataset to identify 108 sites of DNA methylation that show a significant relationship with age (FDR < 0.05). We also develop an age-prediction model using lasso regression that produces highly accurate estimates of age from bone spanning an age range of 49-112 years. Our study demonstrates that DNA methylation levels at specific CpG sites can serve as powerful markers of aging, and can yield more accurate predictions of chronological age in human adults than morphometric markers.

genetics↗

bioRxiv2019

Hunter-gatherer genomes reveal diverse demographic trajectories following the rise of farming in East Africa

A major outstanding question in human prehistory is the fate of hunting and gathering populations following the rise of agriculture and pastoralism. Genomic analysis of ancient and contemporary Europeans suggests that autochthonous groups were either absorbed into or replaced by expanding farmer populations. Many of the hunter-gatherer populations persisting today live in Africa, perhaps because agropastoral transitions occurred later on the continent. Here, we present the first genomic data from the Chabu, a relatively isolated and marginalized hunting-and-gathering group from the Southwestern Ethiopian highlands. The Chabu are a distinct genetic population that carry the highest levels of Southwestern Ethiopian ancestry of any extant population studied thus far. This ancestry has been in situ for at least 4,500 years. We show that the Chabu are undergoing a severe population bottleneck which began around 40 generations ago. We also study other Eastern African populations and demonstrate divergent patterns of historical population size change over the past 60 generations between even closely related groups. We argue that these patterns demonstrate that, unlike in Europe, Africans hunter-gatherers responded to agropastoralism with diverse strategies.

genetics↗

bioRxiv2018

A sex-stratified genome-wide association study of tuberculosis using a multi-ethnic genotyping array

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is a complex disease with a known human genetic component. Males seem to be more affected than females and in most countries the TB notification rate is twice as high in males as in females. While socio-economic status, behaviour and sex hormones influence the male bias they do not fully account for it. Males have only one copy of the X chromosome, while diploid females are subject to X chromosome inactivation. In addition, the X chromosome codes for many immune-related genes, supporting the hypothesis that X-linked genes could contribute to TB susceptibility in a sex-biased manner. We report the first TB susceptibility genome-wide association study (GWAS) with a specific focus on sex-stratified autosomal analysis and the X chromosome. Individuals from an admixed South African population were genotyped using the Illumina Multi Ethnic Genotyping Array, specifically designed as a suitable platform for diverse and admixed populations. Association testing was done on the autosome and X chromosome in a sex stratified and combined manner. SNP association testing was not statistically significant using a stringent cut-off for significance but revealed likely candidate genes that warrant further investigation. A genome wide interaction analysis detected 16 significant interactions. Finally, the results highlight the importance of sex-stratified analysis as strong sex-specific effects were identified on both the autosome and X chromosome.

genetics↗

bioRxiv2017

Localization of adaptive variants in human genomes using averaged one-dependence estimation

Statistical methods for identifying adaptive mutations from population-genetic data face several obstacles: assessing the significance of genomic outliers, integrating correlated measures of selection into one analytic framework, and distinguishing adaptive variants from hitchhiking neutral variants. Here, we introduce SWIF(r), a probabilistic method that detects selective sweeps by learning the distributions of multiple selection statistics under different evolutionary scenarios and calculating the posterior probability of a sweep at each genomic site. SWIF(r) is trained using simulations from a user-specified demographic model and explicitly models the joint distributions of selection statistics, thereby increasing its power to both identify regions undergoing sweeps and localize adaptive mutations. Using array and exome data from 45 {ddagger}Khomani San hunter-gatherers of southern Africa, we identify an enrichment of adaptive signals in genes associated with metabolism and obesity. SWIF(r) provides a transparent probabilistic framework for localizing beneficial mutations that is extensible to a variety of evolutionary scenarios.

evolutionary biology↗

bioRxiv2017

An Unexpectedly Complex Architecture for Skin Pigmentation in Africans

Fewer than 15 genes have been directly associated with skin pigmentation variation in humans, leading to its characterization as a relatively simple trait. However, by assembling a global survey of quantitative skin pigmentation phenotypes, we demonstrate that pigmentation is more complex than previously assumed with genetic architecture varying by latitude. We investigate polygenicity in the Khoe and the San, populations indigenous to southern Africa, who have considerably lighter skin than equatorial Africans. We demonstrate that skin pigmentation is highly heritable, but that known pigmentation loci explain only a small fraction of the variance. Rather, baseline skin pigmentation is a complex, polygenic trait in the KhoeSan. Despite this, we identify canonical and non-canonical skin pigmentation loci, including near SLC24A5, TYRP1, SMARCA2/VLDLR, and SNX13 using a genome-wide association approach complemented by targeted resequencing. By considering diverse, under-studied African populations, we show how the architecture of skin pigmentation can vary across humans subject to different local evolutionary pressures.\n\nHighlightsO_LISkin pigmentation in Africans is far more polygenic than light skin pigmentation in Eurasians.\nC_LIO_LIKhoeSan[§] populations, which diverged early in human prehistory from other populations, have lightened skin pigmentation compared to equatorial Africans.\nC_LIO_LISkin color is highly heritable in the KhoeSan, but pigmentation variability is not well explained by previously discovered pigmentation genes.\nC_LIO_LIWe perform the first GWAS for pigmentation in African KhoeSan populations and identify canonical pigmentation loci near TYRP1 and in SLC24A5, as well as novel associations surrounding SMARCA2 and other genes.\nC_LI

genetics↗