Biology subjects

Tishkoff, S. A.

Publications and source records attributed to Tishkoff, S. A..

6 recordsLinked to original sources

bioRxiv2026

Ciliary regulation of melanogenesis unveils moonlighting roles for Joubert Syndrome proteins

We previously found that skin tone correlates with intronic polymorphisms influencing the expression of the Joubert Syndrome (JS) ciliopathy gene TMEM138, suggesting that primary cilia might regulate pigment production in skin melanocytes. Herein, we show that many ciliary proteins regulate basal pigmentation in wild-type mouse and human melanocytes by facilitating primary cilium-dependent Melanocortin-1 receptor signaling, and downstream activation of the Microphthalmia transcription factor and melanogenic gene expression. Additionally, we identify an extra-ciliary moonlighting role for TMEM138 and other JS proteins in endolysosomal organization required for the biogenesis of melanosomes, the pigment-producing lysosome-related organelle in melanocytes. Our results provide new mechanistic insights into the physiological regulation of pigmentation and suggest that JS-specific pathology might be mediated by ciliary-independent mechanisms.

cell biology↗

bioRxiv2024

Environmentally-mediated selection parallels population divergence across a chimpanzee subspecies contact zone

Species evolve from populations with ancestor-descendant relationships in a bifurcating process shaped by geography, gene flow, genetic drift, and natural selection leading to local adaptation to prevailing environmental and ecological conditions. Building on this foundational understanding, we explored local adaptation in chimpanzees (Pan troglodytes) at a key geographical intersection in Cameroon where the two main chimpanzee phylogenetic lineages converge. The Nigeria-Cameroon chimpanzee (P. t. ellioti) and central chimpanzee (P. t. troglodytes) last shared a common ancestor about 500 thousand years ago, with occasional gene flow between them. The evolutionary processes driving their prolonged separation are not fully understood, but neutral evolutionary mechanisms alone cannot account for the observed divergence pattern. Cameroon is often referred to as Africa in miniature because the Gulf of Guinea Forest, Congo Basin Forest, and savanna converge there, forming an ecotone. Thus, this contact zone between subspecies in Cameroon provides a unique natural laboratory that enabled us to investigate how environmental variation and natural selection shape divergence in chimpanzees. We developed a genome-wide panel of single-nucleotide polymorphisms (SNPs) in 112 wild chimpanzees sampled in multiple habitats across this contact zone. We augmented SNP discovery by sequencing eight new chimpanzee genomes from Cameroon and analyzing them with previously published chimpanzee genomes. We found that P. t. ellioti and P. t. troglodytes diverged from one another around 478,000 years ago and occasionally exchange migrants. We identified 1,690 unique SNPs across 905 genes associated with 31 environmental variables that describe the habitat. These genes are involved in essential biological processes, including immune response, neurological development, behavior, and dietary adaptations. This study highlights the importance of understanding the geographical context of natural selection, paving the way for future studies to interpret evidence for genetic variation with phenotypic traits and deepening our understanding of how populations diverge in response to environmental pressures. Author SummaryWe investigated how local adaptation contributes to shaping the diversification of chimpanzee subspecies at the geographical convergence point for the two major branches of the chimpanzee phylogenetic tree. We analyzed genome-wide SNP genotypes of 112 chimpanzees sampled from natural communities located in this understudied area. We used tiered methods that identified 905 genes subject to selection, each associated with one or more of 31 environmental predictors describing the habitat. We found strong signals of selection in immune response genes that separate P. t. troglodytes from P. t. ellioti, highlighting the important role of different pathogen histories in their evolution. We also found evidence of selection in genes associated with neurological development, behavior, and diet, that separate both the subspecies and populations of P. t. ellioti that occupy different niches. These findings suggest that ecological and cultural factors may also contribute to shaping the diversification of chimpanzees across the contact zone.

genomics↗

bioRxiv2022

The Genetic and Evolutionary Basis of Gene Expression Variation in East Africans

BackgroundMapping of quantitative trait loci (QTL) associated with molecular phenotypes is a powerful approach for identifying the genes and molecular mechanisms underlying human traits and diseases. How the genetic architecture of molecular traits varies across human populations, however, has been less explored. To better understand the genetics of gene regulation in East Africans, we perform expression and splicing QTL mapping in whole blood from a cohort of 162 diverse Africans from Ethiopia and Tanzania. We assess replication of these QTLs in cohorts of predominantly European ancestry and identify candidate genes under selection in human populations. ResultsWe find the gene regulatory architecture of African and non-African populations is broadly shared, though there is a considerable amount of variation at individual loci across populations. Comparing our analyses to an equivalently sized cohort of European Americans, we find that QTL mapping in Africans improves the detection of expression QTLs and fine mapping of causal variation. Integrating our QTL scans with signatures of selection, we find several genes related to immunity and metabolism that are highly differentiated between Africans and non-Africans, as well as a gene associated with pigmentation, TMEM216, with evidence of population-specific selection in Nilo-Saharan speaking pastoralists. ConclusionExtending QTL-mapping studies beyond groups of European ancestry, particularly to diverse indigenous populations, is vital for a complete understanding of the genetic architecture of human traits and can reveal novel functional variation underlying human traits and disease.

genomics↗

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

Origins, admixture dynamics and homogenization of the African gene pool in the Americas

The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed genome-wide analysis of 6,267 individuals from 22 populations and observed an enrichment in West-African ancestry in northern latitudes of the Americas, whereas South/East African ancestry is more prevalent in southern South-America. This pattern results from distinct geographic and geopolitical factors leading to population differentiation. However, we observed a decrease of 68% in the African gene pool between-population diversity within the Americas when compared to the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the US and Southeast-Brazil, respect to historical-demography expectations. Also, in most of the Americas, admixture intensification occurred between 1,750 and 1,850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural and political debate regarding ancestry, race, and admixture in the Americas.\n\nSignificance StatementDifferently from most genetic studies, that have estimated the overall African ancestry in the Americas, we perform a finer geographic analysis and infer how different African groups contributed to North-, South-American and Caribbean populations, in the context of geographic and geopolitical factors. We also perform a formal comparison of information from demographic history records of the Transatlantic Slave Trade with inferences based on genomic diversity of current populations. Our approach reveals the distinct regional African ancestry roots of different populations from North-, South-America and the Caribe and other important aspects of the historical process of mestizaje and its dynamics in the American continent.

genetics↗

bioRxiv2017

A Polymorphic Residue That Attenuates Interferon Lambda 4 Activity in Hominid Lineages

As antimicrobial signalling molecules, type III or lambda interferons (IFN{lambda}s) are critical for defence against infection by diverse pathogens. Counter-intuitively, expression of one member of the family, IFN{lambda}4, is associated with decreased clearance of hepatitis C virus (HCV) in the human population; by contrast, a natural in-frame nucleotide insertion that abrogates IFN{lambda}4 production improves viral clearance. To further understand how genetic variation between and within species affects IFN{lambda}4 function, we screened a panel of extant coding variants of human IFN{lambda}4 and identified three variants that substantially affect antiviral activity (P70S, L79F and K154E). The most notable variant was K154E, which enhanced in vitro activity in a range of antiviral and interferon stimulated gene (ISG) assays. This more active E154 variant of IFN{lambda}4 was found only in African Congo rainforest Pygmy hunter-gatherers. Remarkably, E154 was highly conserved as the ancestral residue in mammalian IFN{lambda}4s yet K154 is the dominant variant throughout evolution of the hominid genus Homo. Compared to chimpanzee IFN{lambda}4, the human orthologue had reduced activity due to amino acid substitution of glutamic acid with lysine at position 154. Meta-analysis of published gene expression data from humans and chimpanzees showed that this difference in activity between K154 and E154 in IFN{lambda}4 is consistent with differences in antiviral gene expression in vivo during HCV infection. Mechanistically, our data suggest that human-specific K154 likely affects IFN{lambda}4 activity by reducing secretion and potency. We postulate that evolution of an IFN{lambda}4 with attenuated activity in humans (K154) likely contributes to distinct host-specific responses to and outcomes of infection, such as HCV.

immunology↗