Search bioRxiv⌕ Search
Home/Archive/bioRxiv

bioRxiv · 10.1101/444737

Adaptive eQTLs reveal the evolutionary impacts of pleiotropy and tissue-specificity, while contributing to health and disease in human populations

Quiver, M. H.·Lachance, J.
View original source ↗Export metadata ↓

Abstract

Regulatory DNA has the potential to be adaptive, and large numbers of expression quantitative trait loci (eQTLs) have recently been identified in humans. For the first time, a comprehensive study of adaptive eQTLs is possible. Many eQTLs have large allele frequency differences between populations, and these differences can be due to natural selection. Here, we combined population branch statistics with tissue-specific eQTL data to identify positively selected loci in human populations. Adaptive eQTLs tend to affect fewer tissues than non-adaptive eQTLs. Because the tissue breadth of an eQTL can be viewed as a measure of pleiotropy, these results suggest that pleiotropy can inhibit adaptation. The proportion of eQTLs that are adaptive varies by tissue, and we find that eQTLs that regulate expression in testis, thyroid, blood, or sun-exposed skin are enriched for adaptive outliers. By contrast, eQTLs that regulate expression in the cerebrum or female-specific tissues have a relative lack of adaptive outliers. These results reveal tissues that have been the targets of adaptation during the last 100,000 years of human evolution. The strongest adaptive signal in many regions of the human genome is an eQTL, including an eQTL associated with the Duffy blood group and malaria resistance. Scans of selection also reveal that many adaptive eQTLs are closely linked to disease-associated loci. Taken together, our results indicate that adaptive eQTLs have played an important role in human evolution.

Source connections

Explore related subjects

genomicsPreprint

Keep this discovery

Explore connections, maps & timelines

BibTeXRIS

Quiver, M. H., Lachance, J.. 2018-10-16. Adaptive eQTLs reveal the evolutionary impacts of pleiotropy and tissue-specificity, while contributing to health and disease in human populations. https://doi.org/10.1101/444737

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Shared and divergent features of the immune response to acute and chronic Trypanosoma cruzi infection in mice revealed by cardiac transcriptomics

Chagas disease is caused by infection with Trypanosoma cruzi and can result in chronic cardiomyopathy. However, the molecular programmes that define infected cardiac tissue, and how they change as the host-parasite relationship moves from acute pathogenic infection to long-term persistence, remain incompletely understood. Here, we used RNA sequencing to characterise host transcriptional responses in cardiac tissue during both acute and chronic infection in a mouse model. Cardiac parasite distribution was defined using bioluminescence imaging and histology, and RNA sequencing was performed on anatomically standardised cardiac tissue samples collected at both stages. Acute infection was associated with a broad interferon-driven immune activation, whereas during chronic infection this network contracted, with preservation of a tightly connected antigen presentation core centred on major histocompatibility complex genes and immunoproteasome components. Genes associated with extracellular matrix remodelling and fibrosis were not broadly activated. These findings indicate that reduced, but sustained immune activation, rather than widespread fibrotic transcriptional remodelling, represents a prominent feature of cardiac tissue in chronically infected mice. They identify a transition from an overtly inflammatory, pathogen-driven acute response to a more restricted chronic host-parasite equilibrium in which immune surveillance remains transcriptionally active despite very low and spatially intermittent cardiac infection. We identified a conserved 20-gene signature shared between acute and chronic stages. This overlap is consistent with continued or episodic parasite-derived stimulation and/or intrinsic host mechanisms that maintain cardiac immune surveillance. Thus, chronic T. cruzi infection can be viewed as a persistent host-parasite association in which biological coexistence does not imply benignity: immune containment and parasite persistence can occur alongside cumulative cardiac injury.

genomics↗
bioRxiv2026

Transcriptional contingency in the early hematopoiesis of inherited bone marrow failure syndromes

The inherited bone marrow failure syndromes (IBMFS) are a group of heterogeneous genetic diseases caused by germline pathogenic variants in genes involved in hematopoiesis and genomic integrity. Despite sharing common phenotypical manifestations that have aided opportune diagnosis, such as bone marrow failure, congenital malformations and an increased predisposition to develop cancer, little is known about the shared and distinctive transcriptional programs in their hematopoietic stem and progenitor cells compartment that underlie the clinical manifestations of each disease. In this work we have successfully integrated and analyzed the publicly available scRNAseq datasets of HSPCs from patients with Fanconi anemia (FA) and Telomere Biology disorders (TBD), as well as healthy controls. Once integrated, we performed quality control metrics, as well as batch effect correction using different methods. Through dimensionality reduction, cell clustering and cell type annotation we found distinctive gene expression profiles per syndrome and per cell type, as well as orchestrated gene expression profiles, including upregulation of inflammatory pathways and cell proliferation pathways. This work shows the integration of datasets from FA and TBD, two major IBMFS, and provides the basis for an accumulative, comparative, and integrated atlas of scRNAseq data from patients with IBMFS.

genomics↗
bioRxiv2026

Recurrent mitotic error and purifying selection shape chromosomal mosaicism across human tissues

Mosaic chromosomal alterations (mCAs) have been extensively studied in cancer and clonal hematopoiesis but less so in healthy solid tissues. Here, we characterized mCAs in 19 tissues across 25 donors (aged 42-89+ years) by analyzing >200x whole-genome sequencing data generated by the Somatic Mosaicism across Human Tissues (SMaHT) Network. Across 722 tissue samples, we identified 1,008 autosomal mCAs >1 Mb in length and ubiquitous losses of sex chromosomes. Surprisingly, the highest levels of Y chromosome loss in males (5-10% cell fraction in elderly donors) were observed in the lung, adrenal gland, and heart. These tissues also tended to experience more X loss in females, revealing a gradient of mitotic error burden across human tissues. Autosomal aneuploidies displayed distinct tissue-specific patterns indicative of negative selection against most events, except in the adrenal gland, in which low-level aneuploidy was pervasive. In contrast to the adrenal gland, testis rarely harbored aneuploidies but frequently experienced low-level copy-neutral loss of heterozygosity (CN-LOH), suggesting increased mitotic recombination in spermatogonial stem cells. Recurrent X chromosome losses within tissues of female donors exhibited allelic skews explained by a combination of genetic and epigenetic effects. Together, these results show that the chromosomal landscape of aging human tissues is shaped by genetics and recurrent mutations, most but not all of which are held in check by purifying selection.

genomics↗