Characterizing transcriptome variation in human populations at single-cell resolution
Year: 2022
Type: conference-paper
Abstract: Phenotypic diversity in human populations is a direct consequence of genetic variation, which acts in conjunction with environmental and behavioral factors to produce phenotypic variation, from eye color and height to disease susceptibility and responses to drugs (1). High population-specific variability in disease’s prevalence have been described, including multiple examples where a disease is strongly overrepresented in a single population, for instance sickle cell anemia in Africans, hemochromatosis in Northern-Europeans or familial Gaucher’s disease in Ashkenazi Jews (2). In addition, population differences in response to drugs have been documented, for instance, 5-Fluorouracil (cancer chemotherapeutic), Warfarin (anticoagulant for preventing thrombosis and embolism) or nicotine (3). In this context, there has been a growing interest in profiling the molecular causes underlying infectious disease-related phenotypic differences across individuals from populations of different genetic backgrounds. Studies using RNA-seq data from primary monocytes, as a model of an innate immunity, have shown that human populations differ in their transcriptional responses to immune challenges, which are largely controlled by genetics and have been shaped by natural selection (4). In addition, a similar work focusing on alternative splicing characterisation upon immune activation highlights the contribution of positive selection to diversify the splicing landscape of human populations (5). Moreover, additional works using single-cell RNA-seq indicate that most of the ancestry effects on the immune response are cell type specific, exceptuating interferon (IFN) response which is strongly correlated with European ancestry after infection with influenza A virus (Figure 1) (6). Also in line with previous evidence, it has been seen that eQTLs explains > 50% of population differences in response to infection, stressing the key role played by genetics in shaping population differences in immune responses (6). This evidence suggests that genetic ancestry is a main driver of inter-individual differences in response to infection. In turn, these findings highlight the importance of studying the effect of human population genetic variation over disease and disease response for developing effective treatments, and in order to lay the foundations for the establishment of personalized medicine. Moreover, the characterisation of the transcriptome differences derived from human genetic variation can provide further insights into the evolution of human populations.
Authors: Chazarra-Gil, Ruben, Melé, Marta
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7027409751