Impact and Evolutionary Determinants of Neanderthal Introgression on Transcriptional and Post-Transcriptional Regulation.

Archaic admixture is increasingly recognized as an important source of diversity in modern humans, and Neanderthal haplotypes cover 1%-3% of the genome of present-day Eurasians. Recent work has shown that archaic introgression has contributed to human phenotypic diversity, mostly through the regulation of gene expression. Yet the mechanisms through which archaic variants alter gene expression and the forces driving the introgression landscape at regulatory regions remain elusive. Here, we explored the impact of archaic introgression on transcriptional and post-transcriptional regulation. We focused on promoters and enhancers across 127 different tissues as well as on microRNA (miRNA)-mediated regulation. Although miRNAs themselves harbor few archaic variants, we found that some of these variants may have a strong impact on miRNA-mediated gene regulation. Enhancers were by far the regulatory elements most affected by archaic introgression: up to one-third of the tissues we tested presented significant enrichments. Specifically, we found strong enrichments of archaic variants in adipose-related tissues and primary T cells, even after accounting for various genomic and evolutionary confounders such as recombination rate and background selection. Interestingly, we identified signatures of adaptive introgression at enhancers of some key regulators of adipogenesis, raising the interesting hypothesis of a possible adaptation of early Eurasians to colder climates. Collectively, this study sheds new light on the mechanisms through which archaic admixture has impacted gene regulation in Eurasians and, more generally, increases our understanding of the contribution of Neanderthals to the regulation of acquired immunity and adipose homeostasis in modern humans.

Population variation in miRNAs and isomiRs and their impact on human immunity to infection.

BACKGROUND: MicroRNAs (miRNAs) are key regulators of the immune system, yet their variation and contribution to intra- and inter-population differences in immune responses is poorly characterized. RESULTS: We generate 977 miRNA-sequencing profiles from primary monocytes from individuals of African and European ancestry following activation of three TLR pathways (TLR4, TLR1/2, and TLR7/8) or infection with influenza A virus. We find that immune activation leads to important modifications in the miRNA and isomiR repertoire, particularly in response to viral challenges. These changes are much weaker than those observed for protein-coding genes, suggesting stronger selective constraints on the miRNA response to stimulation. This is supported by the limited genetic control of miRNA expression variability (miR-QTLs) and the lower occurrence of gene-environment interactions, in stark contrast with eQTLs that are largely context-dependent. We also detect marked differences in miRNA expression between populations, which are mostly driven by non-genetic factors. On average, miR-QTLs explain approximately 60% of population differences in expression of their cognate miRNAs and, in some cases, evolve adaptively, as shown in Europeans for a miRNA-rich cluster on chromosome 14. Finally, integrating miRNA and mRNA data from the same individuals, we provide evidence that the canonical model of miRNA-driven transcript degradation has a minor impact on miRNA-mRNA correlations, which are, in our setting, mainly driven by co-transcription. CONCLUSION: Together, our results shed new light onto the factors driving miRNA and isomiR diversity at the population level and constitute a useful resource for evaluating their role in host differences of immunity to infection.

Genomic Evidence for Local Adaptation of Hunter-Gatherers to the African Rainforest.

African rainforests support exceptionally high biodiversity and host the world's largest number of active hunter-gatherers [1-3]. The genetic history of African rainforest hunter-gatherers and neighboring farmers is characterized by an ancient divergence more than 100,000 years ago, together with recent population collapses and expansions, respectively [4-12]. While the demographic past of rainforest hunter-gatherers has been deeply characterized, important aspects of their history of genetic adaptation remain unclear. Here, we investigated how these groups have adapted-through classic selective sweeps, polygenic adaptation, and selection since admixture-to the challenging rainforest environments. To do so, we analyzed a combined dataset of 566 high-coverage exomes, including 266 newly generated exomes, from 14 populations of rainforest hunter-gatherers and farmers, together with 40 newly generated, low-coverage genomes. We find evidence for a strong, shared selective sweep among all hunter-gatherer groups in the regulatory region of TRPS1-primarily involved in morphological traits. We detect strong signals of polygenic adaptation for height and life history traits such as reproductive age; however, the latter appear to result from pervasive pleiotropy of height-associated genes. Furthermore, polygenic adaptation signals for functions related to responses of mast cells to allergens and microbes, the IL-2 signaling pathway, and host interactions with viruses support a history of pathogen-driven selection in the rainforest. Finally, we find that genes involved in heart and bone development and immune responses are enriched in both selection signals and local hunter-gatherer ancestry in admixed populations, suggesting that selection has maintained adaptive variation in the face of recent gene flow from farmers.

Computational design of fully overlapping coding schemes for protein pairs and triplets.

Gene pairs that overlap in their coding regions are rare except in viruses. They may occur transiently in gene creation and are of biotechnological interest. We have examined the possibility to encode an arbitrary pair of protein domains as a dual gene, with the shorter coding sequence completely embedded in the longer one. For 500 × 500 domain pairs (X, Y), we computationally designed homologous pairs (X', Y') coded this way, using an algorithm that provably maximizes the sequence similarity between (X', Y') and (X, Y). Three schemes were considered, with X' and Y' coded on the same or complementary strands. For 16% of the pairs, an overlapping coding exists where the level of homology of X', Y' to the natural proteins represents an E-value of 10-10 or better. Thus, for an arbitrary domain pair, it is surprisingly easy to design homologous sequences that can be encoded as a fully-overlapping gene pair. The algorithm is general and was used to design 200 triple genes, with three proteins encoded by the same DNA segment. The ease of design suggests overlapping genes may have occurred frequently in evolution and could be readily used to compress or constrain artificial genomes.