Enhancers with tissue-specific activity are enriched in intronic regions.

Tissue function and homeostasis reflect the gene expression signature by which the combination of ubiquitous and tissue-specific genes contribute to the tissue maintenance and stimuli-responsive function. Enhancers are central to control this tissue-specific gene expression pattern. Here, we explore the correlation between the genomic location of enhancers and their role in tissue-specific gene expression. We find that enhancers showing tissue-specific activity are highly enriched in intronic regions and regulate the expression of genes involved in tissue-specific functions, whereas housekeeping genes are more often controlled by intergenic enhancers, common to many tissues. Notably, an intergenic-to-intronic active enhancers continuum is observed in the transition from developmental to adult stages: the most differentiated tissues present higher rates of intronic enhancers, whereas the lowest rates are observed in embryonic stem cells. Altogether, our results suggest that the genomic location of active enhancers is key for the tissue-specific control of gene expression.

Signatures of genetic variation in human microRNAs point to processes of positive selection and population-specific disease risks.

The occurrence of natural variation in human microRNAs has been the focus of numerous studies during the last 20 years. Most of them have been focused on the role of specific mutations in disease, while a minor proportion seek to analyse microRNA diversity in the genomes of human populations. We analyse the latest human microRNA annotations in the light of the most updated catalogue of genetic variation provided by the 1000 Genomes Project. By means of the in silico analysis of microRNA genetic variation we show that the level of evolutionary constraint of these sequences is governed by the interplay of different factors, like their evolutionary age or genomic location. The role of mutations in the shaping of microRNA-driven regulatory interactions is emphasized with the acknowledgement that, while the whole microRNA sequence is highly conserved, the seed region shows a pattern of higher genetic diversity that appears to be caused by the dramatic frequency shifts of a fraction of human microRNAs. We highlight the participation of these microRNAs in population-specific processes by identifying that not only the seed, but also the loop, are particularly differentiated regions among human populations. The quantitative computational comparison of signatures of population differentiation showed that candidate microRNAs with the largest differences are enriched in variants implicated in gene expression levels (eQTLs), selective sweeps and pathological processes. We explore the implication of these evolutionary-driven microRNAs and their SNPs in human diseases, such as different types of cancer, and discuss their role in population-specific disease risk.

PopHuman: the human population genomics browser.

The 1000 Genomes Project (1000GP) represents the most comprehensive world-wide nucleotide variation data set so far in humans, providing the sequencing and analysis of 2504 genomes from 26 populations and reporting >84 million variants. The availability of this sequence data provides the human lineage with an invaluable resource for population genomics studies, allowing the testing of molecular population genetics hypotheses and eventually the understanding of the evolutionary dynamics of genetic variation in human populations. Here we present PopHuman, a new population genomics-oriented genome browser based on JBrowse that allows the interactive visualization and retrieval of an extensive inventory of population genetics metrics. Efficient and reliable parameter estimates have been computed using a novel pipeline that faces the unique features and limitations of the 1000GP data, and include a battery of nucleotide variation measures, divergence and linkage disequilibrium parameters, as well as different tests of neutrality, estimated in non-overlapping windows along the chromosomes and in annotated genes for all 26 populations of the 1000GP. PopHuman is open and freely available at http://pophuman.uab.cat.

Chromosome X-wide Analysis of Positive Selection in Human Populations: Common and Private Signals of Selection and its Impact on Inactivated Genes and Enhancers.

The ability of detecting adaptive (positive) selection in the genome has opened the possibility of understanding the genetic basis of population-specific adaptations genome-wide. Here, we present the analysis of recent selective sweeps, specifically in the X chromosome, in human populations from the third phase of the 1,000 Genomes Project using three different haplotype-based statistics. We describe instances of recent positive selection that fit the criteria of hard or soft sweeps, and detect a higher number of events among sub-Saharan Africans than non-Africans (Europe and East Asia). A global enrichment of neural-related processes is observed and numerous genes related to fertility appear among the top candidates, reflecting the importance of reproduction in human evolution. Commonalities with previously reported genes under positive selection are found, while particularly strong new signals are reported in specific populations or shared across different continental groups. We report an enrichment of signals in genes that escape X chromosome inactivation, which may contribute to the differentiation between sexes. We also provide evidence of a widespread presence of soft-sweep-like signatures across the chromosome and a global enrichment of highly scoring regions that overlap potential regulatory elements. Among these, enhancers-like signatures seem to present putative signals of positive selection which might be in concordance with selection in their target genes. Also, particularly strong signals appear in regulatory regions that show differential activities, which might point to population-specific regulatory adaptations.