Integration and Fixation Preferences of Human and Mouse Endogenous Retroviruses Uncovered with Functional Data Analysis

Abstract

Endogenous retroviruses (ERVs), the remnants of retroviral infections in the germ line, occupy ~8% and ~10% of the human and mouse genomes, respectively, and affect their structure, evolution, and function. Yet we still have a limited understanding of how the genomic landscape influences integration and fixation of ERVs. Here we conducted a genome-wide study of the most recently active ERVs in the human and mouse genome. We investigated 826 fixed and 1,065 in vitro HERV-Ks in human, and 1,624 fixed and 242 polymorphic ETns, as well as 3,964 fixed and 1,986 polymorphic IAPs, in mouse. We quantitated >40 human and mouse genomic features (e.g., non-B DNA structure, recombination rates, and histone modifications) in ±32 kb of these ERVs’ integration sites and in control regions, and analyzed them using Functional Data Analysis (FDA) methodology. In one of the first applications of FDA in genomics, we identified genomic scales and locations at which these features display their influence, and how they work in concert, to provide signals essential for integration and fixation of ERVs. The investigation of ERVs of different evolutionary ages (young in vitro and polymorphic ERVs, older fixed ERVs) allowed us to disentangle integration vs. fixation preferences. As a result of these analyses, we built a comprehensive model explaining the uneven distribution of ERVs along the genome. We found that ERVs integrate in late-replicating AT-rich regions with abundant microsatellites, mirror repeats, and repressive histone marks. Regions favoring fixation are depleted of genes and evolutionarily conserved elements, and have low recombination rates, reflecting the effects of purifying selection and ectopic recombination removing ERVs from the genome. In addition to providing these biological insights, our study demonstrates the power of exploiting multiple scales and localization with FDA. These powerful techniques are expected to be applicable to many other genomic investigations.

Regulatory activities of transposable elements: from conflicts to benefits

“…Because TEs may have an intrinsic preference for integration within ‘open’ transcriptionally permissive chromatin 91,92 and must also replicate in the germline for new insertions to be inherited, these properties may introduce a biased association with genes that are highly expressed in the germline and early embryonic cell types 93–95 . Second, there is probably some level of selection against insertions that significantly alter host gene expression patterns upon insertion, meaning that most TEs retained in the genome might cause minimal changes in host gene expression 96–102 . This bias would also favour the retention of TEs near or within genes that share similar expression profiles, as these insertions are less likely to significantly alter existing gene expression patterns.…”

Infant Weight Gain Trajectories Linked to Oral Microbiome Composition

“…Our study demonstrates the effectiveness of FDA techniques linking children's weight gain trajectories and microbiomes characterization. This suggests that even greater effectiveness could be achieved in similar studies with longitudinal information also on the microbiomes, and indicates the potential of such techniques in a variety of other 'omics' applications (e.g., (Campos-Sánchez et al 2016)).…”

A permutation approach to the analysis of spatiotemporal geochemical data in the presence of heteroscedasticity

“…In the literature, permutation schemes of similar structure have been successfully applied to data sets of relatively large size. For instance, in the work of Campos‐Sánchez, Cremona, Pini, Chiaromonte, and Makova (), several functional data sets of size larger than 1,000 were considered. In our context, computations were relatively fast.…”