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

Alessia Pini, Rebeca Campos-Sánchez, Marzia A. Cremona, Francesca Chiaromonte, Kateryna D. Makova

Risultato della ricerca: Contributo in rivistaArticolo in rivistapeer review

19 Citazioni (Scopus)

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.
Lingua originaleEnglish
pagine (da-a)1-41
Numero di pagine41
RivistaPLoS Computational Biology
Volume12
DOI
Stato di pubblicazionePubblicato - 2016

Keywords

  • Animals
  • Cellular and Molecular Neuroscience
  • Chromosome Mapping
  • Computational Biology
  • Computational Theory and Mathematics
  • DNA Replication
  • Data Interpretation, Statistical
  • Ecology
  • Ecology, Evolution, Behavior and Systematics
  • Endogenous Retroviruses
  • Epigenesis, Genetic
  • Genetics
  • Genome, Human
  • Humans
  • Logistic Models
  • Mice
  • Modeling and Simulation
  • Models, Biological
  • Molecular Biology
  • Recombination, Genetic
  • Repetitive Sequences, Nucleic Acid
  • Selection, Genetic
  • Virus Integration

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