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Reconstruction of full-length LINE-1 progenitors from ancestral genomes.

ABSTRACT: Sequences derived from the Long INterspersed Element-1 (L1) family of retrotransposons occupy at least 17% of the human genome, with 67 distinct subfamilies representing successive waves of expansion and extinction in mammalian lineages. L1s contribute extensively to gene regulation, but their molecular history is difficult to trace, because most are present only as truncated and highly mutated fossils. Consequently, L1 entries in current databases of repeat sequences are composed mainly of short diagnostic subsequences, rather than full functional progenitor sequences for each subfamily. Here, we have coupled 2 levels of sequence reconstruction (at the level of whole genomes and L1 subfamilies) to reconstruct progenitor sequences for all human L1 subfamilies that are more functionally and phylogenetically plausible than existing models. Most of the reconstructed sequences are at or near the canonical length of L1s and encode uninterrupted ORFs with expected protein domains. We also show that the presence or absence of binding sites for KRAB-C2H2 Zinc Finger Proteins, even in ancient-reconstructed progenitor L1s, mirrors binding observed in human ChIP-exo experiments, thus extending the arms race and domestication model. RepeatMasker searches of the modern human genome suggest that the new models may be able to assign subfamily resolution identities to previously ambiguous L1 instances. The reconstructed L1 sequences will be useful for genome annotation and functional study of both L1 evolution and L1 contributions to host regulatory networks.

SUBMITTER: Campitelli LF

PROVIDER: S-EPMC9252281 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:MotivationIt has been argued that whole-genome duplication (WGD) exerted a profound influence on the course of evolution. For the purpose of fully understanding the impact of WGD, several formal algorithms have been developed for reconstructing pre-WGD gene order in yeast and plant. However, to the best of our knowledge, those algorithms have never been successfully applied to WGD events in teleost and vertebrate, impeded by extensive gene shuffling and gene losses.ResultsHere, we present a probabilistic model of macrosynteny (i.e. conserved linkage or chromosome-scale distribution of orthologs), develop a variational Bayes algorithm for inferring the structure of pre-WGD genomes, and study estimation accuracy by simulation. Then, by applying the method to the teleost WGD, we demonstrate effectiveness of the algorithm in a situation where gene-order reconstruction algorithms perform relatively poorly due to a high rate of rearrangement and extensive gene losses. Our high-resolution reconstruction reveals previously overlooked small-scale rearrangements, necessitating a revision to previous views on genome structure evolution in teleost and vertebrate.ConclusionsWe have reconstructed the structure of a pre-WGD genome by employing a variational Bayes approach that was originally developed for inferring topics from millions of text documents. Interestingly, comparison of the macrosynteny and topic model algorithms suggests that macrosynteny can be regarded as documents on ancestral genome structure. From this perspective, the present study would seem to provide a textbook example of the prevalent metaphor that genomes are documents of evolutionary history.Availability and implementationThe analysis data are available for download at http://www.gen.tcd.ie/molevol/supp_data/MacrosyntenyTGD.zip , and the software written in Java is available upon request.Contactyoichiro.nakatani@tcd.ie or aoife.mclysaght@tcd.ie.Supplementary informationSupplementary data are available at Bioinformatics online.

Project description:BackgroundTo reconstruct the evolution history of DNA sequences, novel models of increasing complexity regarding the number of free parameters taken into account in the sequence evolution, as well as faster and more accurate algorithms, and statistical and computational methods, are needed. More particularly, as the principal forces that have led to major structural changes are genome rearrangements (such as translocations, fusions, and so on), understanding their underlying mechanisms, among other things via the ancestral genome reconstruction, are essential. In this problem, since finding the ancestral genomes that minimize the number of rearrangements in a phylogenetic tree is known to be NP-hard for three or more genomes, heuristics are commonly chosen to obtain approximations of the exact solution. The aim of this work is to show that another path is possible.ResultsVarious algorithms and software already deal with the difficult nature of the problem of reconstruction of the ancestral genome, but they do not function with precision, in particular when indels or single nucleotide polymorphisms fall into repeated sequences. In this article, and despite the theoretical NP-hardness of the ancestral reconstruction problem, we show that an exact solution can be found in practice in various cases, encompassing organelles and some bacteria. A practical example proves that an accurate reconstruction, which also allows to highlight homoplasic events, can be obtained. This is illustrated by the reconstruction of ancestral genomes of two bacterial pathogens, belonging in Mycobacterium and Brucella genera.ConclusionsBy putting together automatically reconstructed ancestral regions with handmade ones for problematic cases, we show that an accurate reconstruction of ancestors of the Brucella genus and of the Mycobacterium tuberculosis complex is possible. By doing so, we are able to investigate the evolutionary history of each pathogen by computing their common ancestors. They can be investigated extensively, by studying the gene content evolution over time, the resistance acquisition, and the impacts of mobile elements on genome plasticity.

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Reconstruction of full-length LINE-1 progenitors from ancestral genomes.

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