Positive selection on the nonhomologous end-joining factor Cernunnos-XLF in the human lineage

BACKGROUND: Cernunnos-XLF is a nonhomologous end-joining factor that is mutated in patients with a rare immunodeficiency with microcephaly. Several other microcephaly-associated genes such as ASPM and microcephalin experienced recent adaptive evolution apparently linked to brain size expansion in humans. In this study we investigated whether Cernunnos-XLF experienced similar positive selection during human evolution. RESULTS: We obtained or reconstructed full-length coding sequences of chimpanzee, rhesus macaque, canine, and bovine Cernunnos-XLF orthologs from sequence databases and sequence trace archives. Comparison of coding sequences revealed an excess of nonsynonymous substitutions consistent with positive selection on Cernunnos-XLF in the human lineage. The hotspots of adaptive evolution are concentrated around a specific structural domain, whose analogue in the structurally similar XRCC4 protein is involved in binding of another nonhomologous end-joining factor, DNA ligase IV. CONCLUSION: Cernunnos-XLF is a microcephaly-associated locus newly identified to be under adaptive evolution in humans, and possibly played a role in human brain expansion. We speculate that Cernunnos-XLF may have contributed to the increased number of brain cells in humans by efficient double strand break repair, which helps to prevent frequent apoptosis of neuronal progenitors and aids mitotic cell cycle progression. REVIEWERS: This article was reviewed by Chris Ponting and Richard Emes (nominated by Chris Ponting), Kateryna Makova, Gáspár Jékely and Eugene V. Koonin

Crypton transposons: identification of new diverse families and ancient domestication events

<p>Abstract</p> <p>Background</p> <p>"Domestication" of transposable elements (TEs) led to evolutionary breakthroughs such as the origin of telomerase and the vertebrate adaptive immune system. These breakthroughs were accomplished by the adaptation of molecular functions essential for TEs, such as reverse transcription, DNA cutting and ligation or DNA binding. <it>Cryptons </it>represent a unique class of DNA transposons using tyrosine recombinase (YR) to cut and rejoin the recombining DNA molecules. <it>Cryptons </it>were originally identified in fungi and later in the sea anemone, sea urchin and insects.</p> <p>Results</p> <p>Herein we report new <it>Cryptons </it>from animals, fungi, oomycetes and diatom, as well as widely conserved genes derived from ancient <it>Crypton </it>domestication events. Phylogenetic analysis based on the YR sequences supports four deep divisions of <it>Crypton </it>elements. We found that the domain of unknown function 3504 (DUF3504) in eukaryotes is derived from <it>Crypton </it>YR. DUF3504 is similar to YR but lacks most of the residues of the catalytic tetrad (R-H-R-Y). Genes containing the DUF3504 domain are potassium channel tetramerization domain containing 1 (<it>KCTD1</it>), <it>KIAA1958</it>, zinc finger MYM type 2 (<it>ZMYM2</it>), <it>ZMYM3</it>, <it>ZMYM4</it>, glutamine-rich protein 1 (<it>QRICH1</it>) and "without children" (<it>WOC</it>). The <it>DUF3504 </it>genes are highly conserved and are found in almost all jawed vertebrates. The sequence, domain structure, intron positions and synteny blocks support the view that <it>ZMYM2</it>, <it>ZMYM3</it>, <it>ZMYM4</it>, and possibly <it>QRICH1</it>, were derived from <it>WOC </it>through two rounds of genome duplication in early vertebrate evolution. <it>WOC </it>is observed widely among bilaterians. There could be four independent events of <it>Crypton </it>domestication, and one of them, generating <it>WOC</it>/<it>ZMYM</it>, predated the birth of bilaterian animals. This is the third-oldest domestication event known to date, following the domestication generating telomerase reverse transcriptase (<it>TERT</it>) and <it>Prp8</it>. Many <it>Crypton</it>-derived genes are transcriptional regulators with additional DNA-binding domains, and the acquisition of the DUF3504 domain could have added new regulatory pathways via protein-DNA or protein-protein interactions.</p> <p>Conclusions</p> <p><it>Cryptons </it>have contributed to animal evolution through domestication of their YR sequences. The DUF3504 domains are domesticated YRs of animal <it>Crypton </it>elements.</p

Ginger DNA transposons in eukaryotes and their evolutionary relationships with long terminal repeat retrotransposons

<p>Abstract</p> <p>Background</p> <p>In eukaryotes, long terminal repeat (LTR) retrotransposons such as <it>Copia, BEL </it>and <it>Gypsy </it>integrate their DNA copies into the host genome using a particular type of DDE transposase called integrase (INT). The <it>Gypsy </it>INT-like transposase is also conserved in the <it>Polinton/Maverick </it>self-synthesizing DNA transposons and in the 'cut and paste' DNA transposons known as <it>TDD-4 </it>and <it>TDD-5</it>. Moreover, it is known that INT is similar to bacterial transposases that belong to the IS<it>3</it>, IS<it>481</it>, IS<it>30 </it>and IS<it>630 </it>families. It has been suggested that LTR retrotransposons evolved from a non-LTR retrotransposon fused with a DNA transposon in early eukaryotes. In this paper we analyze a diverse superfamily of eukaryotic cut and paste DNA transposons coding for INT-like transposase and discuss their evolutionary relationship to LTR retrotransposons.</p> <p>Results</p> <p>A new diverse eukaryotic superfamily of DNA transposons, named <it>Ginger </it>(for '<it>Gypsy </it>INteGrasE Related') DNA transposons is defined and analyzed. Analogously to the IS<it>3 </it>and IS<it>481 </it>bacterial transposons, the <it>Ginger </it>termini resemble those of the <it>Gypsy </it>LTR retrotransposons. Currently, <it>Ginger </it>transposons can be divided into two distinct groups named <it>Ginger1 </it>and <it>Ginger2/Tdd</it>. Elements from the <it>Ginger1 </it>group are characterized by approximately 40 to 270 base pair (bp) terminal inverted repeats (TIRs), and are flanked by CCGG-specific or CCGT-specific target site duplication (TSD) sequences. The <it>Ginger1</it>-encoded transposases contain an approximate 400 amino acid N-terminal portion sharing high amino acid identity to the entire <it>Gypsy</it>-encoded integrases, including the YPYY motif, zinc finger, DDE domain, and, importantly, the GPY/F motif, a hallmark of <it>Gypsy </it>and endogenous retrovirus (ERV) integrases. <it>Ginger1 </it>transposases also contain additional C-terminal domains: ovarian tumor (OTU)-like protease domain or Ulp1 protease domain. In vertebrate genomes, at least two host genes, which were previously thought to be derived from the <it>Gypsy </it>integrases, apparently have evolved from the <it>Ginger1 </it>transposase genes. We also introduce a second <it>Ginger </it>group, designated <it>Ginger2/Tdd</it>, which includes the previously reported DNA transposon <it>TDD-4</it>.</p> <p>Conclusions</p> <p>The <it>Ginger </it>superfamily represents eukaryotic DNA transposons closely related to LTR retrotransposons. <it>Ginger </it>elements provide new insights into the evolution of transposable elements and certain transposable element (TE)-derived genes.</p

Families of transposable elements, population structure and the origin of species

<p>Abstract</p> <p>Background</p> <p>Eukaryotic genomes harbor diverse families of repetitive DNA derived from transposable elements (TEs) that are able to replicate and insert into genomic DNA. The biological role of TEs remains unclear, although they have profound mutagenic impact on eukaryotic genomes and the origin of repetitive families often correlates with speciation events. We present a new hypothesis to explain the observed correlations based on classical concepts of population genetics.</p> <p>Presentation of the hypothesis</p> <p>The main thesis presented in this paper is that the TE-derived repetitive families originate primarily by genetic drift in small populations derived mostly by subdivisions of large populations into subpopulations. We outline the potential impact of the emerging repetitive families on genetic diversification of different subpopulations, and discuss implications of such diversification for the origin of new species.</p> <p>Testing the hypothesis</p> <p>Several testable predictions of the hypothesis are examined. First, we focus on the prediction that the number of diverse families of TEs fixed in a representative genome of a particular species positively correlates with the cumulative number of subpopulations (demes) in the historical metapopulation from which the species has emerged. Furthermore, we present evidence indicating that human AluYa5 and AluYb8 families might have originated in separate proto-human subpopulations. We also revisit prior evidence linking the origin of repetitive families to mammalian phylogeny and present additional evidence linking repetitive families to speciation based on mammalian taxonomy. Finally, we discuss evidence that mammalian orders represented by the largest numbers of species may be subject to relatively recent population subdivisions and speciation events.</p> <p>Implications of the hypothesis</p> <p>The hypothesis implies that subdivision of a population into small subpopulations is the major step in the origin of new families of TEs as well as of new species. The origin of new subpopulations is likely to be driven by the availability of new biological niches, consistent with the hypothesis of punctuated equilibria. The hypothesis also has implications for the ongoing debate on the role of genetic drift in genome evolution.</p> <p>Reviewers</p> <p>This article was reviewed by Eugene Koonin, Juergen Brosius and I. King Jordan.</p

Annotation, submission and screening of repetitive elements in Repbase: RepbaseSubmitter and Censor

BACKGROUND: Repbase is a reference database of eukaryotic repetitive DNA, which includes prototypic sequences of repeats and basic information described in annotations. Updating and maintenance of the database requires specialized tools, which we have created and made available for use with Repbase, and which may be useful as a template for other curated databases. RESULTS: We describe the software tools RepbaseSubmitter and Censor, which are designed to facilitate updating and screening the content of Repbase. RepbaseSubmitter is a java-based interface for formatting and annotating Repbase entries. It eliminates many common formatting errors, and automates actions such as calculation of sequence lengths and composition, thus facilitating curation of Repbase sequences. In addition, it has several features for predicting protein coding regions in sequences; searching and including Pubmed references in Repbase entries; and searching the NCBI taxonomy database for correct inclusion of species information and taxonomic position. Censor is a tool to rapidly identify repetitive elements by comparison to known repeats. It uses WU-BLAST for speed and sensitivity, and can conduct DNA-DNA, DNA-protein, or translated DNA-translated DNA searches of genomic sequence. Defragmented output includes a map of repeats present in the query sequence, with the options to report masked query sequence(s), repeat sequences found in the query, and alignments. CONCLUSION: Censor and RepbaseSubmitter are available as both web-based services and downloadable versions. They can be found at (RepbaseSubmitter) and (Censor)

Introduction for the Gene special issue dedicated to the meeting Genomic impact of eukaryotic transposable elements at Asilomar

The issues related to \u27Genomic Impact of Eukaryotic Transposable Elements\u27, which took place in Pacific Grove, California between March 31st and April 4th 2006, are discussed. The meeting celebrated the extraordinary contributions of Dr. Carl W. Schmid to the study of repeated DNA sequences and mobile elements. With the advent of recombinant DNA technology, he led the discovery of human Alu elements, and the discovery of their amplification. The idea of the conference was to gather and disseminate information in transposable elements (TEs) on the state-of-the-art tools and approaches. The core sessions from the conference covered research on transposable elements with a strong emphasis on their impact on genomic stability and evolution. The scientific sessions were complemented by after-dinner workshop sessions focusing on Repbase, computer tools used in annotation and analysis of repetitive DNA and open problems related to the field

Analysis of the human Alu Ye lineage

Background: Alu elements are short (∼300 bp) interspersed elements that amplify in primate genomes through a process termed retroposition. The expansion of these elements has had a significant impact on the structure and function of primate genomes. Approximately 10 % of the mass of the human genome is comprised of Alu elements, making them the most abundant short interspersed element (SINE) in our genome. The majority of Alu amplification occurred early in primate evolution, and the current rate of Alu retroposition is at least 100 fold slower than the peak of amplification that occurred 30-50 million years ago. Alu elements are therefore a rich source of inter- and intra-species primate genomic variation. Results: A total of 153 Alu elements from the Ye subfamily were extracted from the draft sequence of the human genome. Analysis of these elements resulted in the discovery of two new Alu subfamilies, Ye4 and Ye6, complementing the previously described Ye5 subfamily. DNA sequence analysis of each of the Alu Ye subfamilies yielded average age estimates of ∼14, ∼13 and ∼9.5 million years old for the Alu Ye4, Ye5 and Ye6 subfamilies, respectively. In addition, 120 Alu Ye4, Ye5 and Ye6 loci were screened using polymerase chain reaction (PCR) assays to determine their phylogenetic origin and levels of human genomic diversity. Conclusion: The Alu Ye lineage appears to have started amplifying relatively early in primate evolution and continued propagating at a low level as many of its members are found in a variety of hominoid (humans, greater and lesser ape) genomes. Detailed sequence analysis of several Alu pre-integration sites indicated that multiple types of events had occurred, including gene conversions, near-parallel independent insertions of different Alu elements and Alu-mediated genomic deletions. A potential hotspot for Alu insertion in the Fer1L3 gene on chromosome 10 was also identified. © 2005 Salem et al; licensee BioMed Central Ltd

Genomic impact of eukaryotic transposable elements

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Mobile DNA 3 (2012): 19, doi:10.1186/1759-8753-3-19.The third international conference on the genomic impact of eukaryotic transposable elements (TEs) was held 24 to 28 February 2012 at the Asilomar Conference Center, Pacific Grove, CA, USA. Sponsored in part by the National Institutes of Health grant 5 P41 LM006252, the goal of the conference was to bring together researchers from around the world who study the impact and mechanisms of TEs using multiple computational and experimental approaches. The meeting drew close to 170 attendees and included invited floor presentations on the biology of TEs and their genomic impact, as well as numerous talks contributed by young scientists. The workshop talks were devoted to computational analysis of TEs with additional time for discussion of unresolved issues. Also, there was ample opportunity for poster presentations and informal evening discussions. The success of the meeting reflects the important role of Repbase in comparative genomic studies, and emphasizes the need for close interactions between experimental and computational biologists in the years to come.The conference was supported in part by the National Institutes of Health grant 5 P41 LM006252