The Full Monty by GMO Pundit: Collected links and summaries on natural gene evolution.

This post was inspired by Cédric Feschotte and colleagues' paper just below and collects together comments about natural evolution of genes. Much of this topic is covered in GMO Pundit's Natural GMOs series, and collected links to this series are also given below (see Collected GMO Pundit Posts).

What you'll find here is:

Birth of a chimeric [hybrid fusion derived] primate gene by capture of the transposase [DNA movement enzyme] gene from a mobile element
The origin of new genes: glimpses from the young and old.
Positive selection of a gene family during the emergence of humans and African apes.
Retrocopied [DNA version of RNA messages] Genes May Enhance Male Fitness.
P-element homologous sequences are tandemly repeated in the genome of Drosophila guanche.
Perspective: transposable elements, parasitic DNA, and genome evolution (by Margaret Kidwell).
Mobile elements and mammalian genome evolution.
Extensive individual variation in L1 retrotransposition [gene movement via RNA intermediate] capability contributes to human genetic diversity.
Molecular evolution of an ancient mariner transposon, Hsmar1, in the human genome.
Recent horizontal transfer of a mariner transposable element among and between Diptera and Neuroptera.
Molecular characterization of Vulmar1, a complete mariner transposon of sugar beet and diversity of mariner- and En/Spm-like sequences in the genus Beta (sugar beet).
Homologs of Drosophila P transposons were mobile in zebrafish but have been domesticated in a common ancestor of chicken and human.
Collected GMO Pundit Posts on Gene evolution.
Section on gene movement at Academics Review

Two of these GMO Pundit Posts are perhaps most useful to get orientation on this topic and for understanding why Pundit has posted it at this site; they are:

So here you are: an introduction to current science on natural gene evolution:

Birth of a chimeric [hybrid fusion derived] primate gene by capture of the transposase gene from a mobile element

The emergence of new genes and functions is of central importance to the evolution of species. The contribution of various types of duplications to genetic innovation has been extensively investigated. Less understood is the creation of new genes by recycling of coding material from selfish mobile genetic elements. To investigate this process, we reconstructed the evolutionary history of SETMAR, a new primate chimeric gene resulting from fusion of a SET histone methyltransferase gene to the transposase gene of a mobile element. We show that the transposase gene was recruited as part of SETMAR 40-58 million years ago, after the insertion of an Hsmar1 transposon downstream of a preexisting SET gene, followed by the de novo exonization of previously noncoding sequence and the creation of a new intron. The original structure of the fusion gene is conserved in all anthropoid lineages, but only the N-terminal half of the transposase is evolving under strong purifying selection. In vitro assays show that this region contains a DNA-binding domain that has preserved its ancestral binding specificity for a 19-bp motif located within the terminal-inverted repeats of Hsmar1 transposons and their derivatives. The presence of these transposons in the human genome constitutes a potential reservoir of {approx}1,500 perfect or nearly perfect SETMAR-binding sites. Our results not only provide insight into the conditions required for a successful gene fusion, but they also suggest a mechanism by which the circuitry underlying complex regulatory networks may be rapidly established.

Published online before print May 3, 2006
Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0601161103
( transposable elements gene fusion molecular domestication DNA binding regulatory network )
Richard Cordaux, Swalpa Udit, Mark A. Batzer, and Cédric Feschotte

This cites the following:

1. Long, M., Betran, E., Thornton, K.&Wang, W. (2003) Nat. Rev. Genet. 4, 865–875.
The origin of new genes: glimpses from the young and old.

Genome data have revealed great variation in the numbers of genes in different organisms, which indicates that there is a fundamental process of genome evolution: the origin of new genes. However, there has been little opportunity to explore how genes with new functions originate and evolve. The study of ancient genes has highlighted the antiquity and general importance of some mechanisms of gene origination, and recent observations of young genes at early stages in their evolution have unveiled unexpected molecular and evolutionary processes

2. Johnson, M. E., Viggiano, L., Bailey, J. A., Abdul-Rauf, M., Goodwin, G.,
Rocchi, M. & Eichler, E. E. (2001) Nature 413, 514–519.
Positive selection of a gene family during the emergence of humans and African apes.

Gene duplication followed by adaptive evolution is one of the primary forces for the emergence of new gene function. Here we describe the recent proliferation, transposition and selection of a 20-kilobase (kb) duplicated segment throughout 15 Mb of the short arm of human chromosome 16. The dispersal of this segment was accompanied by considerable variation in chromosomal-map location and copy number among hominoid species. In humans, we identified a gene family (morpheus) within the duplicated segment. Comparison of putative protein-encoding exons revealed the most extreme case of positive selection among hominoids. The major episode of enhanced amino-acid replacement occurred after the separation of human and great-ape lineages from the orangutan. Positive selection continued to alter amino-acid composition after the divergence of human and chimpanzee lineages. The rapidity and bias for amino-acid-altering nucleotide changes suggest adaptive evolution of the morpheus gene family during the emergence of humans and African apes. Moreover, some genes emerge and evolve very rapidly, generating copies that bear little similarity to their ancestral precursors. Consequently, a small fraction of human genes may not possess discernible orthologues within the genomes of model organisms.

3. Marques, A. C., Dupanloup, I., Vinckenbosch, N., Reymond, A. & Kaessmann,
H. (2005) PLoS Biol. 3, e357.
Synopsis
Retrocopied Genes May Enhance Male Fitness

“Retrocopied” genes were long viewed as evolutionary dead ends, with little functional relevance. Such a gene copy is generated by a circuitous route. First, a normal gene is copied to make a messenger RNA, which in the usual scheme of things is sent out of the cell nucleus, used to code for protein, and eventually destroyed. Once in a great while, though, the messenger RNA is “reverse transcribed,” coded back into a DNA sequence by the enzyme reverse transcriptase. It can then be inserted back into a chromosome, quite possibly a different chromosome than the one on which its parent gene resides. This process, which is driven by the legions of transposable elements that litter the genome, usually creates a functionless “retropseudogene,” stranded without a promoter and unable to be expressed.

But occasionally, the new gene copy recruits a promoter by, as yet, largely unknown mechanisms, and may thus potentially become functional, able to code for a protein. In the primate lineage, four such genes have been identified to date. In this issue, Henrik Kaessman and colleagues announce the discovery of seven more, and estimate that on average, one such new gene arises every million years. Many of these genes are expressed predominantly in the testes, where at least some of them probably substitute for X-chromosome genes that are inactivated during sperm development.

The authors first used bioinformatics methods to identify almost 4,000 retrocopies in the human genome. Retrocopied genes can be distinguished from their parents because the introns, or noncoding sequences, of the parent are edited out of the original messenger before retrocopying; thus, the DNA coding sequence is initially the same, but lacks the intervening introns of the parent. Of these 4,000, about 700 had not been disabled by mutations that interrupt the coding sequence. The number of other harmless mutations each had accumulated was then used to estimate the time each retrocopy was formed, based on molecular evolution theory that such neutral mutations occur at a predictable rate. While retrocopies have been created continuously over many millions of years of mammalian evolution, the authors' analysis showed a peak around 40 million years ago, after the emergence of primates, but before establishment of the human line. They estimate that 57 functional retrogenes arose in primates, about one per million years of primate evolution.

To pinpoint individual retrogenes, the authors first conducted an evolutionary simulation to estimate, based on sequence changes, which retrocopies were likely to still be functional. They found seven, which originated between 18 and 63 million years ago. These genes play a variety of roles in transcription and translation, as well as chromosome condensation and segregation, which occur just prior to cell division.

They next looked at expression patterns for these genes in 20 human tissues, and discovered that for all seven, expression was restricted mostly or entirely to the testes. Three of the seven genes were copied from genes on the X chromosome to Chromosome 1, 5, and 12, respectively. The authors suggest that such retrogenes functionally replace their silenced parental genes on the X chromosome during spermatogenesis, a resourceful maneuver that may enhance the reproductive fitness of the organism expressing them. This increase in fitness, in turn, preserves the functional retrocopy through natural selection. For two other genes, the authors also infer a function in spermatogenesis based on the parental gene function. One of these genes as well as the two remaining genes appear to have been selectively driven to evolve new or more adapted functional properties compared to their parents. Together, the results suggest that retrogenes were often recruited during primate evolution to enhance male germline functions. —Richard Robinson

DOI: 10.1371/journal.pbio.0030399
Published: October 11, 2005
Copyright: © 2005 Public Library of Science. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Citation: (2005) Retrocopied Genes May Enhance Male Fitness. PLoS Biol 3(11): e399

4. Miller, W. J., Hagemann, S., Reiter, E. & Pinsker, W. (1992) Proc. Natl. Acad. Sci. USA 89, 4018–4022.
P-element homologous sequences are tandemly repeated in the genome of Drosophila guanche.

In Drosophila guanche, P-homologous sequences were found to be located in a tandem repetitive array (copy number: 20-50) at a single genomic site. The cytological position on the polytene chromosomes was determined by in situ hybridization (chromosome O: 85C). Sequencing of one complete repeat unit (3.25 kilobases) revealed high sequence similarity between the central coding region comprising exons 0 to 2 and the corresponding section of the Drosophila melanogaster P element. The rest of the sequence has diverged considerably. Exon 3 has no coding function and the inverted repeats have disappeared. The P homologues of D. guanche apparently have lost their mobility but have retained the coding capacity for a protein similar to the 66-kDa P-element repressor of D. melanogaster. Divergence between different repeat units indicates early amplification of the sequence at this particular genomic site. The presence of a common P-element site at 85C in Drosophila subobscura, Drosophila madeirensis, and D. guanche suggests that clustering of the sequence at this location took place before the phylogenetic radiation of the three species.

5. Kidwell, M. G. & Lisch, D. R. (2001) Evolution Int. J. Org. Evolution 55, 1–24.
Perspective: transposable elements, parasitic DNA, and genome evolution.

The nature of the role played by mobile elements in host genome evolution is reassessed considering numerous recent developments in many areas of biology. It is argued that easy popular appellations such as "selfish DNA" and "junk DNA" may be either inaccurate or misleading and that a more enlightened view of the transposable element-host relationship encompasses a continuum from extreme parasitism to mutualism. Transposable elements are potent, broad spectrum, endogenous mutators that are subject to the influence of chance as well as selection at several levels of biological organization. Of particular interest are transposable element traits that early evolve neutrally at the host level but at a later stage of evolution are co-opted for new host functions.

12. Deininger, P. L., Moran, J. V., Batzer, M. A.&Kazazian, H. H., Jr. (2003) Curr.
Opin. Genet. Dev. 13, 651–658.

Mobile elements and mammalian genome evolution.

Mobile elements make up large portions of most eukaryotic genomes. They create genetic instability, not only through insertional mutation but also by contributing recombination substrates, both during and long after their insertion. The combination of whole-genome sequences and the development of innovative new assays to test the function of mobile elements have increased our understanding of how these elements mobilize and how their insertion impacts genome diversity and human disease.

13. Cordaux, R. & Batzer, M. A. (2006) Proc. Natl. Acad. Sci. USA 103, 1157–1158.

Extensive individual variation in L1 retrotransposition capability contributes to human genetic diversity.

Despite being scarce in the human genome, active L1 retrotransposons continue to play a significant role in its evolution. Because of their recent expansion, many L1s are not fixed in humans, and, when present, their mobilization potential can vary among individuals. Previously, we showed that the great majority of retrotransposition events in humans are caused by highly active, or hot, L1s. Here, in four populations of diverse geographic origins (160 haploid genomes), we investigated the degree of sequence polymorphism of three hot L1s and the extent of individual variation in mobilization capability of their allelic variants. For each locus, we found one previously uncharacterized allele in every three to five genomes, including some with nonsense and insertion/deletion mutations. Single or multiple nucleotide substitutions drastically affected the retrotransposition efficiency of some alleles. One-third of elements were no longer hot, and these so-called cool alleles substantially increased the range of individual susceptibility to retrotransposition events. Adding the activity of the three elements in each individual resulted in a surprising degree of variation in mobilization capability, ranging from 0% to 390% of a reference L1. These data suggest that individual variation in retrotransposition potential makes an important contribution to human genetic diversity.

Discovery of Hsmar1:

Molecular evolution of an ancient mariner transposon, Hsmar1, in the human genome.

A confident consensus sequence for Hsmar1, the first mariner transposon recognized in the human genome, was generated using three genomic and 15 cDNA
sequences. It is thought to represent the ancestrally active copy that invaded an early primate genome. The consensus is 1287 base pairs (bp) long, has 30 bp
perfect inverted terminal repeats (ITRs), and encodes a 343 amino acid (aa) mariner transposase. Each copy has diverged from the consensus largely independently of the others and mostly neutrally, and most are now defective.
They differ from the consensus by an average of 7.8% in DNA sequence and 7.5 indels per kilobase, both of which values indicate that the copies were formed about 50 Myr ago. On average, only 20% of the 73 surmised CpG hypermutable sites in the consensus remain. A remarkable exception to this loss of functionality is revealed by a set of ten cDNA clones derived from a particular genomic copy that has diverged only 2.4% from the consensus, retained 54% of its hypermutable CpG pairs, and which has a full-length transposase open reading frame. The complete sequence of one of these cDNAs (NIB1543) indicates that the transposase gene of this copy may have been conserved because it is spliced to a human cellular gene encoding a SET domain protein. A specific PCR assay was used to reveal the presence of Hsmar1 copies in all primates examined representing all major lineages, but not in close relatives of primates. PCR fragments cloned and sequenced from a representative sample of primates confirmed that Hsmar1 copies are present in all major lineages, and also revealed another cecropia subfamily mariner in prosimians only, and a third highly divergent mariner present in the greater slow loris Nycticebus coucang. There are about 200 copies of Hsmar1 in the human genome, as well as +/-2400 copies of a derived 80 bp paired ITR structure and +/-4600 copies of solo ITRs. Thus, this transposon had a considerable insertional mutagenic effect on past primate genomes

Gene. 1997 Dec 31;205(1-2):203-17.
PMID: 9461395 [PubMed - indexed for MEDLINE]
Robertson HM, Zumpano KL.
Department of Entomology, University of Illinois at Urbana-Champaign, Urbana
61801, USA. hughrobe--AT---uiuc.edu

Recent horizontal transfer of a mariner transposable element among and between Diptera and Neuroptera.

Transposable elements of the mariner family are widespread among insects and other invertebrates, and initial analyses of their relationships indicated frequent occurrence of horizontal transfers between hosts. A specific PCR assay was used to screen for additional members of the irritans subfamily of mariners in more than 400 arthropod species. Phylogenetic analysis of cloned PCR fragments indicated that relatively recent horizontal transfers had occurred into the lineages of a fruit fly Drosophila ananassae, the horn fly Haematobia irritans, the African malaria vector mosquito Anopheles gambiae, and a green lacewing Chrysoperla plorabunda. Genomic dot-blot analysis revealed that the copy number in these species varies widely, from about 17,000 copies in the horn fly to three copies in D. ananassae. Multiple copies were sequenced from genomic clones from each of these species and four others with related elements. These sequences confirmed the PCR results, revealing extremely similar elements in each of these four species (greater than 88% DNA and 95% amino acid identity).
In particular, the consensus sequence of the transposase gene of the horn fly elements differs by just two base pairs out of 1,044 from that of the lacewing elements. The mosquito lineage has diverged from the other Diptera for over 200 Myr, and the neuropteran last shared a common ancestor with them more than 265 Myr ago, so this high similarity implies that these transposons recently transferred horizontally into each lineage. Their presence in only the closest relatives in at least the lacewing lineage supports this hypothesis. Such horizontal transfers provide an explanation for the evolutionary persistence and widespread distribution of mariner transposons. We propose that the ability to transfer horizontally to new hosts before extinction by mutation in the current host constitutes the primary selective constraint maintaining the sequence conservation of mariners and perhaps other DNA-mediated elements.

Mol Biol Evol. 1995 Sep;12(5):850-62.
Robertson HM, Lampe DJ.
PMID: 7476131

Molecular characterization of Vulmar1, a complete mariner transposon of sugar
beet and diversity of mariner- and En/Spm-like sequences in the genus Beta.

Transposons of the Tc1-mariner superfamily are widespread in eukaryotic genomes. We have isolated the mariner element Vulmar1 from Beta vulgaris L., which is 3909 bp long and bordered by perfect terminal inverted repeats of 32 bp with homology to terminal inverted repeats of transposons from soybean and rice.
According to a characteristic amino acid signature, Vulmar1 can be assigned to the DD39D group of mariner transposons. Vulmar1 is flanked by a 5'-TA-3' target site duplication that is typical for mariner transposons. Southern hybridization revealed that mariner-like copies are highly abundant in Beta species, and sequence analysis of 10 transposase fragments from representative species of the four Beta sections revealed an identity between 34% and 100% after conceptual translation. By fluorescent in situ hybridization, Vulmar1 was detected in distal euchromatin as well as in some intercalary and pericentromeric regions of all B. vulgaris chromosomes. In addition, using PCR, we were able to amplify fragments of the transposase gene of En/Spm-like transposons in the genus Beta.
En/Spm-like transposase sequences are highly amplified in four Beta sections and showed a considerable degree of conservation (88.5-100%) at the protein level,while the homology to corresponding regions of En/Spm transposons of other plant species ranges from 49.5% to 62.5%. By fluorescent in situ hybridization,En/Spm-like transposon signals of strong intensity were detected on all chromosomes of B. vulgaris.

Genome. 2004 Dec;47(6):1192-201.
Jacobs G, Dechyeva D, Menzel G, Dombrowski C, Schmidt T.
PMID: 15644978 [PubMed - indexed for MEDLINE]

Homologs of Drosophila P transposons were mobile in zebrafish but have been
domesticated in a common ancestor of chicken and human.

A substantial fraction of vertebrate and invertebrate genomes is composed of mobile elements and their derivatives. One of the most intensively studied transposon families, the P elements of Drosophila, was thought to exist exclusively in the genomes of dipteran insects. Based on the data provided by the human genome project, in 2001 our group has identified a P element-homologous sequence in the human genome. This P element-homologous human
gene, named Phsa, is 19,533 nucleotides long, comprises six exons and five introns, and encodes a protein of still unknown function with a length of 903 amino acid residues. The N-terminal THAP domain of the putative Phsa protein shows similarities to the site-specific DNA-binding domain of the Drosophila P element transposase. In the present study, FISH analysis and the screening of a human lambda genomic library revealed a single copy of Phsa located on the long
arm of chromosome 4, upstream of a gene coding for the hypothetical protein DKFZp686L1814. The same gene arrangement was found for the homologous gene Pgga in the genome of chicken, thus, displaying Pgga at orthologous position on the long arm of chromosome 4. The single-copy gene status and the absence of terminal inverted repeats and target-site duplications indicate that Phsa and Pgga constitute domesticated stationary sequences. In contrast, a considerable
number of P-homologous sequences with terminal inverted repeats and intact target-site duplications could be identified in zebrafish, strongly indicating that Pdre elements were mobile within the zebrafish genome. Pdre elements are the first P-like transposons identified in a vertebrate species. With respect to Phsa, gene expression studies showed that Phsa is expressed in a broad range of human tissues, suggesting that the putative Phsa protein plays a not yet understood but essential role in a specific metabolic pathway. We demonstrate that P-homologous DNA sequences occur in the genomes of 21 analyzed vertebrates but only as rudiments in the rodents. Finally, the evolutionary history of P element-homologous vertebrate sequences is discussed in the context of the "molecular domestication" hypothesis versus the "source gene hypothesis."

In humans, at least 45% of the genome belong to transposable elements, and a number of single-copy genes seem to have originated from them. Until now, 48 domesticated human genes probably originating from up to 39 different transposon copies could be identified (Hagemann and Pinsker 2001; International Human Genome Sequencing Consortium 2001; Nekrutenko and Li 2001). Most of them originated from DNA transposons, although only about 6% of the human transposable elements belong to this transposon type.

Molecular Domestication History of P-Homologous Sequences
Two hypotheses have been discussed to explain active P element transposons in some dipteran species and stationary P element transposon–derived sequences in others. The "domestication hypothesis" considers those stationary sequences as degenerated transposons that have lost the structural features necessary for transposition like terminal inverted repeats and, thus, are not able to move any more. In some cases, these now immobile transposon derivates have acquired a novel function and represent a stable functional component within their host genome (Pinsker et al. 2001). In contrast, the "source gene hypothesis" argues for an evolutionary scenario in which active P element transposons are direct descendants of an ancient source gene that gave rise to a transposon by acquisition of terminal inverted repeats.

In zebrafish, P-homologous sequences are spread throughout the genome, indicating their transposable activity and contributing to two different scenarios that can be observed within the zebrafish genome: the terminally truncated Pdre sequences represent immobile components of the genome, whereas Pdre2 and the analyzed internally deleted copies show structural features typical for DNA transposons. Quite contrary features can be described for Phsa in human and Pgga in chicken, where they represent stationary single-copy genes. Phsa, Pgga, and the P-homologous mouse and rat rudiments are located at orthologous positions, thus, favoring the "source gene hypothesis." Although the immobile terminally truncated Pdre elements are located at paralogous positions compared with Pgga and the mammalian P-homologous sequences, the data obtained from zebrafish do not support the "source gene hypothesis." They indicate that P-homologous sequences as immobile and subsequently stable components of the genome were generated by "molecular domestication." As a consequence of this explanation, the domestication event of the Phsa/Pgga sequence has occurred by immobilization of an active transposon within a common ancestor before the separation of mammalians and birds about 310 MYA (Nelson 1996).

P-homologous sequences are not the only examples of domesticated transposons. A considerable number of domesticated transposable-element copies now contribute to transcriptionally regulatory elements or to protein-coding regions of cellular genes (Smit 1999, International Human Genome Sequencing Consortium 2001, Jordan et al. 2003). The high number of known transposon-derived domesticated genes provides further evidence that the stable vertebrate P-homologous sequences were recruited as novel genes from their respective host genomes by "molecular domestication" of a former active transposon copy.

Mol Biol Evol. 2005 Apr;22(4):833-44. Epub 2004 Dec 22.
Hammer SE, Strehl S, Hagemann S.
PMID: 15616143 [PubMed - indexed for MEDLINE]

Section 5 Content:

The Full Monty by GMO Pundit

Friday, May 05, 2006

Collected links and summaries on natural gene evolution.

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