Analysis of the platypus genome suggests a transposon origin for mammalian imprinting
TL;DR: Comparisons between prototherian and therian mammals provide strong support for the host defence hypothesis and show that the platypus has significantly fewer repeats of certain classes in the regions of the genome that have become imprinted in therian mammal.
Abstract: Background: Genomic imprinting is an epigenetic phenomenon that results in monoallelic gene expression. Many hypotheses have been advanced to explain why genomic imprinting evolved in mammals, but few have examined how it arose. The host defence hypothesis suggests that imprinting evolved from existing mechanisms within the cell that act to silence foreign DNA elements that insert into the genome. However, the changes to the mammalian genome that accompanied the evolution of imprinting have been hard to define due to the absence of large scale genomic resources between all extant classes. The recent release of the platypus genome has provided the first opportunity to perform comparisons between prototherian (monotreme; which appear to lack imprinting) and therian (marsupial and eutherian; which have imprinting) mammals. Results: We compared the distribution of repeat elements known to attract epigenetic silencing across the entire genome from monotremes and therian mammals, particularly focusing on the orthologous imprinted regions. There is a significant accumulation of certain repeat elements within imprinted regions of therian mammals compared to the platypus. Conclusions: Our analyses show that the platypus has significantly fewer repeats of certain classes in the regions of the genome that have become imprinted in therian mammals. The accumulation of repeats, especially long terminal repeats and DNA elements, in therian imprinted genes and gene clusters is coincident with, and may have been a potential driving force in, the development of mammalian genomic imprinting. These data provide strong support for the host defence hypothesis.
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TL;DR: The progress in understanding how imprinted protein-coding genes are silenced is described and the role of macro ncRNAs that have broad relevance as a potential new layer of regulatory information in the mammalian genome is focused on.
Abstract: Genomic imprinting is an epigenetic process leading to parental-specific expression of one to two percent of mammalian genes that offers one of the best model systems for a molecular analysis of epigenetic regulation in development and disease. In the twenty years since the first imprinted gene was identified, this model has had a significant impact on decoding epigenetic information in mammals. So far it has led to the discovery of long-range cis-acting control elements whose epigenetic state regulates small clusters of genes and of unusual macro noncoding RNAs (ncRNAs) that directly repress genes in cis, and critically, it has demonstrated that one biological role of DNA methylation is to allow expression of genes normally repressed by default. This review describes the progress in understanding how imprinted protein-coding genes are silenced; in particular, it focuses on the role of macro ncRNAs that have broad relevance as a potential new layer of regulatory information in the mammalian genome.
256 citations
TL;DR: The current understanding of vertebrate TE diversity and evolution is reviewed and the current bottleneck in genome analyses lies in the proper annotation of TEs and examples where superficial analyses led to misleading conclusions about genome evolution are provided.
Abstract: Transposable elements (TEs) are selfish genetic elements that mobilize in genomes via transposition or retrotransposition and often make up large fractions of vertebrate genomes. Here, we review the current understanding of vertebrate TE diversity and evolution in the context of recent advances in genome sequencing and assembly techniques. TEs make up 4-60% of assembled vertebrate genomes, and deeply branching lineages such as ray-finned fishes and amphibians generally exhibit a higher TE diversity than the more recent radiations of birds and mammals. Furthermore, the list of taxa with exceptional TE landscapes is growing. We emphasize that the current bottleneck in genome analyses lies in the proper annotation of TEs and provide examples where superficial analyses led to misleading conclusions about genome evolution. Finally, recent advances in long-read sequencing will soon permit access to TE-rich genomic regions that previously resisted assembly including the gigantic, TE-rich genomes of salamanders and lungfishes.
197 citations
TL;DR: Imprinted expression of a number of genes is conserved between monocots and dicots, suggesting that long-term selection can maintain imprinted expression at some loci.
Abstract: Genomic imprinting, the differential expression of an autosomal gene that is dependent on its parent of origin, has independently evolved in flowering plants and mammals. In both of these organism classes, imprinting occurs in embryo-nourishing tissues—the placenta and the endosperm, respectively. It has been proposed that some imprinted genes control nutrient flow from the mother to the offspring. Genome-wide analyses of imprinted genes in plants have revealed that many imprinted genes are located in the vicinity of transposon or repeat sequences, implying that transposon insertions are associated with the evolution of imprinted loci. Imprinted expression of a number of genes is conserved between monocots and dicots, suggesting that long-term selection can maintain imprinted expression at some loci. In terms of epigenetic mechanisms, imprinted expression is largely controlled by an antagonistic action of DNA methylation and Polycomb group–mediated histone methylation in the vicinity of imprinted genes, w...
189 citations
TL;DR: Differential allelic expression is correlated with active DNA demethylation by DNA glycosylases and repressive targeting by the Polycomb group proteins and could be important for maintaining the epigenome in the embryo as well as for establishing gene imprinting.
Abstract: Imprinted gene expression--the biased expression of alleles dependent on their parent of origin--is an important type of epigenetic gene regulation in flowering plants and mammals. In plants, genes are imprinted primarily in the endosperm, the triploid placenta-like tissue that surrounds and nourishes the embryo during its development. Differential allelic expression is correlated with active DNA demethylation by DNA glycosylases and repressive targeting by the Polycomb group proteins. Imprinted gene expression is one consequence of a large-scale remodeling to the epigenome, primarily directed at transposable elements, that occurs in gametes and seeds. This remodeling could be important for maintaining the epigenome in the embryo as well as for establishing gene imprinting.
154 citations
TL;DR: This work greatly improve thread scaling in many scenarios, including on the recent Intel Xeon Phi architecture and highlights how bottlenecks are exacerbated by variable-record-length file formats like FASTQ and suggest changes that enable superior scaling.
Abstract: General-purpose processors can now contain many dozens of processor cores and support hundreds of simultaneous threads of execution. To make best use of these threads, genomics software must contend with new and subtle computer architecture issues. We discuss some of these and propose methods for improving thread scaling in tools that analyze each read independently, such as read aligners. We implement these methods in new versions of Bowtie, Bowtie 2 and HISAT. We greatly improve thread scaling in many scenarios, including on the recent Intel Xeon Phi architecture. We also highlight how bottlenecks are exacerbated by variable-record-length file formats like FASTQ and suggest changes that enable superior scaling.
152 citations
References
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TL;DR: In this paper, a simple and widely accepted multiple test procedure of the sequentially rejective type is presented, i.e. hypotheses are rejected one at a time until no further rejections can be done.
Abstract: This paper presents a simple and widely ap- plicable multiple test procedure of the sequentially rejective type, i.e. hypotheses are rejected one at a tine until no further rejections can be done. It is shown that the test has a prescribed level of significance protection against error of the first kind for any combination of true hypotheses. The power properties of the test and a number of possible applications are also discussed.
20,459 citations
"Analysis of the platypus genome sug..." refers methods in this paper
...T e Holm m thod of c rection mul iple e i g was used [25]....
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...The Holm method of correction for multiple testing was applied [25]....
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TL;DR: It is shown that CpG islands in methylated genomes are maintained, despite a tendency for 5mCpG to mutate by deamination to TpG+CpA, by the structural stability of a high G+C content alone, and that C pG islands associated with exons result from some selective importance of the arginine codon CGX.
3,321 citations
"Analysis of the platypus genome sug..." refers background or methods in this paper
...%) that attract methylation in imprinted regions in eutherian mammals were identified using a modified version of the CpGLH program by G Miklem and L Hillier [19]....
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...CpG islands (defined as more than 200 bp of continuous sequence with a C-G percentage greater than 60%) that attract methylation in imprinted regions in eutherian mammals were identified using a modified version of the CpGLH program by G Miklem and L Hillier [19]....
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...CpG island distribution In the eutherians, the predominant mechanism of gene silencing is due to differential methylation of CpG islands, located in or near imprinted genes [19-21]....
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TL;DR: Both LAGAN and Multi-LAGAN compare favorably with other leading alignment methods in correctly aligning protein-coding exons, especially between distant homologs such as human and chicken, or human and fugu.
Abstract: Comparing genomic sequences across related species is a fruitful source of biological insight, because functional elements such as exons tend to exhibit significant sequence similarity, whereas regions that are not functional tend to be less conserved. The first step in comparing genomic sequences is to align them—that is, to map the letters of one sequence to those of the others. There are several categories of alignments: local alignments that identify local similarities between regions of each sequence, and global alignments that find a monotonically increasing map between the letters of each sequence; pairwise alignments that compare two sequences, and multiple alignments that compare several sequences.
Local pairwise alignment methods such as Smith-Waterman (1981), BLAST (Altschul et al. 1990, 1997), BLASTZ (Schwartz et al. 2000), SSAHA (Ning et al. 2001), and BLAT (Kent 2002) are able to pinpoint locations of rearrangements between two sequences, and are suitable for aligning draft sequences or individual reads. Global alignments are important because they reveal the shared order of biological features in the compared species, and produce a more accurate alignment at the base-pair level when the features are in the same order. The best-known global alignment algorithm is Needleman-Wunsch (1970), which requires time proportional to the product of the lengths of the aligned sequences. Unfortunately this algorithm is too inefficient for comparing long genomic sequences. Faster methods have been developed recently: DIALIGN (Morgenstern et al. 1998, Brudno and Morgenstern 2002), MUMmer (Delcher et al. 1999, 2002), GLASS (Batzoglou et al. 2000), WABA (Kent and Zahler 2000), and AVID (Bray et al. 2003). Most of these methods have proven effective in aligning genomic sequences from two closely related organisms, such as human and mouse or Caenorhabditis elegans and C. briggsae, but have not been tested in alignments between distant relatives such as human and fugu.
Multiple alignments, a natural extension of two-sequence comparisons, are a powerful way to study biological sequences. Even weak similarity across several sequences usually reveals an important conserved biological feature (Dubchak et al. 2000; Gottgens et al. 2002). Moreover, multiple alignments enable the computation of local rates of evolution, giving a quantitative measure of the strength of evolutionary constraints and the functional importance of local regions (Simon et al. 2002). Multiple alignments are considerably more difficult to compute than are pairwise alignments: the running time scales as the product of the lengths of all the sequences. Formally, the problem is NP-complete (Wang and Jiang 1994; Bonizzoni and Vedova 2001). For this reason heuristic approaches are usually applied, of which the most widely used is progressive alignment, which constructs a multiple alignment by successive applications of a pairwise alignment algorithm. The best-known system based on progressive alignment is perhaps CLUSTALW (Thompson et al. 1994). Some other systems include MULTALIGN (Barton and Sternberg 1987), MULTAL (Taylor 1988), YAMA (Hardison et al. 1993, 1994), and PRRP (Gotoh 1996). DIALIGN (Morgenstern 1999) does not use progressive alignment; instead it uses another heuristic approach to chain local conserved blocks between several sequences into a multiple alignment. These systems can effectively align proteins and relatively short genomic regions, but are not efficient enough to align entire genomes. MGA (Hohl et al. 2002) is a rapid multiple aligner suitable for comparing very close homologs, such as different strains of a bacterium, but is not designed to align distant homologs.
Here we describe novel systems for pairwise and multiple alignment of genomic sequences: LAGAN (Limited Area Global Alignment of Nucleotides), an efficient and reliable pairwise aligner that is suitable for genomic comparison of distantly related organisms, and MLAGAN (Multi-LAGAN), a multiple aligner based on progressive alignment with LAGAN. We tested our systems on sequence from 12 species generated for the genomic segment harboring the cystic fibrosis transmembrane conductance regulator (CFTR) gene (J.W. Thomas, J.W. Touchman, R.W. Blakesley, G.G. Bouffard, S.M. Beckstrom-Sternberg, E.H. Margulies, M. Blanchette, A.C. Siepel, P.J. Thomas, J.C. McDowell, B. Maskeri, N.F. Hansen, M.S. Schwartz, R.J. Weber, W.J. Kent, D. Karolchik, T.C. Bruen, R. Bevan, D.J. Cutler, S. Schwartz, L. Elnitski, J.R. Idol, A.B. Prasad, S.-Q. Lee-Lin, V.V.B. Maduro, M.E. Portnoy, N.L. Dietrich, N. Akhter, K. Ayele, B. Benjamin, K. Cariaga, C.P. Brinkley, S.Y. Brooks, S. Granite, X. Guan, J. Gupta, P. Haghighi, S-L. Ho, M.C. Huang, E. Karlins, P.L. Laric, R. Legaspi, M.J. Lim, Q.L. Maduro, C.A. Masiello, S.D. Mastrian, J.C. McCloskey, R. Pearson, S. Stantripop, E.E. Tiongson, J.T. Tran, C. Tsurgeon, J.L. Vogt, M.A. Walker, K.D. Wetherby, L.S. Wiggins, A.C. Young, L-H. Zhang, K. Osoegawa, B. Zhu, B. Zhao, C.L. Shu, P.J. De Jong, C.E. Lawrence, A.F. Smit, A. Chakravarti, D. Haussler, P. Green, W. Miller, and E.D. Green, in prep.). Based on comparisons with other available alignment programs and benchmarking on standard desktop computer systems, we conclude that LAGAN and MLAGAN are practical and reliable methods for large-scale pairwise and multiple genomic alignment that should prove useful for obtaining alignments of the entire human, mouse, fugu, rat, and other genomes in the context of a whole-genome alignment pipeline.
1,106 citations
Washington University in St. Louis1, Australian National University2, University of Oxford3, University of Adelaide4, University of Sydney5, Pennsylvania State University6, Wellcome Trust Sanger Institute7, University of Cambridge8, University of Oviedo9, University of Washington10, Walter and Eliza Hall Institute of Medical Research11, Weizmann Institute of Science12, Institute for Systems Biology13, University of Melbourne14, Hudson Institute of Medical Research15, Louisiana State University16, University of Canterbury17, University of Münster18, Howard Hughes Medical Institute19, Monash University20, West Virginia University21, New York University22, Institut national de la recherche agronomique23, Iowa State University24, Broad Institute25
TL;DR: It is found that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypUS biology.
Abstract: We present a draft genome sequence of the platypus, Ornithorhynchus anatinus This monotreme exhibits a fascinating combination of reptilian and mammalian characters For example, platypuses have a coat of fur adapted to an aquatic lifestyle; platypus females lactate, yet lay eggs; and males are equipped with venom similar to that of reptiles Analysis of the first monotreme genome aligned these features with genetic innovations We find that reptile and platypus venom proteins have been co-opted independently from the same gene families; milk protein genes are conserved despite platypuses laying eggs; and immune gene family expansions are directly related to platypus biology Expansions of protein, non-protein-coding RNA and microRNA families, as well as repeat elements, are identified Sequencing of this genome now provides a valuable resource for deep mammalian comparative analyses, as well as for monotreme biology and conservation
653 citations
TL;DR: Three hypotheses claim to have found a countervailing selective advantage of parent-specific expression, proposed to have evolved because it enhances evolvability in a changing environment, protects females against the ravages of invasive trophoblast, or because natural selection acts differently on genes of maternal and paternal origin in interactions among kin.
Abstract: Parent-specific gene expression (genomic imprinting) is an evolutionary puzzle because it forgoes an important advantage of diploidy--protection against the effects of deleterious recessive mutations. Three hypotheses claim to have found a countervailing selective advantage of parent-specific expression. Imprinting is proposed to have evolved because it enhances evolvability in a changing environment, protects females against the ravages of invasive trophoblast, or because natural selection acts differently on genes of maternal and paternal origin in interactions among kin. The last hypothesis has received the most extensive theoretical development and seems the best supported by the properties of known imprinted genes. However, the hypothesis is yet to provide a compelling explanation for many examples of imprinting.
453 citations
"Analysis of the platypus genome sug..." refers background in this paper
...This suggests that imprinting evolved to regulate nutrient exchange between the mother and the developing fetus [4]....
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...The most widely accepted hypothesis to explain why mammalian imprinting may have been retained is the 'kinship hypothesis' [3,4]....
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