%0 Journal Article %J Science %D 2021 %T Population sequencing data reveal a compendium of mutational processes in the human germ line. %A Seplyarskiy, Vladimir B %A Soldatov, Ruslan A %A Koch, Evan %A McGinty, Ryan J %A Goldmann, Jakob M %A Hernandez, Ryan D %A Barnes, Kathleen %A Correa, Adolfo %A Burchard, Esteban G %A Ellinor, Patrick T %A McGarvey, Stephen T %A Mitchell, Braxton D %A Vasan, Ramachandran S %A Redline, Susan %A Silverman, Edwin %A Weiss, Scott T %A Arnett, Donna K %A Blangero, John %A Eric Boerwinkle %A He, Jiang %A Montgomery, Courtney %A Rao, D C %A Rotter, Jerome I %A Taylor, Kent D %A Brody, Jennifer A %A Chen, Yii-Der Ida %A de Las Fuentes, Lisa %A Hwu, Chii-Min %A Rich, Stephen S %A Manichaikul, Ani W %A Mychaleckyj, Josyf C %A Palmer, Nicholette D %A Smith, Jennifer A %A Kardia, Sharon L R %A Peyser, Patricia A %A Bielak, Lawrence F %A O'Connor, Timothy D %A Emery, Leslie S %A Gilissen, Christian %A Wong, Wendy S W %A Kharchenko, Peter V %A Sunyaev, Shamil %K Algorithms %K CpG Islands %K DNA Damage %K DNA Demethylation %K DNA Mutational Analysis %K DNA Replication %K Genetic Variation %K Genome, Human %K Germ Cells %K Germ-Line Mutation %K Humans %K Long Interspersed Nucleotide Elements %K Mutagenesis %K Oocytes %K Transcription, Genetic %X

Biological mechanisms underlying human germline mutations remain largely unknown. We statistically decompose variation in the rate and spectra of mutations along the genome using volume-regularized nonnegative matrix factorization. The analysis of a sequencing dataset (TOPMed) reveals nine processes that explain the variation in mutation properties between loci. We provide a biological interpretation for seven of these processes. We associate one process with bulky DNA lesions that are resolved asymmetrically with respect to transcription and replication. Two processes track direction of replication fork and replication timing, respectively. We identify a mutagenic effect of active demethylation primarily acting in regulatory regions and a mutagenic effect of long interspersed nuclear elements. We localize a mutagenic process specific to oocytes from population sequencing data. This process appears transcriptionally asymmetric.

%B Science %V 373 %P 1030-1035 %8 2021 Aug 27 %G eng %N 6558 %1 https://www.ncbi.nlm.nih.gov/pubmed/34385354?dopt=Abstract %R 10.1126/science.aba7408 %0 Journal Article %J Science %D 2012 %T Landscape of somatic retrotransposition in human cancers. %A Lee, Eunjung %A Iskow, Rebecca %A Yang, Lixing %A Gokcumen, Omer %A Haseley, Psalm %A Luquette, Lovelace J %A Lohr, Jens G %A Harris, Christopher C %A Ding, Li %A Wilson, Richard K %A Wheeler, David A %A Gibbs, Richard A %A Kucherlapati, Raju %A Lee, Charles %A Kharchenko, Peter V %A Park, Peter J %K Base Sequence %K Cell Transformation, Neoplastic %K Colorectal Neoplasms %K DNA Methylation %K Female %K Gene Expression Regulation, Neoplastic %K Genes, Neoplasm %K Genome, Human %K Glioblastoma %K Humans %K Long Interspersed Nucleotide Elements %K Male %K Microsatellite Instability %K Molecular Sequence Annotation %K Molecular Sequence Data %K Multiple Myeloma %K Mutagenesis, Insertional %K Mutation %K Ovarian Neoplasms %K Prostatic Neoplasms %K Retroelements %K Sequence Analysis, DNA %X

Transposable elements (TEs) are abundant in the human genome, and some are capable of generating new insertions through RNA intermediates. In cancer, the disruption of cellular mechanisms that normally suppress TE activity may facilitate mutagenic retrotranspositions. We performed single-nucleotide resolution analysis of TE insertions in 43 high-coverage whole-genome sequencing data sets from five cancer types. We identified 194 high-confidence somatic TE insertions, as well as thousands of polymorphic TE insertions in matched normal genomes. Somatic insertions were present in epithelial tumors but not in blood or brain cancers. Somatic L1 insertions tend to occur in genes that are commonly mutated in cancer, disrupt the expression of the target genes, and are biased toward regions of cancer-specific DNA hypomethylation, highlighting their potential impact in tumorigenesis.

%B Science %V 337 %P 967-71 %8 2012 Aug 24 %G eng %N 6097 %1 https://www.ncbi.nlm.nih.gov/pubmed/22745252?dopt=Abstract %R 10.1126/science.1222077 %0 Journal Article %J Mol Cancer Res %D 2012 %T SINE retrotransposons cause epigenetic reprogramming of adjacent gene promoters. %A Estécio, Marcos R H %A Gallegos, Juan %A Dekmezian, Mhair %A Lu, Yue %A Liang, Shoudan %A Issa, Jean-Pierre J %K Adaptor Proteins, Signal Transducing %K Alu Elements %K Animals %K Antigens, CD %K Cadherins %K Cellular Reprogramming %K Chromatin %K Cyclin-Dependent Kinase Inhibitor p19 %K DNA Methylation %K Epigenesis, Genetic %K Gene Silencing %K Genes %K Humans %K Insulator Elements %K Long Interspersed Nucleotide Elements %K Mice %K MutL Protein Homolog 1 %K NIH 3T3 Cells %K Nuclear Proteins %K Promoter Regions, Genetic %K Protein Binding %K Short Interspersed Nucleotide Elements %K Transcription Initiation Site %K Transcription, Genetic %K Tumor Suppressor Protein p14ARF %X

Almost half of the human genome and as much as 40% of the mouse genome is composed of repetitive DNA sequences. The majority of these repeats are retrotransposons of the SINE and LINE families, and such repeats are generally repressed by epigenetic mechanisms. It has been proposed that these elements can act as methylation centers from which DNA methylation spreads into gene promoters in cancer. Contradictory to a methylation center function, we have found that retrotransposons are enriched near promoter CpG islands that stay methylation-free in cancer. Clearly, it is important to determine which influence, if any, these repetitive elements have on nearby gene promoters. Using an in vitro system, we confirm here that SINE B1 elements can influence the activity of downstream gene promoters, with acquisition of DNA methylation and loss of activating histone marks, thus resulting in a repressed state. SINE sequences themselves did not immediately acquire DNA methylation but were marked by H3K9me2 and H3K27me3. Moreover, our bisulfite sequencing data did not support that gain of DNA methylation in gene promoters occurred by methylation spreading from SINE B1 repeats. Genome-wide analysis of SINE repeats distribution showed that their enrichment is directly correlated with the presence of USF1, USF2, and CTCF binding, proteins with insulator function. In summary, our work supports the concept that SINE repeats interfere negatively with gene expression and that their presence near gene promoters is counter-selected, except when the promoter is protected by an insulator element.

%B Mol Cancer Res %V 10 %P 1332-42 %8 2012 Oct %G eng %N 10 %1 https://www.ncbi.nlm.nih.gov/pubmed/22952045?dopt=Abstract %R 10.1158/1541-7786.MCR-12-0351 %0 Journal Article %J Nature %D 2004 %T Sequence and comparative analysis of the chicken genome provide unique perspectives on vertebrate evolution. %K Animals %K Avian Proteins %K Chickens %K Conserved Sequence %K DNA Transposable Elements %K Evolution, Molecular %K Gene Duplication %K Genes %K Genome %K Genomics %K Humans %K Long Interspersed Nucleotide Elements %K Multigene Family %K Mutagenesis %K Physical Chromosome Mapping %K Pseudogenes %K Retroviridae %K RNA, Untranslated %K Sequence Analysis, DNA %K Short Interspersed Nucleotide Elements %K Synteny %K Vertebrates %X

We present here a draft genome sequence of the red jungle fowl, Gallus gallus. Because the chicken is a modern descendant of the dinosaurs and the first non-mammalian amniote to have its genome sequenced, the draft sequence of its genome--composed of approximately one billion base pairs of sequence and an estimated 20,000-23,000 genes--provides a new perspective on vertebrate genome evolution, while also improving the annotation of mammalian genomes. For example, the evolutionary distance between chicken and human provides high specificity in detecting functional elements, both non-coding and coding. Notably, many conserved non-coding sequences are far from genes and cannot be assigned to defined functional classes. In coding regions the evolutionary dynamics of protein domains and orthologous groups illustrate processes that distinguish the lineages leading to birds and mammals. The distinctive properties of avian microchromosomes, together with the inferred patterns of conserved synteny, provide additional insights into vertebrate chromosome architecture.

%B Nature %V 432 %P 695-716 %8 2004 Dec 09 %G eng %N 7018 %1 https://www.ncbi.nlm.nih.gov/pubmed/15592404?dopt=Abstract %R 10.1038/nature03154