Conservation of Neutral Substitution Rate and Substitutional Asymmetries in Mammalian Genes

Local variation in neutral substitution rate across mammalian genomes is governed by several factors, including sequence context variables and structural variables. In addition, the interplay of replication and transcription, known to induce a strand bias in mutation rate, gives rise to variation in substitutional strand asymmetries. Here, we address the conservation of variation in mutation rate and substitutional strand asymmetries using primate- and rodent-specific repeat elements located within the introns of protein-coding genes. We find significant but weak conservation of local mutation rates between human and mouse orthologs. Likewise, substitutional strand asymmetries are conserved between human and mouse, where substitution rate asymmetries show a higher degree of conservation than mutation rate. Moreover, we provide evidence that replication and transcription are correlated to the strength of substitutional asymmetries. The effect of transcription is particularly visible for genes with highly conserved gene expression. In comparison with replication and transcription, mutation rate influences the strength of substitutional asymmetries only marginally.

[1]  Alain Arneodo,et al.  Human gene organization driven by the coordination of replication and transcription. , 2007, Genome research.

[2]  Terence Hwa,et al.  Substantial Regional Variation in Substitution Rates in the Human Genome: Importance of GC Content, Gene Density, and Telomere-Specific Effects , 2005, Journal of Molecular Evolution.

[3]  Y. Xing,et al.  Probe Selection and Expression Index Computation of Affymetrix Exon Arrays , 2006, PloS one.

[4]  R. Schaaper,et al.  Transcription-repair coupling determines the strandedness of ultraviolet mutagenesis in Escherichia coli. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[5]  S. Batzoglou,et al.  Characterization of evolutionary rates and constraints in three Mammalian genomes. , 2004, Genome research.

[6]  M. Meyer,et al.  A genomic region evolving toward different GC contents in humans and chimpanzees indicates a recent and regionally limited shift in the mutation pattern. , 2005, Molecular biology and evolution.

[7]  D. Niu,et al.  Strand compositional asymmetries in vertebrate large genes , 2008, Molecular Biology Reports.

[8]  David Haussler,et al.  Comparative recombination rates in the rat, mouse, and human genomes. , 2004, Genome research.

[9]  R C Hardison,et al.  Exponential decay of GC content detected by strand-symmetric substitution rates influences the evolution of isochore structure. , 2008, Molecular biology and evolution.

[10]  H. Ochman,et al.  Asymmetries Generated by Transcription-Coupled Repair in Enterobacterial Genes , 1996, Science.

[11]  Laurent Duret,et al.  Genome-wide studies highlight indirect links between human replication origins and gene regulation , 2008, Proceedings of the National Academy of Sciences.

[12]  A. Jeffreys,et al.  The rise and fall of a human recombination hot spot , 2009, Nature Genetics.

[13]  Alan Hodgkinson,et al.  Cryptic Variation in the Human Mutation Rate , 2009, PLoS biology.

[14]  A Grigoriev,et al.  Analyzing genomes with cumulative skew diagrams. , 1998, Nucleic acids research.

[15]  T. Kunkel,et al.  Evidence for Preferential Mismatch Repair of Lagging Strand DNA Replication Errors in Yeast , 2003, Current Biology.

[16]  G. Schwarz.  Estimating the Dimension of a Model , 1978 .

[17]  A. Bhagwat,et al.  Correlation between transcription and C to T mutations in the non-transcribed DNA strand. , 1998, Biological chemistry.

[18]  Martin Peifer,et al.  Transcription-induced mutational strand bias and its effect on substitution rates in human genes. , 2008, Molecular biology and evolution.

[19]  Mouse Genome Sequencing Consortium.  Initial sequencing and comparative analysis of the mouse genome , 2002, Nature.

[20]  Hans Ellegren,et al.  Deterministic mutation rate variation in the human genome. , 2002, Genome research.

[21]  A. Jacquier.  The complex eukaryotic transcriptome: unexpected pervasive transcription and novel small RNAs , 2009, Nature Reviews Genetics.

[22]  A. Grollman,et al.  Mutagenesis by 8-oxoguanine: an enemy within. , 1993, Trends in genetics : TIG.

[23]  Jianzhi Zhang,et al.  Evolutionary conservation of expression profiles between human and mouse orthologous genes. , 2006, Molecular biology and evolution.

[24]  J. Hartigan,et al.  Asynchronous distance between homologous DNA sequences. , 1987, Biometrics.

[25]  A. Klungland,et al.  8-Oxoguanine-mediated transcriptional mutagenesis causes Ras activation in mammalian cells , 2008, Proceedings of the National Academy of Sciences.

[26]  Alain Arneodo,et al.  Replication-associated strand asymmetries in mammalian genomes: toward detection of replication origins. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Jacek Majewski,et al.  Dependence of mutational asymmetry on gene-expression levels in the human genome. , 2003, American journal of human genetics.

[28]  R. Hudson,et al.  Single-nucleotide mutation rate increases close to insertions/deletions in eukaryotes , 2008, Nature.

[29]  David Haussler,et al.  Covariation in frequencies of substitution, deletion, transposition, and recombination during eutherian evolution. , 2003, Genome research.

[30]  Jean L. Chang,et al.  Initial sequence of the chimpanzee genome and comparison with the human genome , 2005, Nature.

[31]  S. Batzoglou,et al.  Quantitative estimates of sequence divergence for comparative analyses of mammalian genomes. , 2003, Genome research.

[32]  T. Lindahl.  Instability and decay of the primary structure of DNA , 1993, Nature.

[33]  A. Bhagwat,et al.  Transcription-induced mutations: increase in C to T mutations in the nontranscribed strand during transcription in Escherichia coli. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[34]  Y. Xing,et al.  Assessing the conservation of mammalian gene expression using high-density exon arrays. , 2007, Molecular biology and evolution.

[35]  T. Kunkel,et al.  A sensitive genetic assay for the detection of cytosine deamination: determination of rate constants and the activation energy. , 1990, Biochemistry.

[36]  H. Ellegren,et al.  Mutation rate variation in the mammalian genome. , 2003, Current opinion in genetics & development.

[37]  W. Miller,et al.  Human-macaque comparisons illuminate variation in neutral substitution rates , 2008, Genome Biology.

[38]  H. Ochman,et al.  Strand asymmetries in DNA evolution. , 1997, Trends in genetics : TIG.

[39]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

[40]  H. Akaike.  A new look at the statistical model identification , 1974 .

[41]  Terrence S. Furey,et al.  The UCSC Table Browser data retrieval tool , 2004, Nucleic Acids Res..

[42]  J. Lobry.  Asymmetric substitution patterns in the two DNA strands of bacteria. , 1996, Molecular biology and evolution.

[43]  H. Ochman,et al.  Deamination as the basis of strand-asymmetric evolution in transcribed Escherichia coli sequences. , 2001, Molecular biology and evolution.

[44]  Jeffrey H. Chuang,et al.  Weak preservation of local neutral substitution rates across mammalian genomes , 2009, BMC Evolutionary Biology.

[45]  I. Mellon.  Transcription-coupled repair: a complex affair. , 2005, Mutation research.

[46]  J. Svejstrup.  Transcription: Mechanisms of transcription-coupled DNA repair , 2002, Nature Reviews Molecular Cell Biology.

[47]  C. Semple,et al.  Chromatin structure and evolution in the human genome , 2007, BMC Evolutionary Biology.

[48]  P. Green,et al.  Transcription-associated mutational asymmetry in mammalian evolution , 2003, Nature Genetics.

[49]  C. Polychronakos,et al.  Strand bias in complementary single-nucleotide polymorphisms of transcribed human sequences: evidence for functional effects of synonymous polymorphisms , 2006, BMC Genomics.