Temporal ordering of substitutions in RNA evolution: Uncovering the structural evolution of the Human Accelerated Region 1.

The Human Accelerated Region 1 (HAR1) is the most rapidly evolving region in the human genome. It is part of two overlapping long non-coding RNAs, has a length of only 118 nucleotides and features 18 human specific changes compared to an ancestral sequence that is extremely well conserved across non-human primates. The human HAR1 forms a stable secondary structure that is strikingly different from the one in chimpanzee as well as other closely related species, again emphasizing its human-specific evolutionary history. This suggests that positive selection has acted to stabilize human-specific features in the ensemble of HAR1 secondary structures. To investigate the evolutionary history of the human HAR1 structure, we developed a computational model that evaluates the relative likelihood of evolutionary trajectories as a probabilistic version of a Hamiltonian path problem. The model predicts that the most likely last step in turning the ancestral primate HAR1 into the human HAR1 was exactly the substitution that distinguishes the modern human HAR1 sequence from that of Denisovan, an archaic human, providing independent support for our model. The MutationOrder software is available for download and can be applied to other instances of RNA structure evolution.

[1]  John B. Shoven,et al.  I , Edinburgh Medical and Surgical Journal.

[2]  Rory Johnson,et al.  Human accelerated region 1 noncoding RNA is repressed by REST in Huntington's disease. , 2010, Physiological genomics.

[3]  Adrian W. Briggs,et al.  A High-Coverage Genome Sequence from an Archaic Denisovan Individual , 2012, Science.

[4]  Richard Bellman,et al.  Dynamic Programming Treatment of the Travelling Salesman Problem , 1962, JACM.

[5]  Steven J. M. Jones,et al.  Circos: an information aesthetic for comparative genomics. , 2009, Genome research.

[6]  Andreas Björklund.  Determinant Sums for Undirected Hamiltonicity , 2014, SIAM J. Comput..

[7]  M. Huynen,et al.  Smoothness within ruggedness: the role of neutrality in adaptation. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[8]  Núria Queralt-Rosinach,et al.  DisGeNET: a comprehensive platform integrating information on human disease-associated genes and variants , 2016, Nucleic Acids Res..

[9]  Sonja J. Prohaska,et al.  Algebraic Dynamic Programming over general data structures , 2015, BMC Bioinformatics.

[10]  D. Turner,et al.  A set of nearest neighbor parameters for predicting the enthalpy change of RNA secondary structure formation , 2006, Nucleic acids research.

[11]  Dan Tulpan,et al.  Pairwise visual comparison of small RNA secondary structures with base pair probabilities , 2019, BMC Bioinformatics.

[12]  Ralf Hinze,et al.  Histo- and dynamorphisms revisited , 2013, WGP '13.

[13]  Eric Westhof,et al.  Distinctive structures between chimpanzee and human in a brain noncoding RNA. , 2008, RNA.

[14]  Gabor T. Marth,et al.  A global reference for human genetic variation , 2015, Nature.

[15]  Weinberger,et al.  RNA folding and combinatory landscapes. , 1993, Physical review. E, Statistical physics, plasmas, fluids, and related interdisciplinary topics.

[16]  D. Haussler,et al.  An RNA gene expressed during cortical development evolved rapidly in humans , 2006, Nature.

[17]  Harald Schwalbe,et al.  NMR Studies of HAR1 RNA Secondary Structures Reveal Conformational Dynamics in the Human RNA , 2012, Chembiochem : a European journal of chemical biology.

[18]  Sonja J. Prohaska,et al.  The relativity of biological function , 2015, Theory in Biosciences.

[19]  Michael T. Wolfinger,et al.  Barrier Trees of Degenerate Landscapes , 2002 .

[20]  P. Stadler,et al.  Selection Pressures on RNA Sequences and Structures , 2019, Evolutionary bioinformatics online.

[21]  Sree Rohit Raj Kolora,et al.  Divergent evolution in the genomes of closely related lacertids, Lacerta viridis and L. bilineata, and implications for speciation , 2018, GigaScience.

[22]  Peter F. Stadler,et al.  ViennaRNA Package 2.0 , 2011, Algorithms for Molecular Biology.

[23]  Peter F. Stadler,et al.  SSS-test: a novel test for detecting positive selection on RNA secondary structure , 2019, BMC Bioinformatics.

[24]  P. Schuster,et al.  From sequences to shapes and back: a case study in RNA secondary structures , 1994, Proceedings of the Royal Society of London. Series B: Biological Sciences.

[25]  Sean R. Eddy,et al.  Infernal 1.1: 100-fold faster RNA homology searches , 2013, Bioinform..

[26]  Jan Gorodkin,et al.  RNAsnp: Efficient Detection of Local RNA Secondary Structure Changes Induced by SNPs , 2013, Human mutation.

[27]  M. Lares.  Synthesis, purification and crystallization of a putative critical bulge of HAR1 RNA , 2019, PloS one.