Robustness against point mutations of genetic code extensions under consideration of wobble-like effects.

Many theories of the evolution of the genetic code assume that the genetic code has always evolved in the direction of increasing the supply of amino acids to be encoded (Barbieri, 2019; Di Giulio, 2005; Wong, 1975). In order to reduce the risk of the formation of a non-functional protein due to point mutations, nature is said to have built in control mechanisms. Using graph theory the authors have investigated in Blazej et al. (2019) if this robustness is optimal in the sense that a different codon-amino acid assignment would not generate a code that is even more robust. At present, efforts to expand the genetic code are very relevant in biotechnological applications, for example, for the synthesis of new drugs (Anderson et al., 2004; Chin, 2017; Dien et al., 2018; Kimoto et al., 2009; Neumann et al., 2010). In this paper we generalize the approach proposed in Blazej et al. (2019) and will explore hypothetical extensions of the standard genetic code with respect to their optimal robustness in two ways: (1) We keep the usual genetic alphabet but move from codons to longer words, such as tetranucleotides. This increases the supply of coding words and thus makes it possible to encode non-canonical amino acids. (2) We expand the genetic alphabet by introducing non-canonical base pairs. In addition, the approach from Blazej et al. (2019) and Blazej et al. (2018) is extended by incorporating the weights of single point-mutations into the model. The weights can be interpreted as probabilities (appropriately normalized) or degrees of severity of a single point mutation. In particular, this new approach allows us to take a closer look at the wobble effects in the translation of codons into amino acids. According to the results from Blazej et al. (2019) and Blazej et al. (2018), the standard genetic code is not optimal in terms of its robustness to point mutations if the weights of single point mutations are not taken into account. After incorporation into the model weights that mimic the wobble effect, the results of the present work show that it is much more robust, almost optimal in that respect. We hope, that this theoretical analysis might help to assess extended genetic codes and their abilities to encode new amino acids.

Motif lengths of circular codes in coding sequences.

Protein synthesis is a crucial process in any cell. Translation, in which mRNA is translated into proteins, can lead to several errors, notably frame shifts where the ribosome accidentally skips or re-reads one or more nucleotides. So-called circular codes are capable of discovering frame shifts and their codons can be found disproportionately often in coding sequences. Here, we analyzed motifs of circular codes, i.e. sequences only containing codons of circular codes, in biological and artificial sequences. The lengths of these motifs were compared to a statistical model in order to elucidate if coding sequences contain significantly longer motifs than non-coding sequences. Our findings show that coding sequences indeed show on average greater motif lengths than expected by chance. On the other hand, the motifs are too short for a possible frame shift recognition to take place within an entire coding sequence. This suggests that as much as circular codes might have been used in ancient life forms in order to prevent frame shift errors, it remains to be seen whether they are still functional in current organisms.

The Quality of Genetic Code Models in Terms of Their Robustness Against Point Mutations.

In this paper, we investigate the quality of selected models of theoretical genetic codes in terms of their robustness against point mutations. To deal with this problem, we used a graph representation including all possible single nucleotide point mutations occurring in codons, which are building blocks of every protein-coding sequence. Following graph theory, the quality of a given code model is measured using the set conductance property which has a useful biological interpretation. Taking this approach, we found the most robust genetic code structures for a given number of coding blocks. In addition, we tested several properties of genetic code models generated by the binary dichotomic algorithms (BDA) and compared them with randomly generated genetic code models. The results indicate that BDA-generated models possess better properties in terms of the conductance measure than the majority of randomly generated genetic code models and, even more, that BDA-models can achieve the best possible conductance values. Therefore, BDA-generated models are very robust towards changes in encoded information generated by single nucleotide substitutions.

ALES: cell lineage analysis and mapping of developmental events.

MOTIVATION: Animals build their bodies by altering the fates of cells. The way in which they do so is reflected in the topology of cell lineages and the fates of terminal cells. Cell lineages should, therefore, contain information about the molecular events that determined them. Here we introduce new tools for visualizing, manipulating, and extracting the information contained in cell lineages. Our tools enable us to analyze very large cell lineages, where previously analyses have only been carried out on cell lineages no larger than a few dozen cells. RESULTS: Ales (A Lineage Evaluation System) allows the display, evaluation and comparison of cell lineages with the aim of identifying molecular and cellular events underlying development. Ales introduces a series of algorithms that locate putative developmental events. The distribution of these predicted events can then be compared to gene expression patterns or other cellular characteristics. In addition, artificial lineages can be generated, or existing lineages modified, according to a range of models, in order to test hypotheses about lineage evolution. AVAILABILITY: The program can run on any operating system with a compliant Java 2 environment. Ales is free for academic use and can be downloaded from http://mbi.dkfz-heidelberg.de/mbi/research/cellsim/ales.