Emanuel Maldonado. Daniela Almeida. Tibisay Escalona. Agostinho Antunes.
Maldonado et al. Recent advances in genome sequencing technologies have remarkably increased the efficiency to pinpoint genes involved in the adaptive evolution of phenotypes. Reliability of such findings is most often examined with statistical and computational methods using Maximum Likelihood codon-based models i. While these models represent a well-defined workflow for documenting adaptive evolution, in practice they can be challenging for researchers having a vast amount of data, as multiple types of relevant codon-based datasets are generated, making the overall process hard and tedious to handle, error-prone and time-consuming.
Results: We introduce LMAP Lightweight Multigene Analyses in PAML , a user-friendly command-line and interactive package, designed to handle the codeml workflow, namely: directory organization, execution, results gathering and organization for Likelihood Ratio Test estimations with minimal manual user intervention. LMAP was developed for the workstation multi-core environment and provides a unique advantage for processing one, or more, if not all codeml codon-based models for multiple datasets at a time.
Our software, proved efficiency throughout the codeml workflow, including, but not limited, to simultaneously handling more than 20 datasets. Conclusions: We have developed a simple and versatile LMAP package, with outstanding performance, enabling researchers to analyze multiple different codon-based datasets in a high-throughput fashion. At minimum, two file types are required within a single input directory: one for the multiple sequence alignment and another for the phylogenetic tree.
To our knowledge, no other software combines all codeml codon substitution models of adaptive evolution. LMAP has been developed as an open-source package, allowing its integration into more complex open-source bioinformatics pipelines. Uncovering references for further information. It employs different site has long been of interest to the evolutionary biologist.
In class specific models: i the alternative classes which in- this regard, the advent of new genome sequencing tech- cludes model 3 M3 , 2 M2a and 8 M8 and, ii the null nologies has remarkably increased the efficiency of con- classes which includes model 0 M0 , 1 M1 , 7 M7 and temporary molecular research [1—3]. In particular, 8a M8a. Models are pairwise compared M0 vs. M3, M1a significant progress has been made towards the discov- vs.
M2a, M7 vs. M8, M8a vs.
M8 [12, 21, 22] using LRT. This has prompted an enor- identified by the Bayes Empirical Bayes BEB analysis , mous collection of new genome sequence data requiring except for the M0 vs. M3 comparison, since it does not fast and efficient specialized bioinformatics software for allow detection of positive selection  and M3 does not assisting researchers in downstream analyses [2, 3]. Although a or lineages . Additional information on technical large number of applications integrating this framework aspects can be found in PAML documentation.
Although PAML package  is the most widely used in the lit- various model comparisons are possible, this generally in- erature, statistically robust and accurate in examining se- volves performing two LRT comparisons among three lective pressure [6—11]. Henceforth, codeml will only models [14, 28]. The first is accomplished by testing the refer to codon substitution models.
If TrU fits the data two stages. First, codeml executes different model ap- better, then the second LRT comparison can be tested in proaches, each of which uses different assumptions order to validate signals of divergence. Second, for all BM and allows the detection of episodic selection oc- models, a Likelihood Ratio Test LRT [12, 19, 20] is curring along few lineages [7, 16]. In tions are possible , i one configuring a model that the single-task software group, SM executions are possible allows positive selection on the foreground branches, in all software, while BM and BSM are also possible in Ar- the alternative model A MA , and ii the other, a madillo and PAMLX.
This last one additionally allows model that allows neutral and negative selection both CM executions. Despite providing an important advancement in selection pressures acting among sites and lineages, allow- large scale analyses, they are however, too complex to ing the detection of divergent selection among clades, install and configure , and usually require unavailable whether in the foreground or background branches. For instance, the gco- Under CM, a phylogeny can incorporate more than two deml is mainly intended for production managers .
The significance of site-specific divergence among viding a reasonable amount of processing capacity. CmC [8, 32]. If the CmC is sig- scribed, there are also web-server implementations avail- nificant, then the BEB analysis can be used to identify sites able, namely PSP , PhyleasProg  and Selecton experiencing divergence among clades.
To further decide version 2. Despite all these attempts, bottom. However, it can be highly Here we propose LMAP Lightweight Multigene Ana- challenging in practice due to the huge amount of infor- lyses in PAML , a high-throughput user-friendly soft- mation, as data integration and analysis involves often ware package designed to simplify evolutionary analyses multiple tasks that need to be manually performed by performed with any of the described codon substitution the researcher, including gathering and organizing input models SM, BM, BSM and CM.
LMAP package is data , manipulating software configuration files, and composed of six command-line and interactive Perl  running and analyzing the results. Specifically in the applications designed to handle step-by-step the codeml codeml workflow, it is necessary to generate i MSAs, workflow, thus minimizing user intervention. Although ii phylogenetic trees, iii edit the parameter files, iv there are six applications, one of them lmap. LRT comparisons in spreadsheet documents.
Moreover, To enable LMAP trial and testing, an example dataset the challenge is even greater when performing these consisting of the mitochondrial DNA of 20 freshwater tasks repetitively for multiple datasets i. They can be organized in acity. BMC Bioinformatics Page 4 of 11 introduce the example dataset with which are performed selection of values, can be used to perform independent benchmarking tests.
It consists of six tree files in the templates. In the case of MSA vi lmap. In the case of the phylogenetic tree s , the no- executions for which are required the UNIX sendmail menclature depends on the existence of labeling. Tree  and screen  utility programs ; iii in gmap. Therefore, these two procedures require different statistics functions involved in estimation of LRTs; and identities. In the SM case, the user needs to type the v in all applications, for handling files and directories. In the BRM case, tree labeling gramming skills.
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By contrast, our package implements depends on the branch partitions scheme hypothesis all necessary functions, excluding the cases mentioned defined by the researcher. Hence, the tree file should be above hereby requiring minimal installation efforts. It is eter estimates. LMAP management of codeml parameters and templates An advantage of this design is that it allows the user Since all codon substitution models SM, BM, BSM and to combine in a single step one or more, if not all CM require different codeml control file configurations, unique MSAs, with as many as required phylogenetic we have defined nine templates Additional file 1: Tables tree files or hypotheses to be run, regardless of the S1—S4.
Please see the manual included in LMAP package for Some parameters on these templates are automatically ad- more information. Before getting started, the user is In this section, we describe how the mmap. To this end, any structure. Because the total number of tasks can be very large, most probably surpassing the total number of CPU cores, the application provides the command-line option CLO -n to define the maximum tasks to be run. This will define the maximum number of cores utilized one task per core. When used, a value for this option must be defined, or otherwise the value is automatically estimated.
In this case, the application quantifies an ap- proximate number of available CPU cores, which in con- sequence defines the maximum number of codeml tasks to be run.
This is achieved by calculating the difference of total number of cores to the overall CPU load. Under these circumstances, the quantification of available CPUs by the application makes sense, since it maximizes the performance of the whole scheduling. It is noteworthy, that the greater the number of CPU cores available, the faster the execution of the mmap.
Please see the Example dataset and benchmarking section for more information. Results and discussion Fig. Flowchart exhibiting the lmap. The sixth and last applica- Figure S2 , where N is the branch partition number see tion, lmap. We describe therein. In the first, codeml input files are orga- take place at any time, before the codeml executions.
Moreover, the options -K and -O Fig. Through the monitoring, the user is able to avoid local optima , resulting in multiple executions quickly understand whether the codeml instances are run- starting from different initial parameter values. The sec- ning correctly Fig. Having found during which a cladogram character-based layout is dis- unwanted or problematic instances, these can be termi- played with numbers identifying tree nodes.
Another useful functionality of mmap. The phylogenetic tree file from the included dataset is displayed as a cladogram, allowing the user to make the necessary labeling. This screen shows various information from left to right , such as the total number of nodes modified or affected, the total number of nodes labeled, the current selected display mode, which enables alternative display of phylogenetic tree information i. This informa- 0. Proceeding in this manner, the users need only to quently organized and summarized using the interactive specify minimal CLOs requirements Additional file 2: application omap.
This application compre- quired to estimate LRTs. During the lmap. For the LRTs to be esti- requires several separate executions. The simplicity of mated all alternative and null models must be paired in lmap. Through all its applications ity and requirements section.
Further fea- command. Additionally, four applications cmap. Nonetheless, LMAP is not constraints of file identity or formats, rather they can be applicable in Windows OS due to its main dependency employed in any existing directory structures that have on the screen utility program. This required compatibil- manually been created by the user. In this way, by adjust- ity feature, could be solved through the development of ing the command-line options accordingly, it is possible a Graphical User Interface GUI.
It would be interesting to use cmap. Regardless, the LMAP package will be publication. This path is decomposed in columns by omap. This additional on-screen information complements the codeml maximum likelihood parameter estimates simplifying overall data perception, advantageous for organization processes. It is possible to adjust visible table information, by scrolling and by un hiding columns or defining number of visible rows. Below the table, from left to right, various information is shown in cyan , such as the total number of rows and of columns, the number of selected rows, the number of visible rows and the number of hidden columns.
Likewise, the CLO -j users explore and experience the workflow of the package. To fulfil the work- genome sequences from turtle species 9 freshwater from station CPU capacity, the maximum number of desired the superfamily Tryonichia—Tryonichidae and Carettoche- tasks was indicated through the CLO -n, which in our ex- lyidae—and 11 terrestrial from the family Testudinidae ample was For purposes of benchmarking, through were retrieved from the online NCBI database.
All hypotheses were separated and organized from the initial User Table Fig. These columns are always defined in the following order, i the LRT comparison column C13 , whose parameter estimates define the following columns; ii deltaLnL column C14 , for twice the difference on the lnL scores; iii degrees of freedom df — column C15 ; iv p-value column C16 and v conclusion column C17 , where two acceptance results are possible: H0 for null models or H1 for alternative models.
Remaining aspects of this figure are as explained in Fig.
From there on, the protein folds across the front surface of CD in reverse orientation to a substrate, thus blocking the cleft. Footnotes The authors declare no conflict of interest. East Dane Designer Men's Fashion. Subnational authority is exercised by individual regions, and this measure is the first that takes individual regions as the unit of analysis. It employs different site has long been of interest to the evolutionary biologist. Department of the Treasury.
To notification when results are ready. To our knowledge, summarize, our package does not interfere in the execu- currently there is no other software that combines in tion time required by PAML, but instead mitigates how one all the described codeml models. LMAP has been much the researcher spends overseeing each step of the developed as an open-source command-line and inter- workflow, from the moment the input files are ready to be active package of tools, allowing its integration into analyzed, which may be none or minimal.
Despite this mediation, the process is much simpler than Installation if performed with often slow spreadsheets.
Additionally, The LMAP package provides two additional applications LMAP allows users to carry out phylogenetic tree label- to easily enable LMAP functionality and installation: i ing; as well as to monitor and control executing codeml the install. References Additional files 1.
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