Modeling and simulation of interlocus gene conversion

Les regions duplicades del genoma, com ara les duplicacions de segments (SDs), són una característica comuna dels genomes eucariotes i han estat associades a canvis fenotípics. Donada la seva rellevància evolutiva, tenir un model neutre per descriure la seva evolució és essencial. En aquesta tesi, descric el desenvolupament de SeDuS, un simulador computacional endavant en el temps de l'evolució neutra de SDs. Les duplicacions estan sotmeses a un procés de recombinació, anomenat conversió gènica interlocus (IGC), que afecta els patrons de variació i de desequilibri de lligament dins i entre duplicacions. Aquí descric els efectes de sobreposar regions susceptibles de recombinació homòloga amb regions susceptibles d'IGC i d'incorporar dependència d'IGC en la similitud de seqüències. Addicionalment, ja que les SDs són objectius potencial de la selecció natural, informo sobre possibles alteracions a proves estadístiques quan aquestes s'apliquen a regions duplicades sotmeses a IGC. Finalment, exploro la possibilitat de combinar resultats de diferents proves estadístiques aplicades al llarg de tot el genoma per detectar la presència de duplicacions col·lapsades.Duplicated regions of the genome, such as Segmental Duplications (SDs), are a pervasive feature of eukaryotic genomes and have been linked to phenotypic changes. Given their evolutionary relevance, having a neutral model to describe their evolution is essential. In this thesis, I report the development of SeDuS, a forward-in-time computer simulator of SD neutral evolution. Duplications are known to undergo a recombination process, termed interlocus gene conversion (IGC), which is known to affect the patterns of variation and linkage disequilibrium within and between duplicates. Here I describe the effects of overlapping crossover and IGC susceptible regions and of incorporating sequence similarity dependence of IGC. Furthermore, since SDs are potential targets of natural selection, I report potential confounding effects of IGC on test statistics when these are applied to duplications. Finally, I explore the possibility of combining results of different test statistics applied genome-wide to detect the presence of collapsed duplications

Modeling and simulation of interlocus gene conversion

Les regions duplicades del genoma, com ara les duplicacions de segments (SDs), són una característica comuna dels genomes eucariotes i han estat associades a canvis fenotípics. Donada la seva rellevància evolutiva, tenir un model neutre per descriure la seva evolució és essencial. En aquesta tesi, descric el desenvolupament de SeDuS, un simulador computacional endavant en el temps de l'evolució neutra de SDs. Les duplicacions estan sotmeses a un procés de recombinació, anomenat conversió gènica interlocus (IGC), que afecta els patrons de variació i de desequilibri de lligament dins i entre duplicacions. Aquí descric els efectes de sobreposar regions susceptibles de recombinació homòloga amb regions susceptibles d'IGC i d'incorporar dependència d'IGC en la similitud de seqüències. Addicionalment, ja que les SDs són objectius potencial de la selecció natural, informo sobre possibles alteracions a proves estadístiques quan aquestes s'apliquen a regions duplicades sotmeses a IGC. Finalment, exploro la possibilitat de combinar resultats de diferents proves estadístiques aplicades al llarg de tot el genoma per detectar la presència de duplicacions col·lapsades.Duplicated regions of the genome, such as Segmental Duplications (SDs), are a pervasive feature of eukaryotic genomes and have been linked to phenotypic changes. Given their evolutionary relevance, having a neutral model to describe their evolution is essential. In this thesis, I report the development of SeDuS, a forward-in-time computer simulator of SD neutral evolution. Duplications are known to undergo a recombination process, termed interlocus gene conversion (IGC), which is known to affect the patterns of variation and linkage disequilibrium within and between duplicates. Here I describe the effects of overlapping crossover and IGC susceptible regions and of incorporating sequence similarity dependence of IGC. Furthermore, since SDs are potential targets of natural selection, I report potential confounding effects of IGC on test statistics when these are applied to duplications. Finally, I explore the possibility of combining results of different test statistics applied genome-wide to detect the presence of collapsed duplications

Interplay of interlocus gene conversion and crossover in segmental duplications under a neutral scenario

Interlocus gene conversion is a major evolutionary force that drives the concerted evolution of duplicated genomic regions. Theoretical models successfully have addressed the effects of interlocus gene conversion and the importance of crossover in the evolutionary fate of gene families and duplications but have not considered complex recombination scenarios, such as the presence of hotspots. To study the interplay between interlocus gene conversion and crossover, we have developed a forward-time simulator that allows the exploration of a wide range of interlocus gene conversion rates under different crossover models. Using it, we have analyzed patterns of nucleotide variation and linkage disequilibrium within and between duplicate regions, focusing on a neutral scenario with constant population size and validating our results with the existing theoretical models. We show that the interaction of gene conversion and crossover is nontrivial and that the location of crossover junctions is a fundamental determinant of levels of variation and linkage disequilibrium in duplicated regions. We also show that if crossover activity between duplications is strong enough, recurrent interlocus gene conversion events can break linkage disequilibrium within duplicates. Given the complex nature of interlocus gene conversion and crossover, we provide a framework to explore their interplay to help increase knowledge on molecular evolution within segmental duplications under more complex scenarios, such as demographic changes or natural selection.This work has been supported by the Spanish National Institute of Bioinfomatics, a platform of the Instituto de Salud Carlos III (PT13/0001/0026), and the Spanish Government, Grant BFU2012-38236 to A.N.; by grants to D.H. from Conacyt and CSIC (Predoctoral JAE grant); and by the Fondo Europeo de Desarrollo Regional (FEDER) and the Fondo Social Europeo (FSE

SeDuS: segmental duplication simulator

SUMMARY: SeDuS is the first flexible and user-friendly forward-in-time simulator of patterns of molecular evolution within segmental duplications undergoing interlocus gene conversion and crossover. SeDuS introduces known features of interlocus gene conversion such as biased directionality and dependence on local sequence identity. Additionally, it includes aspects such as different selective pressures acting upon copy number and flexible crossover distributions. A graphical user interface allows fast fine-tuning of relevant parameters and straightforward real-time analysis of the evolution of duplicates. AVAILABILITY AND IMPLEMENTATION: SeDuS is implemented in C++ and can be run via command line or through a graphical user interface developed using Qt C++. Source code and binary executables for Linux, OS X and Windows are freely available at www.biologiaevolutiva.org/sedus/. A tutorial with a detailed description of implementation, parameters and output files is available online.This work was supported by the Spanish National Institute of Bioinformatics, a platform of the Instituto de Salud Carlos III (PT13/0001/0026), and the Spanish Government, Grant BFU2012-38236 to A.N.; by grants to D.A.H. from Conacyt and CSIC (JAE Predoc); by the Fondo Europeo de Desarrollo Regional (FEDER) and the Fondo Social Europeo (FSE) and by a grant to M.B.-V. from AGAUR (FI – DGR 2015

SeDuS: segmental duplication simulator

SUMMARY: SeDuS is the first flexible and user-friendly forward-in-time simulator of patterns of molecular evolution within segmental duplications undergoing interlocus gene conversion and crossover. SeDuS introduces known features of interlocus gene conversion such as biased directionality and dependence on local sequence identity. Additionally, it includes aspects such as different selective pressures acting upon copy number and flexible crossover distributions. A graphical user interface allows fast fine-tuning of relevant parameters and straightforward real-time analysis of the evolution of duplicates. AVAILABILITY AND IMPLEMENTATION: SeDuS is implemented in C++ and can be run via command line or through a graphical user interface developed using Qt C++. Source code and binary executables for Linux, OS X and Windows are freely available at www.biologiaevolutiva.org/sedus/. A tutorial with a detailed description of implementation, parameters and output files is available online.This work was supported by the Spanish National Institute of Bioinformatics, a platform of the Instituto de Salud Carlos III (PT13/0001/0026), and the Spanish Government, Grant BFU2012-38236 to A.N.; by grants to D.A.H. from Conacyt and CSIC (JAE Predoc); by the Fondo Europeo de Desarrollo Regional (FEDER) and the Fondo Social Europeo (FSE) and by a grant to M.B.-V. from AGAUR (FI – DGR 2015

Copy number variants and fixed duplications among 198 rhesus macaques (Macaca mulatta)

The rhesus macaque is an abundant species of Old World monkeys and a valuable model organism for biomedical research due to its close phylogenetic relationship to humans. Copy number variation is one of the main sources of genomic diversity within and between species and a widely recognized cause of inter-individual differences in disease risk. However, copy number differences among rhesus macaques and between the human and macaque genomes, as well as the relevance of this diversity to research involving this nonhuman primate, remain understudied. Here we present a high-resolution map of sequence copy number for the rhesus macaque genome constructed from a dataset of 198 individuals. Our results show that about one-eighth of the rhesus macaque reference genome is composed of recently duplicated regions, either copy number variable regions or fixed duplications. Comparison with human genomic copy number maps based on previously published data shows that, despite overall similarities in the genome-wide distribution of these regions, there are specific differences at the chromosome level. Some of these create differences in the copy number profile between human disease genes and their rhesus macaque orthologs. Our results highlight the importance of addressing the number of copies of target genes in the design of experiments and cautions against human-centered assumptions in research conducted with model organisms. Overall, we present a genome-wide copy number map from a large sample of rhesus macaque individuals representing an important novel contribution concerning the evolution of copy number in primate genomes.This work was supported in part by NIH grants R24-OD011173 to J.R., UM1-HG008898 to R.A.H., AGAUR (FI – DGR 2015) to M.B.-V., BFU2017-86471-P (MINECO/FEDER, UE), Howard Hughes International Early Career, Obra Social "La Caixa" and Secretaria d’Universitats i Recerca and CERCA Programme del Departament d’Economia i Coneixement de la Generalitat de Catalunya (GRC 2017 SGR 880) to T.M.B. D.J. is supported by Juan de la Cierva fellowship (FJCI-2016-29558) from MICINN. In addition, we wish to acknowledge NIH grant R24-OD010962 to J. Capitanio which supported the development of the Biobehavioral Assessment resource and associated DNA samples from California NPRC rhesus macaques. We also acknowledge NIH grant support to specific National Primate Research Centers: California NPRC (OD011107) and Oregon NPRC (OD011092 and OD021324). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript