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

Collapsed duplications? What to expect amd what to look for

Trabajo presentado en la Annual Meeting of the Society for Molecular Biology and Evolution (SMBE 2015), celebrada en Viena del 12 al 16 de julio de 2015.Segmental duplications (SDs), defined as >1 kb regions of the genome with >90% similarity between copies, are an ubiquitous characteristic of eukaryotic genomes. Their evolution is known to be complex for several reasons: first, because SDs undergo interlocus gene conversion (IGC), a possible source of variation; second, reduced selective pressures may allow variants to increase in frequency more easily; and third, SDs are mediators of NAHR and formation of CNVs, which in turn are associated with susceptibility to disease. SD detection and characterization has been recognized as being of great importance. Ironically, most of the efforts dedicated to these tasks are aimed at eliminating SDs from genome-wide scans in order to avoid spurious signals coming from duplicated regions. Given that SDs are likely to be possible targets of natural selection, it would seem natural to look for SNPs under selection in duplications. However, to date there is no adequate test to detect selection in duplications precisely because none takes into account their complex evolution. Furthermore, the effect of applying neutrality tests to collapsed duplications is mostly ignored.N

To convert or not to convert: homology requirements for meiotic gene conversion

Trabajo presentado en la Annual Meeting of the Society for Molecular Biology and Evolution (SMBE 2016), celebrada en Gold Coast (Queensland, Australia) del 3 al 7 de julio de 2016.Gene conversion is a recombination mechanism in which information is unilaterally transferred from one DNA duplex to another. During meiosis, double-strand-breaks might be repaired by different mechanisms of homologous recombination such as single-strand a nnealing, double-strand-break repair or synthesis-dependent strand annealing. The latter is thought to be the cause of the large majority of meiotic gene conversion events and extensive experimental work has been performed to understand the precise molecular mechanisms and molecules involved in this pathway. For gene conversion to occur, there needs to be a high degree of homology between the invading strand of DNA and the invaded donor strand from which complementary DNA will be synthesized. In fact, there seems to be a minimal efficient processing segment, that is, a 100% identity tract between donor and receptor strands, necessary for the gene conversion process to initiate. Further evidence indicates that there might also be an identity requirement for the resolution of the repair pathway. Additionally, experiments performed in yeast suggest that the mismatch-repair machinery is not only involved in the repair of heteroduplexes formed during meiosis, but is also responsible for ensuring homologous recombination. In light of this new evidence, we present a complete model of gene conversion that includes identity requirements and mismatch-repair. Results from our simulations suggest that the length of gene conversion tracts are a consequence of the action of these mechanisms and are consistent with the synthesis-dependent strand annealing model for gene conversion.N

Exploring the role of segmental duplications in the phenotypic differences between humans and other great apes

Trabajo presentado en la Annual Meeting of the Society for Molecular Biology and Evolution (SMBE 2016), celebrada en Gold Coast (Queensland, Australia) del 3 al 7 de julio de 2016.Duplicated sequences are one of the main sources of variation in eukaryotic genomes and are known to give rise to new genes and functions. Large (1-200 Kb) and highly identical (≥90%) duplications named segmental duplications (SDs) had a particularly important role in the evolution of African great apes (including humans). SDs compose around 5% of the human genome and are shared with the other African great apes more than what one would expect given their nucleotide divergence. In other words, the rate at which SDs appeared was specially high in the Africa n great ape ancestor, after the split from orangutans. SDs that arose during that period are strong candidates to account for part of the phenotypic differences between these species that point-mutations cannot explain. Here, we use inferences of copy-numb er along great ape genomes to classify human SDs according to the period of time in which they appeared. We identify, first, human specific SDs, second, human SDs that appeared during the burst of duplications and, finally, older human SDs that are shared with all great apes, including orangutans. We explore the characteristics of these three groups of duplications trying to understand both the causes of the increase in duplication rate during the time of the African great ape ancestor and its phenotypic consequences. We also differentiate between tandem, non-tandem intrachromosomal and interchromosomal SDs. We find differences in length, gene content and Alu content between these groups. These differences point towards different duplication mechanisms of the SDs in these three types of duplications. Moreover, we use sequence similarity inside and outside shared exons in duplications to identify candidate signals of selection in human SDs.N

Genetic innovation through duplication in humans and Great Apes

Trabajo presentado en la Annual Meeting of the Society for Molecular Biology and Evolution (SMBE 2015), celebrada en Viena del 12 al 16 de julio de 2015.Duplications are a very important feature of eukaryotic genomes and an essential source of genetic innovation. Large (1-200 Kb) and highly identical (≥90%) duplications, known as segmental duplications (SDs), conform around 5% of the human genome and can include several functional elements. Despite their fundamental role in the generation of novel genetic material, most of the mechanisms underlying the molecular evolution of nucleotide sequences of duplicated regions are still not well understood. Two outstanding gaps in our knowledge are the way in which these regions undergo concerted evolution and the non-standard signature that natural selection may leave on their patterns of variation. Under neutrality, differences between duplicates are expected to follow a stochastic distribution along the duplicated region. Analyzing Great Ape and human genomes, we have identified some cases of coincident patterns of divergence between SD copies across species, which may be indicative of a common selective pressure acting independently on the same pair of SDs on different branches. Furthermore, SDs suffer a decay of identity around their edges with time. By analyzing the flanking regions of currently annotated SDs, we have been able to identify regions that had once undergone concerted evolution and have now become single-copy regions of new formation and possible novel function. We show that duplication-specific approaches allow for the identification of regions of genetic innovation that may have been under selective pressure during recent human evolution and have contributed to a better understanding of the mechanisms through which new genes and functions arise within SDs.N

Criticality, adaptability and early-warning signals in time series in a discrete quasispecies model

Complex systems from different fields of knowledge often do not allow a mathematical description or modeling, because of their intricate structure composed of numerous interacting components. As an alternative approach, it is possible to study the way in which observables associated with the system fluctuate in time. These time series may provide valuable information about the underlying dynamics. It has been suggested that complex dynamic systems, ranging from ecosystems to financial markets and the climate, produce generic early-warning signals at the >tipping points,> where they announce a sudden shift toward a different dynamical regime, such as a population extinction, a systemic market crash, or abrupt shifts in the weather. On the other hand, the framework of Self-Organized Criticality (SOC), suggests that some complex systems, such as life itself, may spontaneously converge toward a critical point. As a particular example, the quasispecies model suggests that RNA viruses self-organize their mutation rate near the error-catastrophe threshold, where robustness and evolvability are balanced in such a way that survival is optimized. In this paper, we study the time series associated to a classical discrete quasispecies model for different mutation rates, and identify early-warning signals for critical mutation rates near the error-catastrophe threshold, such as irregularities in the kurtosis and a significant increase in the autocorrelation range, reminiscent of 1/f noise. In the present context, we find that the early-warning signals, rather than broadcasting the collapse of the system, are the fingerprint of survival optimization. © 2013 Higher Education Press and Springer-Verlag Berlin Heidelberg.We acknowledge financial support from CONACYT (grants CB-2011-01-167441, CB-2010-01-155663 and I010/266/2011/C-410-11) and PAPIIT-DGAPA (grant IN114411). This work was partly funded by the project FP7-PEOPLE-2009-IRSES-247541-MATSI-QEL. R.F. acknowledges financial support from the Instituto Nacional de Geriatría (project DI-PI-002/2012).Peer Reviewe

Interplay of gene conversion and crossover in the molecular evolution of multigene families

Trabajo presentado en la 4th Meeting of the Spanish Society of the Evolutionary Biology (SESBE 2013) celebrada en Barcelona del 27 al 29 de noviembre de 2013.N