Hypermutability of genes in Homo sapiens due to the hosting of long mono-SSR.

Simple sequence repeats (SSRs) are very common short repeats in eukaryotic genomes. "Long" SSRs are considered "hypermutable" sequences because they exhibit a high rate of expansion and contraction. Because they are potentially deleterious, long SSRs tend to be uncommon in coding sequences. However, several genes contain long SSRs in their exonic sequences. Here, we identify 1,291 human genes that host a mononucleotide SSR long enough to be prone to expansion or contraction, being called hypermutable hereafter. On the basis of Gene Ontology annotations, we show that only a restricted number of functions are overrepresented among those hypermutable genes including cell cycle and maintenance of DNA integrity. Using a probabilistic model, we show that genes involved in these functions are expected to host long SSRs because they tend to be long and/or are biased in nucleotide composition. Finally, we show that for almost all functions we observe fewer hypermutable sequences than expected under a neutral model. There are however interesting exceptions, for example, genes involved in protein and RNA transport, as well as meiosis and mismatch repair functions that have as many hypermutable genes as expected under neutrality. Conversely, there are functions (e.g., collagen-related genes) where hypermutable genes are more often avoided than in other functions. Our results show that, even though several functions harbor unusually long SSR in their exons, long SSRs are deleterious sequences in almost all functions and are removed by purifying selection. The strength of this purifying selection however greatly varies from function to function. We discuss possible explanations for this intriguing result.

Lgals6, a 2-million-year-old gene in mice: a case of positive Darwinian selection and presence/absence polymorphism.

Duplications of genes are widely considered to be a driving force in the evolutionary process. The fate of such duplicated genes (paralogs) depends mainly on the early stages of their evolution. Therefore, the study of duplications that have already started to diverge is useful to better understand their evolution. We present here the example of a 2-million-year-old segmental duplication at the origin of the Lgals4 and Lgals6 genes in the mouse genome. We analyzed the distribution of these genes in samples from 110 wild individuals and wild-derived inbred strains belonging to eight mouse species from Mus (Coelomys) pahari to M. musculus and 28 laboratory strains. Using a maximum-likelihood method, we show that the sequence of the Lgals6 gene has evolved under the influence of strong positive selection that is likely to result in its neofunctionalization. Surprisingly, despite this selection pressure, the Lgals6 gene is present in some mouse species, but not all. Furthermore, even within the species and populations where it is present, the Lgals6 gene is never fixed. To explain this paradox, we propose different hypotheses such as balanced selection and neutral retention of ancient polymophism and we discuss this unexpected result with regard to known galectin properties and response to infections by pathogens.

Associations between inverted repeats and the structural evolution of bacterial genomes.

The stability of the structure of bacterial genomes is challenged by recombination events. Since major rearrangements (i.e., inversions) are thought to frequently operate by homologous recombination between inverted repeats, we analyzed the presence and distribution of such repeats in bacterial genomes and their relation to the conservation of chromosomal structure. First, we show that there is a strong under-representation of inverted repeats, relative to direct repeats, in most chromosomes, especially among the ones regarded as most stable. Second, we show that the avoidance of repeats is frequently associated with the stability of the genomes. Closely related genomes reported to differ in terms of stability are also found to differ in the number of inverted repeats. Third, when using replication strand bias as a proxy for genome stability, we find a significant negative correlation between this strand bias and the abundance of inverted repeats. Fourth, when measuring the recombining potential of inverted repeats and their eventual impact on different features of the chromosomal structure, we observe a tendency of repeats to be located in the chromosome in such a way that rearrangements produce a smaller strand switch and smaller asymmetries than expected by chance. Finally, we discuss the limitations of our analysis and the influence of factors such as the nature of repeats, e.g., transposases, or the differences in the recombination machinery among bacteria. These results shed light on the challenges imposed on the genome structure by the presence of inverted repeats.

Evolution of coding microsatellites in primate genomes.

Microsatellites (SSRs) are highly susceptible to expansions and contractions. When located in a coding sequence, the insertion or the deletion of a single unit for a mono-, di-, tetra-, or penta(nucleotide)-SSR creates a frameshift. As a consequence, one would expect to find only very few of these SSRs in coding sequences because of their strong deleterious potential. Unexpectedly, genomes contain many coding SSRs of all types. Here, we report on a study of their evolution in a phylogenetic context using the genomes of four primates: human, chimpanzee, orangutan, and macaque. In a set of 5,015 orthologous genes unambiguously aligned among the four species, we show that, except for tri- and hexa-SSRs, for which insertions and deletions are frequently observed, SSRs in coding regions evolve mainly by substitutions. We show that the rate of substitution in all types of coding SSRs is typically two times higher than in the rest of coding sequences. Additionally, we observe that although numerous coding SSRs are created and lost by substitutions in the lineages, their numbers remain constant. This last observation suggests that the coding SSRs have reached equilibrium. We hypothesize that this equilibrium involves a combination of mutation, drift, and selection. We thus estimated the fitness cost of mono-SSRs and show that it increases with the number of units. We finally show that the cost of coding mono-SSRs greatly varies from function to function, suggesting that the strength of the selection that acts against them can be correlated to gene functions.

Expression patterns suggest that despite considerable functional redundancy, galectin-4 and -6 play distinct roles in normal and damaged mouse digestive tract.

The galectin-4 protein is mostly expressed in the digestive tract and is associated with lipid raft stabilization, protein apical trafficking, wound healing, and inflammation. While most mammalian species, including humans, have a single Lgals4 gene, some mice have two paralogues: Lgals4 and Lgals6. So far, their significant similarities have hindered the analysis of their respective expression and function. We took advantage of two antibodies that discriminate between the galectin-4 and galectin-6 proteins to document their patterns of expression in the normal and the dextran sodium sulfate (DSS)-damaged digestive tract in the mouse. In the normal digestive tract, their pattern of expression from tongue to colon is quite similar, which suggests functional redundancy. However, the presence of galectin-4, but not galectin-6, in the lamina propria of the DSS-damaged colon, its association with luminal colonic bacteria, and differences in subcellular localization of these proteins suggest that they also have distinct roles in the normal and the damaged mouse digestive tract. Our results provide a rare example of ancestral and derived functions evolving after tandem gene duplication.