Elena de la Casa-Esperón

Natural selection and the function of genome imprinting: beyond the silenced minority

Most hypotheses of the evolutionary origin of genome imprinting assume that the biochemical character on which natural selection has operated is the expression of the allele from only one parent at an affected locus. We propose an alternative - that natural selection has operated on differences in the chromatin structure of maternal and paternal chromosomes to facilitate pairing during meiosis and to maintain the distinction between homologues during DNA repair and recombination in both meiotic and mitotic cells. Maintenance of differences in chromatin structure in somatic cells can sometimes result in the transcription of only one allele at a locus. This pattern of transcription might be selected, in some instances, for reasons that are unrelated to the original establishment of the imprint. Differences in the chromatin structure of homologous chromosomes might facilitate pairing and recombination during meiosis, but some such differences could also result in non-random segregation of chromosomes, leading to parental-origin-dependent transmission ratio distortion. This hypothesis unites two broad classes of parental origin effects under a single selective force and identifies a single substrate through which Mendels first and second laws might be violated.

Evolution of the Schlafen genes, a gene family associated with embryonic lethality, meiotic drive, immune processes and orthopoxvirus virulence

Genes of the Schlafen family, first discovered in mouse, are expressed in hematopoietic cells and are involved in immune processes. Previous results showed that they are candidate genes for two major phenomena: meiotic drive and embryonic lethality (DDK syndrome). However, these genes remain poorly understood, mostly due to the limitations imposed by their similarity, close location and the potential functional redundancy of the gene family members. Here we use genomic and phylogenetic studies to investigate the evolution and role of this family of genes. Our results show that the Schlafen family is widely distributed in mammals, where we recognize four major clades that experienced lineage-specific expansions or contractions in various orders, including primates and rodents. In addition, we identified members of the Schlafen family in Chondrichthyes and Amphibia, indicating an ancient origin of these genes. We find evidence that positive selection has acted on many Schlafen genes. Moreover, our analyses indicate that a member of the Schlafen family was horizontally transferred from murine rodents to orthopoxviruses, where it is hypothesized to play a role in allowing the virus to survive host immune defense mechanisms. The functional relevance of the viral Schlafen sequences is further underscored by our finding that they are evolving under purifying selection. This is of particular importance, since orthopoxviruses infect mammals and include variola, the causative agent of smallpox, and monkeypox, an emerging virus of great concern for human health.

The Paternal Gene of the DDK Syndrome Maps to the Schlafen Gene Cluster on Mouse Chromosome 11

The DDK syndrome is an early embryonic lethal phenotype observed in crosses between females of the DDK inbred mouse strain and many non-DDK males. Lethality results from an incompatibility between a maternal DDK factor and a non-DDK paternal gene, both of which have been mapped to the Ovum mutant (Om) locus on mouse chromosome 11. Here we define a 465-kb candidate interval for the paternal gene by recombinant progeny testing. To further refine the candidate interval we determined whether males from 17 classical and wild-derived inbred strains are interfertile with DDK females. We conclude that the incompatible paternal allele arose in the Mus musculus domesticus lineage and that incompatible strains should share a common haplotype spanning the paternal gene. We tested for association between paternal allele compatibility/incompatibility and 167 genetic variants located in the candidate interval. Two diallelic SNPs, located in the Schlafen gene cluster, are completely predictive of the polar-lethal phenotype. These SNPs also predict the compatible or incompatible status of males of five additional strains.

The maternal DDK syndrome phenotype is determined by modifier genes that are not linked to Om

Abstract. The DDK syndrome is a polar, early embryonic lethal phenotype caused by incompatibility between a maternal factor of DDK origin and a paternal gene of non-DDK origin. Both maternal factor and paternal gene have been mapped to the Om locus on mouse Chromosome (Chr) 11. The paternal contribution to the syndrome has been shown to segregate as a single locus. Although the inheritance of the maternal contribution has not been characterized in depth, it as been assumed to segregate as a single locus. We have now characterized the segregation of the DDK fertility phenotype in over 240 females. Our results demonstrate that females require at least one DDK allele at Om to manifest the syndrome. However, the DDK syndrome inter-strain cross-fertility phenotype of heterozygous females is highly variable and spans the gamut from completely infertile to completely fertile. Our results indicate that this phenotypic variability has a genetic basis and that the modifiers of the DDK syndrome segregate independently of Om.

Horizontal Transfer and the Evolution of Host-Pathogen Interactions

Horizontal gene transfer has been long known in viruses and prokaryotes, but its importance in eukaryotes has been only acknowledged recently. Close contact between organisms, as it occurs between pathogens and their hosts, facilitates the occurrence of DNA transfer events. Once inserted in a foreign genome, DNA sequences have sometimes been coopted by pathogens to improve their survival or infectivity, or by hosts to protect themselves against the harm of pathogens. Hence, horizontal transfer constitutes a source of novel sequences that can be adopted to change the host-pathogen interactions. Therefore, horizontal transfer can have an important impact on the coevolution of pathogens and their hosts.Horizontal gene transfer has been long known in viruses and prokaryotes, but its importance in eukaryotes has been only acknowledged recently. Close contact between organisms, as it occurs between pathogens and their hosts, facilitates the occurrence of DNA transfer events. Once inserted in a foreign genome, DNA sequences have sometimes been coopted by pathogens to improve their survival or infectivity, or by hosts to protect themselves against the harm of pathogens. Hence, horizontal transfer constitutes a source of novel sequences that can be adopted to change the host-pathogen interactions. Therefore, horizontal transfer can have an important impact on the coevolution of pathogens and their hosts.

Recapitulation of the Ovum Mutant (Om) Phenotype and Loss of Om Locus Polarity in Cloned Mouse Embryos

Abstract The ovum mutant (Om) locus in mice affects early interactions between sperm and egg that in turn affect viability of embryos beyond the morula stage. Crosses of DDK females to males of many other inbred strains are 95% lethal around the morula stage, whereas reciprocal crosses are fully viable. Available data indicate that the early lethality is the result of an interaction between a factor in the ooplasm and the paternal genome. In this study, we examined whether this lethal interaction would likewise occur in cloned embryos produced by somatic cell nuclear transfer. We find that the Om effect is recapitulated but that the parental origin effect at the Om locus is no longer evident in cloned embryos.

Nonmammalian Parent-of-Origin Effects

Chromosomes acquire different epigenetic marks during oogenesis and spermatogenesis. After fertilization, if retained and selected, these differences may result in imprinting effects. Rather than being an oddity, imprinting effects have been found in many sexually reproducing organisms. Interestingly, imprinting can result in disparate effects under different selective forces. At the same time, epigenetic mechanisms and selective pressures shared by sexually reproducing organisms could underlie common imprinting effects. Large-scale studies are revealing that parent-of-origin effects are more common than previously thought and supporting the important contribution of imprinting to many traits and diseases.Chromosomes acquire different epigenetic marks during oogenesis and spermatogenesis. After fertilization, if retained and selected, these differences may result in imprinting effects. Rather than being an oddity, imprinting effects have been found in many sexually reproducing organisms. Interestingly, imprinting can result in disparate effects under different selective forces. At the same time, epigenetic mechanisms and selective pressures shared by sexually reproducing organisms could underlie common imprinting effects. Large-scale studies are revealing that parent-of-origin effects are more common than previously thought and supporting the important contribution of imprinting to many traits and diseases.

From mammals to viruses: the Schlafen genes in developmental, proliferative and immune processes

Abstract The Schlafen genes have been associated with proliferation control and with several differentiation processes, as well as with disparate phenotypes such as immune response, embryonic lethality and meiotic drive. They constitute a gene family with widespread distribution in mammals, where they are expressed in several tissues, predominantly those of the immune system. Moreover, horizontal transfer of these genes to orthopoxviruses suggests a role of the viral Schlafens in evasion to the host immune response. The expression and functional studies of this gene family will be reviewed under the prism of their evolution and diversification, the challenges they pose and the future avenues of research.

Intronic parent-of-origin dependent differential methylation at the Actn1 gene is conserved in rodents but is not associated with imprinted expression.

Parent-of-origin differential DNA methylation has been associated with regulation of the preferential expression of paternal or maternal alleles of imprinted genes. Based on this association, recent studies have searched for parent-of-origin dependent differentially methylated regions in order to identify new imprinted genes in their vicinity. In a previous genome-wide analysis of mouse brain DNA methylation, we found a novel differentially methylated region in a CpG island located in the last intron of the alpha 1 Actinin (Actn1) gene. In this region, preferential methylation of the maternal allele was observed; however, there were no reports of imprinted expression of Actn1. Therefore, we have tested if differential methylation of this region is common to other tissues and species and affects the expression of Actn1. We have found that Actn1 differential methylation occurs in diverse mouse tissues. Moreover, it is also present in other murine rodents (rat), but not in the orthologous human region. In contrast, we have found no indication of an imprinted effect on gene expression of Actn1 in mice: expression is always biallelic regardless of sex, tissue type, developmental stage or isoform. Therefore, we have identified a novel parent-of-origin dependent differentially methylated region that has no apparent association with imprinted expression of the closest genes. Our findings sound a cautionary note to genome-wide searches on the use of differentially methylated regions for the identification of imprinted genes and suggest that parent-of-origin dependent differential methylation might be conserved for functions other that the control of imprinted expression.