Unique roles of vaginal Megasphaera phylotypes in reproductive health

The composition of the human vaginal microbiome has been extensively studied and is known to influence reproductive health. However, the functional roles of individual taxa and their contributions to negative health outcomes have yet to be well characterized. Here, we examine two vaginal bacterial taxa grouped within the genus Megasphaera that have been previously associated with bacterial vaginosis (BV) and pregnancy complications. Phylogenetic analyses support the classification of these taxa as two distinct species. These two phylotypes, Megasphaera phylotype 1 (MP1) and Megasphaera phylotype 2 (MP2), differ in genomic structure and metabolic potential, suggestive of differential roles within the vaginal environment. Further, these vaginal taxa show evidence of genome reduction and changes in DNA base composition, which may be common features of host dependence and/or adaptation to the vaginal environment. In a cohort of 3870 women, we observed that MP1 has a stronger positive association with bacterial vaginosis whereas MP2 was positively associated with trichomoniasis. MP1, in contrast to MP2 and other common BV-associated organisms, was not significantly excluded in pregnancy. In a cohort of 52 pregnant women, MP1 was both present and transcriptionally active in 75.4 % of vaginal samples. Conversely, MP2 was largely absent in the pregnant cohort. This study provides insight into the evolutionary history, genomic potential and predicted functional role of two clinically relevant vaginal microbial taxa.

Distinct nucleotide patterns among three subgenomes of bread wheat and their potential origins during domestication after allopolyploidization

Background The speciation and fast global domestication of bread wheat have made a great impact on three subgenomes of bread wheat. DNA base composition is an essential genome feature, which follows the individual-strand base equality rule and [AT]-increase pattern at the genome, chromosome, and polymorphic site levels among thousands of species. Systematic analyses on base compositions of bread wheat and its wild progenitors could facilitate further understanding of the evolutionary pattern of genome/subgenome-wide base composition of allopolyploid species and its potential causes. Results Genome/subgenome-wide base-composition patterns were investigated by using the data of polymorphic site in 93 accessions from worldwide populations of bread wheat, its diploid and tetraploid progenitors, and their corresponding reference genome sequences. Individual-strand base equality rule and [AT]-increase pattern remain in recently formed hexaploid species bread wheat at the genome, subgenome, chromosome, and polymorphic site levels. However, D subgenome showed the fastest [AT]-increase across polymorphic site from Aegilops tauschii to bread wheat than that on A and B subgenomes from wild emmer to bread wheat. The fastest [AT]-increase could be detected almost all chromosome windows on D subgenome, suggesting different mechanisms between D and other two subgenomes. Interestingly, the [AT]-increase is mainly contributed by intergenic regions at non-selective sweeps, especially the fastest [AT]-increase of D subgenome. Further transition frequency and sequence context analysis indicated that three subgenomes shared same mutation type, but D subgenome owns the highest mutation rate on high-frequency mutation type. The highest mutation rate on D subgenome was further confirmed by using a bread-wheat-private SNP set. The exploration of loci/genes related to the [AT] value of D subgenome suggests the fastest [AT]-increase of D subgenome could be involved in DNA repair systems distributed on three subgenomes of bread wheat. Conclusions The highest mutation rate is detected on D subgenome of bread wheat during domestication after allopolyploidization, leading to the fastest [AT]-increase pattern of D subgenome. The phenomenon may come from the joint action of multiple repair systems inherited from its wild progenitors.

A predictable conserved DNA base composition signature defines human core DNA replication origins

DNA replication initiates from multiple genomic locations called replication origins. In metazoa, DNA sequence elements involved in origin specification remain elusive. Here, we examine pluripotent, primary, differentiating, and immortalized human cells, and demonstrate that a class of origins, termed core origins, is shared by different cell types and host ~80% of all DNA replication initiation events in any cell population. We detect a shared G-rich DNA sequence signature that coincides with most core origins in both human and mouse genomes. Transcription and G-rich elements can independently associate with replication origin activity. Computational algorithms show that core origins can be predicted, based solely on DNA sequence patterns but not on consensus motifs. Our results demonstrate that, despite an attributed stochasticity, core origins are chosen from a limited pool of genomic regions. Immortalization through oncogenic gene expression, but not normal cellular differentiation, results in increased stochastic firing from heterochromatin and decreased origin density at TAD borders.

Unique roles of vaginal Megasphaera phylotypes in reproductive health

ABSTRACTThe composition of the human vaginal microbiome has been extensively studied and is known to influence reproductive health. However, the functional roles of individual taxa and their contributions to negative health outcomes have yet to be well characterized. Here, we examine two vaginal bacterial taxa grouped within the genus Megasphaera that have been previously associated with bacterial vaginosis (BV) and pregnancy complications. Phylogenetic analyses support the classification of these taxa as two distinct species. These two phylotypes, Megasphaera phylotype 1 (MP1) and Megasphaera phylotype 2 (MP2), differ in genomic structure and metabolic potential, suggestive of differential roles within the vaginal environment. Further, these vaginal taxa show evidence of genome reduction and changes in DNA base composition, which may be common features of host dependence and/or adaptation to the vaginal environment. In a cohort of 3,870 women, we observed that MP1 has a stronger positive association with bacterial vaginosis whereas MP2 was positively associated with trichomoniasis. MP1, in contrast to MP2 and other common BV-associated organisms, was not significantly excluded in pregnancy. In a cohort of 52 pregnant women, MP1 was both present and transcriptionally active in 75.4% of vaginal samples. Conversely, MP2 was largely absent in the pregnant cohort. This study provides insight into the evolutionary history, genomic potential and predicted functional role of two clinically relevant vaginal microbial taxa.

SALL4 controls cell fate in response to DNA base composition

SummaryMammalian genomes contain long domains with distinct average compositions of A/T versus G/C base pairs. In a screen for proteins that might interpret base composition by binding to AT-rich motifs, we identified the stem cell factor SALL4 which contains multiple zinc-fingers. Mutation of the domain responsible for AT binding drastically reduced SALL4 genome occupancy and prematurely up-regulated genes in proportion to their AT content. Inactivation of this single AT-binding zinc-finger cluster mimicked defects seen in Sall4-null cells, including precocious differentiation of embryonic stem cells and embryonic lethality in mice. In contrast, deletion of two other zinc-finger clusters was phenotypically neutral. Our data indicate that loss of pluripotency is triggered by down-regulation of SALL4, leading to de-repression of a set of AT-rich genes that promotes neuronal differentiation. We conclude that base composition is not merely a passive by-product of genome evolution, but constitutes a signal that aids control of cell fate.

DNA sequence-dependent chromatin architecture and nuclear hubs formation

In this study, by exploring chromatin conformation capture data, we show that the nuclear segregation of Topologically Associated Domains (TADs) is contributed by DNA sequence composition. GC-peaks and valleys of TADs strongly influence interchromosomal interactions and chromatin 3D structure. To gain insight on the compositional and functional constraints associated with chromatin interactions and TADs formation, we analysed intra-TAD and intra-loop GC variations. This led to the identification of clear GC-gradients, along which, the density of genes, super-enhancers, transcriptional activity, and CTCF binding sites occupancy co-vary non-randomly. Further, the analysis of DNA base composition of nucleolar aggregates and nuclear speckles showed strong sequence-dependant effects. We conjecture that dynamic DNA binding affinity and flexibility underlay the emergence of chromatin condensates, their growth is likely promoted in mechanically soft regions (GC-rich) of the lowest chromatin and nucleosome densities. As a practical perspective, the strong linear association between sequence composition and interchromosomal contacts can help define consensus chromatin interactions, which in turn may be used to study alternative states of chromatin architecture.

Selective advantages favour high genomic AT-contents in intracellular elements

Extrachromosomal genetic elements generally exhibit increased AT-contents relative to their hosts’ DNA. The AT-bias of endosymbiotic genomes is commonly explained by neutral evolutionary processes. Here we show experimentally that an increased AT-content of host-dependent elements can be selectively favoured on the host level. Manipulating the nucleotide composition of bacterial cells by introducing A+T-or G+C-rich plasmids, we demonstrate that cells containing GC-rich plasmids are less fit than cells containing AT-rich plasmids. Moreover, the cost of GC-rich elements could be compensated by providing G+C-, but not A+T-precursors, thus linking the observed fitness effects to the cytoplasmic availability of nucleotides. Our work identifies selection as a strong evolutionary force that drives the genomes of intracellular genetic elements toward higher A+T contents.Author SummaryGenomes of endosymbiotic bacteria are commonly more AT-rich than the ones of their free-living relatives. Interestingly, genomes of other intracellular elements like plasmids or bacteriophages also tend to be richer in AT than the genomes of their hosts. The AT-bias of endosymbiotic genomes is commonly explained by neutral evolutionary processes. However, since A+T nucleotides are both more abundant and energetically less expensive than G+C nucleotides, an alternative explanation is that selective advantages drive the nucleotide composition of intracellular elements. Here we provide strong experimental evidence that intracellular elements, whose genome is more AT-rich than the genome of the host, are selectively favored on the host level. Thus, our results emphasize the importance of selection for shaping the DNA base composition of extrachromosomal genetic elements.