The gene products that drive early development are critical for setting up developmental trajectories in all animals. The earliest stages of development are fueled by maternally provided mRNAs until the zygote can take over transcription of its own genome. In early development, both maternally deposited and zygotically transcribed gene products have been well characterized in model systems. Previously, we demonstrated that across the genus Drosophila, maternal and zygotic mRNAs are largely conserved but also showed a surprising amount of change across species, with more differences evolving at the zygotic stage than the maternal stage. In this study, we use comparative methods to elucidate the regulatory mechanisms underlying maternal deposition and zygotic transcription across species. Through motif analysis, we discovered considerable conservation of regulatory mechanisms associated with maternal transcription, as compared to zygotic transcription. We also found that the regulatory mechanisms active in the maternal and zygotic genomes are quite different. For maternally deposited genes, we uncovered many signals that are consistent with transcriptional regulation at the level of chromatin state through factors enriched in the ovary, rather than precisely controlled gene-specific factors. For genes expressed only by the zygotic genome, we found evidence for previously identified regulators such as Zelda and GAGA-factor, with multiple analyses pointing toward gene-specific regulation. The observed mechanisms of regulation are consistent with what is known about regulation in these two genomes: during oogenesis, the maternal genome is optimized to quickly produce a large volume of transcripts to provide to the oocyte; after zygotic genome activation, mechanisms are employed to activate transcription of specific genes in a spatiotemporally precise manner. Thus the genetic architecture of the maternal and zygotic genomes, and the specific requirements for the transcripts present at each stage of embryogenesis, determine the regulatory mechanisms responsible for transcripts present at these stages.

1The gene products that drive early development are critical for setting up developmental trajectories in 2 all animals. The earliest stages of development are fueled by maternally provided mRNAs until the 3 zygote can take over transcription of its own genome. In early development, both maternally deposited 4 and zygotically transcribed gene products have been well characterized in model systems. Previously, 5 we demonstrated that across the genus Drosophila, maternal and zygotic mRNAs are largely conserved 6 but also showed a surprising amount of change across species, with more differences evolving at the 7 zygotic stage than the maternal stage. In this study, we use comparative methods to elucidate the 8 regulatory mechanisms underlying maternal deposition and zygotic transcription across species. 9Through motif analysis, we discovered considerable conservation of regulatory mechanisms associated 10 with maternal transcription, as compared to zygotic transcription. We also found that the regulatory 11 mechanisms active in the two genomes, maternal versus zygotic, are quite different. For maternally 12 deposited genes, we uncovered many signals that are consistent with transcriptional regulation through 13 control at the level of chromatin through factors enriched in the ovary, rather than precisely controlled 14 gene-specific factors. For genes expressed only by the zygotic genome, we found evidence for previously 15 identified regulators such as Zelda and GAGA-factor, with multiple analyses pointing toward gene-16 specific regulation. The observed mechanisms of regulation are consistent with what is known about 17 regulation in these two genomes: during oogenesis, the maternal genome is optimized to quickly 18 produce a large volume of transcripts to provide to the oocyte; after zygotic genome activation, 19 mechanisms are employed to activate transcription of specific genes in a spatiotemporally precise 20 manner. Thus the genetic architecture of the maternal and zygotic genomes and the specific 21 requirements for the transcripts present at each stage of embryogenesis determine the regulatory 22 mechanisms responsible for transcripts present at these stages. 23 the maternal to zygotic transition (MZT), is complex from a regulatory standpoint. Critical housekeeping 39 genes retain a steady transcript level, despite changing the genome of origin. New transcripts must be 40 synthesized from the newly activated zygotic genome, and maternal transcripts must be degraded, in a 41 highly regulated and time-specific manner [8]. This transition is well studied in model systems such as 42Drosophila melanogaster, where maternal mRNA degradation regulators such as smaug (smg) [8] and 43 regulators critical to the activation of the zygotic genome such as zelda (zld) [9,10] have been identified. 44When the transition of developmental control between the two genomes is complete, the zygotic 45 genome must be poised to carry out the rest of development in a precise manner. One process that 46 3 exemplifies the precisi...

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The complements of mRNAs in early embryonic development are crucial for setting up developmental trajectories in animals. The earliest stages of development are regulated by mRNAs deposited into the egg by the mother, until the zygote can become competent to transcribe its own genome. Previously, we showed that the set of maternally deposited and early transcribed zygotic mRNAs in Drosophila are generally conserved across species, but with some notable variation. We also showed that a majority of regulators of these two types of transcripts are shared. In this study, we examine the differences in regulatory motifs associated with maternal deposition and early zygotic transcription across species of Drosophila. For maternal transcripts, while the regulators are mostly conserved, we find the Drosophila pseudoobscura species subgroup appears to contain numerous novel regulatory motifs unique to these species. These novel motifs are enriched in transposable elements exclusive to this group. As this species group had been previously identified as having the largest divergence in early embryonic transcripts given their divergence time, this change in regulation may be responsible. However, transcripts that are present at the maternal stage only in these species are equally enriched in novel (group-specific) and conserved binding sites, so the novel regulation is not the sole cause of regulatory divergence in these species. At the zygotic stage, we observe a wide variety of species-specific motifs. Additionally, at both stages we observe motifs conserved across species having different effects on gene expression in different species, and regulating different sets of genes in different species. By examining changes in motif content across species, we find that changes in motif content alone is generally insufficient to drive gene expression changes across species.

Mutations in the complement factor I (CFI) gene have previously been identified as causes of recurrent CNS inflammation. We present a case of a 26-year-old man with 18 episodes of recurrent meningitis, who had a variant inCFI(c.859G>A,p.Gly287Arg) not previously associated with neurologic manifestations. He achieved remission with canakinumab, a human monoclonal antibody targeted at interleukin-1 beta.