Rafael Galupa

The X chromosome (chrX) is the eighth largest human chromosome, harbouring an estimated total of 839 protein-coding genes. Historically, the chrX has been described as enriched for genes related to brain development, sexual differentiation and reproduction, earning the epithet of “smart and sexy chromosome”. Many studies have confirmed that the chrX is indeed “smart”, including a recent systematic analysis of human chrX genes which found an enrichment in genes relevant to brain functions. However, it is less clear whether the chrX being “sexy” still holds true. Here we reviewed the origins of this idea and we evaluated human X-linked genes in terms of their expression across several tissues, their annotated functions and their association with monogenic disorders related to sexual differentiation and reproduction (SDR). We found that sex-specific tissues show higher expression levels from chrX genes than from autosomal genes except in testis, but that X-linked genes are significantly enriched among the most highly expressed genes in testis, specifically within spermatogonia and Sertoli cells. Yet, we found no evidence for an enrichment of genes on the X with annotated functions related to male or female SDR. When analysing SDR-related monogenic disorders, we found a significant enrichment of genes on chrX associated with clinical terms related to male SDR but not with clinical terms related to female or general SDR. Overall, our results support the notion of a somewhat “sexy” X chromosome, shaped by X-linked expression patterns and clinical associations rather than current annotated gene functions.

Neste artigo, identifica-se e problematiza-se o contributo que as universidades públicas portuguesas (UPP) têm dado no domínio da capacitação e na área da avaliação de projetos de educação em ciência em âmbito de cooperação para o desenvolvimento, concretamente em Timor-Leste e em São Tomé e Príncipe. Metodologicamente, esta investigação assume-se como qualitativa e quantitativa. Numa primeira fase, realizou-se a análise de conteúdo dos diferentes planos estratégicos das UPP; numa segunda, procedeu-se à análise da produção científica dessas universidades com análise dos respetivos repositórios institucionais. Recorreu-se a uma lista de palavras-chave: avaliação, cooperação, projetos de educação em ciência ou projetos de educação, Timor-Leste e São Tomé e Príncipe, definida de forma estratégica para melhor se compreender qual(ais) o(s) eixo(s) teórico(s) que se apresenta(m), ou não, como área(s) de foco. Com isto, perceberam-se as fragilidades e os pontos fortes que servem de suporte para investigações e acordos de cooperação futuros. Conclui-se de um modo geral que as UPP têm contribuído pouco para o desenvolvimento de investigações na interseção dos eixos teóricos como a avaliação, a cooperação e os projetos de educação em ciência, ainda que a cooperação, no geral, apresenta-se mais expressiva no contexto santomense que no timorense.

Changes in gene dosage can have tremendous evolutionary potential (e.g. whole-genome duplications), but without compensatory mechanisms, they can also lead to gene dysregulation and pathologies. Sex chromosomes are a paradigmatic example of naturally occurring gene dosage differences and their compensation. In species with chromosome-based sex determination, individuals within the same population necessarily show ‘natural’ differences in gene dosage for the sex chromosomes. In this Review, we focus on the mammalian X chromosome and discuss recent new insights into the dosage-compensation mechanisms that evolved along with the emergence of sex chromosomes, namely X-inactivation and X-upregulation. We also discuss the evolution of the genetic loci and molecular players involved, as well as the regulatory diversity and potentially different requirements for dosage compensation across mammalian species.

The authors wish to make the following changes to their paper

Developmental enhancers are DNA sequences that when bound to transcription factors dictate specific patterns of gene expression during development. It has been proposed that the evolution of such cis-regulatory elements is a major source of adaptive evolution; however, the regulatory and evolutionary potential of such elements remains little understood, masked by selective constraints, drift and contingency. Here, using mutation libraries in Drosophila melanogaster embryos, we observed that most mutations in classical developmental enhancers led to changes in gene expression levels but rarely resulted in novel expression outside of the native cell- and tissue-types. In contrast, random sequences often acted as developmental enhancers, driving expression across a range of levels and cell-types, in patterns consistent with transcription factor motifs therein; random sequences including motifs for transcription factors with pioneer activity acted as enhancers even more frequently and resulting in higher levels of expression. Together, our findings suggest that the adaptive phenotypic landscapes of developmental enhancers are constrained by both enhancer architecture and chromatin accessibility. We propose that the evolution of existing enhancers is limited in its capacity to generate novel phenotypes, whereas the activity of de novo elements is a primary source of phenotypic novelty. QUOTE: “Chance and chance alone has a message for us.” Milan Kundera, The Unbearable Lightness of Being

The interplay between the topological organization of the genome and the regulation of gene expression remains unclear. Depletion of molecular factors (e.g. CTCF) underlying topologically associating domains (TADs) leads to modest alterations in gene expression, whereas genomic rearrangements involving TAD boundaries disrupt normal gene expression and can lead to pathological phenotypes. Here, we targeted the TAD neighboring that of the noncoding transcript Xist, which controls X-chromosome inactivation. Inverting 245 kb within the TAD led to expected rearrangement of CTCF-based contacts but revealed heterogeneity in the ‘contact’ potential of different CTCF sites. Expression of most genes therein remained unaffected in mouse embryonic stem cells and during differentiation. Interestingly, expression of Xist was ectopically upregulated. The same inversion in mouse embryos led to biased Xist expression. Smaller inversions and deletions of CTCF clusters led to similar results: rearrangement of contacts and limited changes in local gene expression, but significant changes in Xist expression in embryos. Our study suggests that the wiring of regulatory interactions within a TAD can influence the expression of genes in neighboring TADs, highlighting the existence of mechanisms of inter-TAD communication.

How epigenetic modulators of gene regulation affect the development and evolution of animals has been difficult to ascertain. Despite the widespread presence of histone 3 lysine 4 monomethylation (H3K4me1) on enhancers, hypomethylation appears to have minor effects on animal development and viability. In this study, we performed quantitative, unbiased and multi-dimensional explorations of key phenotypes on Drosophila melanogaster with genetically induced hypomethylation. Hypomethylation reduced transcription factor enrichment in nuclear microenvironments, leading to reduced gene expression, and phenotypes outside of standard laboratory conditions. Our developmental phenomics survey further showed that H3K4me1 hypomethylation led to context-dependent changes in morphology, metabolism, and behavior. Therefore, H3K4me1 may contribute to phenotypic evolution as a phenotypic capacitor by buffering the effects of chance, genotypes and environmental conditions on transcriptional enhancers. Quote: “Developmental biologists are often not so much opposed to a role for ecology as they simply ignore it” –Doug Erwin ¹