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Therian mammals have among the oldest and most conserved sex-determining systems known to date. Any deviation from the standard XX/XY mammalian sex chromosome constitution usually leads to sterility or poor fertility, due to the high differentiation and specialization of the X and Y chromosomes. Nevertheless, a handful of rodents harbor so-called unusual sex-determining systems. While in some species, fertile XY females are found, some others have completely lost their Y chromosome. These atypical species have fascinated researchers for over 60 years, and constitute unique natural models for the study of fundamental processes involved in sex determination in mammals and vertebrates. In this article, we review current knowledge of these species, discuss their similarities and differences, and attempt to expose how the study of their exceptional sex-determining systems can further our understanding of general processes involved in sex chromosome and sex determination evolution.

The critical mutation rate (CMR) determines the shift between survival-of-the-fittest and survival of individuals with greater mutational robustness (“flattest”). We identify an inverse relationship between CMR and sequence length in an in silico system with a two-peak fitness landscape; CMR decreases to no more than five orders of magnitude above estimates of eukaryotic per base mutation rate. We confirm the CMR reduces exponentially at low population sizes, irrespective of peak radius and distance, and increases with the number of genetic crossovers. We also identify an inverse relationship between CMR and the number of genes, confirming that, for a similar number of genes to that for the plant Arabidopsis thaliana (25,000), the CMR is close to its known wild-type mutation rate; mutation rates for additional organisms were also found to be within one order of magnitude of the CMR. This is the first time such a simulation model has been assigned input and produced output within range for a given biological organism. The decrease in CMR with population size previously observed is maintained; there is potential for the model to influence understanding of populations undergoing bottleneck, stress, and conservation strategy for populations near extinction.

Hemoglobin (Hb) released from erythrocytes may cause oxidation of lipids and proteins. Haptoglobin (Hp), which occurs in the plasma of all mammals, binds free Hb and inhibits its oxidative activity. It is not known whether this protective protein also exists in lower vertebrates. By analyzing available genomic sequences, we have found that bony fish, but not more primitive animals, have a gene coding for a protein homologous to mammalian Hp. Furthermore, we show that this protein is present in the plasma of Japanese pufferfish (Takifugu rubripes) and that it binds Hb. These results, together with a phylogenetic analysis, suggest that Hp evolved from a complement-associated protein (mannose-binding lectin-associated serine proteinase, MASP), with the emergence of fish. Surprisingly, we found that both chicken (Gallus gallus) and the Western clawed frog (Xenopus tropicalis) lack the Hp gene. In chicken plasma, however, we identified a different type of Hbbinding protein, PIT54, which has been reported to be a potent antioxidant. PIT54 is a soluble member of the family of scavenger receptor cysteine-rich proteins, and we found that its gene exists only in birds. We also show that the plasma of ostrich (Strutio camelus), a primitive bird, contains both PIT54 and Hp. Collectively, our data suggest that PIT54 has successively taken over the function of Hp during the evolution of the avian lineage and has completely replaced the latter protein in chicken.

X and Y chromosomes in mammals are different in size and gene content due to an evolutionary process of differentiation and degeneration of the Y chromosome. Nevertheless, these chromosomes usually share a small region of homology, the pseudoautosomal region (PAR), which allows them to perform a partial synapsis and undergo reciprocal recombination during meiosis, which ensures their segregation. However, in some mammalian species the PAR has been lost, which challenges the pairing and segregation of sex chromosomes in meiosis. The African pygmy mouse Mus mattheyi shows completely differentiated sex chromosomes, representing an uncommon evolutionary situation among mouse species. We have performed a detailed analysis of the location of proteins involved in synaptonemal complex assembly (SYCP3), recombination (RPA, RAD51 and MLH1) and sex chromosome inactivation (γH2AX) in this species. We found that neither synapsis nor chiasmata are found between sex chromosomes and their pairing is notably delayed compared to autosomes. Interestingly, the Y chromosome only incorporates RPA and RAD51 in a reduced fraction of spermatocytes, indicating a particular DNA repair dynamic on this chromosome. The analysis of segregation revealed that sex chromosomes are associated until metaphase-I just by a chromatin contact. Unexpectedly, both sex chromosomes remain labelled with γH2AX during first meiotic division. This chromatin contact is probably enough to maintain sex chromosome association up to anaphase-I and, therefore, could be relevant to ensure their reductional segregation. The results presented suggest that the regulation of both DNA repair and epigenetic modifications in the sex chromosomes can have a great impact on the divergence of sex chromosomes and their proper transmission, widening our understanding on the relationship between meiosis and the evolution of sex chromosomes in mammals.

Key Points Genomes of multicellular organisms produce thousands of different long non-coding RNA (lncRNA) species. lncRNAs have crucial roles in gene expression control during developmental and differentiation processes. lncRNAs can regulate gene expression by several mechanisms in both the nucleus and the cytoplasm. lncRNAs drive the formation of ribonucleoprotein complexes and guide them to specific targets to regulate gene expression. Different in vitro and in vivo systems have shown the importance of lncRNAs in developmental processes, such as in dosage compensation, genomic imprinting, cell differentiation and organogenesis. lncRNAs can form regulative networks with other RNA species, such as microRNAs and mRNAs. Our knowledge of the diverse types and roles of long non-coding RNAs (lncRNAs) is rapidly increasing. This Review discusses our latest understanding of lncRNAs that have validated functional roles in various differentiation and developmental processes. Genomes of multicellular organisms are characterized by the pervasive expression of different types of non-coding RNAs (ncRNAs). Long ncRNAs (lncRNAs) belong to a novel heterogeneous class of ncRNAs that includes thousands of different species. lncRNAs have crucial roles in gene expression control during both developmental and differentiation processes, and the number of lncRNA species increases in genomes of developmentally complex organisms, which highlights the importance of RNA-based levels of control in the evolution of multicellular organisms. In this Review, we describe the function of lncRNAs in developmental processes, such as in dosage compensation, genomic imprinting, cell differentiation and organogenesis, with a particular emphasis on mammalian development.

Transposable elements (TEs) promote genetic innovation but also threaten genome stability. Despite multiple layers of host defence, TEs actively shape mammalian-specific developmental processes, particularly during pre-implantation and extra-embryonic development and at the maternal–fetal interface. Here, we review how TEs influence mammalian genomes both directly by providing the raw material for genetic change and indirectly via co-evolving TE-binding Krüppel-associated box zinc finger proteins (KRAB-ZFPs). Throughout mammalian evolution, individual activities of ancient TEs were co-opted to enable invasive placentation that characterizes live-born mammals. By contrast, the widespread activity of evolutionarily young TEs may reflect an ongoing co-evolution that continues to impact mammalian development.In this Review, Senft and Macfarlan discuss the diverse ways by which transposable elements (TEs) contribute to mammalian development and evolution, including direct contributions through TE-derived regulatory elements, RNAs and proteins, as well as indirect effects through the evolution of a TE repression system, the Krüppel-associated box zinc finger proteins (KRAB-ZFPs).

Key Points The mammalian circadian clock mechanism is cell autonomous and composed of a transcription–translation negative-feedback loop. These clocks are distributed throughout the body and regulate tissue-specific rhythmic functions. The core circadian transcriptional regulators drive gene expression rhythms in thousands of genes. The targets of the CLOCK–BMAL1 complex in the mouse liver regulate genes in all fundamental metabolic pathways, thus indicating that the clock system is closely embedded in cellular metabolism. Circadian activators and repressors recruit a wide array of chromatin modifiers that mediate dynamic changes in the poising of the genome with time of day. RNA polymerase II is recruited and initiated genome-wide in a circadian manner in the mouse liver, leading to genome-wide circadian changes in histone modifications. Circadian CLOCK–BMAL1 gene targets are directly linked to metabolism, immune function, cell proliferation, cancer and signalling. Next-generation sequencing approaches have yielded new insights into circadian function. Here, Takahashi reviews genome-wide analyses of the clock transcriptional feedback loop in mammals, which reveal a global circadian regulation of transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription and chromatin remodelling. Circadian clocks are endogenous oscillators that control 24-hour physiological and behavioural processes in organisms. These cell-autonomous clocks are composed of a transcription–translation-based autoregulatory feedback loop. With the development of next-generation sequencing approaches, biochemical and genomic insights into circadian function have recently come into focus. Genome-wide analyses of the clock transcriptional feedback loop have revealed a global circadian regulation of processes such as transcription factor occupancy, RNA polymerase II recruitment and initiation, nascent transcription, and chromatin remodelling. The genomic targets of circadian clocks are pervasive and are intimately linked to the regulation of metabolism, cell growth and physiology.

Transposable elements (TEs) comprise about half of the mammalian genome. TEs often contain sequences capable of recruiting the host transcription machinery, which they use to express their own products and promote transposition. However, the regulatory sequences carried by TEs may affect host transcription long after the TEs have lost the ability to transpose. Recent advances in genome analysis and engineering have facilitated systematic interrogation of the regulatory activities of TEs. In this Review, we discuss diverse mechanisms by which TEs contribute to transcription regulation. Notably, TEs can donate enhancer and promoter sequences that influence the expression of host genes, modify 3D chromatin architecture and give rise to novel regulatory genes, including non-coding RNAs and transcription factors. We discuss how TEs spur regulatory evolution and facilitate the emergence of genetic novelties in mammalian physiology and development. By virtue of their repetitive and interspersed nature, TEs offer unique opportunities to dissect the effects of mutation and genomic context on the function and evolution of cis-regulatory elements. We argue that TE-centric studies hold the key to unlocking general principles of transcription regulation and evolution.The regulatory sequences carried by transposable elements (TEs) often recruit the transcription machinery and affect host gene expression. Recent studies have revealed mechanisms by which TEs contribute to transcription regulation, including donation of enhancer and promoter sequences, modification of 3D chromatin architecture, and generation of novel regulatory non-coding RNAs and transcription factors.

Alternative splicing (AS) is pervasive in mammalian genomes, yet cross-species comparisons have been largely restricted to adult tissues and the functionality of most AS events remains unclear. We assessed AS patterns across pre- and postnatal development of seven organs in six mammals and a bird. Our analyses revealed that developmentally dynamic AS events, which are especially prevalent in the brain, are substantially more conserved than nondynamic ones. Cassette exons with increasing inclusion frequencies during development show the strongest signals of conserved and regulated AS. Newly emerged cassette exons are typically incorporated late in testis development, but those retained during evolution are predominantly brain specific. Our work suggests that an intricate interplay of programs controlling gene expression levels and AS is fundamental to organ development, especially for the brain and heart. In these regulatory networks, AS affords substantial functional diversification of genes through the generation of tissue- and time-specific isoforms from broadly expressed genes. Analysis of RNA-seq datasets from seven organs across seven species generates an alternative splicing (AS) atlas and shows that AS events provide functional gene diversification through generation of tissue- and time-specific transcript isoforms.

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research.