High fitness paths can connect proteins with low sequence overlap.

The structure and function of a protein are determined by its amino acid sequence. While random mutations change a protein's sequence, evolutionary forces shape its structural fold and biological activity. Studies have shown that neutral networks can connect a local region of sequence space by single residue mutations that preserve viability.

High fitness paths can connect proteins with low sequence overlap.

The structure and function of a protein are determined by its amino acid sequence. While random mutations change a protein's sequence, evolutionary forces shape its structural fold and biological activity. Studies have shown that neutral networks can connect a local region of sequence space by single residue mutations that preserve viability.

Hallmarks of uterine receptivity predate placental mammals.

Embryo implantation requires tightly coordinated signaling between the blastocyst and the endometrium, and is crucial for the establishment of a uteroplacental unit that persists until term in eutherian mammals. In contrast, marsupials, with a unique life cycle and short gestation, make only brief fetal-maternal contact and lack implantation. To better understand the evolutionary link between eutherian implantation and its ancestral equivalent in marsupials, we compare single-cell transcriptomes from the receptive and non-receptive endometrium of the mouse and guinea pig with that of the opossum, a marsupial.

Metabolic complementation between cells drives the evolution of tissues and organs.

Although evolutionary transitions of individuality have been extensively theorized, little attention has been paid to the origin of levels of organization within organisms. How and why do specialized cells become organized into specialized tissues or organs? What spurs a transition in organizational level in cases where the function is already present in constituent cell types? We propose a hypothesis for this kind of evolutionary transition based on two features of cellular metabolism: metabolic constraints on functional performance and the capacity for metabolic complementation between parenchymal and supporting cells. These features suggest a scenario whereby pre-existing specialized cell types are integrated into tissues when changes to the internal or external environment favour offloading metabolic burdens from a primary specialized cell type onto supporting cells.

Evolutionary innovations in germline biology of placental mammals identified by transcriptomics of first-wave spermatogenesis in opossum.

Mammalian spermatogenesis is a highly stereotyped and conserved developmental process that is essential for fitness. At the same time, gene expression in spermatogenic cells is rapidly evolving. This combination of features has been suggested to drive rapid fixation of new gene expression patterns.

The mammary hair of Monodelphis domestica and homology of the mammary pilosebacous unit.

The unitary mammary gland is a synapomorphy of therian mammals and is thought to have evolved from the pilosebaceous organ in the mammalian stem lineage from which the lactogenic patch of monotremes is also derived. One of the key lines of evidence for the homology of the nipple and the lactogenic patch is that marsupials have retained a transient hair associated with developing mammary glands. However, these structures have not been documented since the early 20th-century drawings of Ernst Bresslau.

Pseudo-perplexity in One Fell Swoop for Protein Fitness Estimation.

Protein language models trained on the masked language modeling objective learn to predict the identity of hidden amino acid residues within a sequence using the remaining observable sequence as context. They do so by embedding the residues into a high dimensional space that encapsulates the relevant contextual cues. These embedding vectors serve as an informative context-sensitive representation that not only aids with the defined training objective, but can also be used for other tasks by downstream models.

Pseudo-perplexity in One Fell Swoop for Protein Fitness Estimation.

Protein language models trained on the masked language modeling objective learn to predict the identity of hidden amino acid residues within a sequence using the remaining observable sequence as context. They do so by embedding the residues into a high dimensional space that encapsulates the relevant contextual cues. These embedding vectors serve as an informative context-sensitive representation that not only aids with the defined training objective, but can also be used for other tasks by downstream models.

Cell type and cell signaling innovations underlying mammalian pregnancy.

Unlabelled: How fetal and maternal cell types have co-evolved to enable mammalian placentation poses a unique evolutionary puzzle. Here, we present a multi-species atlas integrating single-cell transcriptomes from six species bracketing therian mammal diversity. We find that invasive trophoblasts share a gene-expression signature across eutherians, and evidence that endocrine decidual cells evolved stepwise from an immunomodulatory cell type retained in with affinity to human decidua of menstruation.

Reading the palimpsest of cell interactions: What questions may we ask of the data?

Biological function depends on the composition and structure of the organism, the latter describing the organization of interactions between parts. While cells in multicellular organisms are capable of a remarkable degree of autonomy, most functions do require cell communication: the coordination of functions (growth, differentiation, and apoptosis), the compartmentalization of cellular processes, and the integration of cells into higher levels of structural organization. A wealth of data on putative cell interactions has become available, yet its biological interpretation depends on our expectations about the structure of interaction networks.

Experimental and phylogenetic evidence for correlated gene expression evolution in endometrial and skin fibroblasts.

Gene expression change is a dominant mode of evolution. Mutations, however, can affect gene expression in multiple cell types. Therefore, gene expression evolution in one cell type can lead to similar gene expression changes in another cell type.

The hierarchical basis of serial homology and evolutionary novelty.

Given the pervasiveness of gene sharing in evolution and the extent of homology across the tree of life, why is everything not homologous with everything else? The continuity and overlapping genetic contributions to diverse traits across lineages seem to imply that no discrete determination of homology is possible. Although some argue that the widespread overlap in parts and processes should be acknowledged as "partial" homology, this threatens a broad base of presumed comparative morphological knowledge accepted by most biologists. Following a long scientific tradition, we advocate a strategy of "theoretical articulation" that introduces further distinctions to existing concepts to produce increased contrastive resolution among the labels used to represent biological phenomena.

The value of broad taxonomic comparisons in evolutionary medicine: Disease is not a trait but a !

In this short paper, we argue that there is a fundamental connection between the medical sciences and evolutionary biology as both are sciences of biological variation. Medicine studies pathological variation among humans (and domestic animals in veterinary medicine) and evolutionary biology studies variation within and among species in general. A key principle of evolutionary biology is that genetic differences among species have arisen first from mutations originating within populations.

Evolution of higher mesenchymal CD44 expression in the human lineage: A gene linked to cancer malignancy.

CD44 is an extracellular matrix receptor implicated in cancer progression. CD44 increases the invasibility of skin (SF) and endometrial stromal fibroblasts (ESF) by cancer and trophoblast cells. We reasoned that the evolution of CD44 expression can affect both, the fetal-maternal interaction through CD44 in ESF as well as vulnerability to malignant cancer through expression in SF.

Proteotype coevolution and quantitative diversity across 11 mammalian species.

Evolutionary profiling has been largely limited to the nucleotide level. Using consistent proteomic methods, we quantified proteomic and phosphoproteomic layers in fibroblasts from 11 common mammalian species, with transcriptomes as reference. Covariation analysis indicates that transcript and protein expression levels and variabilities across mammals remarkably follow functional role, with extracellular matrix-associated expression being the most variable, demonstrating strong transcriptome-proteome coevolution.

Histone H3K4me3 breadth in hypoxia reveals endometrial core functions and stress adaptation linked to endometriosis.

Trimethylation of histone H3 at lysine 4 (H3K4me3) is a marker of active promoters. Broad H3K4me3 promoter domains have been associated with cell type identity, but H3K4me3 dynamics upon cellular stress have not been well characterized. We assessed this by exposing endometrial stromal cells to hypoxia, which is a major cellular stress condition.

Reframing research on evolutionary novelty and co-option: Character identity mechanisms versus deep homology.

A central topic in research at the intersection of development and evolution is the origin of novel traits. Despite progress on understanding how developmental mechanisms underlie patterns of diversity in the history of life, the problem of novelty continues to challenge researchers. Here we argue that research on evolutionary novelty and the closely associated phenomenon of co-option can be reframed fruitfully by: (1) specifying a conceptual model of mechanisms that underwrite character identity, (2) providing a richer and more empirically precise notion of co-option that goes beyond common appeals to "deep homology", and (3) attending to the nature of experimental interventions that can determine whether and how the co-option of identity mechanisms can help to explain novel character origins.

The Coevolution of Placentation and Cancer.

Analogies between placentation, in particular the behavior of trophoblast cells, and cancer have been noted since the beginning of the twentieth century. To what degree these can be explained as a consequence of the evolution of placentation has been unclear. In this review, we conclude that many similarities between trophoblast and cancer cells are shared with other, phylogenetically older processes than placentation.

Single-cell analysis of prostaglandin E2-induced human decidual cell in vitro differentiation: a minimal ancestral deciduogenic signal†.

The decidua is a hallmark of reproduction in many placental mammals. Differentiation of decidual stromal cells is known to be induced by progesterone and the cyclic AMP/protein kinase A (cAMP/PKA) pathway. Several candidates have been identified as the physiological stimulus for adenylyl cyclase activation, but their relative importance remains unclear.

Cooption of polyalanine tract into a repressor domain in the mammalian transcription factor HoxA11.

An enduring problem in biology is explaining how novel functions of genes originated and how those functions diverge between species. Despite detailed studies on the functional evolution of a few proteins, the molecular mechanisms by which protein functions have evolved are almost entirely unknown. Here, we show that a polyalanine tract in the homeodomain transcription factor HoxA11 arose in the stem-lineage of mammals and functions as an autonomous repressor module by physically interacting with the PAH domains of SIN3 proteins.

Molecular Evolution of CatSper in Mammals and Function of Sperm Hyperactivation in Gray Short-Tailed Opossum.

Males have evolved species-specifical sperm morphology and swimming patterns to adapt to different fertilization environments. In eutherians, only a small fraction of the sperm overcome the diverse obstacles in the female reproductive tract and successfully migrate to the fertilizing site. Sperm arriving at the fertilizing site show hyperactivated motility, a unique motility pattern displaying asymmetric beating of sperm flagella with increased amplitude.

Hidden limbs in the "limbless skink" Brachymeles lukbani: Developmental observations.

Reduced limbs and limblessness have evolved independently in many lizard clades. Scincidae exhibit a wide range of limb-reduced morphologies, but only some species have been used to study the embryology of limb reduction (e.g.