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The glycocalyx of human cells differs from that of many other mammals by the lack of the sialic acid N-glycolylneuraminic acid (Neu5Gc) and increased abundance of its precursor N-acetylneuraminic acid (Neu5Ac). Most humans also have circulating antibodies specifically targeting the non-human sialic acid Neu5Gc. Recently, several additional mammalian species have been found to also lack Neu5Gc. In all cases, loss-of-function mutations in the gene encoding the sialic acid-modifying enzyme CMAH are responsible for the drastic change in these species. Unlike other glycan antigens, Neu5Gc apparently cannot be produced by microbes, raising the question about the origin of these antibodies in humans. Dietary exposure and presentation on bacteria coating themselves with Neu5Gc from the diet are distinct possibilities. However, the majority of the non-human species that lack Neu5Gc do not consume diets rich in Neu5Gc, making it unlikely that they will have been immunized against this sialic acid. A notable exception are mustelids (ferrets, martens and their relatives) known for preying on various small mammal species rich in Neu5Gc. No studies exist on levels of anti-Neu5Gc antibodies in non-human species. Evolutionary scenarios for the repeated, independent fixation of loss-of-function mutations at various time points in the past include strong selection by parasites, especially enveloped viruses, stochastic effects of genetic drift, and directional selection via female immunity to paternal Neu5Gc. Convergent evolution of losses of the vertebrate-specific self-glycan Neu5Gc are puzzling and may represent a prominent way in which glycans become agents of evolutionary change in their own right. Such change may include the reconfiguration of innate immune lectins that use self-sialic acids as recognition patterns.

Bacterial vaginosis (BV) is a polymicrobial condition of the vaginal microbiota associated with a variety of sexually transmitted infections, infections of maternal and fetal tissues during pregnancy, and even some infections outside of the reproductive tract, including the urinary tract and mouth. BV has also been associated with conditions in which the body generates prominent inflammatory reactions to microbes, including infections of the cervix and other upper genital tract tissues. For reasons still not understood, BV is a highly recurrent and often difficult-to-treat condition, complicating attempts to prevent these associated infections. An additional layer of complexity arises from the increasing awareness that the presence of BV-associated bacteria in the vagina is not always symptomatic or associated with adverse outcomes. In this concise Review, we summarize and synthesize three groups of factors grounded in the literature that may be fueling the associations between BV and infection: (a) aspects of society and culture; (b) pathogens, virulence factors, and processes of microbial antagonism and synergy; and (c) host factors, such as genetics and immunity. Our goal is to understand what contexts and combinations of microbial, host, and social factors conspire to make BV virulent in some individuals but not others. Disrupting these patterns more systematically may achieve healthier outcomes.

Key Points Here we provide an overview of the major findings related to human-lineage-specific (HLS) genomic and genetic changes and describe how these findings might relate to human-specific traits. The range of HLS changes extends from large-scale (for example, cytogenetic) to small-scale (for example, single-nucleotide substitutions), and current advances in genomic technologies are allowing genomic comparisons to be made with unprecedented scope and detail. A representative sampling of several types of genetic changes that can occur, as well as several important gene families that have undergone multiple HLS events, is presented alongside the possible phenotypic implications of these changes. Associating HLS genetic changes with a trait is one of the most challenging tasks for human evolutionary genomic research. A discussion of strategies to connect the two is presented, along with a list of current data available. There is emerging evidence that many HLS genetic and genomic changes colocalize with disease-associated genomic regions, suggesting a mechanistic link between the two. The growing availability of primate genome sequences has allowed an evaluation of the genetic and genomic changes that may have contributed to human-specific traits. This article focuses on these unique changes and the potential mechanisms by which they may have occurred. Given the unprecedented tools that are now available for rapidly comparing genomes, the identification and study of genetic and genomic changes that are unique to our species have accelerated, and we are entering a golden age of human evolutionary genomics. Here we provide an overview of these efforts, highlighting important recent discoveries, examples of the different types of human-specific genomic and genetic changes identified, and salient trends, such as the localization of evolutionary adaptive changes to complex loci that are highly enriched for disease associations. Finally, we discuss the remaining challenges, such as the incomplete nature of current genome sequence assemblies and difficulties in linking human-specific genomic changes to human-specific phenotypic traits.

Human sialic acid biology is unusual and thought to be unique among mammals. Humans lack a functional cytidine monophosphate- N -acetylneuraminic acid hydroxylase (CMAH) protein and cannot synthesize the sugar Neu5Gc, an innate mammalian signal of self. Losing this sugar changed how humans interact with some of our deadliest pathogens: malaria, influenza, and streptococcus among others. We show that the New World monkeys, comprising the third of all primate species, have human-like sialic acid biology. They have lost Neu5Gc because of an independent CMAH inactivation ~30 million years ago (mya) (compared to ~3 mya in hominids). This parallel loss of Neu5Gc opens sialic acid biology to comparative phylogenetic analysis and reveals an unexpected conservation priority. New World monkeys risk infection by human pathogens that can recognize cells in the absence of Neu5Gc. This striking molecular convergence provides a mechanism that could explain the long-standing observation that New World monkeys are susceptible to some human diseases that cannot be transmitted to other primates.

For a sperm to successfully fertilize an egg, it must first undergo capacitation in the female reproductive tract and later undergo acrosomal reaction (AR) upon encountering an egg surrounded by its vestment. How premature AR is avoided despite rapid surges in signaling cascades during capacitation remains unknown. Using a combination of conditional knockout (cKO) mice and cell-penetrating peptides, we show that GIV ( CCDC88A ), a guanine nucleotide-exchange modulator (GEM) for trimeric GTPases, is highly expressed in spermatocytes and is required for male fertility. GIV is rapidly phosphoregulated on key tyrosine and serine residues in human and murine spermatozoa. These phosphomodifications enable GIV-GEM to orchestrate two distinct compartmentalized signaling programs in the sperm tail and head; in the tail, GIV enhances PI3K→Akt signals, sperm motility and survival, whereas in the head it inhibits cAMP surge and premature AR. Furthermore, GIV transcripts are downregulated in the testis and semen of infertile men. These findings exemplify the spatiotemporally segregated signaling programs that support sperm capacitation and shed light on a hitherto unforeseen cause of infertility in men.

We report here that human T cells give much stronger proliferative responses to specific activation via the T cell receptor (TCR) than those from chimpanzees, our closest evolutionary relatives. Nonspecific activation using phytohemagglutinin was robust in chimpanzee T cells, indicating that the much lower response to TCR simulation is not due to any intrinsic inability to respond to an activating stimulus. CD33-related Siglecs are inhibitory signaling molecules expressed on most immune cells and are thought to down-regulate cellular activation pathways via cytosolic immunoreceptor tyrosine-based inhibitory motifs. Among human immune cells, T lymphocytes are a striking exception, expressing little to none of these molecules. In stark contrast, we find that T lymphocytes from chimpanzees as well as the other closely related \"great apes\" (bonobos, gorillas, and orangutans) express several CD33related Siglecs on their surfaces. Thus, human-specific loss of T cell Siglec expression occurred after our last common ancestor with great apes, potentially resulting in an evolutionary difference with regard to inhibitory signaling. We confirmed this by studying Siglec-5, which is prominently expressed on chimpanzee lymphocytes, including CD4 T cells. Ab-mediated clearance of Siglec-5 from chimpanzee T cells enhanced TCR-mediated activation. Conversely, primary human T cells and Jurkat cells transfected with Siglec-5 become less responsive; i.e., they behave more like chimpanzee T cells. This human-specific loss of T cell Siglec expression associated with T cell hyperactivity may help explain the strikingly disparate prevalence and severity of T cell-mediated diseases such as AIDS and chronic active hepatitis between humans and chimpanzees.

Humans are genetically unable to produce the sialic acid N-glycolylneuraminic acid (Neu5Gc), because of a mutation that occurred after our last common ancestor with great apes. Although Neu5Gc is presumed absent from normal humans, small amounts have been claimed to exist in human tumors and fetal meconium. We have generated an antibody with high specificity and avidity for Neu5Gc. Fetal tissues, normal adult tissues, and breast carcinomas from humans showed reactivity to this antibody, primarily within secretory epithelia and blood vessels. The presence of small amounts of Neu5Gc was confirmed by MS. Absent any known alternate pathway for its synthesis, we reasoned that these small amounts of Neu5Gc might originate from exogenous sources. Indeed, human cells fed with Neu5Gc incorporated it into endogenous glycoproteins. When normal human volunteers ingested Neu5Gc, a portion was absorbed and eliminated in urine, and small quantities were incorporated into newly synthesized glycoproteins. Neu5Gc has never been reported in plants or microbes to our knowledge. We found that Neu5Gc is rare in poultry and fish, common in milk products, and enriched in red meats. Furthermore, normal humans have variable amounts of circulating IgA, IgM, and IgG antibodies against Neu5Gc, with the highest levels comparable to those of the previously known anti-α-galactose xenoreactive antibodies. This finding represents an instance wherein humans absorb and metabolically incorporate a nonhuman dietary component enriched in foods of mammalian origin, even while generating xenoreactive, and potentially autoreactive, antibodies against the same molecule. Potential implications for human diseases are briefly discussed.

Aging is a multifactorial process that includes the lifelong accumulation of molecular damage, leading to age-related frailty, disability and disease, and eventually death. In this study, we report evidence of a significant correlation between the number of genes encoding the immunomodulatory CD33-related sialic acid-binding immunoglobulin-like receptors (CD33rSiglecs) and maximum lifespan in mammals. In keeping with this, we show that mice lacking Siglec-E, the main member of the CD33rSiglec family, exhibit reduced survival. Removal of Siglec-E causes the development of exaggerated signs of aging at the molecular, structural, and cognitive level. We found that accelerated aging was related both to an unbalanced ROS metabolism, and to a secondary impairment in detoxification of reactive molecules, ultimately leading to increased damage to cellular DNA, proteins, and lipids. Taken together, our data suggest that CD33rSiglecs co-evolved in mammals to achieve a better management of oxidative stress during inflammation, which in turn reduces molecular damage and extends lifespan. As we get older, we are more likely to become frail, be less mobile and develop heart disease, diabetes, and other age-related diseases. This is partly due to damage to tissues and organs that accumulates over the course of our lifetime. How quickly we age is controlled both by our genetics and by the environment we live in. It is thought that damage to DNA, proteins, and other molecules in the body caused by chemically active molecules called reactive oxygen species (ROS) can influence aging. ROS are produced during respiration, immune responses, and other important processes in cells, but in excessive amounts they can be extremely harmful. To avoid damage to DNA and other important molecules, cells have several ways to control the levels of ROS. One of the other hallmarks of aging is the development of chronic inflammation in tissues around the body, which is partly triggered by the immune system in response to cell damage. A group of genes called the CD33rSIGLEC genes are involved in controlling inflammation. The genomes of different mammal species carry different numbers of these genes, but it is not clear whether this alters the aging process in these animals. In this study, Schwarz et al. investigated whether the CD33rSIGLEC genes influence the lifespans of mammals. Species with a higher number of CD33rSIGLEC genes generally have a longer lifespan than those with fewer of these genes. Mice that were missing one of these genes and were subjected to inflammation early in life showed signs of accelerated aging and had shortened lifespans compared with normal mice. As predicted, these mice also had higher levels of ROS, which led to a greater amount of damage to the DNA and other molecules in their bodies. Schwarz et al.'s findings suggest that the CD33rSIGLECs co-evolved in mammals to help control the levels of ROS during inflammation, thereby reducing the damage to cells and extending the lifespan of the animals. Given that individual humans have different numbers of working CD33rSIGLEC genes, it would be interesting to see if this influences human lifespan.

Sialic acids (Sias) are nonulosonic acid (NulO) sugars prominently displayed on vertebrate cells and occasionally mimicked by bacterial pathogens using homologous biosynthetic pathways. It has been suggested that Sias were an animal innovation and later emerged in pathogens by convergent evolution or horizontal gene transfer. To better illuminate the evolutionary processes underlying the phenomenon of Sia molecular mimicry, we performed phylogenomic analyses of biosynthetic pathways for Sias and related higher sugars derived from 5,7-diamino-3,5,7,9-tetradeoxynon-2-ulosonic acids. Examination of [almost equal to]1,000 sequenced microbial genomes indicated that such biosynthetic pathways are far more widely distributed than previously realized. Phylogenetic analysis, validated by targeted biochemistry, was used to predict NulO types (i.e., neuraminic, legionaminic, or pseudaminic acids) expressed by various organisms. This approach uncovered previously unreported occurrences of Sia pathways in pathogenic and symbiotic bacteria and identified at least one instance in which a human archaeal symbiont tentatively reported to express Sias in fact expressed the related pseudaminic acid structure. Evaluation of targeted phylogenies and protein domain organization revealed that the \"unique\" Sia biosynthetic pathway of animals was instead a much more ancient innovation. Pathway phylogenies suggest that bacterial pathogens may have acquired Sia expression via adaptation of pathways for legionaminic acid biosynthesis, one of at least 3 evolutionary paths for de novo Sia synthesis. Together, these data indicate that some of the long-standing paradigms in Sia biology should be reconsidered in a wider evolutionary context of the extended family of NulO sugars.