Olfactory detection of viruses shapes brain immunity and behavior in zebrafish.

Olfactory sensory neurons (OSNs) are constantly exposed to pathogens, including viruses. However, serious brain infection via the olfactory route rarely occurs. When OSNs detect a virus, they coordinate local antiviral immune responses to stop virus progression to the brain. Despite effective immune control in the olfactory periphery, pathogen-triggered neuronal signals reach the CNS via the olfactory bulb (OB). We hypothesized that neuronal detection of a virus by OSNs initiates neuroimmune responses in the OB that prevent pathogen invasion. Using zebrafish ( Danio rerio ) as a model, we demonstrate viral-specific neuronal activation of OSNs projecting into the OB, indicating that OSNs are electrically activated by viruses. Further, behavioral changes are seen in both adult and larval zebrafish after viral exposure. By profiling the transcription of single cells in the OB after OSNs are exposed to virus, we found that both microglia and neurons enter a protective state. Microglia and macrophage populations in the OB respond within minutes of nasal viral delivery followed decreased expression of neuronal differentiation factors and enrichment of genes in the neuropeptide signaling pathway in neuronal clusters. Pituitary adenylate-cyclase-activating polypeptide ( pacap ), a known antimicrobial, was especially enriched in a neuronal cluster. We confirm that PACAP is antiviral in vitro and that PACAP expression increases in the OB 1 day post-viral treatment. Our work reveals how encounters with viruses in the olfactory periphery shape the vertebrate brain by inducing antimicrobial programs in neurons and by altering host behavior.

Social isolation modulates appetite and avoidance behavior via a common oxytocinergic circuit in larval zebrafish.

Animal brains have evolved to encode social stimuli and transform these representations into advantageous behavioral responses. The commonalities and differences of these representations across species are not well-understood. Here, we show that social isolation activates an oxytocinergic (OXT), nociceptive circuit in the larval zebrafish hypothalamus and that chemical cues released from conspecific animals are potent modulators of this circuit's activity. We delineate an olfactory to subpallial pathway that transmits chemical social cues to OXT circuitry, where they are transformed into diverse outputs simultaneously regulating avoidance and feeding behaviors. Our data allow us to propose a model through which social stimuli are integrated within a fundamental neural circuit to mediate diverse adaptive behaviours.

Coordination of two enhancers drives expression of olfactory trace amine-associated receptors.

Olfactory sensory neurons (OSNs) are functionally defined by their expression of a unique odorant receptor (OR). Mechanisms underlying singular OR expression are well studied, and involve a massive cross-chromosomal enhancer interaction network. Trace amine-associated receptors (TAARs) form a distinct family of olfactory receptors, and here we find that mechanisms regulating Taar gene choice display many unique features. The epigenetic signature of Taar genes in TAAR OSNs is different from that in OR OSNs. We further identify that two TAAR enhancers conserved across placental mammals are absolutely required for expression of the entire Taar gene repertoire. Deletion of either enhancer dramatically decreases the expression probabilities of different Taar genes, while deletion of both enhancers completely eliminates the TAAR OSN populations. In addition, both of the enhancers are sufficient to drive transgene expression in the partially overlapped TAAR OSNs. We also show that the TAAR enhancers operate in cis to regulate Taar gene expression. Our findings reveal a coordinated control of Taar gene choice in OSNs by two remote enhancers, and provide an excellent model to study molecular mechanisms underlying formation of an olfactory subsystem.

Navigational strategies underlying temporal phototaxis in Drosophila larvae.

Navigating across light gradients is essential for survival for many animals. However, we still have a poor understanding of the algorithms that underlie such behaviors. Here, we developed a novel closed-loop phototaxis assay for Drosophila larvae in which light intensity is always spatially uniform but updates depending on the location of the animal in the arena. Even though larvae can only rely on temporal cues during runs, we find that they are capable of finding preferred areas of low light intensity. Further detailed analysis of their behavior reveals that larvae turn more frequently and that heading angle changes increase when they experience brightness increments over extended periods of time. We suggest that temporal integration of brightness change during runs is an important - and so far largely unexplored - element of phototaxis.

Larval Zebrafish Use Olfactory Detection of Sodium and Chloride to Avoid Salt Water.

Salinity levels constrain the habitable environment of all aquatic organisms. Zebrafish are freshwater fish that cannot tolerate high-salt environments and would therefore benefit from neural mechanisms that enable the navigation of salt gradients to avoid high salinity. Yet zebrafish lack epithelial sodium channels, the primary conduit land animals use to taste sodium. This suggests fish may possess novel, undescribed mechanisms for salt detection. In the present study, we show that zebrafish indeed respond to small temporal increases in salt by reorienting more frequently. Further, we use calcium imaging techniques to identify the olfactory system as the primary sense used for salt detection, and we find that a specific subset of olfactory receptor neurons encodes absolute salinity concentrations by detecting monovalent anions and cations. In summary, our study establishes that zebrafish larvae have the ability to navigate and thus detect salinity gradients and that this is achieved through previously undescribed sensory mechanisms for salt detection.

Phenotypic Landscape of Schizophrenia-Associated Genes Defines Candidates and Their Shared Functions.

Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologs of 132 human schizophrenia-associated genes. We created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus, and tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.

Neanderthal and Denisova genetic affinities with contemporary humans: introgression versus common ancestral polymorphisms.

Analyses of the genetic relationships among modern humans, Neanderthals and Denisovans have suggested that 1-4% of the non-Sub-Saharan African gene pool may be Neanderthal derived, while 6-8% of the Melanesian gene pool may be the product of admixture between the Denisovans and the direct ancestors of Melanesians. In the present study, we analyzed single nucleotide polymorphism (SNP) diversity among a worldwide collection of contemporary human populations with respect to the genetic constitution of these two archaic hominins and Pan troglodytes (chimpanzee). We partitioned SNPs into subsets, including those that are derived in both archaic lineages, those that are ancestral in both archaic lineages and those that are only derived in one archaic lineage. By doing this, we have conducted separate examinations of subsets of mutations with higher probabilities of divergent phylogenetic origins. While previous investigations have excluded SNPs from common ancestors in principal component analyses, we included common ancestral SNPs in our analyses to visualize the relative placement of the Neanderthal and Denisova among human populations. To assess the genetic similarities among the various hominin lineages, we performed genetic structure analyses to provide a comparison of genetic patterns found within contemporary human genomes that may have archaic or common ancestral roots. Our results indicate that 3.6% of the Neanderthal genome is shared with roughly 65.4% of the average European gene pool, which clinally diminishes with distance from Europe. Our results suggest that Neanderthal genetic associations with contemporary non-Sub-Saharan African populations, as well as the genetic affinities observed between Denisovans and Melanesians most likely result from the retention of ancient mutations in these populations.

Neolithic patrilineal signals indicate that the Armenian plateau was repopulated by agriculturalists.

Armenia, situated between the Black and Caspian Seas, lies at the junction of Turkey, Iran, Georgia, Azerbaijan and former Mesopotamia. This geographic position made it a potential contact zone between Eastern and Western civilizations. In this investigation, we assess Y-chromosomal diversity in four geographically distinct populations that represent the extent of historical Armenia. We find a striking prominence of haplogroups previously implicated with the Agricultural Revolution in the Near East, including the J2a-M410-, R1b1b1(*)-L23-, G2a-P15- and J1-M267-derived lineages. Given that the Last Glacial Maximum event in the Armenian plateau occured a few millennia before the Neolithic era, we envision a scenario in which its repopulation was achieved mainly by the arrival of farmers from the Fertile Crescent temporally coincident with the initial inception of farming in Greece. However, we detect very restricted genetic affinities with Europe that suggest any later cultural diffusions from Armenia to Europe were not associated with substantial amounts of paternal gene flow, despite the presence of closely related Indo-European languages in both Armenia and Southeast Europe.

Increased Y-chromosome resolution of haplogroup O suggests genetic ties between the Ami aborigines of Taiwan and the Polynesian Islands of Samoa and Tonga.

The Austronesian expansion has left its fingerprint throughout two thirds of the circumference of the globe reaching the island of Madagascar in East Africa to the west and Easter Island, off the coast of Chile, to the east. To date, several theories exist to explain the current genetic distribution of Austronesian populations, with the "slow boat" model being the most widely accepted, though other conjectures (i.e., the "express train" and "entangled bank" hypotheses) have also been widely discussed. In the current study, 158 Y chromosomes from the Polynesian archipelagos of Samoa and Tonga were typed using high resolution binary markers and compared to populations across Mainland East Asia, Taiwan, Island Southeast Asia, Melanesia and Polynesia in order to establish their patrilineal genetic relationships. Y-STR haplotypes on the C2 (M38), C2a (M208), O1a (M119), O3 (M122) and O3a2 (P201) backgrounds were utilized in an attempt to identify the differing sources of the current Y-chromosomal haplogroups present throughout Polynesia (of Melanesian and/or Asian descent). We find that, while haplogroups C2a, S and K3-P79 suggest a Melanesian component in 23%-42% of the Samoan and Tongan Y chromosomes, the majority of the paternal Polynesian gene pool exhibits ties to East Asia. In particular, the prominence of sub-haplogroup O3a2c* (P164), which has previously been observed at only minimal levels in Mainland East Asians (2.0-4.5%), in both Polynesians (ranging from 19% in Manua to 54% in Tonga) and Ami aborigines from Taiwan (37%) provides, for the first time, evidence for a genetic connection between the Polynesian populations and the Ami.

Paternal lineages signal distinct genetic contributions from British Loyalists and continental Africans among different Bahamian islands.

Over the past 500 years, the Bahamas has been influenced by a wide array of settlers, some of whom have left marked genetic imprints throughout the archipelago. To assess the extent of each group's genetic contributions, high-resolution Y-chromosome analyses were performed, for the first time, to delineate the patriarchal ancestry of six islands in the Northwest (Abaco and Grand Bahama) and Central (Eleuthera, Exuma, Long Island, and New Providence) Bahamas and their genetic relationships with previously published reference populations. Our results reveal genetic signals emanating primarily from African and European sources, with the predominantly sub-Saharan African and Western European haplogroups E1b1a-M2 and R1b1b1-M269, respectively, accounting for greater than 75% of all Bahamian patrilineages. Surprisingly, we observe notable discrepancies among the six Bahamian populations in their distribution of these lineages, with E1b1a-M2 predominating Y-chromosomes in the collections from Abaco, Exuma, Eleuthera, Grand Bahama, and New Providence, whereas R1b1b1-M269 is found at elevated levels in the Long Island population. Substantial Y-STR haplotype variation within sub-haplogroups E1b1a7a-U174 and E1b1ba8-U175 (greater than any continental African collection) is also noted, possibly indicating genetic influences from a variety of West and Central African groups. Furthermore, differential European genetic contributions in each island (with the exception of Exuma) reflect settlement patterns of the British Loyalists subsequent to the American Revolution.

Regionalized autosomal STR profiles among Armenian groups suggest disparate genetic influences.

The archeology and ethnology of Armenia suggest that this region has acted as a crossroads for human migrations from Europe and the Middle East since at least the Neolithic. Near continual foreign influx has, in turn, led to the supposition that the gene pools of geographically separated Armenian populations may have diverged as differing historical influences potentially left distinct genetic traces in the various regions of the Armenian plateau. In this study, we seek to address whether any evidence for such genetic regional partitioning in Armenians exists by analyzing, for the first time, 15 autosomal short tandem repeat (STR) loci in 404 Armenians from four geographically well-characterized collections (Ararat Valley, Gardman, Sasun, and Lake Van) that represent distinct communities from across Historical Armenia. In addition, to determine whether genetic differences among these four Armenian populations are the result of differential affinities to populations of known historical influence in Armenia, we utilize 27 biogeographically targeted reference populations for phylogenetic and admixture analyses. From these examinations, we find that while close genetic affiliations exist between the two easternmost Armenian groups analyzed, Ararat Valley and Gardman, the remaining two populations display substantial distinctions. In particular, Sasun is distinguished by evidence for genetic contributions from Turkey, while a stronger Balkan component is detected in Lake Van, potentially suggestive of remnant genetic influences from ancient Greek and Phrygian populations in this region.

To what extent did Neanderthals and modern humans interact?

Neanderthals represent an extinct hominid lineage that existed in Europe and Asia for nearly 400,000 years. They thrived in these regions for much of this time, but declined in numbers and went extinct around 30,000 years ago. Interestingly, their disappearance occurred subsequent to the arrival of modern humans into these areas, which has prompted some to argue that Neanderthals were displaced by better suited and more adaptable modern humans. Still others have postulated that Neanderthals were assimilated into the gene pool of modern humans by admixture. Until relatively recently, conclusions about the relationships between Neanderthals and contemporary humans were based solely upon evidence left behind in the fossil and archaeological records. However, in the last decade, we have witnessed the introduction of metagenomic analyses, which have provided novel tools with which to study the levels of genetic interactions between this fascinating Homo lineage and modern humans. Were Neanderthals replaced by contemporary humans through dramatic extinction resulting from competition and/or hostility or through admixture? Were Neanderthals and modern humans two independent, genetically unique species or were they a single species, capable of producing fertile offspring? Here, we review the current anthropological, archaeological and genetic data, which shed some light on these questions and provide insight into the exact nature of the relationships between these two groups of humans.