Mice Lacking Full Length Adgrb1 (bai1) Exhibit Social Deficits, Increased Seizure Susceptibility, and Altered Brain Development

The adhesion G protein-coupled receptor BAI1/ADGRB1 plays an important role in suppressing angiogenesis, mediating phagocytosis, and acting as a brain tumor suppressor. BAI1 is also a critical regulator of dendritic spine and excitatory synapse development and interacts with several autism-relevant proteins. However, little is known about the relationship between altered BAI1 function and clinically relevant phenotypes. Therefore, we studied the effect of reduced expression of full length Bai1 on behavior, seizure susceptibility, and brain morphology in Adgrb1 mutant mice. We compared homozygous (Adgrb1−/−), heterozygous (Adgrb1+/−), and wild-type (WT) littermates using a battery of tests to assess social behavior, anxiety, repetitive behavior, locomotor function, and seizure susceptibility. We found that Adgrb1−/− mice showed significant social behavior deficits and increased vulnerability to seizures. Adgrb1−/− mice also showed delayed growth and reduced brain weight. Furthermore, reduced neuron density and increased apoptosis during brain development were observed in the hippocampus of Adgrb1−/− mice, while levels of astrogliosis and microgliosis were comparable to WT littermates. These results show that reduced levels of full length Bai1 is associated with a broader range of clinically relevant phenotypes than previously reported

High level of complexity and global diversity of the 3q29 locus revealed by optical mapping and long-read sequencing.

BACKGROUND: High sequence identity between segmental duplications (SDs) can facilitate copy number variants (CNVs) via non-allelic homologous recombination (NAHR). These CNVs are one of the fundamental causes of genomic disorders such as the 3q29 deletion syndrome (del3q29S). There are 21 protein-coding genes lost or gained as a result of such recurrent 1.6-Mbp deletions or duplications, respectively, in the 3q29 locus. While NAHR plays a role in CNV occurrence, the factors that increase the risk of NAHR at this particular locus are not well understood. METHODS: We employed an optical genome mapping technique to characterize the 3q29 locus in 161 unaffected individuals, 16 probands with del3q29S and their parents, and 2 probands with the 3q29 duplication syndrome (dup3q29S). Long-read sequencing-based haplotype resolved de novo assemblies from 44 unaffected individuals, and 1 trio was used for orthogonal validation of haplotypes and deletion breakpoints. RESULTS: In total, we discovered 34 haplotypes, of which 19 were novel haplotypes. Among these 19 novel haplotypes, 18 were detected in unaffected individuals, while 1 novel haplotype was detected on the parent-of-origin chromosome of a proband with the del3q29S. Phased assemblies from 44 unaffected individuals enabled the orthogonal validation of 20 haplotypes. In 89% (16/18) of the probands, breakpoints were confined to paralogous copies of a 20-kbp segment within the 3q29 SDs. In one del3q29S proband, the breakpoint was confined to a 374-bp region using long-read sequencing. Furthermore, we categorized del3q29S cases into three classes and dup3q29S cases into two classes based on breakpoints. Finally, we found no evidence of inversions in parent-of-origin chromosomes. CONCLUSIONS: We have generated the most comprehensive haplotype map for the 3q29 locus using unaffected individuals, probands with del3q29S or dup3q29S, and available parents, and also determined the deletion breakpoint to be within a 374-bp region in one proband with del3q29S. These results should provide a better understanding of the underlying genetic architecture that contributes to the etiology of del3q29S and dup3q29S

Galaxy Mergers and Dark Matter Halo Mergers in LCDM: Mass, Redshift, and Mass-Ratio Dependence

We employ a high-resolution LCDM N-body simulation to present merger rate predictions for dark matter halos and investigate how common merger-related observables for galaxies--such as close pair counts, starburst counts, and the morphologically disturbed fraction--likely scale with luminosity, stellar mass, merger mass ratio, and redshift from z=0 to z=4. We provide a simple 'universal' fitting formula that describes our derived merger rates for dark matter halos a function of dark halo mass, merger mass ratio, and redshift, and go on to predict galaxy merger rates using number density-matching to associate halos with galaxies. For example, we find that the instantaneous merger rate of m/M>0.3 mass ratio events into typical L > f L* galaxies follows the simple relation dN/dt=0.03(1+f)(1+z)^2.1 Gyr^-1. Despite the rapid increase in merger rate with redshift, only a small fraction of >0.4 L* high-redshift galaxies (~3% at z=2) should have experienced a major merger (m/M >0.3) in the very recent past (t< 100 Myr). This suggests that short-lived, merger-induced bursts of star formation should not contribute significantly to the global star formation rate at early times, in agreement with observational indications. We emphasize that great care must be made in comparisons to observations because the predicted observables depend very sensitively on galaxy luminosity, redshift, overall mass ratio, and uncertain relaxation timescales for merger remnants. We show that the majority of bright galaxies at z=3 should have undergone a major merger (>0.3) in the last 700 Myr and conclude that mergers almost certainly play an important role in delivering baryons and influencing the kinematic properties of Lyman Break Galaxies (LBGs). (abridged)Comment: 11 pages, 4 figures, 2 tables; v2 updated to match published version in ApJ. Includes expanded discussion, and fixes typo in "galaxy stellar mass mergers" fitting paramters. Primary results and conclusions unchange

Infall Times for Milky Way Satellites From Their Present-Day Kinematics

We analyze subhalos in the Via Lactea II (VL2) cosmological simulation to look for correlations among their infall times and z = 0 dynamical properties. We find that the present day orbital energy is tightly correlated with the time at which subhalos last crossed into the virial radius. This energy-infall correlation provides a means to infer infall times for Milky Way satellite galaxies. Assuming that the Milky Way's assembly can be modeled by VL2, we show that the infall times of some satellites are well constrained given only their Galactocentric positions and line-of-sight velocities. The constraints sharpen for satellites with proper motion measurements. We find that Carina, Ursa Minor, and Sculptor were all accreted early, more than 8 Gyr ago. Five other dwarfs, including Sextans and Segue 1, are also probable early accreters, though with larger uncertainties. On the other extreme, Leo T is just falling into the Milky Way for the first time while Leo I fell in \sim 2 Gyr ago and is now climbing out of the Milky Way's potential after its first perigalacticon. The energies of several other dwarfs, including Fornax and Hercules, point to intermediate infall times, 2 - 8 Gyr ago. We compare our infall time estimates to published star formation histories and find hints of a dichotomy between ultrafaint and classical dwarfs. The classical dwarfs appear to have quenched star formation after infall but the ultrafaint dwarfs tend to be quenched long before infall, at least for the cases in which our uncertainties allow us to discern differences. Our analysis suggests that the Large Magellanic Cloud crossed inside the Milky Way virial radius recently, within the last \sim 4 billion years.Comment: 15 pages, 7 figures, all figures include colors, submitted for publication in MNRA

Phenotypic and genotypic differences between Indian and Scandinavian women with gestational diabetes mellitus

Objective Gestational diabetes mellitus (GDM) is a transient form of diabetes characterized by impaired insulin secretion and action during pregnancy. Population-based differences in prevalence exist which could be explained by phenotypic and genetic differences. The aim of this study was to examine these differences in pregnant women from Punjab, India and Scandinavia. Methods Eighty-five GDM/T2D loci in European and/or Indian populations from previous studies were assessed for association with GDM based on Swedish GDM criteria in 4018 Punjabi Indian and 507 Swedish pregnant women. Selected loci were replicated in Scandinavian cohorts, Radiel (N = 398, Finnish) and STORK/STORK-G (N = 780, Norwegian). Results Punjabi Indian women had higher GDM prevalence, lower insulin secretion and better insulin sensitivity than Swedish women. There were significant frequency differences of GDM/T2D risk alleles between both populations. rs7178572 at HMG20A, previously associated with GDM in South Indian and European women, was replicated in North Indian women. The T2D risk SNP rs11605924 in the CRY2 gene was associated with increased GDM risk in Scandinavian but decreased GDM risk in Punjabi Indian women. No other overlap was seen between GDM loci in both populations. Conclusions Gestational diabetes mellitus is more common in Indian than Swedish women, which partially can be attributed to differences in insulin secretion and action. There was marked heterogeneity in the GDM phenotypes between the populations which could only partially be explained by genetic differences.Peer reviewe

Common Variants within MECP2 Confer Risk of Systemic Lupus Erythematosus

Systemic lupus erythematosus (SLE) is a predominantly female autoimmune disease that affects multiple organ systems. Herein, we report on an X-chromosome gene association with SLE. Methyl-CpG-binding protein 2 (MECP2) is located on chromosome Xq28 and encodes for a protein that plays a critical role in epigenetic transcriptional regulation of methylation-sensitive genes. Utilizing a candidate gene association approach, we genotyped 21 SNPs within and around MECP2 in SLE patients and controls. We identify and replicate association between SLE and the genomic element containing MECP2 in two independent SLE cohorts from two ethnically divergent populations. These findings are potentially related to the overexpression of methylation-sensitive genes in SLE

Association between SNPs and gene expression in multiple regions of the human brain

Identifying the genetic cis associations between DNA variants (single-nucleotide polymorphisms (SNPs)) and gene expression in brain tissue may be a promising approach to find functionally relevant pathways that contribute to the etiology of psychiatric disorders. In this study, we examined the association between genetic variations and gene expression in prefrontal cortex, hippocampus, temporal cortex, thalamus and cerebellum in subjects with psychiatric disorders and in normal controls. We identified cis associations between 648 transcripts and 6725 SNPs in the various brain regions. Several SNPs showed brain regional-specific associations. The expression level of only one gene, PDE4DIP, was associated with a SNP, rs12124527, in all the brain regions tested here. From our data, we generated a list of brain cis expression quantitative trait loci (eQTL) genes that we compared with a list of schizophrenia candidate genes downloaded from the Schizophrenia Forum (SZgene) database (http://www.szgene.org/). Of the SZgene candidate genes, we found that the expression levels of four genes, HTR2A, PLXNA2, SRR and TCF4, were significantly associated with cis SNPs in at least one brain region tested. One gene, SRR, was also involved in a coexpression module that we found to be associated with disease status. In addition, a substantial number of cis eQTL genes were also involved in the module, suggesting eQTL analysis of brain tissue may identify more reliable susceptibility genes for schizophrenia than case–control genetic association analyses. In an attempt to facilitate the identification of genetic variations that may underlie the etiology of major psychiatric disorders, we have integrated the brain eQTL results into a public and online database, Stanley Neuropathology Consortium Integrative Database (SNCID; http://sncid.stanleyresearch.org)

Auditory temporal resolution of a wild white-beaked dolphin (Lagenorhynchus albirostris)

Author Posting. © The Author(s), 2009. This is the author's version of the work. It is posted here by permission of Springer for personal use, not for redistribution. The definitive version was published in Journal of Comparative Physiology A: Neuroethology, Sensory, Neural, and Behavioral Physiology 195 (2009): 375-384, doi:10.1007/s00359-009-0415-x.Adequate temporal resolution is required across taxa to properly utilize amplitude modulated acoustic signals. Among mammals, odontocete marine mammals are considered to have relatively high temporal resolution, which is a selective advantage when processing fast traveling underwater sound. However, multiple methods used to estimate auditory temporal resolution have left comparisons among odontocetes and other mammals somewhat vague. Here we present the estimated auditory temporal resolution of an adult male white-beaked dolphin, (Lagenorhynchus albirostris), using auditory evoked potentials and click stimuli. Ours is the first of such studies performed on a wild dolphin in a capture-and-release scenario. The white-beaked dolphin followed rhythmic clicks up to a rate of approximately 1125-1250 Hz, after which the modulation rate transfer function (MRTF) cut-off steeply. However, 10% of the maximum response was still found at 1450 Hz indicating high temporal resolution. The MRTF was similar in shape and bandwidth to that of other odontocetes. The estimated maximal temporal resolution of white-beaked dolphins and other odontocetes was approximately twice that of pinnipeds and manatees, and more than ten-times faster than humans and gerbils. The exceptionally high temporal resolution abilities of odontocetes are likely due primarily to echolocation capabilities that require rapid processing of acoustic cues.We wish to thank the Danish Natural Science Research Council for major financial support (grant no. 272-05-0395)

Association Analysis of the FTO Gene with Obesity in Children of Caucasian and African Ancestry Reveals a Common Tagging SNP

Recently an association was demonstrated between the single nucleotide polymorphism (SNP), rs9939609, within the FTO locus and obesity as a consequence of a genome wide association (GWA) study of type 2 diabetes in adults. We examined the effects of two perfect surrogates for this SNP plus 11 other SNPs at this locus with respect to our childhood obesity cohort, consisting of both Caucasians and African Americans (AA). Utilizing data from our ongoing GWA study in our cohort of 418 Caucasian obese children (BMI≥95th percentile), 2,270 Caucasian controls (BMI<95th percentile), 578 AA obese children and 1,424 AA controls, we investigated the association of the previously reported variation at the FTO locus with the childhood form of this disease in both ethnicities. The minor allele frequencies (MAF) of rs8050136 and rs3751812 (perfect surrogates for rs9939609 i.e. both r2 = 1) in the Caucasian cases were 0.448 and 0.443 respectively while they were 0.391 and 0.386 in Caucasian controls respectively, yielding for both an odds ratio (OR) of 1.27 (95% CI 1.08–1.47; P = 0.0022). Furthermore, the MAFs of rs8050136 and rs3751812 in the AA cases were 0.449 and 0.115 respectively while they were 0.436 and 0.090 in AA controls respectively, yielding an OR of 1.05 (95% CI 0.91–1.21; P = 0.49) and of 1.31 (95% CI 1.050–1.643; P = 0.017) respectively. Investigating all 13 SNPs present on the Illumina HumanHap550 BeadChip in this region of linkage disequilibrium, rs3751812 was the only SNP conferring significant risk in AA. We have therefore replicated and refined the association in an AA cohort and distilled a tag-SNP, rs3751812, which captures the ancestral origin of the actual mutation. As such, variants in the FTO gene confer a similar magnitude of risk of obesity to children as to their adult counterparts and appear to have a global impact