Patterns and rates of exonic de novo mutations in autism spectrum disorders

Autism spectrum disorders (ASD) are believed to have genetic and environmental origins, yet in only a modest fraction of individuals can specific causes be identified. To identify further genetic risk factors, here we assess the role of de novo mutations in ASD by sequencing the exomes of ASD cases and their parents (n = 175 trios). Fewer than half of the cases (46.3%) carry a missense or nonsense de novo variant, and the overall rate of mutation is only modestly higher than the expected rate. In contrast, the proteins encoded by genes that harboured de novo missense or nonsense mutations showed a higher degree of connectivity among themselves and to previous ASD genes as indexed by protein-protein interaction screens. The small increase in the rate of de novo events, when taken together with the protein interaction results, are consistent with an important but limited role for de novo point mutations in ASD, similar to that documented for de novo copy number variants. Genetic models incorporating these data indicate that most of the observed de novo events are unconnected to ASD; those that do confer risk are distributed across many genes and are incompletely penetrant (that is, not necessarily sufficient for disease). Our results support polygenic models in which spontaneous coding mutations in any of a large number of genes increases risk by 5- to 20-fold. Despite the challenge posed by such models, results from de novo events and a large parallel case-control study provide strong evidence in favour of CHD8 and KATNAL2 as genuine autism risk factors.     

Discovery of a sensory organ that coordinates lunge feeding in rorqual whales

Top ocean predators have evolved multiple solutions to the challenges of feeding in the water. At the largest scale, rorqual whales (Balaenopteridae) engulf and filter prey-laden water by lunge feeding, a strategy that is unique among vertebrates. Lunge feeding is facilitated by several morphological specializations, including bilaterally separate jaws that loosely articulate with the skull, hyper-expandable throat pleats, or ventral groove blubber, and a rigid y-shaped fibrocartilage structure branching from the chin into the ventral groove blubber. The linkages and functional coordination among these features, however, remain poorly understood. Here we report the discovery of a sensory organ embedded within the fibrous symphysis between the unfused jaws that is present in several rorqual species, at both fetal and adult stages. Vascular and nervous tissue derived from the ancestral, anterior-most tooth socket insert into this organ, which contains connective tissue and papillae suspended in a gel-like matrix. These papillae show the hallmarks of a mechanoreceptor, containing nerves and encapsulated nerve termini. Histological, anatomical and kinematic evidence indicate that this sensory organ responds to both the dynamic rotation of the jaws during mouth opening and closure, and ventral groove blubber expansion through direct mechanical linkage with the y-shaped fibrocartilage structure. Along with vibrissae on the chin, providing tactile prey sensation, this organ provides the necessary input to the brain for coordinating the initiation, modulation and end stages of engulfment, a paradigm that is consistent with unsteady hydrodynamic models and tag data from lunge-feeding rorquals. Despite the antiquity of unfused jaws in baleen whales since the late Oligocene (～23-28 million years ago), this organ represents an evolutionary novelty for rorquals, based on its absence in all other lineages of extant baleen whales. This innovation has a fundamental role in one of the most extreme feeding methods in aquatic vertebrates, which facilitated the evolution of the largest vertebrates ever.     

Systematic variation of the stellar initial mass function in early-type galaxies

Much of our knowledge of galaxies comes from analysing the radiation emitted by their stars, which depends on the present number of each type of star in the galaxy. The present number depends on the stellar initial mass function (IMF), which describes the distribution of stellar masses when the population formed, and knowledge of it is critical to almost every aspect of galaxy evolution. More than 50 years after the first IMF determination, no consensus has emerged on whether it is universal among different types of galaxies. Previous studies indicated that the IMF and the dark matter fraction in galaxy centres cannot both be universal, but they could not convincingly discriminate between the two possibilities. Only recently were indications found that massive elliptical galaxies may not have the same IMF as the Milky Way. Here we report a study of the two-dimensional stellar kinematics for the large representative ATLAS(3D) sample of nearby early-type galaxies spanning two orders of magnitude in stellar mass, using detailed dynamical models. We find a strong systematic variation in IMF in early-type galaxies as a function of their stellar mass-to-light ratios, producing differences of a factor of up to three in galactic stellar mass. This implies that a galaxy's IMF depends intimately on the galaxy's formation history.     

Counterfactual quantum computation through quantum interrogation

The logic underlying the coherent nature of quantum information processing often deviates from intuitive reasoning, leading to surprising effects. Counterfactual computation constitutes a striking example: the potential outcome of a quantum computation can be inferred, even if the computer is not run. Relying on similar arguments to interaction-free measurements (or quantum interrogation), counterfactual computation is accomplished by putting the computer in a superposition of 'running' and 'not running' states, and then interfering the two histories. Conditional on the as-yet-unknown outcome of the computation, it is sometimes possible to counterfactually infer information about the solution. Here we demonstrate counterfactual computation, implementing Grover's search algorithm with an all-optical approach. It was believed that the overall probability of such counterfactual inference is intrinsically limited, so that it could not perform better on average than random guesses. However, using a novel 'chained' version of the quantum Zeno effect, we show how to boost the counterfactual inference probability to unity, thereby beating the random guessing limit. Our methods are general and apply to any physical system, as illustrated by a discussion of trapped-ion systems. Finally, we briefly show that, in certain circumstances, counterfactual computation can eliminate errors induced by decoherence.     

Digenic inheritance of severe insulin resistance in a human pedigree

Impaired insulin action is a key feature of type 2 diabetes and is also found, to a more extreme degree, in familial syndromes of insulin resistance. Although inherited susceptibility to insulin resistance may involve the interplay of several genetic loci, no clear examples of interactions among genes have yet been reported. Here we describe a family in which five individuals with severe insulin resistance, but no unaffected family members, were doubly [corrected] heterozygous with respect to frameshift/premature stop mutations in two unlinked genes, PPARG and PPP1R3A these encode peroxisome proliferator activated receptor gamma, which is highly expressed in adipocytes, and protein phosphatase 1, regulatory subunit 3, the muscle-specific regulatory subunit of protein phosphatase 1, which are centrally involved in the regulation of carbohydrate and lipid metabolism, respectively. That mutant molecules primarily involved in either carbohydrate or lipid metabolism can combine to produce a phenotype of extreme insulin resistance provides a model of interactions among genes that may underlie common human metabolic disorders such as type 2 diabetes.     

Role for DNA methylation in the control of cell type specific maspin expression

The major histocompatibility complex (MHC) is a source of unique individual odors that influence individual recognition, mating preferences, nesting behavior and selective block of pregnancy in animals. Such phenomena have been difficult to study in humans, because the human leukocyte antigen (HLA, human MHC) loci are the most polymorphic loci in the human genome, with the potential to generate millions of unique combinations of genotypes. In addition, high variability in background odors, encoded by the rest of the genome and influenced by cultural practices, contribute to a low signal-to-noise ratio that could mask HLA-based olfactory cues. Here we show that women can detect differences of one HLA allele among male odor donors with different MHC genotypes. Notably, the mechanism for a woman's ability to discriminate and choose odors is based on HLA alleles inherited from her father but not her mother. The parents' HLA alleles that she does not inherit show no relationship with odor choice, despite exposure to these HLA-encoded odors throughout her life. Our data indicate that paternally inherited HLA-associated odors influence odor preference and may serve as social cues.     

Adaptation in the chemotactic guidance of nerve growth cones

Pathfinding by growing axons in the developing nervous system may be guided by gradients of extracellular guidance factors. Analogous to the process of chemotaxis in microorganisms, we found that axonal growth cones of cultured Xenopus spinal neurons exhibit adaptation during chemotactic migration, undergoing consecutive phases of desensitization and resensitization in the presence of increasing basal concentrations of the guidance factor netrin-1 or brain-derived neurotrophic factor. The desensitization is specific to the guidance factor and is accompanied by a reduction of Ca2+ signalling, whereas resensitization requires activation of mitogen-associated protein kinase and local protein synthesis. Such adaptive behaviour allows the growth cone to re-adjust its sensitivity over a wide range of concentrations of the guidance factor, an essential feature for long-range chemotaxis.