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Inexpensive genotyping methods are essential to modern genomics. Here we present QUILT, which performs diploid genotype imputation using low-coverage whole-genome sequence data. QUILT employs Gibbs sampling to partition reads into maternal and paternal sets, facilitating rapid haploid imputation using large reference panels. We show this partitioning to be accurate over many megabases, enabling highly accurate imputation close to theoretical limits and outperforming existing methods. Moreover, QUILT can impute accurately using diverse technologies, including long reads from Oxford Nanopore Technologies, and a new form of low-cost barcoded Illumina sequencing called haplotagging, with the latter showing improved accuracy at low coverages. Relative to DNA genotyping microarrays, QUILT offers improved accuracy at reduced cost, particularly for diverse populations that are traditionally underserved in modern genomic analyses, with accuracy nearly doubling at rare SNPs. Finally, QUILT can accurately impute (four-digit) human leukocyte antigen types, the first such method from low-coverage sequence data.

AbstractAcromelic dysplasias are a group of skeletal dysplasias characterised by short-limbed short stature with other distinctive phenotypic features including small hands and feet and stiff joints. Geleophysic dysplasia is an acromelic dysplasia that is associated with characteristic facial features, progressive cardiac valvular thickening, and tracheal stenosis. Owing to overlapping clinical features with other types of short-limbed skeletal dysplasias, it is important to make a precise diagnosis as they have different cardiac morbidity and mortality. We present the cases of three patients with geleophysic dysplasia and progressive mitral valve disease to emphasise the natural history of this disorder and provide guidance regarding cardiac health supervision in these individuals.

Transcription activator-like effectors (TALEs) are a class of naturally occurring DNA-binding proteins found in the plant pathogen Xanthomonas sp. The DNA-binding domain of each TALE consists of tandem 34–amino acid repeat modules that can be rearranged according to a simple cipher to target new DNA sequences. Customized TALEs can be used for a wide variety of genome engineering applications, including transcriptional modulation and genome editing. Here we describe a toolbox for rapid construction of custom TALE transcription factors (TALE-TFs) and nucleases (TALENs) using a hierarchical ligation procedure. This toolbox facilitates affordable and rapid construction of custom TALE-TFs and TALENs within 1 week and can be easily scaled up to construct TALEs for multiple targets in parallel. We also provide details for testing the activity in mammalian cells of custom TALE-TFs and TALENs using quantitative reverse-transcription PCR and Surveyor nuclease, respectively. The TALE toolbox described here will enable a broad range of biological applications.

Neu–Laxova syndrome (NLS) is a lethal, autosomal recessive multiple malformation syndrome with many features resulting from severe skin restriction and decreased fetal movement. It is characterized by ichthyosis, marked intrauterine growth restriction (IUGR), microcephaly, short neck, central nervous system (CNS) anomalies, limb deformities, hypoplastic lungs, edema, and abnormal facial features including severe proptosis with ectropion, hypertelorism, micrognathia, flattened nose, and malformed ears. We present two new patients with NLS with striking prenatal diagnostic findings and detailed post-mortem examinations and review the previously described cases in the literature. Data from these patients suggest that the NLS represents a heterogeneous phenotype. Prenatal ultrasound findings of marked ocular proptosis in a growth restricted, edematous fetus should prompt consideration of a diagnosis of the NLS. © 2003 Wiley-Liss, Inc.

Time‐resolved and off‐line synchrotron wide‐angle and small‐angle x‐ray scattering (WAXS and SAXS) was used to study the structure formation in poly‐p‐phenylenebenzobisoxazole (PBO) fibers during various stages of spinning, coagulation, and heating processes. WAXS data could be explained in terms of liquid‐crystalline structures of varying degrees of order. A structure model is proposed that is in accordance with the observed SAXS four‐point pattern.

Combined wide-angle X-ray diffraction (WAXD) and small-angle X-ray scattering (SAXS) studies using synchrotron radiation were carried out to investigate the structural development during in-situ solution spinning of poly(p-phenylenebenzobisoxazole) (PBO) in poly(phosphoric acid) (PPA). WAXD patterns indicated that the structure in the extruded PBO/PPA dope before coagulation (in water) possessed lyotropic “biaxial nematic” nematic order involving PBO−PPA complex as the mesogenic unit. A different biaxial nematic order in pure PBO was found to develop immediately upon coagulation in water. When the coagulation time exceeded 30 min, the complex PBO/PPA structure completely disappeared, and well-oriented PBO crystals were formed. The meridian peaks exhibited long streaks, indicating a translational disorder of PBO molecules in the fiber direction. SAXS patterns of the PBO fiber after coagulation showed equatorial streaks with no further maxima observed, which is attributed to a microvoid structure.

A parametric model has been developed to predict the performance of body armor systems under impact by a chunky steel projectile of arbitrary mass, shape, impact velocity, and impact obliquity. The model, which is based on a six-dimensional non linear regression analysis of extensive test data for Kevlar 29, is capable of predicting the performance of these body armor systems with user-defined areal density. The model partitions the energy absorbed by the body armor system into strain and kinetic energy; at impact velocities well above the ballistic limit of the system, the predominant mechanism of energy absorption is through kinetic energy transfer. The implications of this fact on the design of lightweight armor systems are discussed, along with the development of the model and suggestions for its use in designing, optimizing, and evaluating the functional utility of body armor systems.

Following a brief review of prior work on fabric-based armor systems, the system effects that occur during the ballistic impact of woven fabric body armor materials are discussed from a conceptual framework developed to relate single yarn impact mechanics to fabric impact mechanics. The consequence of assembling yarns into single-ply fabric structures is discussed from this perspective. A steep strain gradient along yarns in the region of the transverse deflection of the fabric is related to the constraint imposed on them by neighboring yarns. Striking and residual velocity data, collected for single-ply fabric systems of Spectra®, Kevlar® 29, and nylon with various different yarn deniers and weave types, are used to establish the response of spaced armor systems. The system effects of assembling fabric plies into body armor systems are determined by comparing the response of spaced armor systems to actual multiple-ply systems. There is a pronounced decrease in energy absorption capacity for the Spectra and nylon systems; this deleterious effect is ascribed to increased transverse stresses and possible interference of the deflection characteristics of fabric plies by subsequent plies.

Previous studies suggest that autism may be more common in the offspring of older parents. There is also a positive association between birth order, parental age, and autism, and a number of reports have shown firstborn children to be at increased risk. The aim of this prospective population-based cohort study was to determine whether advancing maternal and paternal ages were each independent risk factors for the development of autism spectrum disorder (ASD) in a large, population-based cohort of US children. Data were obtained from the Centers for Disease Control and Prevention’s Autism and Developmental Disabilities Monitoring Network, a group of 10 participating centers, which monitored 253,347 live births and had complete information from birth certificates on parental age, birth order, and other variables. The study group was comprised of 1251 children aged 8 years from this birth cohort who met the criteria for an ASD set forth in the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision.