High incidence of clinical fragility fractures in postmenopausal women with rheumatoid arthritis. A case-control study.

Objectives: To estimate the incidence of clinical fragility fractures in postmenopausal women with rheumatoid arthritis (RA) and analyze risk factors for fracture.

Methods: Incidence of clinical fragility fractures in 330 postmenopausal women with RA was compared to that of a control population of 660 age-matched postmenopausal Spanish women. Clinical fractures during the previous five years were recorded.

Retrotransposons Are the Major Contributors to the Expansion of the Muller F Element.

The discordance between genome size and the complexity of eukaryotes can partly be attributed to differences in repeat density. The Muller F element (∼5.2 Mb) is the smallest chromosome in , but it is substantially larger (>18.

Targeted sequencing identifies 91 neurodevelopmental-disorder risk genes with autism and developmental-disability biases.

Gene-disruptive mutations contribute to the biology of neurodevelopmental disorders (NDDs), but most of the related pathogenic genes are not known. We sequenced 208 candidate genes from >11,730 cases and >2,867 controls. We identified 91 genes, including 38 new NDD genes, with an excess of de novo mutations or private disruptive mutations in 5.

Discovery and genotyping of structural variation from long-read haploid genome sequence data.

In an effort to more fully understand the full spectrum of human genetic variation, we generated deep single-molecule, real-time (SMRT) sequencing data from two haploid human genomes. By using an assembly-based approach (SMRT-SV), we systematically assessed each genome independently for structural variants (SVs) and indels resolving the sequence structure of 461,553 genetic variants from 2 bp to 28 kbp in length. We find that >89% of these variants have been missed as part of analysis of the 1000 Genomes Project even after adjusting for more common variants (MAF > 1%).

De novo genic mutations among a Chinese autism spectrum disorder cohort.

Recurrent de novo (DN) and likely gene-disruptive (LGD) mutations contribute significantly to autism spectrum disorders (ASDs) but have been primarily investigated in European cohorts. Here, we sequence 189 risk genes in 1,543 Chinese ASD probands (1,045 from trios). We report an 11-fold increase in the odds of DN LGD mutations compared with expectation under an exome-wide neutral model of mutation.

Disruption of POGZ Is Associated with Intellectual Disability and Autism Spectrum Disorders.

Intellectual disability (ID) and autism spectrum disorders (ASD) are genetically heterogeneous, and a significant number of genes have been associated with both conditions. A few mutations in POGZ have been reported in recent exome studies; however, these studies do not provide detailed clinical information. We collected the clinical and molecular data of 25 individuals with disruptive mutations in POGZ by diagnostic whole-exome, whole-genome, or targeted sequencing of 5,223 individuals with neurodevelopmental disorders (ID primarily) or by targeted resequencing of this locus in 12,041 individuals with ASD and/or ID.

Excess of rare, inherited truncating mutations in autism.

To assess the relative impact of inherited and de novo variants on autism risk, we generated a comprehensive set of exonic single-nucleotide variants (SNVs) and copy number variants (CNVs) from 2,377 families with autism. We find that private, inherited truncating SNVs in conserved genes are enriched in probands (odds ratio = 1.14, P = 0.

The contribution of de novo coding mutations to autism spectrum disorder.

Whole exome sequencing has proven to be a powerful tool for understanding the genetic architecture of human disease. Here we apply it to more than 2,500 simplex families, each having a child with an autistic spectrum disorder. By comparing affected to unaffected siblings, we show that 13% of de novo missense mutations and 43% of de novo likely gene-disrupting (LGD) mutations contribute to 12% and 9% of diagnoses, respectively.

Palindromic GOLGA8 core duplicons promote chromosome 15q13.3 microdeletion and evolutionary instability.

Recurrent deletions of chromosome 15q13.3 associate with intellectual disability, schizophrenia, autism and epilepsy. To gain insight into the instability of this region, we sequenced it in affected individuals, normal individuals and nonhuman primates.

Whole-genome sequencing of individuals from a founder population identifies candidate genes for asthma.

Asthma is a complex genetic disease caused by a combination of genetic and environmental risk factors. We sought to test classes of genetic variants largely missed by genome-wide association studies (GWAS), including copy number variants (CNVs) and low-frequency variants, by performing whole-genome sequencing (WGS) on 16 individuals from asthma-enriched and asthma-depleted families. The samples were obtained from an extended 13-generation Hutterite pedigree with reduced genetic heterogeneity due to a small founding gene pool and reduced environmental heterogeneity as a result of a communal lifestyle.

Hominoid fission of chromosome 14/15 and the role of segmental duplications.

Ape chromosomes homologous to human chromosomes 14 and 15 were generated by a fission event of an ancestral submetacentric chromosome, where the two chromosomes were joined head-to-tail. The hominoid ancestral chromosome most closely resembles the macaque chromosome 7. In this work, we provide insights into the evolution of human chromosomes 14 and 15, performing a comparative study between macaque boundary region 14/15 and the orthologous human regions.

Transmission disequilibrium of small CNVs in simplex autism.

We searched for disruptive, genic rare copy-number variants (CNVs) among 411 families affected by sporadic autism spectrum disorder (ASD) from the Simons Simplex Collection by using available exome sequence data and CoNIFER (Copy Number Inference from Exome Reads). Compared to high-density SNP microarrays, our approach yielded ∼2× more smaller genic rare CNVs. We found that affected probands inherited more CNVs than did their siblings (453 versus 394, p = 0.

Great ape genetic diversity and population history.

Most great ape genetic variation remains uncharacterized; however, its study is critical for understanding population history, recombination, selection and susceptibility to disease. Here we sequence to high coverage a total of 79 wild- and captive-born individuals representing all six great ape species and seven subspecies and report 88.8 million single nucleotide polymorphisms.

Accelerated exon evolution within primate segmental duplications.

Background: The identification of signatures of natural selection has long been used as an approach to understanding the unique features of any given species. Genes within segmental duplications are overlooked in most studies of selection due to the limitations of draft nonhuman genome assemblies and to the methodological reliance on accurate gene trees, which are difficult to obtain for duplicated genes.

Results: In this work, we detected exons with an accumulation of high-quality nucleotide differences between the human assembly and shotgun sequencing reads from single human and macaque individuals.

Multiplex targeted sequencing identifies recurrently mutated genes in autism spectrum disorders.

Exome sequencing studies of autism spectrum disorders (ASDs) have identified many de novo mutations but few recurrently disrupted genes. We therefore developed a modified molecular inversion probe method enabling ultra-low-cost candidate gene resequencing in very large cohorts. To demonstrate the power of this approach, we captured and sequenced 44 candidate genes in 2446 ASD probands.

Estimating the human mutation rate using autozygosity in a founder population.

Knowledge of the rate and pattern of new mutation is critical to the understanding of human disease and evolution. We used extensive autozygosity in a genealogically well-defined population of Hutterites to estimate the human sequence mutation rate over multiple generations. We sequenced whole genomes from 5 parent-offspring trios and identified 44 segments of autozygosity.

Structural diversity and African origin of the 17q21.31 inversion polymorphism.

The 17q21.31 inversion polymorphism exists either as direct (H1) or inverted (H2) haplotypes with differential predispositions to disease and selection. We investigated its genetic diversity in 2,700 individuals, with an emphasis on African populations.

Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.

It is well established that autism spectrum disorders (ASD) have a strong genetic component; however, for at least 70% of cases, the underlying genetic cause is unknown. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes--so-called sporadic or simplex families--we sequenced all coding regions of the genome (the exome) for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 that were previously reported. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19), for a total of 677 individual exomes from 209 families.

The evolution of African great ape subtelomeric heterochromatin and the fusion of human chromosome 2.

Chimpanzee and gorilla chromosomes differ from human chromosomes by the presence of large blocks of subterminal heterochromatin thought to be composed primarily of arrays of tandem satellite sequence. We explore their sequence composition and organization and show a complex organization composed of specific sets of segmental duplications that have hyperexpanded in concert with the formation of subterminal satellites. These regions are highly copy number polymorphic between and within species, and copy number differences involving hundreds of copies can be accurately estimated by assaying read-depth of next-generation sequencing data sets.

Detection of structural variants and indels within exome data.

We report an algorithm to detect structural variation and indels from 1 base pair (bp) to 1 Mbp within exome sequence data sets. Splitread uses one end-anchored placements to cluster the mappings of subsequences of unanchored ends to identify the size, content and location of variants with high specificity and sensitivity. The algorithm discovers indels, structural variants, de novo events and copy number-polymorphic processed pseudogenes missed by other methods.

Relative burden of large CNVs on a range of neurodevelopmental phenotypes.

While numerous studies have implicated copy number variants (CNVs) in a range of neurological phenotypes, the impact relative to disease severity has been difficult to ascertain due to small sample sizes, lack of phenotypic details, and heterogeneity in platforms used for discovery. Using a customized microarray enriched for genomic hotspots, we assayed for large CNVs among 1,227 individuals with various neurological deficits including dyslexia (376), sporadic autism (350), and intellectual disability (ID) (501), as well as 337 controls. We show that the frequency of large CNVs (>1 Mbp) is significantly greater for ID-associated phenotypes compared to autism (p = 9.

Exome sequencing in sporadic autism spectrum disorders identifies severe de novo mutations.

Evidence for the etiology of autism spectrum disorders (ASDs) has consistently pointed to a strong genetic component complicated by substantial locus heterogeneity. We sequenced the exomes of 20 individuals with sporadic ASD (cases) and their parents, reasoning that these families would be enriched for de novo mutations of major effect. We identified 21 de novo mutations, 11 of which were protein altering.