Genome assembly and geospatial phylogenomics of the bed bug Cimex lectularius.

The common bed bug (Cimex lectularius) has been a persistent pest of humans for thousands of years, yet the genetic basis of the bed bug's basic biology and adaptation to dense human environments is largely unknown. Here we report the assembly, annotation and phylogenetic mapping of the 697.9-Mb Cimex lectularius genome, with an N50 of 971 kb, using both long and short read technologies.

Two further blood pressure loci identified in ion channel genes with a gene-centric approach.

Background: Blood pressure (BP) is highly heritable, but our understanding of the genetic causes underlying variations in BP is incomplete. In this study, we explored whether novel loci associated with BP could be identified using a genecentric approach in 3 community-based cohorts with accurate BP measurements.

Methods And Results: Genotyping of 1857 single nucleotide polymorphisms (SNPs) in 91 ion channel genes was performed in a discovery cohort (n=358).

Clozapine-induced agranulocytosis is associated with rare HLA-DQB1 and HLA-B alleles.

Clozapine is a particularly effective antipsychotic medication but its use is curtailed by the risk of clozapine-induced agranulocytosis/granulocytopenia (CIAG), a severe adverse drug reaction occurring in up to 1% of treated individuals. Identifying genetic risk factors for CIAG could enable safer and more widespread use of clozapine. Here we perform the largest and most comprehensive genetic study of CIAG to date by interrogating 163 cases using genome-wide genotyping and whole-exome sequencing.

Tibetans living at sea level have a hyporesponsive hypoxia-inducible factor system and blunted physiological responses to hypoxia.

Tibetan natives have lived on the Tibetan plateau (altitude ∼ 4,000 m) for at least 25,000 years, and as such they are adapted to life and reproduction in a hypoxic environment. Recent studies have identified two genetic loci, EGLN1 and EPAS1, that have undergone natural selection in Tibetans, and further demonstrated an association of EGLN1/EPAS1 genotype with hemoglobin concentration. Both genes encode major components of the hypoxia-inducible factor (HIF) transcriptional pathway, which coordinates an organism's response to hypoxia.

A genome-wide association study of resistance to HIV infection in highly exposed uninfected individuals with hemophilia A.

Human genetic variation contributes to differences in susceptibility to HIV-1 infection. To search for novel host resistance factors, we performed a genome-wide association study (GWAS) in hemophilia patients highly exposed to potentially contaminated factor VIII infusions. Individuals with hemophilia A and a documented history of factor VIII infusions before the introduction of viral inactivation procedures (1979-1984) were recruited from 36 hemophilia treatment centers (HTCs), and their genome-wide genetic variants were compared with those from matched HIV-infected individuals.

Mutation in TECPR2 reveals a role for autophagy in hereditary spastic paraparesis.

We studied five individuals from three Jewish Bukharian families affected by an apparently autosomal-recessive form of hereditary spastic paraparesis accompanied by severe intellectual disability, fluctuating central hypoventilation, gastresophageal reflux disease, wake apnea, areflexia, and unique dysmorphic features. Exome sequencing identified one homozygous variant shared among all affected individuals and absent in controls: a 1 bp frameshift TECPR2 deletion leading to a premature stop codon and predicting significant degradation of the protein. TECPR2 has been reported as a positive regulator of autophagy.

Host genetics of HIV acquisition and viral control.

Since the discovery of HIV as the cause of AIDS, numerous insights have been gained from studies of its natural history and epidemiology. It has become clear that there are substantial interindividual differences in the risk of HIV acquisition and course of disease. Meanwhile, the field of human genetics has undergone a series of rapid transitions that have fundamentally altered the approach to studying HIV host genetics.

Exome sequencing and functional validation in zebrafish identify GTDC2 mutations as a cause of Walker-Warburg syndrome.

Whole-exome sequencing (WES), which analyzes the coding sequence of most annotated genes in the human genome, is an ideal approach to studying fully penetrant autosomal-recessive diseases, and it has been very powerful in identifying disease-causing mutations even when enrollment of affected individuals is limited by reduced survival. In this study, we combined WES with homozygosity analysis of consanguineous pedigrees, which are informative even when a single affected individual is available, to identify genetic mutations responsible for Walker-Warburg syndrome (WWS), a genetically heterogeneous autosomal-recessive disorder that severely affects the development of the brain, eyes, and muscle. Mutations in seven genes are known to cause WWS and explain 50%-60% of cases, but multiple additional genes are expected to be mutated because unexplained cases show suggestive linkage to diverse loci.

Using ERDS to infer copy-number variants in high-coverage genomes.

Although there are many methods available for inferring copy-number variants (CNVs) from next-generation sequence data, there remains a need for a system that is computationally efficient but that retains good sensitivity and specificity across all types of CNVs. Here, we introduce a new method, estimation by read depth with single-nucleotide variants (ERDS), and use various approaches to compare its performance to other methods. We found that for common CNVs and high-coverage genomes, ERDS performs as well as the best method currently available (Genome STRiP), whereas for rare CNVs and high-coverage genomes, ERDS performs better than any available method.

Prioritizing genetic variants for causality on the basis of preferential linkage disequilibrium.

To date, the widely used genome-wide association studies (GWASs) of the human genome have reported thousands of variants that are significantly associated with various human traits. However, in the vast majority of these cases, the causal variants responsible for the observed associations remain unknown. In order to facilitate the identification of causal variants, we designed a simple computational method called the "preferential linkage disequilibrium (LD)" approach, which follows the variants discovered by GWASs to pinpoint the causal variants, even if they are rare compared with the discovery variants.

Exome sequencing followed by large-scale genotyping suggests a limited role for moderately rare risk factors of strong effect in schizophrenia.

Schizophrenia is a severe psychiatric disorder with strong heritability and marked heterogeneity in symptoms, course, and treatment response. There is strong interest in identifying genetic risk factors that can help to elucidate the pathophysiology and that might result in the development of improved treatments. Linkage and genome-wide association studies (GWASs) suggest that the genetic basis of schizophrenia is heterogeneous.

Exome sequencing followed by large-scale genotyping fails to identify single rare variants of large effect in idiopathic generalized epilepsy.

Idiopathic generalized epilepsy (IGE) is a complex disease with high heritability, but little is known about its genetic architecture. Rare copy-number variants have been found to explain nearly 3% of individuals with IGE; however, it remains unclear whether variants with moderate effect size and frequencies below what are reliably detected with genome-wide association studies contribute significantly to disease risk. In this study, we compare the exome sequences of 118 individuals with IGE and 242 controls of European ancestry by using next-generation sequencing.

De novo mutations in ATP1A3 cause alternating hemiplegia of childhood.

Alternating hemiplegia of childhood (AHC) is a rare, severe neurodevelopmental syndrome characterized by recurrent hemiplegic episodes and distinct neurological manifestations. AHC is usually a sporadic disorder and has unknown etiology. We used exome sequencing of seven patients with AHC and their unaffected parents to identify de novo nonsynonymous mutations in ATP1A3 in all seven individuals.

Clinical application of exome sequencing in undiagnosed genetic conditions.

Background: There is considerable interest in the use of next-generation sequencing to help diagnose unidentified genetic conditions, but it is difficult to predict the success rate in a clinical setting that includes patients with a broad range of phenotypic presentations.

Methods: The authors present a pilot programme of whole-exome sequencing on 12 patients with unexplained and apparent genetic conditions, along with their unaffected parents. Unlike many previous studies, the authors did not seek patients with similar phenotypes, but rather enrolled any undiagnosed proband with an apparent genetic condition when predetermined criteria were met.

The association of genetic variants with hepatic steatosis in patients with genotype 1 chronic hepatitis C infection.

Background: Single-nucleotide polymorphisms (SNPs) in the IL28B and PNPLA3 gene regions have been associated with hepatic steatosis in genotype 1 (G1) chronic HCV infection but their clinical impacts remain to be determined.

Aim: We sought to validate these associations and to explore their impact on treatment response to peginterferon and ribavirin therapy.

Methods: A total of 972 G1 HCV-infected Caucasian patients were genotyped for the SNPs rs12979860 (IL28B) and rs2896019 (PNPLA3).

Interleukin 28B polymorphisms are the only common genetic variants associated with low-density lipoprotein cholesterol (LDL-C) in genotype-1 chronic hepatitis C and determine the association between LDL-C and treatment response.

Low-density lipoprotein cholesterol (LDL-C) levels and interleukin 28B (IL28B) polymorphism are associated with sustained viral response (SVR) to peginterferon/ribavirin (pegIFN/RBV) for chronic hepatitis C (CHC) infection. IL28B has been linked with LDL-C levels using a candidate gene approach, but it is not known whether other genetic variants are associated with LDL-C, nor how these factors definitively affect SVR. We assessed genetic predictors of serum lipid and triglyceride levels in 1604 patients with genotype 1 (G1) chronic hepatitis C virus (HCV) infection by genome-wide association study and developed multivariable predictive models of SVR.

Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions.

Aims: An association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other common variants across the genome as markers for cutaneous adverse drug reactions (cADRs) attributed to lamotrigine and phenytoin.

Materials & Methods: We recruited patients with lamotrigine-induced cADRs (n = 46) and patients with phenytoin-cADRs (n = 44) and the 1958 British birth cohort was used as a control (n = 1296).

Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

Background: Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance.

Methods: We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays.

Genomewide association study for determinants of HIV-1 acquisition and viral set point in HIV-1 serodiscordant couples with quantified virus exposure.

Background: Host genetic factors may be important determinants of HIV-1 sexual acquisition. We performed a genome-wide association study (GWAS) for host genetic variants modifying HIV-1 acquisition and viral control in the context of a cohort of African HIV-1 serodiscordant heterosexual couples. To minimize misclassification of HIV-1 risk, we quantified HIV-1 exposure, using data including plasma HIV-1 concentrations, gender, and condom use.

Variants in the ITPA gene protect against ribavirin-induced hemolytic anemia in HIV/HCV-coinfected patients with all HCV genotypes.

Background: A recent genome-wide association study reported a strong association with a single-nucleotide polymorphism (SNP) in the inosine triphosphate (ITPA) gene and hemolytic anemia in patients infected with hepatitis C virus (HCV) receiving pegylated interferon and ribavirin. We investigate these polymorphisms in a cohort of human immunodeficiency virus (HIV)/HCV-coinfected patients.

Methods: DNA was available for 161 patients with validated outcomes.

Copy number variation of KIR genes influences HIV-1 control.

A genome-wide screen for large structural variants showed that a copy number variant (CNV) in the region encoding killer cell immunoglobulin-like receptors (KIR) associates with HIV-1 control as measured by plasma viral load at set point in individuals of European ancestry. This CNV encompasses the KIR3DL1-KIR3DS1 locus, encoding receptors that interact with specific HLA-Bw4 molecules to regulate the activation of lymphocyte subsets including natural killer (NK) cells. We quantified the number of copies of KIR3DS1 and KIR3DL1 in a large HIV-1 positive cohort, and showed that an increase in KIR3DS1 count associates with a lower viral set point if its putative ligand is present (p = 0.

Single nucleotide polymorphism upstream of interleukin 28B associated with phase 1 and phase 2 of early viral kinetics in patients infected with HCV genotype 1.

Background & Aims: We studied the relationship between IL28B gene-related SNP rs12979860 and early viral kinetics (day 0-28) during peginterferon and ribavirin treatment, in 173 African Americans (AA) and 188 Caucasian Americans (CA) with HCV genotype 1.

Methods: We studied the relationship between IL28B 16 gene-related SNP rs12979860 and early viral kinetics (day 0-28) 17 during peginterferon and ribavirin treatment, in 171 African 18 Americans (AA) and 188 Caucasian Americans (CA) with HCV 19 genotype 1.

Results: Compared to non-C/C genotypes, C/C was associated with greater declines in serum HCV RNA during phase 1 (day 0-2), phase 2 (day 7-28), and day 0-28 and higher response (undetected HCV RNA) rates at weeks 4 and 12 in AA and CA.

Alpha-nicotinic acetylcholine receptor and tobacco smoke exposure: effects on bronchial hyperresponsiveness in children.

Background: The CHRNA 3 and 5 genes on chromosome 15 encode the alpha subunits of the nicotinic acetylcholine receptor, mediating airway cholinergic activity. Polymorphisms are associated with cigarette smoking, chronic obstructive pulmonary disease, and lung cancer.

Aims: To determine possible associations between CHRNA 3/5 SNP rs8034191 and asthma or lung function in children in one local and one replicate multinational population, and assess if tobacco smoke modified the associations.

Exome sequencing: the expert view.

To complement our special issue on exome sequencing, Genome Biology asked several leaders in the field for their views on this new approach. Leslie G Biesecker (LGB), Jim C Mullikin (JM) and Kevin V Shianna (KVS) discuss the reasons for the popularity of exome sequencing and its contribution to genomics.