Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Quantitative Analysis of Ellipsoid Zone in Acute Posterior Multifocal Placoid Pigment Epitheliopathy

PURPOSE:: Quantitative end points for uveitis are needed. Here we quantify the rate of ellipsoid zone (EZ) recovery on optical coherence tomography (OCT) and correlate it with visual acuity (VA) improvement in patients with acute posterior multifocal placoid pigmented epitheliopathy (APMPPE). We use automated and manually graded EZ area analysis to assess EZ recovery in APMPPE. METHODS:: We performed a retrospective review of 9 APMPPE cases (18 eyes) that had characteristic clinical examination and fluorescein angiography findings, outer retinal disruption on spectral-domain OCT, and treatment with systemic steroids after an unambiguous laboratory workup. The EZ was delineated using custom software to perform automated analysis and manual grading by 2 independent physicians. Quantitation of EZ changes was performed in ImageJ (National Institutes of Health). EZ maps were compared with equivalent findings from EZ en face OCT segmentation. RESULTS:: The 9 cases in our study were followed for an average of 198 days. Symptomatic improvement occurred in all eyes. VA recovery occurred in 83% of eyes and depended on presenting foveal involvement. Positive slopes of EZ area over time demonstrated recovery. EZ recovery profiles determined by manual and automated software demonstrated high Pearson correlation coefficients (0.78-0.94). Slab en face EZ analysis demonstrated moderate agreement. CONCLUSIONS:: EZ recovery correlates with symptomatic and VA recovery. Automated EZ analysis shows strong agreement with manually graded EZ analysis in APMPPE. EZ recovery in patients with APMPPE provides a biomarker for recovery and may be applied to other diseases affecting the outer retina

The application of optical coherence tomography angiography in uveitis and inflammatory eye diseases

Since its introduction in the early 1990s, optical coherence tomography (OCT) has evolved in resolution and technological advances, and in recent years its initial application of assessing the morphology of a tissue has been implemented by the study of its functional blood flow, through optical coherence tomography angiography (OCTA). This novel technique details capillary networks by comparing the amount of light returned from static and moving targets without the need for intravenous dye administration. While this imaging modality has been used for various ocular conditions, the application OCTA to uveitis conditions remains sparse. This review aims to establish the basis of OCTA and its current application to ocular inflammatory disorders, with an emphasis on monitoring progression and response to treatment, as well as predicting visual complications. In particular, this review explores the use of OCTA in iris vessel dilation seen in various forms of iritis, as a predictive factor for further episodes of inflammation. OCTA can also depict ischemia in the deep plexus layers of the retina and identify true choroicapillaris ischemia in cases of placoid diseases or masking of the indocyanine green dye, as in multiple evanescent white dot syndrome. In addition, OCTA can depict neovascularization in granulomatous disease of the retina or choroid not previously depicted with previous imaging methods. While OCTA provides several advancements in the imaging, management and prognosis of uveitis diseases, we emphasize that further studies are required to fully understand its application to these conditions

The application of optical coherence tomography angiography in uveitis and inflammatory eye diseases

Since its introduction in the early 1990s, optical coherence tomography (OCT) has evolved in resolution and technological advances, and in recent years its initial application of assessing the morphology of a tissue has been implemented by the study of its functional blood flow, through optical coherence tomography angiography (OCTA). This novel technique details capillary networks by comparing the amount of light returned from static and moving targets without the need for intravenous dyeadministration. While this imaging modality has been used for various ocular conditions, the application OCTA to uveitis conditions remains sparse. This review aims to establish the basis of OCTA and its current application to ocular inflammatory disorders, with an emphasis on monitoring progression and response to treatment, as well as predicting visual complications. In particular, this review explores the use of OCTA in iris vessel dilation seen in various forms of iritis, as a predictive factor for further episodes of inflammation. OCTA can also depict ischemia in the deep plexus layers of the retina and identify true choroicapillaris ischemia in cases of placoid diseases or masking of the indocyanine green dye, as in multiple evanescent white dot syndrome. In addition, OCTA can depict neovascularization in granulomatous disease of the retina or choroid not previously depicted with previous imaging methods. While OCTA provides several advancements in the imaging, management and prognosis of uveitis diseases, we emphasize that further studies are required to fully understand its application to these conditions

Association analysis identifies 65 new breast cancer risk loci.

Breast cancer risk is influenced by rare coding variants in susceptibility genes, such as BRCA1, and many common, mostly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. Here we report the results of a genome-wide association study of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry. We identified 65 new loci that are associated with overall breast cancer risk at P < 5 × 10-8. The majority of credible risk single-nucleotide polymorphisms in these loci fall in distal regulatory elements, and by integrating in silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all single-nucleotide polymorphisms in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the use of genetic risk scores for individualized screening and prevention

A transcriptome-wide association study of 229,000 women identifies new candidate susceptibility genes for breast cancer

The breast cancer risk variants identified in genome-wide association studies explain only a small fraction of the familial relative risk, and the genes responsible for these associations remain largely unknown. To identify novel risk loci and likely causal genes, we performed a transcriptome-wide association study evaluating associations of genetically predicted gene expression with breast cancer risk in 122,977 cases and 105,974 controls of European ancestry. We used data from the Genotype-Tissue Expression Project to establish genetic models to predict gene expression in breast tissue and evaluated model performance using data from The Cancer Genome Atlas. Of the 8,597 genes evaluated, significant associations were identified for 48 at a Bonferroni-corrected threshold of P < 5.82 × 10-6, including 14 genes at loci not yet reported for breast cancer. We silenced 13 genes and showed an effect for 11 on cell proliferation and/or colony-forming efficiency. Our study provides new insights into breast cancer genetics and biology

Associations of obesity and circulating insulin and glucose with breast cancer risk: a Mendelian randomization analysis.

BackgroundIn addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear.MethodsWe conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium.ResultsAll sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p  =  5.09  ×  10-4], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p  =  4.02  ×  10-4), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p  =  5.05  ×  10-19) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p  =  9.22  ×  10-6). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2-h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer.ConclusionsWe confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer