Genomics

Joshi PK, Esko T, Mattsson H, Eklund N, Gandin I, Nutile T, Jackson AU, Schurmann C, Smith AV, Zhang W, Okada Y, Stančáková A, Faul JD, Zhao W, Bartz TM, Concas MP, Franceschini N, Enroth S, Vitart V, Trompet S, Guo X, Chasman DI, O'Connel JR, Corre T, Nongmaithem SS, Chen Y, Mangino M, Ruggiero D, Traglia M, Farmaki A-E, Kacprowski T, Bjonnes A, van der Spek A, Wu Y, Giri AK, Yanek LR, Wang L, Hofer E, Rietveld CA, McLeod O, Cornelis MC, Pattaro C, Verweij N, Baumbach C, Abdellaoui A, Warren HR, Vuckovic D, Mei H, Bouchard C, Perry JRB, Cappellani S, Mirza SS, Benton MC, Broeckel U, Medland SE, Lind PA, Malerba G, Drong A, Yengo L, Bielak LF, Zhi D, van der Most PJ, Shriner D, Mägi R, Hemani G, Karaderi T, Wang Z, Liu T, Demuth I, Zhao JH, Meng W, Lataniotis L, van der Laan SW, Bradfield JP, Wood AR, Bonnefond A, Ahluwalia TS, Hall LM, Salvi E, Yazar S, Carstensen L, de Haan HG, Abney M, Afzal U, Allison MA, Amin N, Asselbergs FW, Bakker SJL, Barr GR, Baumeister SE, Benjamin DJ, Bergmann S, Boerwinkle E, Bottinger EP, Campbell A, Chakravarti A, Chan Y, Chanock SJ, Chen C, Chen IY-D, Collins FS, Connell J, Correa A, Cupples AL, Smith GD, Davies G, Dörr M, Ehret G, Ellis SB, Feenstra B, Feitosa MF, Ford I, Fox CS, Frayling TM, Friedrich N, Geller F, Scotland G, Gillham-Nasenya I, Gottesman O, Graff M, Grodstein F, Gu C, Haley C, Hammond CJ, Harris SE, Harris TB, Hastie ND, Heard-Costa NL, Heikkilä K, Hocking LJ, Homuth G, Hottenga J-J, Huang J, Huffman JE, Hysi PG, Ikram AM, Ingelsson E, Joensuu A, Johansson Å, Jousilahti P, Jukema WJ, Kähönen M, Kamatani Y, Kanoni S, Kerr SM, Khan NM, Koellinger P, Koistinen HA, Kooner MK, Kubo M, Kuusisto J, Lahti J, Launer LJ, Lea RA, Lehne B, Lehtimäki T, Liewald DCM, Lind L, Loh M, Lokki M-L, London SJ, Loomis SJ, Loukola A, Lu Y, Lumley T, Lundqvist A, Männistö S, Marques-Vidal P, Masciullo C, Matchan A, Mathias RA, Matsuda K, Meigs JB, Meisinger C, Meitinger T, Menni C, Mentch FD, Mihailov E, Milani L, Montasser ME, Montgomery GW, Morrison A, Myers RH, Nadukuru R, Navarro P, Nelis M, Nieminen MS, Nolte IM, O'Connor GT, Ogunniyi A, Padmanabhan S, Palmas WR, Pankow JS, Patarcic I, Pavani F, Peyser PA, Pietilainen K, Poulter N, Prokopenko I, Ralhan S, Redmond P, Rich SS, Rissanen H, Robino A, Rose LM, Rose R, Sala C, Salako B, Salomaa V, Sarin A-P, Saxena R, Schmidt H, Scott LJ, Scott WR, Sennblad B, Seshadri S, Sever P, Shrestha S, Smith BH, Smith JA, Soranzo N, Sotoodehnia N, Southam L, Stanton AV, Stathopoulou MG, Strauch K, Strawbridge RJ, Suderman MJ, Tandon N, Tang S-T, Taylor KD, Tayo BO, Töglhofer AM, Tomaszewski M, Tšernikova N, Tuomilehto J, Uitterlinden AG, Vaidya D, van Hylckama Vlieg A, van Setten J, Vasankari T, Vedantam S, Vlachopoulou E, Vozzi D, Vuoksimaa E, Waldenberger M, Ware EB, Wentworth-Shields W, Whitfield JB, Wild S, Willemsen G, Yajnik CS, Yao J, Zaza G, Zhu X, Zhu X, Salem RM, Melbye M, Bisgaard H, Samani NJ, Cusi D, Mackey DA, Cooper RS, Froguel P, Pasterkamp G, Grant SFA, Hakonarson H, Ferrucci L, Scott RA, Morris AD, Palmer CNA, Dedoussis G, Deloukas P, Bertram L, Lindenberger U, Berndt SI, Lindgren CM, Timpson NJ, Tönjes A, Munroe PB, Sørensen TIA, Rotimi CN, Arnett DK, Oldehinkel AJ, Kardia SLR, Balkau B, Gambaro G, Morris AP, Eriksson JG, Wright MJ, Martin NG, Hunt SC, Starr JM, Deary IJ, Griffiths LR, Tiemeier H, Pirastu N, Kaprio J, Wareham NJ, Pérusse L, Wilson JG, Girotto G, Caulfield MJ, Raitakari O, Boomsma DI, Gieger C, van der Harst P, Hicks AA, Kraft P, Sinisalo J, Knekt P, Johannesson M, Magnusson PKE, Hamsten A, Schmidt R, Borecki IB, Vartiainen E, Becker DM, Bharadwaj D, Mohlke KL, Boehnke M, van Duijn CM, Sanghera DK, Teumer A, Zeggini E, Metspalu A, Gasparini P, Ulivi S, Ober C, Toniolo D, Rudan I, Porteous DJ, Ciullo M, Spector TD, Hayward C, Dupuis J, Loos RJF, Wright AF, Chandak GR, Vollenweider P, Shuldiner AR, Ridker PM, Rotter JI, Sattar N, Gyllensten U, North KE, Pirastu M, Psaty BM, Weir DR, Laakso M, Gudnason V, Takahashi A, Chambers JC, Kooner JS, Strachan DP, Campbell H, Hirschhorn JN, Perola M, Polašek O, Wilson JF. Directional dominance on stature and cognition indiverse human populations. Nature 2015;523(7561):459-62.Abstract

Homozygosity has long been associated with rare, often devastating, Mendelian disorders, and Darwin was one of the first to recognize that inbreeding reduces evolutionary fitness. However, the effect of the more distant parental relatedness that is common in modern human populations is less well understood. Genomic data now allow us to investigate the effects of homozygosity on traits of public health importance by observing contiguous homozygous segments (runs of homozygosity), which are inferred to be homozygous along their complete length. Given the low levels of genome-wide homozygosity prevalent in most human populations, information is required on very large numbers of people to provide sufficient power. Here we use runs of homozygosity to study 16 health-related quantitative traits in 354,224 individuals from 102 cohorts, and find statistically significant associations between summed runs of homozygosity and four complex traits: height, forced expiratory lung volume in one second, general cognitive ability and educational attainment (P < 1 × 10(-300), 2.1 × 10(-6), 2.5 × 10(-10) and 1.8 × 10(-10), respectively). In each case, increased homozygosity was associated with decreased trait value, equivalent to the offspring of first cousins being 1.2 cm shorter and having 10 months' less education. Similar effect sizes were found across four continental groups and populations with different degrees of genome-wide homozygosity, providing evidence that homozygosity, rather than confounding, directly contributes to phenotypic variance. Contrary to earlier reports in substantially smaller samples, no evidence was seen of an influence of genome-wide homozygosity on blood pressure and low density lipoprotein cholesterol, or ten other cardio-metabolic traits. Since directional dominance is predicted for traits under directional evolutionary selection, this study provides evidence that increased stature and cognitive function have been positively selected in human evolution, whereas many important risk factors for late-onset complex diseases may not have been.

Weinberger AD, Gilmore MS. A CRISPR View of Cleavage. Cell 2015;161(5):964-6.Abstract

Seminal studies showed that CRISPR-Cas systems provide adaptive immunity in prokaryotes and promising gene-editing tools from bacteria to humans. Yet, reports diverged on whether some CRISPR systems naturally target DNA or RNA. Here, Samai and colleagues unify the studies, showing that a single type III CRISPR-Cas system cleaves both DNA and RNA targets, independently.

Huang T, Zheng Y, Qi Q, Xu M, Ley SH, Li Y, Kang JH, Wiggs J, Pasquale LR, Chan AT, Rimm EB, Hunter DJ, Manson JAE, Willett WC, Hu FB, Qi L. DNA Methylation Variants at HIF3A Locus, B-Vitamin Intake, and Long-term Weight Change: Gene-Diet Interactions in Two U.S. Cohorts. Diabetes 2015;64(9):3146-54.Abstract

The first epigenome-wide association study of BMI identified DNA methylation at an HIF3A locus associated with BMI. We tested the hypothesis that DNA methylation variants are associated with BMI according to intake of B vitamins. In two large cohorts, we found significant interactions between the DNA methylation-associated HIF3A single nucleotide polymorphism (SNP) rs3826795 and intake of B vitamins on 10-year changes in BMI. The association between rs3826795 and BMI changes consistently increased across the tertiles of total vitamin B2 and B12 intake (all P for interaction <0.01). The differences in the BMI changes per increment of minor allele were -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.12 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B2 intake and -0.10 (SE 0.06), -0.01 (SE 0.06), and 0.10 (SE 0.07) within subgroups defined by increasing tertiles of total vitamin B12 intake. In two independent cohorts, a DNA methylation variant in HIF3A was associated with BMI changes through interactions with total or supplemental vitamin B2, vitamin B12, and folate. These findings suggest a potential causal relation between DNA methylation and adiposity.

de Almeida LM, Pires C, Cerdeira LT, de Oliveira TGM, McCulloch JA, Perez-Chaparro PJ, Sacramento AG, Brito AC, da Silva JL, de Araújo MRE, Lincopan N, Martin MJ, Gilmore MS, Mamizuka EM. Complete Genome Sequence of Linezolid-Susceptible Staphylococcus haemolyticus Sh29/312/L2, a Clonal Derivative of a Linezolid-Resistant Clinical Strain. Genome Announc 2015;3(3)Abstract

We report the whole-genome sequence (WGS) of an in vitro susceptible derivative revertant mutant from a bloodstream isolate involved in a nosocomial outbreak in Brazil. The WGS comprises 2.5 Mb with 2,500 protein-coding sequences, 16rRNA genes, and 60 tRNA genes.

Vandenberghe LH. What Is Next for Retinal Gene Therapy?. Cold Spring Harb Perspect Med 2015;Abstract

The field of gene therapy for retinal blinding disorders is experiencing incredible momentum, justified by hopeful results in early stage clinical trials for inherited retinal degenerations. The premise of the use of the gene as a drug has come a long way, and may have found its niche in the treatment of retinal disease. Indeed, with only limited treatment options available for retinal indications, gene therapy has been proven feasible, safe, and effective and may lead to durable effects following a single injection. Here, we aim at putting into context the promise and potential, the technical, clinical, and economic boundaries limiting its application and development, and speculate on a future in which gene therapy is an integral component of ophthalmic clinical care.

Mlynarski EE, Sheridan MB, Xie M, Guo T, Racedo SE, McDonald-McGinn DM, Gai X, Chow EWC, Vorstman J, Swillen A, Devriendt K, Breckpot J, Digilio MC, Marino B, Dallapiccola B, Philip N, Simon TJ, Roberts AE, Piotrowicz M, Bearden CE, Eliez S, Gothelf D, Coleman K, Kates WR, Devoto M, Zackai E, Heine-Suñer D, Shaikh TH, Bassett AS, Goldmuntz E, Morrow BE, Emanuel BS, Consortium IC22q11 2. Copy-Number Variation of the Glucose Transporter Gene SLC2A3 and Congenital Heart Defects in the 22q11.2 Deletion Syndrome. Am J Hum Genet 2015;96(5):753-64.Abstract
The 22q11.2 deletion syndrome (22q11DS; velocardiofacial/DiGeorge syndrome; VCFS/DGS) is the most common microdeletion syndrome and the phenotypic presentation is highly variable. Approximately 65% of individuals with 22q11DS have a congenital heart defect (CHD), mostly of the conotruncal type, and/or an aortic arch defect. The etiology of this phenotypic variability is not currently known. We hypothesized that copy-number variants (CNVs) outside the 22q11.2 deleted region might increase the risk of being born with a CHD in this sensitized population. Genotyping with Affymetrix SNP Array 6.0 was performed on two groups of subjects with 22q11DS separated by time of ascertainment and processing. CNV analysis was completed on a total of 949 subjects (cohort 1, n = 562; cohort 2, n = 387), 603 with CHDs (cohort 1, n = 363; cohort 2, n = 240) and 346 with normal cardiac anatomy (cohort 1, n = 199; cohort 2, n = 147). Our analysis revealed that a duplication of SLC2A3 was the most frequent CNV identified in the first cohort. It was present in 18 subjects with CHDs and 1 subject without (p = 3.12 × 10(-3), two-tailed Fisher's exact test). In the second cohort, the SLC2A3 duplication was also significantly enriched in subjects with CHDs (p = 3.30 × 10(-2), two-tailed Fisher's exact test). The SLC2A3 duplication was the most frequent CNV detected and the only significant finding in our combined analysis (p = 2.68 × 10(-4), two-tailed Fisher's exact test), indicating that the SLC2A3 duplication might serve as a genetic modifier of CHDs and/or aortic arch anomalies in individuals with 22q11DS.
and Consortium CCG, Cornelis MC, Byrne EM, Esko T, Nalls MA, Ganna A, Paynter N, Monda KL, Amin N, Fischer K, Renstrom F, Ngwa JS, Huikari V, Cavadino A, Nolte IM, Teumer A, Yu K, Marques-Vidal P, Rawal R, Manichaikul A, Wojczynski MK, Vink JM, Zhao JH, Burlutsky G, Lahti J, Mikkilä V, Lemaitre RN, Eriksson J, Musani SK, Tanaka T, Geller F, Luan J, Hui J, Mägi R, Dimitriou M, Garcia ME, Ho W-K, Wright MJ, Rose LM, Magnusson PKE, Pedersen NL, Couper D, Oostra BA, Hofman A, Ikram MA, Tiemeier HW, Uitterlinden AG, van Rooij FJA, Barroso I, Johansson I, Xue L, Kaakinen M, Milani L, Power C, Snieder H, Stolk RP, Baumeister SE, Biffar R, Gu F, Bastardot F, Kutalik Z, Jacobs DR, Forouhi NG, Mihailov E, Lind L, Lindgren C, Michaëlsson K, Morris A, Jensen M, Khaw K-T, Luben RN, Wang JJ, Männistö S, Perälä M-M, Kähönen M, Lehtimäki T, Viikari J, Mozaffarian D, Mukamal K, Psaty BM, Döring A, Heath AC, Montgomery GW, Dahmen N, Carithers T, Tucker KL, Ferrucci L, Boyd HA, Melbye M, Treur JL, Mellström D, Hottenga JJ, Prokopenko I, Tönjes A, Deloukas P, Kanoni S, Lorentzon M, Houston DK, Liu Y, Danesh J, Rasheed A, Mason MA, Zonderman AB, Franke L, Kristal BS, Kristal BS, Kristal BS, Kristal BS, Karjalainen J, Reed DR, Westra H-J, Evans MK, Saleheen D, Harris TB, Dedoussis G, Curhan G, Stumvoll M, Beilby J, Pasquale LR, Feenstra B, Bandinelli S, Ordovas JM, Chan AT, Peters U, Ohlsson C, Gieger C, Martin NG, Waldenberger M, Siscovick DS, Raitakari O, Eriksson JG, Mitchell P, Hunter DJ, Kraft P, Rimm EB, Boomsma DI, Borecki IB, Loos RJF, Wareham NJ, Vollenweider P, Caporaso N, Grabe HJ, Neuhouser ML, Wolffenbuttel BHR, Hu FB, Hyppönen E, Järvelin M-R, Cupples LA, Franks PW, Ridker PM, van Duijn CM, Heiss G, Metspalu A, North KE, Ingelsson E, Nettleton JA, van Dam RM, Chasman DI. Genome-wide meta-analysis identifies six novel loci associated with habitual coffee consumption. Mol Psychiatry 2015;20(5):647-56.Abstract
Coffee, a major dietary source of caffeine, is among the most widely consumed beverages in the world and has received considerable attention regarding health risks and benefits. We conducted a genome-wide (GW) meta-analysis of predominately regular-type coffee consumption (cups per day) among up to 91 462 coffee consumers of European ancestry with top single-nucleotide polymorphisms (SNPs) followed-up in ~30 062 and 7964 coffee consumers of European and African-American ancestry, respectively. Studies from both stages were combined in a trans-ethnic meta-analysis. Confirmed loci were examined for putative functional and biological relevance. Eight loci, including six novel loci, met GW significance (log10Bayes factor (BF)>5.64) with per-allele effect sizes of 0.03-0.14 cups per day. Six are located in or near genes potentially involved in pharmacokinetics (ABCG2, AHR, POR and CYP1A2) and pharmacodynamics (BDNF and SLC6A4) of caffeine. Two map to GCKR and MLXIPL genes related to metabolic traits but lacking known roles in coffee consumption. Enhancer and promoter histone marks populate the regions of many confirmed loci and several potential regulatory SNPs are highly correlated with the lead SNP of each. SNP alleles near GCKR, MLXIPL, BDNF and CYP1A2 that were associated with higher coffee consumption have previously been associated with smoking initiation, higher adiposity and fasting insulin and glucose but lower blood pressure and favorable lipid, inflammatory and liver enzyme profiles (P<5 × 10(-8)).Our genetic findings among European and African-American adults reinforce the role of caffeine in mediating habitual coffee consumption and may point to molecular mechanisms underlying inter-individual variability in pharmacological and health effects of coffee.
Li Z, Allingham RR, Nakano M, Jia L, Chen Y, Ikeda Y, Mani B, Chen L-J, Kee C, Garway-Heath DF, Sripriya S, Fuse N, Abu-Amero KK, Huang C, Namburi P, Burdon K, Perera SA, Gharahkhani P, Lin Y, Ueno M, Ozaki M, Mizoguchi T, Krishnadas SR, Osman EA, Lee MC, Chan ASY, Tajudin L-SA, Do T, Goncalves A, Reynier P, Zhang H, Bourne R, Goh D, Broadway D, Husain R, Negi AK, Hsu D, Ho C-L, Blanco AA, Leung CKS, Wong TT, Yakub A, Liu Y, Nongpiur ME, Han JC, Hon DN, Shantha B, Zhao B, Sang J, Zhang N, Sato R, Yoshii K, Panda-Jonas S, Ashley Koch AE, Herndon LW, Moroi SE, Challa P, Foo JN, Bei J-X, Zeng Y-X, Simmons CP, Bich Chau TN, Sharmila PF, Chew M, Lim B, Tam POS, Chua E, Ng XY, Yong VHK, Chong YF, Meah WY, Vijayan S, Seongsoo S, Xu W, Teo YY, Cooke Bailey JN, Kang JH, Haines JL, Cheng CY, Saw S-M, Tai E-S, Tai E-S, Tai E-S, Richards JE, Ritch R, Gaasterland DE, Pasquale LR, Liu J, Jonas JB, Milea D, George R, Al-Obeidan SA, Mori K, Macgregor S, Hewitt AW, Girkin CA, Zhang M, Sundaresan P, Vijaya L, Mackey DA, Wong TY, Craig JE, Sun X, Kinoshita S, Wiggs JL, Khor C-C, Yang Z, Pang CP, Wang N, Hauser MA, Tashiro K, Aung T, Vithana EN. A common variant near TGFBR3 is associated with primary open angle glaucoma. Hum Mol Genet 2015;24(13):3880-92.Abstract

Primary open angle glaucoma (POAG), a major cause of blindness worldwide, is a complex disease with a significant genetic contribution. We performed Exome Array (Illumina) analysis on 3504 POAG cases and 9746 controls with replication of the most significant findings in 9173 POAG cases and 26 780 controls across 18 collections of Asian, African and European descent. Apart from confirming strong evidence of association at CDKN2B-AS1 (rs2157719 [G], odds ratio [OR] = 0.71, P = 2.81 × 10(-33)), we observed one SNP showing significant association to POAG (CDC7-TGFBR3 rs1192415, ORG-allele = 1.13, Pmeta = 1.60 × 10(-8)). This particular SNP has previously been shown to be strongly associated with optic disc area and vertical cup-to-disc ratio, which are regarded as glaucoma-related quantitative traits. Our study now extends this by directly implicating it in POAG disease pathogenesis.

Venturini G, Koskiniemi-Kuendig H, Harper S, Berson EL, Rivolta C. Two specific mutations are prevalent causes of recessive retinitis pigmentosa in North American patients of Jewish ancestry. Genet Med 2015;17(4):285-90.Abstract

PURPOSE: Retinitis pigmentosa is a Mendelian disease with a very elevated genetic heterogeneity. Most mutations are responsible for less than 1% of cases, making molecular diagnosis a multigene screening procedure. In this study, we assessed whether direct testing of specific alleles could be a valuable screening approach in cases characterized by prevalent founder mutations. METHODS: We screened 275 North American patients with recessive/isolate retinitis pigmentosa for two mutations: an Alu insertion in the MAK gene and the p.Lys42Glu missense in the DHDDS gene. All patients were unrelated; 35 reported Jewish ancestry and the remainder reported mixed ethnicity. RESULTS: We identified the MAK and DHDDS mutations homozygously in only 2.1% and 0.8%, respectively, of patients of mixed ethnicity, but in 25.7% and 8.6%, respectively, of cases reporting Jewish ancestry. Haplotype analyses revealed that inheritance of the MAK mutation was attributable to a founder effect. CONCLUSION: In contrast to most mutations associated with retinitis pigmentosa-which are, in general, extremely rare-the two alleles investigated here cause disease in approximately one-third of North American patients reporting Jewish ancestry. Therefore, their screening constitutes an alternative procedure to large-scale tests for patients belonging to this ethnic group, especially in time-sensitive situations.Genet Med 17 4, 285-290.

Gabel HW, Kinde B, Stroud H, Gilbert CS, Harmin DA, Kastan NR, Hemberg M, Ebert DH, Greenberg ME. Disruption of DNA-methylation-dependent long gene repression in Rett syndrome. Nature 2015;Abstract

Disruption of the MECP2 gene leads to Rett syndrome (RTT), a severe neurological disorder with features of autism. MECP2 encodes a methyl-DNA-binding protein that has been proposed to function as a transcriptional repressor, but despite numerous mouse studies examining neuronal gene expression in Mecp2 mutants, no clear model has emerged for how MeCP2 protein regulates transcription. Here we identify a genome-wide length-dependent increase in gene expression in MeCP2 mutant mouse models and human RTT brains. We present evidence that MeCP2 represses gene expression by binding to methylated CA sites within long genes, and that in neurons lacking MeCP2, decreasing the expression of long genes attenuates RTT-associated cellular deficits. In addition, we find that long genes as a population are enriched for neuronal functions and selectively expressed in the brain. These findings suggest that mutations in MeCP2 may cause neurological dysfunction by specifically disrupting long gene expression in the brain.

Andzelm MM, Cherry TJ, Harmin DA, Boeke AC, Lee C, Hemberg M, Pawlyk B, Malik AN, Flavell SW, Sandberg MA, Raviola E, Greenberg ME. MEF2D Drives Photoreceptor Development through a Genome-wide Competition for Tissue-Specific Enhancers. Neuron 2015;86(1):247-63.Abstract

Organismal development requires the precise coordination of genetic programs to regulate cell fate and function. MEF2 transcription factors (TFs) play essential roles in this process but how these broadly expressed factors contribute to the generation of specific cell types during development is poorly understood. Here we show that despite being expressed in virtually all mammalian tissues, in the retina MEF2D binds to retina-specific enhancers and controls photoreceptor cell development. MEF2D achieves specificity by cooperating with a retina-specific factor CRX, which recruits MEF2D away from canonical MEF2 binding sites and redirects it to retina-specific enhancers that lack the consensus MEF2-binding sequence. Once bound to retina-specific enhancers, MEF2D and CRX co-activate the expression of photoreceptor-specific genes that are critical for retinal function. These findings demonstrate that broadly expressed TFs acquire specific functions through competitive recruitment to enhancers by tissue-specific TFs and through selective activation of these enhancers to regulate tissue-specific genes.

Farkas MH, Au ED, Sousa ME, Pierce EA. RNA-Seq: Improving Our Understanding of Retinal Biology and Disease. Cold Spring Harb Perspect Med 2015;Abstract

Over the past several years, rapid technological advances have allowed for a dramatic increase in our knowledge and understanding of the transcriptional landscape, because of the ability to study gene expression in greater depth and with more detail than previously possible. To this end, RNA-Seq has quickly become one of the most widely used methods for studying transcriptomes of tissues and individual cells. Unlike previously favored analysis methods, RNA-Seq is extremely high-throughput, and is not dependent on an annotated transcriptome, laying the foundation for novel genetic discovery. Additionally, RNA-Seq derived transcriptomes provide a basis for widening the scope of research to identify potential targets in the treatment of retinal disease.

Mundell NA, Beier KT, Pan AY, Lapan SW, Göz Aytürk D, Berezovskii VK, Wark AR, Drokhlyansky E, Bielecki J, Born RT, Schier AF, Cepko CL. Vesicular stomatitis virus enables gene transfer and transsynaptic tracing in a wide range of organisms. J Comp Neurol 2015;523(11):1639-63.Abstract

Current limitations in technology have prevented an extensive analysis of the connections among neurons, particularly within nonmammalian organisms. We developed a transsynaptic viral tracer originally for use in mice, and then tested its utility in a broader range of organisms. By engineering the vesicular stomatitis virus (VSV) to encode a fluorophore and either the rabies virus glycoprotein (RABV-G) or its own glycoprotein (VSV-G), we created viruses that can transsynaptically label neuronal circuits in either the retrograde or anterograde direction, respectively. The vectors were investigated for their utility as polysynaptic tracers of chicken and zebrafish visual pathways. They showed patterns of connectivity consistent with previously characterized visual system connections, and revealed several potentially novel connections. Further, these vectors were shown to infect neurons in several other vertebrates, including Old and New World monkeys, seahorses, axolotls, and Xenopus. They were also shown to infect two invertebrates, Drosophila melanogaster, and the box jellyfish, Tripedalia cystophora, a species previously intractable for gene transfer, although no clear evidence of transsynaptic spread was observed in these species. These vectors provide a starting point for transsynaptic tracing in most vertebrates, and are also excellent candidates for gene transfer in organisms that have been refractory to other methods.

Balasubramanian R, Chew S, MacKinnon SE, Kang PB, Andrews C, Chan W-M, Engle EC. Expanding the phenotypic spectrum and variability of endocrine abnormalities associated with TUBB3 E410K syndrome. J Clin Endocrinol Metab 2015;100(3):E473-7.Abstract

CONTEXT: A heterozygous de novo c.1228G>A mutation (E410K) in the TUBB3 gene encoding the neuronal-specific β-tubulin isotype 3 (TUBB3) causes the TUBB3 E410K syndrome characterized by congenital fibrosis of the extraocular muscles (CFEOM), facial weakness, intellectual and social disabilities, and Kallmann syndrome (anosmia with hypogonadotropic hypogonadism). All TUBB3 E410K subjects reported to date are sporadic cases. OBJECTIVE: This study aimed to report the clinical, genetic, and molecular features of a familial presentation of the TUBB3 E410K syndrome. DESIGN: Case report of a mother and three affected children with clinical features of the TUBB3 E410K syndrome. SETTING: Academic Medical Center. MAIN OUTCOME MEASURES: Genetic analysis of the TUBB3 gene and clinical evaluation of endocrine and nonendocrine phenotypes. RESULTS: A de novo TUBB3 c.1228G>A mutation arose in a female proband who displayed CFEOM, facial weakness, intellectual and social disabilities, and anosmia. However, she underwent normal sexual development at puberty and had three spontaneous pregnancies with subsequent autosomal-dominant inheritance of the mutation by her three boys. All sons displayed nonendocrine features of the TUBB3 E410K syndrome similar to their mother but, in addition, had variable features suggestive of additional endocrine abnormalities. CONCLUSIONS: This first report of an autosomal-dominant inheritance of the TUBB3 c.1228G>A mutation in a family provides new insights into the spectrum and variability of endocrine phenotypes associated with the TUBB3 E410K syndrome. These observations emphasize the need for appropriate clinical evaluation and complicate genetic counseling of patients and families with this syndrome.

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