Nature Genetics 40, 1385 (2008). doi:10.1038/ng1208-1385

Tissue-specific expression of mRNA isoforms and interindividual differences in isoform usage can now be quantitated by genome-wide assays, both by custom microarray and by next-generation sequencing.

Nature Genetics 40, 1391 (2008). doi:10.1038/ng1208-1391

Author: V Narry Kim

Embryonic stem (ES) cells undergo rapid cell division without compromising their ability to differentiate into virtually all cell types. Using ES cells deficient for a microRNA biogenesis factor, Dgcr8, a new report uncovers the importance of specific microRNAs in the ES cell cycle transition from G1 to S phase.

Nature Genetics 40, 1394 (2008). doi:10.1038/ng1208-1394

Author: Karen L Mohlke

Fat accumulation in the liver is a common trait that may progress to severe liver disease. A new study identifies common and rare nonsynonymous variants in PNPLA3 that are associated with hepatic triglyceride content and that may explain some of the population differences in prevalence.

Nature Genetics 40, 1392 (2008). doi:10.1038/ng1208-1392

Authors: Michael C O'Donovan, George Kirov & Michael J Owen

Copy number variation has emerged as an important type of genetic risk factor for developmental disorders, including the neurodevelopmental disorders schizophrenia, autism and mental retardation. The highly pleiotropic effects observed for specific copy number variants (CNVs) challenge current classification of these disorders, but also provide opportunities to understand their origins and the relationships between them.

Nature Genetics 40, 1402 (2008). doi:10.1038/ng.251

Authors: Yurii S Aulchenko, Ilse A Hoppenbrouwers, Sreeram V Ramagopalan, Linda Broer, Naghmeh Jafari, Jan Hillert, Jenny Link, Wangko Lundström, Eva Greiner, A Dessa Sadovnick, Dirk Goossens, Christine Van Broeckhoven, Jurgen Del-Favero, George C Ebers, Ben A Oostra, Cornelia M van Duijn & Rogier Q Hintzen

The few loci associated with multiple sclerosis (MS) are all related to immune function. We report a GWA study identifying a new locus replicated in 2,679 cases and 3,125 controls. An rs10492972[C] variant located in the KIF1B gene was associated with MS with an odds ratio of 1.35 (P = 2.5 × 10−10). KIF1B is a neuronally expressed gene plausibly implicated in the irreversible axonal loss characterizing MS in the long term.

Nature Genetics 40, 1399 (2008). doi:10.1038/ng.249

Authors: Jason D Cooper, Deborah J Smyth, Adam M Smiles, Vincent Plagnol, Neil M Walker, James E Allen, Kate Downes, Jeffrey C Barrett, Barry C Healy, Josyf C Mychaleckyj, James H Warram & John A Todd

Nature Genetics 40, 1410 (2008). doi:10.1038/ng.252

Authors: Hans Christian Hennies, Uwe Kornak, Haikuo Zhang, Johannes Egerer, Xin Zhang, Wenke Seifert, Jirko Kühnisch, Birgit Budde, Marc Nätebus, Francesco Brancati, William R Wilcox, Dietmar Müller, Paige B Kaplan, Anna Rajab, Giuseppe Zampino, Valentina Fodale, Bruno Dallapiccola, William Newman, Kay Metcalfe, Jill Clayton-Smith, May Tassabehji, Beat Steinmann, Francis A Barr, Peter Nürnberg, Peter Wieacker & Stefan Mundlos

Gerodermia osteodysplastica is an autosomal recessive disorder characterized by wrinkly skin and osteoporosis. Here we demonstrate that gerodermia osteodysplastica is caused by loss-of-function mutations in SCYL1BP1, which is highly expressed in skin and osteoblasts. The protein localizes to the Golgi apparatus and interacts with Rab6, identifying SCYL1BP1 as a golgin. These results associate abnormalities of the secretory pathway with age-related changes in connective tissues.

Nature Genetics 40, 1404 (2008). doi:10.1038/ng.254

Authors: James D McKay, Rayjean J Hung, Valerie Gaborieau, Paolo Boffetta, Amelie Chabrier, Graham Byrnes, David Zaridze, Anush Mukeria, Neonilia Szeszenia-Dabrowska, Jolanta Lissowska, Peter Rudnai, Eleonora Fabianova, Dana Mates, Vladimir Bencko, Lenka Foretova, Vladimir Janout, John McLaughlin, Frances Shepherd, Alexandre Montpetit, Steven Narod, Hans E Krokan, Frank Skorpen, Maiken Bratt Elvestad, Lars Vatten, Inger Njølstad, Tomas Axelsson, Chu Chen, Gary Goodman, Matt Barnett, Melissa M Loomis, Jan Lubiñski, Joanna Matyjasik, Marcin Lener, Dorota Oszutowska, John Field, Triantafillos Liloglou, George Xinarianos, Adrian Cassidy, Diana Zelenika, Anne Boland, Marc Delepine, Mario Foglio, Doris Lechner, Fumihiko Matsuda, Helene Blanche, Ivo Gut, Simon Heath, Mark Lathrop & Paul Brennan

We carried out a genome-wide association study of lung cancer (3,259 cases and 4,159 controls), followed by replication in 2,899 cases and 5,573 controls. Two uncorrelated disease markers at 5p15.33, rs402710 and rs2736100 were detected by the genome-wide data (P = 2 × 10−7 and P = 4 × 10−6) and replicated by the independent study series (P = 7 × 10−5 and P = 0.016). The susceptibility region contains two genes, TERT and CLPTM1L, suggesting that one or both may have a role in lung cancer etiology.

Nature Genetics 40, 1413 (2008). doi:10.1038/ng.259

Authors: Qun Pan, Ofer Shai, Leo J Lee, Brendan J Frey & Benjamin J Blencowe

We carried out the first analysis of alternative splicing complexity in human tissues using mRNA-Seq data. New splice junctions were detected in ∼20% of multiexon genes, many of which are tissue specific. By combining mRNA-Seq and EST-cDNA sequence data, we estimate that transcripts from ∼95% of multiexon genes undergo alternative splicing and that there are ∼100,000 intermediate- to high-abundance alternative splicing events in major human tissues. From a comparison with quantitative alternative splicing microarray profiling data, we also show that mRNA-Seq data provide reliable measurements for exon inclusion levels.

Nature Genetics 40, 1407 (2008). doi:10.1038/ng.273

Authors: Yufei Wang, Peter Broderick, Emily Webb, Xifeng Wu, Jayaram Vijayakrishnan, Athena Matakidou, Mobshra Qureshi, Qiong Dong, Xiangjun Gu, Wei Vivien Chen, Margaret R Spitz, Timothy Eisen, Christopher I Amos & Richard S Houlston

We conducted a genome-wide association (GWA) study of lung cancer comparing 511,919 SNP genotypes in 1,952 cases and 1,438 controls. The most significant association was attained at 15q25.1 (rs8042374; P = 7.75 × 10−12), confirming recent observations. Pooling data with two other GWA studies (5,095 cases, 5,200 controls) and with replication in an additional 2,484 cases and 3,036 controls, we identified two newly associated risk loci mapping to 6p21.33 (rs3117582, BAT3-MSH5; Pcombined = 4.97 × 10−10) and 5p15.33 (rs401681, CLPTM1L; Pcombined = 7.90 × 10−9).

Nature Genetics 40, 1416 (2008). doi:10.1038/ng.264

Authors: John C Castle, Chaolin Zhang, Jyoti K Shah, Amit V Kulkarni, Auinash Kalsotra, Thomas A Cooper & Jason M Johnson

Nature Genetics 40, 1426 (2008). doi:10.1038/ng.262

Authors:

Nature Genetics 40, 1436 (2008). doi:10.1038/ng.256

Authors: Victoria Marsh, Douglas J Winton, Geraint T Williams, Nicole Dubois, Andreas Trumpp, Owen J Sansom & Alan R Clarke

Nature Genetics 40, 1454 (2008). doi:10.1038/ng.267

Authors: Jennifer L Stubbs, Isao Oishi, Juan Carlos Izpisúa Belmonte & Chris Kintner

Nature Genetics 40, 1445 (2008). doi:10.1038/ng.263

Authors: Xianwen Yu, Chee Peng Ng, Hermann Habacher & Sudipto Roy

Nature Genetics 40, 1472 (2008). doi:10.1038/ng.240

Authors: Kaya Bilguvar, Katsuhito Yasuno, Mika Niemelä, Ynte M Ruigrok, Mikael von und zu Fraunberg, Cornelia M van Duijn, Leonard H van den Berg, Shrikant Mane, Christopher E Mason, Murim Choi, Emília Gaál, Yasar Bayri, Luis Kolb, Zulfikar Arlier, Sudhakar Ravuri, Antti Ronkainen, Atsushi Tajima, Aki Laakso, Akira Hata, Hidetoshi Kasuya, Timo Koivisto, Jaakko Rinne, Juha Öhman, Monique M B Breteler, Cisca Wijmenga, Matthew W State, Gabriel J E Rinkel, Juha Hernesniemi, Juha E Jääskeläinen, Aarno Palotie, Ituro Inoue, Richard P Lifton & Murat Günel

Stroke is the world's third leading cause of death. One cause of stroke, intracranial aneurysm, affects ∼2% of the population and accounts for 500,000 hemorrhagic strokes annually in mid-life (median age 50), most often resulting in death or severe neurological impairment. The pathogenesis of intracranial aneurysm is unknown, and because catastrophic hemorrhage is commonly the first sign of disease, early identification is essential. We carried out a multistage genome-wide association study (GWAS) of Finnish, Dutch and Japanese cohorts including over 2,100 intracranial aneurysm cases and 8,000 controls. Genome-wide genotyping of the European cohorts and replication studies in the Japanese cohort identified common SNPs on chromosomes 2q, 8q and 9p that show significant association with intracranial aneurysm with odds ratios 1.24–1.36. The loci on 2q and 8q are new, whereas the 9p locus was previously found to be associated with arterial diseases, including intracranial aneurysm. Associated SNPs on 8q likely act via SOX17, which is required for formation and maintenance of endothelial cells, suggesting a role in development and repair of the vasculature; CDKN2A at 9p may have a similar role. These findings have implications for the pathophysiology, diagnosis and therapy of intracranial aneurysm.

Nature Genetics 40, 1466 (2008). doi:10.1038/ng.279

Authors: Nicola Brunetti-Pierri, Jonathan S Berg, Fernando Scaglia, John Belmont, Carlos A Bacino, Trilochan Sahoo, Seema R Lalani, Brett Graham, Brendan Lee, Marwan Shinawi, Joseph Shen, Sung-Hae L Kang, Amber Pursley, Timothy Lotze, Gail Kennedy, Susan Lansky-Shafer, Christine Weaver, Elizabeth R Roeder, Theresa A Grebe, Georgianne L Arnold, Terry Hutchison, Tyler Reimschisel, Stephen Amato, Michael T Geragthy, Jeffrey W Innis, Ewa Obersztyn, Beata Nowakowska, Sally S Rosengren, Patricia I Bader, Dorothy K Grange, Sayed Naqvi, Adolfo D Garnica, Saunder M Bernes, Chin-To Fong, Anne Summers, W David Walters, James R Lupski, Pawel Stankiewicz, Sau Wai Cheung & Ankita Patel

Chromosome region 1q21.1 contains extensive and complex low-copy repeats, and copy number variants (CNVs) in this region have recently been reported in association with congenital heart defects, developmental delay, schizophrenia and related psychoses. We describe 21 probands with the 1q21.1 microdeletion and 15 probands with the 1q21.1 microduplication. These CNVs were inherited in most of the cases in which parental studies were available. Consistent and statistically significant features of microcephaly and macrocephaly were found in individuals with microdeletion and microduplication, respectively. Notably, a paralog of the HYDIN gene located on 16q22.2 and implicated in autosomal recessive hydrocephalus was inserted into the 1q21.1 region during the evolution of Homo sapiens; we found this locus to be deleted or duplicated in the individuals we studied, making it a probable candidate for the head size abnormalities observed. We propose that recurrent reciprocal microdeletions and microduplications within 1q21.1 represent previously unknown genomic disorders characterized by abnormal head size along with a spectrum of developmental delay, neuropsychiatric abnormalities, dysmorphic features and congenital anomalies. These phenotypes are subject to incomplete penetrance and variable expressivity.

Nature Genetics 40, 1493 (2008). doi:10.1038/ng.281

Authors: Mary J Dunlop, Robert Sidney Cox, Joseph H Levine, Richard M Murray & Michael B Elowitz

Gene regulatory interactions are context dependent, active in some cellular states but not in others. Stochastic fluctuations, or 'noise', in gene expression propagate through active, but not inactive, regulatory links. Thus, correlations in gene expression noise could provide a noninvasive means to probe the activity states of regulatory links. However, global, 'extrinsic', noise sources generate correlations even without direct regulatory links. Here we show that single-cell time-lapse microscopy, by revealing time lags due to regulation, can discriminate between active regulatory connections and extrinsic noise. We demonstrate this principle mathematically, using stochastic modeling, and experimentally, using simple synthetic gene circuits. We then use this approach to analyze dynamic noise correlations in the galactose metabolism genes of Escherichia coli. We find that the CRP-GalS-GalE feed-forward loop is inactive in standard conditions but can become active in a GalR mutant. These results show how noise can help analyze the context dependence of regulatory interactions in endogenous gene circuits.

Nature Genetics 40, 1499 (2008). doi:10.1038/ng.280

Authors: Katy C Kao & Gavin Sherlock

The classical model of adaptive evolution in an asexual population postulates that each adaptive clone is derived from the one preceding it. However, experimental evidence has suggested more complex dynamics, with theory predicting the fixation probability of a beneficial mutation as dependent on the mutation rate, population size and the mutation's selection coefficient. Clonal interference has been demonstrated in viruses and bacteria but not in a eukaryote, and a detailed molecular characterization is lacking. Here we use three different fluorescent markers to visualize the dynamics of asexually evolving yeast populations. For each adaptive clone within one of our evolving populations, we identified the underlying mutations, monitored their population frequencies and used microarrays to characterize changes in the transcriptome. These results represent the most detailed molecular characterization of experimental evolution to date and provide direct experimental evidence supporting both the clonal interference and the multiple mutation models.

Nature Genetics 40, 1489 (2008). doi:10.1038/ng.253

Authors: Siegbert Melzer, Frederic Lens, Jerôme Gennen, Steffen Vanneste, Antje Rohde & Tom Beeckman

Plants have evolved annual and perennial life forms as alternative strategies to adapt reproduction and survival to environmental constraints. In isolated situations, such as islands, woody perennials have evolved repeatedly from annual ancestors. Although the molecular basis of the rapid evolution of insular woodiness is unknown, the molecular difference between perennials and annuals might be rather small, and a change between these life strategies might not require major genetic innovations. Developmental regulators can strongly affect evolutionary variation and genes involved in meristem transitions are good candidates for a switch in growth habit. We found that the MADS box proteins SUPPRESSOR OF OVEREXPRESSION OF CONSTANS 1 (SOC1) and FRUITFULL (FUL) not only control flowering time, but also affect determinacy of all meristems. In addition, downregulation of both proteins established phenotypes common to the lifestyle of perennial plants, suggesting their involvement in the prevention of secondary growth and longevity in annual life forms.

Nature Genetics 40, 1461 (2008). doi:10.1038/ng.257

Authors: Stefano Romeo, Julia Kozlitina, Chao Xing, Alexander Pertsemlidis, David Cox, Len A Pennacchio, Eric Boerwinkle, Jonathan C Cohen & Helen H Hobbs

Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem of unknown etiology that varies in prevalence among ancestry groups. To identify genetic variants contributing to differences in hepatic fat content, we carried out a genome-wide association scan of nonsynonymous sequence variations (n = 9,229) in a population comprising Hispanic, African American and European American individuals. An allele in PNPLA3 (rs738409[G], encoding I148M) was strongly associated with increased hepatic fat levels (P = 5.9 × 10−10) and with hepatic inflammation (P = 3.7 × 10−4). The allele was most common in Hispanics, the group most susceptible to NAFLD; hepatic fat content was more than twofold higher in PNPLA3 rs738409[G] homozygotes than in noncarriers. Resequencing revealed another allele of PNPLA3 (rs6006460[T], encoding S453I) that was associated with lower hepatic fat content in African Americans, the group at lowest risk of NAFLD. Thus, variation in PNPLA3 contributes to ancestry-related and inter-individual differences in hepatic fat content and susceptibility to NAFLD.

Nature Genetics 40, 1484 (2008). doi:10.1038/ng.258

Authors: Timothy Wai, Daniella Teoli & Eric A Shoubridge

In mammals, mitochondrial DNA (mtDNA) sequence variants are observed to segregate rapidly between generations despite the high mtDNA copy number in the oocyte. This has led to the concept of a genetic bottleneck for the transmission of mtDNA, but the mechanism remains contentious. Several studies have suggested that the bottleneck occurs during embryonic development, as a result of a marked reduction in germline mtDNA copy number. Mitotic segregation of mtDNAs during preimplantation, or during the expansion of primordial germ cells (PGCs) before they colonize the gonad, is thought to account for the increase in genotypic variance observed among mature oocytes from heteroplasmic mothers. This view has, however, been challenged by studies suggesting that the bottleneck occurs without a reduction in germline mtDNA content. To resolve this controversy, we measured mtDNA heteroplasmy and copy number in single germ cells isolated from heteroplasmic mice. By directly tracking the evolution of mtDNA genotypic variance during oogenesis, we show that the genetic bottleneck occurs during postnatal folliculogenesis and not during embryonic oogenesis.

Nature Genetics 40, 1478 (2008). doi:10.1038/ng.250

Authors: Yangming Wang, Scott Baskerville, Archana Shenoy, Joshua E Babiarz, Lauren Baehner & Robert Blelloch

Dgcr8 knockout embryonic stem (ES) cells lack microprocessor activity and hence all canonical microRNAs (miRNAs). These cells proliferate slowly and accumulate in G1 phase of the cell cycle. Here, by screening a comprehensive library of individual miRNAs in the background of the Dgcr8 knockout ES cells, we report that multiple ES cell–specific miRNAs, members of the miR-290 family, rescue the ES cell proliferation defect. Furthermore, rescued cells no longer accumulate in the G1 phase of the cell cycle. These miRNAs function by suppressing several key regulators of the G1-S transition. These results show that post-transcriptional regulation by miRNAs promotes the G1-S transition of the ES cell cycle, enabling rapid proliferation of these cells. Our screening strategy provides an alternative and powerful approach for uncovering the role of individual miRNAs in biological processes, as it overcomes the common problem of redundancy and saturation in the miRNA system.