Insights into seven diseases revealed

Potential drug for atherosclerosis and type 2 diabetes, DNA damage contributes to stem cell ageing, MicroRNAs and tumour suppression, Hurricanes: Back to normal?, Evolution: It’s all so predictable and finally Fishy genome swims into view

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This press release is copyright Nature. VOL.447 NO.7145 DATED 07 JUNE 2007

This press release contains:

· Summaries of newsworthy papers:

Genomics: Insights into seven diseases revealed

Metabolic disease: Potential drug for atherosclerosis and type 2 diabetes

Stem cells: DNA damage contributes to stem cell ageing

Oncology: MicroRNAs and tumour suppression

Hurricanes: Back to normal?

Evolution: It’s all so predictable

And finally… Fishy genome swims into view

· Mention of papers to be published at the same time with the same embargo

· Geographical listing of authors

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[1], [2] & [3] Genomics: Insights into seven diseases revealed (pp 661-678; N&V; DOI: 10.1038/ng2061; DOI: 10.1038/ng2068)

The true potential of the human genome is uncovered in an article published in Nature this week. The study compares 2,000 cases each of seven common diseases with 3,000 shared control patients, and unveils new genetic associations with these disorders. A pair of related papers in Nature Genetics offer further insights into two of the seven diseases investigated.

In the Nature article, researchers from the Wellcome Trust Case Control Consortium report genetic variants associated with the development of bipolar disorder, Crohn’s disease, coronary heart disease, type 1 and type 2 diabetes, rheumatoid arthritis and hypertension. In the first study from this large scope, the scientists found one genetic region newly associated with bipolar disorder, and another with coronary artery disease. A separate group of three markers are associated with rheumatoid arthritis. The authors also identify nine new genetic associations for Crohn’s disease and ten chromosome regions that contain genes related to diabetes.

Separate papers in Nature Genetics support the new insights into the chromosome regions involved in Crohn’s disease—reporting strong association for six new loci—and detail replication of some of the results for type 1 diabetes.

Peter Donnelly, Miles Parkes, John Todd and colleagues believe their findings offer avenues of research for each of the seven disorders. This work represents a major step towards dissecting the biological bases of common diseases; future work is already focusing on translating the findings into improvements in human health.

CONTACT

Peter Donnelly (Chair, Wellcome Trust Case Control Consortium, University of Oxford, UK)

Author paper [1]

Tel: +44 1865 285 385; E-mail: [email protected]

Craig Brierley (Media Officer, Wellcome Trust, London, UK)

Tel: +44 20 7611 7329; E-mail: [email protected]

Anne M. Bowcock (Washington University School of Medicine, St Louis, MO, USA) N&V author

Tel: +1 314 747 3264; E-mail: [email protected]

Miles Parkes (Addenbrooke's Hospital & University of Cambridge, UK) Author paper [2]

Tel: +44 1223 216 389; E-mail: [email protected]

John Todd (Addenbrooke's Hospital & University of Cambridge, UK) Author paper [3]

Tel: +44 1223 762 101; E-mail: [email protected]

[4] Metabolic disease: Potential drug for atherosclerosis and type 2 diabetes (AOP)

DOI: 10.1038/nature05844

***This paper will be published electronically on Nature's website on 06 June at 1800 London time / 1300 US Eastern time (which is also when the embargo lifts) as part of our AOP (ahead of print) programme. Although we have included it on this release to avoid multiple mailings it will not appear in print on 07 June, but at a later date.***

A small-molecule inhibitor that has been successfully tested in mice may prove useful against chronic metabolic diseases such as atherosclerosis, obesity and type 2 diabetes, a Nature paper published online this week suggests.

Gökhan S. Hotamisligil and colleagues treated genetic mice models of various metabolic diseases with a drug that inhibits a protein called aP2. When given orally, the drug molecule reduced the size of atherosclerotic lesions in blood vessels. It also decreased blood glucose levels and increased insulin sensitivity in a model of obesity and insulin resistance.

aP2 is expressed in fat cells and scavenging white blood cells called macrophages, where it mediates metabolic and inflammatory reactions. It's already known that mice genetically manipulated to lack the protein are protected against various aspects of metabolic disease, suggesting that aP2 may prove a useful drug target for these conditions. This study backs this idea up, hinting that aP2 inhibitors may aid the treatment of human cardiovascular disease and diabetes.

CONTACT

Gökhan S. Hotamisligil (Harvard School of Public Health, Boston, MA, USA)
Tel: +1 617 432 1950; E-mail: [email protected]

[5] & [6] Stem cells: DNA damage contributes to stem cell ageing (pp 686-690; 725-729)

DNA damage can cause premature ageing in bone-marrow-derived stem cells, making it harder for them to function, two papers appearing in this week’s Nature suggest. The finding has implications for the use of adult stem cells in transplantation.

Long-lived multicellular organisms depend on small pools of slowly dividing stem cells to replenish lost tissue, and it's important that these reserves are self-renewed and maintained with minimal mutations throughout life.

Derrick J. Rossi and colleagues now show that blood-forming stem cells from the bone marrow of mice accumulate DNA damage with age. This, they say, might underlie the reduced capacity of stem cells to yield new tissues and repair injury over time.

Richard J. Cornall and colleagues studied bone-marrow-derived stem cells from a mouse strain that has problems repairing DNA damage, and arrived at a similar conclusion — under physiological conditions, unrepaired DNA damage in stem cells can lead to an age-dependent decline in their numbers.

CONTACT

Derrick J. Rossi (Stanford University, CA, USA) Author paper [5]
Tel: +1 650 723 7389; E-mail: [email protected]

Richard J. Cornall (Oxford University, UK) Author paper [6]
Tel: +44 1865 287 790; E-mail: [email protected]

Ruth Collier (Press Officer, Oxford University, UK)

Tel: +44 1865 280 532; E-mail: [email protected]

[7] Oncology: MicroRNAs and tumour suppression (AOP)

DOI: 10.1038/nature05939

***This paper will be published electronically on Nature's website on 06 June at 1800 London time / 1300 US Eastern time (which is also when the embargo lifts) as part of our AOP (ahead of print) programme. Although we have included it on this release to avoid multiple mailings it will not appear in print on 07 June, but at a later date.***

The tumour suppressor p53 acts directly on a family of small RNAs that are vital for cell growth and replication, according to a paper published online in Nature this week. Already well known for its indirect effects, p53 is now shown to target the miR-34 family of microRNAs (miRNAs), which itself suppresses cell proliferation.

A global decrease in miRNA levels is often observed in human cancers, indicating that small RNAs may have a part to play in tumour suppression. However, little is known about how miRNA expression is regulated. Gregory J. Hannon and colleagues compared the miRNA expression profiles of wild-type and p53-deficient mouse cells. They identified a family of non-coding miRNAs — miR-34 — that is the direct target of, and thus regulated by, p53, and show that the ectopic expression of these miRNAs leads to growth arrest and, in some cases, cell senescence. This suggests that the miR-34 family acts as components of p53-mediated growth and arrest pathways, and the authors describe several miR-34 target genes that have roles in cell cycle progression.

miR-34 is one of only 18 mammalian miRNA families that are also present in Drosophila and the nematode worm Caenorhabditis elegans. This raises the possibility that the link between p53 and miR-34 might have arisen early in the evolution of the p53 network and may be important in p53 function in diverse species, the authors speculate. The paper represents one of the first discoveries of direct transcriptional regulators for miRNAs and is likely to be the tip of the iceberg.

CONTACT

Gregory J. Hannon (Cold Spring Harbor Laboratory, NY, USA)
Tel: +1 516 367 8889; E-mail: [email protected]

[8] Hurricanes: Back to normal? (pp 698-701; N&V)

The increase in the number of major Atlantic hurricanes since 1995 could be a recovery to normal activity, rather than a rise to unusually high levels, suggests a report in this week’s Nature. According to the study, which uses proxy records of vertical wind shear and sea surface temperature to reconstruct the number of major Atlantic hurricanes over the past 270 years, the storm frequency was anomalously low during the 1970s and 1980s.

The frequency of major hurricanes over the Atlantic Ocean has risen significantly since 1995, but it remains unclear whether this change is due to global warming or natural variability. One way to address this question is to consider changes in hurricane activity in the past, but reliable observations only cover the past few decades.

Johan Nyberg and colleagues used proxy records from corals and a marine sediment core that reflect changes in the two main parameters that influence hurricane activity — vertical wind shear and sea surface temperature — to reconstruct the frequency of major hurricanes over the Atlantic since 1730. The records show that the lull in hurricane activity from the late 1960s to early 1990s is an exception, and that the current active period from 1995 onwards reflects a return to ‘normal’ activity, rather than a direct response to increasing sea surface temperature. The records indicate that variations in vertical wind shear may have been responsible for the changes in hurricane frequency, although the underlying causes of changes in this parameter remain uncertain. The authors suggest that it is therefore crucial to understand future changes in the magnitude of vertical wind shear, because they may have a significant influence on hurricane activity.

CONTACT

Johan Nyberg (Geological Survey of Sweden, Uppsala, Sweden)
Tel: +46 18 17 91 94; E-mail: [email protected]

James B. Elsner (Florida State University, Tallahassee, FL, USA) N&V author

Tel: +1 850 877 4039; E-mail: [email protected]

[9] Evolution: It’s all so predictable (pp 706-709)

Sometimes evolution isn’t the random process that people might think. The long petals of columbine (Aquilegia) flowers may have evolved in an entirely predictable way, but not for the reason that Darwin predicted.

Justen B. Whittall and Scott A. Hodges assessed the evolutionary relatedness of Aquilegia, a group of herbaceous perennial plants with distinctive flowers — each petal is modified into an elongated nectar spur. In this week’s Nature, they show that the nectar spurs evolved in a recurring and directional fashion, getting longer and longer over time.

The team thinks that the shape evolved in a punctuated manner, with plants adapting to new species of unrelated pollinators, each one with a longer tongue than its predecessor. This is at odds with Darwin’s prediction that a co-evolutionary ‘arms race’ drove the increase in length of both nectar spur and pollinator’s tongue.

CONTACT

Justen B. Whittall (University of California, Davis, CA, USA)
Tel:+1 530 574 3341; E-mail: [email protected]

[10] And finally… Fishy genome swims into view (pp 714-719)

The medaka fish (Oryzias latipes), a popular pet in Japan and model organism in the laboratory, has had its genome sequenced. The data, reported in this week’s Nature, offer novel insights into vertebrate genome evolution.

Shinichi Morishita and colleagues estimate that the small egg-laying freshwater fish’s genome contains approximately 20,000 genes, of which around 2,900 appear new and unique to medaka.

Teleosts (fish with bony skeletons), such as the medaka fish, make up more than half of all vertebrate species and have adapted to life in a variety of marine and freshwater habitats. The evolution and diversification of their genomes is therefore crucial to understanding how vertebrates evolved.

The team compared their high-quality draft sequence against human, pufferfish (Tetraodon) and zebrafish genomes. It’s already known that at some point in the past the whole teleost genome doubled. The new study shows that the last common ancestor of medaka, pufferfish and zebrafish experienced 8 major rearrangements between chromosomes within just 50 million years of this event. But where the zebrafish genome has changed considerably since it diverged from the last common ancestor some 320 million years ago, the medaka genome has remained remarkably unchanged for over 300 million years.

CONTACT

Shinichi Morishita (University of Tokyo, Chiba, Japan)
Tel: +81 47 136 3984; E-mail: [email protected]

ALSO IN THIS ISSUE…

[11] High-resolution, high-sensitivity NMR of nanolitre anisotropic samples by coil spinning (pp 694-697; N&V)

[12] Boron and oxygen isotope evidence for recycling of subducted components over the past 2.5 Gyr (pp 702-705)

[13] Dscam2 mediates axonal tiling in the Drosophila visual system (pp 720-724)

[14] The ATM repair pathway inhibits RNA polymerase I transcription in response to chromosome breaks (pp 730-734)

[15] Control of DNA methylation and heterochromatic silencing by histone H2B deubiquitination (pp 735-738)

ADVANCE ONLINE PUBLICATION

***This paper will be published electronically on Nature's website on 06 June at 1800 London time / 1300 US Eastern time (which is also when the embargo lifts) as part of our AOP (ahead of print) programme. Although we have included it on this release to avoid multiple mailings it will not appear in print on 07 June, but at a later date.***

[16] Akt/PKB regulates hepatic metabolism by directly inhibiting PGC-1a transcription coactivator

DOI: 10.1038/nature05861

GEOGRAPHICAL LISTING OF AUTHORS…

The following list of places refers to the whereabouts of authors on the papers numbered in this release. For example, London: 4 - this means that on paper number four, there will be at least one author affiliated to an institute or company in London. The listing may be for an author's main affiliation, or for a place where they are working temporarily. Please see the PDF of the paper for full details.

AUSTRALIA

Canberra: 6

Clayton: 12

Sydney: 12

FINLAND

Helsinki: 3

FRANCE

Gif-sur-Yvette: 11

Paris: 1

GAMBIA

Fajara: 1

ITALY

Pisa: 12

Trieste: 6

JAPAN

Kanagawa: 4

Mishima: 10

Niigata: 10

Tokyo: 10

Yokohama: 10

NETHERLANDS

Rotterdam: 5

PUERTO RICO

Puerto Rico: 8

ROMANIA

Bucharest: 3

SWEDEN

Goteborg: 8

Lund: 5

Uppsala: 8

UNITED KINGDOM

Aberdeen: 1

Birmingham: 1, 3

Brentwood: 1

Brighton: 6

Bristol: 1, 2

Cambridge: 1, 2, 3

Cardiff: 1

Edinburgh: 1, 2

Exeter: 1

Glasgow: 1

Leeds: 1

Leicester: 1

Little Chesterford: 1

London: 1, 2, 3

Manchester: 1

Newcastle: 1

Oxford: 1, 2, 6

Pontyclun: 1

Sheffield: 1

Southampton: 1

Sutton: 1

Uxbridge: 6

UNITED STATES OF AMERICA

California

Davis: 9

Foster City: 7

Los Altos: 14

Los Angeles: 13

Riverside: 15

Santa Barbara: 9

Stanford: 5

Colorado

Boulder: 8

Florida

St Petersburg: 8

Indiana

West Lafayette: 15

Maryland

Bethesda: 5, 14

Massachusetts

Boston: 4

Danvers: 16

New Jersey

Princeton: 4

New York

Cold Spring Harbor: 7

New York: 7

Stony Brook: 7

North Carolina

Durham: 4

Oregon

Eugene: 12

Pennsylvania

Philadelphia: 16

Tennessee

Nashville: 4

Texas

Austin: 8

Virginia

Arlington: 12

Washington

Seattle: 7

Wisconsin

Madison: 12

PRESS CONTACTS…

For North America and Canada

Katie McGoldrick, Nature Washington

Tel: +1 202 737 2355; E-mail: [email protected]

For Japan, Korea, China, Singapore and Taiwan

Mika Nakano, Nature Tokyo

Tel: +81 3 3267 8751; E-mail: [email protected]

For the UK/Europe/other countries not listed above

Helen Jamison, Nature London

Tel: +44 20 7843 4658; E-mail [email protected]

About NPG

Nature Publishing Group (NPG) is a division of Macmillan Publishers Ltd, dedicated to serving the academic, professional scientific and medical communities. NPG's flagship title, Nature, was first published in 1869. Other publications include Nature research journals, Nature Reviews, Nature Clinical Practice and a range of prestigious academic journals including society-owned publications. NPG also provides news content through [email protected]. Scientific career information and free job postings are offered on Naturejobs.

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Published: 06 Jun 2007

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