Featured
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Letter |
EZH2 inhibition as a therapeutic strategy for lymphoma with EZH2-activating mutations
EZH2 is a methyltransferase that is mutated in lymphoma; here a potent small molecule inhibitor of EZH2 is described, which inhibits the proliferation of EZH2 mutant cell lines and growth of EZH2 mutant xenografts in mice, thus providing a potential treatment for EZH2 mutant lymphoma.
- Michael T. McCabe
- , Heidi M. Ott
- & Caretha L. Creasy
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News & Views |
The rate of human mutation
A comprehensive analysis of human spontaneous mutation has revealed a strong influence of paternal age, suggesting a link between an increasing number of older fathers and the rise in disorders such as autism. See Article p.471
- Alexey Kondrashov
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Article |
Rate of de novo mutations and the importance of father’s age to disease risk
Whole-genome sequencing of 78 Icelandic parent–offspring trios is used to study the de novo mutation rate at the genome-wide level; the rate is shown to increase by about two mutations a year as a function of the increasing age of the father at conception, highlighting the importance of father’s age on the risk of diseases such as autism and schizophrenia.
- Augustine Kong
- , Michael L. Frigge
- & Kari Stefansson
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News & Views |
Exploiting collateral damage
Some mutations in tumour cells play no part in causing cancer, but they generate cellular weak spots that may allow tumour cells to be selectively killed by drugs. See Article p.337
- Ben Lehner
- & Solip Park
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News & Views |
A protective mutation
A rare gene variant has been found that decreases the peptide deposition seen in the brains of people with Alzheimer's disease. The mutation may also slow the normal cognitive decline that occurs with age. See Letter p.96
- Bart De Strooper
- & Thierry Voet
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Letter |
Chromatin organization is a major influence on regional mutation rates in human cancer cells
Mutation rates in cancer genomes are closely related to chromatin organization, indicating that the arrangement of the genome into heterochromatin- and euchromatin-like domains may be a dominant influence on variation in regional mutation rate in human somatic cells.
- Benjamin Schuster-Böckler
- & Ben Lehner
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Letter |
Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis
Mutations in the profilin 1 (PFN1) gene, which is crucial for the conversion of monomeric to filamentous actin, can cause familial amyotrophic lateral sclerosis, suggesting that alterations in cytoskeletal pathways contribute to disease pathogenesis.
- Chi-Hong Wu
- , Claudia Fallini
- & John E. Landers
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News |
Gene mutation sought to explain mysterious language problem
A family that struggles to recall words could provide a window into the biology of language cognition.
- Ewen Callaway
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Article
| Open Access
Whole-genome analysis informs breast cancer response to aromatase inhibition
Whole-genome analysis of oestrogen-receptor-positive tumours in patients treated with aromatase inhibitors show that distinct phenotypes are associated with specific patterns of somatic mutations; however, most recurrent mutations are relatively infrequent so prospective clinical trials will require comprehensive sequencing and large study populations.
- Matthew J. Ellis
- , Li Ding
- & Elaine R. Mardis
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Letter |
A tumour suppressor network relying on the polyamine–hypusine axis
AMD1 and eIF5A are identified as two genes involved in the polyamine–hypusine pathway, a new tumour suppressor network regulating apoptosis.
- Claudio Scuoppo
- , Cornelius Miething
- & Scott W. Lowe
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Letter |
The mutational landscape of lethal castration-resistant prostate cancer
Exome sequencing is used to investigate the role of mutations and copy number aberrations in metastatic castration-resistant prostate cancer, revealing recurrent mutations in multiple chromatin/histone modifying genes, as well as genes involved in androgen signalling.
- Catherine S. Grasso
- , Yi-Mi Wu
- & Scott A. Tomlins
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Letter |
The landscape of cancer genes and mutational processes in breast cancer
A study of breast cancers shows that the number of somatic mutations in each varies markedly and is strongly correlated with age at diagnosis and cancer histological grade.
- Philip J. Stephens
- , Patrick S. Tarpey
- & Michael R. Stratton
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Research Highlights |
Gene duplication for bigger brains
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News |
Study links genes to melanoma development
Sequencing of skin cancers reveals genetic effects of sun damage.
- Erika Check Hayden
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Letter
| Open Access
Melanoma genome sequencing reveals frequent PREX2 mutations
Whole-genome sequencing of 25 metastatic melanomas and matched germline DNA in humans reveals that the highest mutation load is associated with chronic sun exposure, and that the PREX2 gene is mutated in approximately 14 per cent of cases
- Michael F. Berger
- , Eran Hodis
- & Levi A. Garraway
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News |
Blonde hair evolved more than once
Golden locks of dark-skinned Melanesians have different genetic basis to those of Europeans.
- Zoë Corbyn
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News |
Human brain shaped by duplicate genes
Multiple copies of a gene may have boosted the computational power of our ancestors' brains.
- Ewen Callaway
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Letter |
Evidence of non-random mutation rates suggests an evolutionary risk management strategy
The local mutation rate in Escherichia coli has evolved to reduce the risk of deleterious mutations, leading to a non-random occurrence of mutations and suggesting that DNA protection and repair mechanisms preferentially target more important genes.
- Iñigo Martincorena
- , Aswin S. N. Seshasayee
- & Nicholas M. Luscombe
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Letter |
Validation of ITD mutations in FLT3 as a therapeutic target in human acute myeloid leukaemia
Internal tandem duplication mutations in FLT3, known to be associated with a poor prognosis in acute myeloid leukaemia, are now shown to be a valid therapeutic target for the disease.
- Catherine C. Smith
- , Qi Wang
- & Neil P. Shah
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News |
Genome analysis homes in on malaria-drug resistance
Researchers find genetic changes that may reduce effectiveness of artemisinin.
- Melissa Lee Phillips
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News |
Mutations behind flu spread revealed
Details of one of two controversial mutant flu papers discussed in London.
- Ed Yong
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News |
Stickleback genomes reveal path of evolution
Fish have used pre-existing genetic variation to colonize fresh water many times.
- Helen Shen
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Letter |
De novo mutations revealed by whole-exome sequencing are strongly associated with autism
Rare de novo single nucleotide variants in brain-expressed genes are found to be associated with autism spectrum disorders and to carry large effects.
- Stephan J. Sanders
- , Michael T. Murtha
- & Matthew W. State
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Letter |
Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations
Exome sequencing on a large cohort of parent–child trios with sporadic autism spectrum disorders shows that de novo point mutations are mainly paternal in origin and positively correlate with paternal age, and identifies a highly interconnected network formed from the products of the most severe mutations.
- Brian J. O’Roak
- , Laura Vives
- & Evan E. Eichler
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Letter |
Patterns and rates of exonic de novo mutations in autism spectrum disorders
Exome sequencing of 175 autism spectrum disorder parent–child trios reveals that few de novo point mutations have a role in autism spectrum disorder and those that do are distributed across many genes and are incompletely penetrant, further supporting extreme genetic heterogeneity of this spectrum disorder.
- Benjamin M. Neale
- , Yan Kou
- & Mark J. Daly
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Letter |
The clonal and mutational evolution spectrum of primary triple-negative breast cancers
Primary triple-negative breast cancers are shown to vary widely and continuously in the degree of clonal evolution and mutational content at the time of diagnosis, with implications for future studies of the disease.
- Sohrab P. Shah
- , Andrew Roth
- & Samuel Aparicio
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News |
Gene behind van Gogh’s sunflowers pinpointed
‘Double-flowered’ mutation sheds light on the evolution of an iconic bouquet.
- Helen Thompson
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News |
Cancer screen yields drug clues
Huge drug survey brings personalized cancer therapy a step closer.
- Heidi Ledford
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Research Highlights |
James Crow on sabotaging sperm
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Research Highlights |
Loss-of-function found in droves
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News & Views |
Evolution after tumour spread
A genetic study of brain cancers in mice and humans reveals distinct mutations in primary tumours and their metastases, suggesting that the two disease 'compartments' may require different treatments.
- Steven C. Clifford
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News |
Cancer-causing mutations yield their secrets
Changes to metabolism disrupt cells' ability to differentiate.
- Heidi Ledford
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Letter |
Transformation by the (R)-enantiomer of 2-hydroxyglutarate linked to EGLN activation
The (R)-enantiomer of 2-hydroxyglutarate, which is produced when IDH is mutated in human tumours, is shown to stimulate the activity of the EGLN prolyl 4-hydroxylases, leading to diminished levels of HIF and enhanced human astrocyte proliferation.
- Peppi Koivunen
- , Sungwoo Lee
- & William G. Kaelin Jr
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Letter |
IDH mutation impairs histone demethylation and results in a block to cell differentiation
Cancer-associated IDH mutants that produce 2-hydroxyglutarate are shown to prevent the histone demethylation that is required for lineage-specific progenitor cells to differentiate into terminally differentiated cells.
- Chao Lu
- , Patrick S. Ward
- & Craig B. Thompson
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Letter |
IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype
Mutation of isocitrate dehydrogenase 1 (IDH1) is shown to induce DNA hypermethylation and to remodel the epigenome to resemble that of gliomas with the CpG island methylator phenotype.
- Sevin Turcan
- , Daniel Rohle
- & Timothy A. Chan
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Research Highlights |
Chemo spans generations
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News |
Cancer drugs affect mouse genomes for generations
DNA mutations continue to accumulate in offspring of treated mice.
- Heidi Ledford
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Letter |
Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
Recurrent histone mutations are linked to paediatric glioblastoma multiforme, an aggressive type of brain tumour.
- Jeremy Schwartzentruber
- , Andrey Korshunov
- & Nada Jabado
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Letter |
Unresponsiveness of colon cancer to BRAF(V600E) inhibition through feedback activation of EGFR
Inhibition of activated BRAF has been ineffective in colon cancers with the mutation; here, this is shown to be due to the feedback activation of the epidermal growth factor receptor (EGFR) in response to BRAF inhibition.
- Anirudh Prahallad
- , Chong Sun
- & René Bernards
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Research Highlights |
Mutation and infection to blame
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Letter |
Mutations in kelch-like 3 and cullin 3 cause hypertension and electrolyte abnormalities
Exome sequencing identifies mutations in kelch-like 3 and cullin 3 as causes of a syndrome featuring high blood pressure and electrolyte abnormalities.
- Lynn M. Boyden
- , Murim Choi
- & Richard P. Lifton
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Letter
| Open Access
Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing
The sequencing of AML genomes of eight patients before and after relapse reveals two major patterns of clonal evolution, with chemotherapy appearing to have a role in both patterns.
- Li Ding
- , Timothy J. Ley
- & John F. DiPersio
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Outlook |
Skin: Into the breach
A focus on skin barrier disorders has opened up new thinking about how allergies kick in.
- Claire Ainsworth
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Article |
Mutations causing syndromic autism define an axis of synaptic pathophysiology
The mutations that underlie the diseases tuberous sclerosis complex and fragile X syndrome produce abnormalities in synaptic plasticity and function that can be corrected by treatments that modulate metabotropic glutamate receptor 5 in opposite directions.
- Benjamin D. Auerbach
- , Emily K. Osterweil
- & Mark F. Bear
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News |
'Language gene' speeds learning
Mouse study suggests that mutation to FOXP2 gene may have helped humans learn the muscle movements for speech.
- Ewen Callaway
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News & Views |
Generations of longevity
The lifespan of some organisms can be extended by mutations that alter how DNA is packaged in their cells. A study reveals that this effect can last for generations, even in descendants that are genetically normal. See Article p.365
- Susan E. Mango
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News |
Targeted treatment tested as potential cancer cure
Trial will deploy genetically targeted therapy early, rather than as last resort.
- Erika Check Hayden
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Letter |
A SUMOylation-defective MITF germline mutation predisposes to melanoma and renal carcinoma
- Corine Bertolotto
- , Fabienne Lesueur
- & Brigitte Bressac-de Paillerets
Progressive degeneration of human neural stem cells caused by pathogenic LRRK2
Second mutant flu paper published