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Nature Genetics
Delivering essential function
Procedures and priorities
Myles Axton - September 2005
Nature Genetics
founded in 1992 as sister journal to
Nature
NPG Research Journals
Nature Biotechnology
Nature Methods
Nature Cell Biology
Nature Medicine
Nature Neuroscience
Nature Structural and Molecular Biology
Landmarks
 1992
p53 binding site defined
 1995
Linkage applied to complex traits
 1996
Cell cycle microarray
 1997
Genetics of obesity
Nature Genetics
 Impact factor
 Seminal research papers
 Definitive strategic advice
 Exacting expert referees
 Professional editors and production staff
Sponsored Supplements
User’s guide to the human genome II (Nov 2003)
FAQ for all users
Genetics for the Human Race (October 2004)
Genetic epidemiology with variants distributed across continental ancestry
groups
Chipping Forecast III (June 2005)
Applications of microarrays to cancer
User’s guide to the mouse (November 2005)
Optimal strategy given the mouse and rat genomes, new gene trap and ES cell
resources
Scope
Common/complex diseases
Gene networks
Cancer
Human disease genetics
Pharmacological genomics
Epigenetics
Developmental genetics
Functional genomics
Stem cell genetics
Genetic technology
Genome evolution
Technical Reports
Nature Genetics
Biological insights from perturbation of gene networks
by mutation, transgenic manipulation, natural variation and evolution
Nature Biotechnology
The degree of control gained over a biological system
can be as important as the basic finding
Bioinformatics
Proteomics
Systems biology
Commercial applications
Nature Methods
When the strategy rather than the biological insight is new
Molecular biology methods of interest outside genetics and genomics
Protocols
Career best work
Nature and Nature Genetics
EMBO Journal
EMBO Reports
Molecular Systems Biology
Heredity
Get priority for your paper
Story
Is this a comprehensive and integrated set of experiments addressing
a coherent and important question? Nature Genetics referees are rarely keen
on work they see as preliminary, incremental or descriptive.
Abstract
How the experimental methods led to the conclusion
This is a qualitative conceptual advance over which work?
Why previous experiments have not addressed this point.
State of the art
For a geneticist: access to several datasets and robust statistical
procedures.
For functional studies (molecular biology or biochemistry): first, is
the basic genetics sound?
If you work with cells, do your results hold up in vivo?
Get priority for your paper (2)
Consult
Talk with an editor about current criteria, these evolve and are reviewed
regularly by the editorial team, but may not yet have found their way
into a recent editorial.
Referees
Recommended for particular expertise
Excluded for reasons of competition, recent collaboration or bias
Expediting
We can ensure fast review if given name and date of competing author
or journal but we will not publish any work before it meets our
standards.
Problem areas
Biological insight is usually the issue
Clinical report on one individual
Gene identification in model organism without transferrable conclusion
Pure bioinformatics
Disease model copies human phenotype
Modification of existing technique
Descriptive gene expression profile
Human gene identification with sensitive/general phenotype
Oncogene/tumor suppressor gene identification in cell culture
Methylation correlation
Add value to your paper
Will your results transfer to other disciplines?
eg. medicine, anthropology, bioinformatics, bioethics.
Share research materials
NCBI, GEO, ArrayExpress, BIND, HapMap etc.
MIAME - gene expression by microarray
aCGH - genome copy number changes
Genotypes - quality of data, use to others, clinical data can
be separated
Submit large datasets before review but control access
Association for genetic component of
common disease
Criteria from:
Ioannidis et al. Nat. Genet. 29, 306-309 (2001)
Meta-analysis used to recommend minimum size for association
studies and to converge on best estimate of conferred risk (odds ratio).
Lohmueller et al. Nat. Genet. 33, 177-182 (2003)
25% of association studies repeated, those that repeated did so many
times. First published studies overestimate conferred risk but
publication bias not main cause. Must replicate in second
population.
Page et al. Am. J. Hum. Genet. 73, 711-719 (2003)
Sherlock Holmes/ Karl Popper criteria for causation. Try to eliminate other
explanations yourself.
Genetic association criteria
(genetics before function)
Report actual genotypes obtained and odds ratio
Replicate in a second population
Linkage disequilibrium - Analyze LD if markers are not themselves functional
variants of a candidate gene.
Multiple hypothesis testing - How was the statistical analysis corrected for
the many phenotypes and genotypes studied and the tests performed?
Stratification - Attempt to control systematic variation in genotype between
cases and controls that may result from other population genetic or
demographic factors.
Complex traits
Rice salt tolerance QTL
Ren, Gao, Li et al. September 2005. A rice quantitative trait locus for
salt tolerance encodes a sodium transporter
 Mapped QTL by crossing salt tolerant
O.s.indica Nona Bokra with salt sensitive
O.s. japonica Koshihikari
Complementation by cDNA transgenesis
In Xenopus oocytes, KSKC1 product has
lower Na+ transport activity than NSKC1
QTL affects accumulation of K+ as well
as Na+ in whole plant
Resembles a loss of function saltsensitive allele of Arabidopsis AtHKT1
Genomics
Schistosome cDNAs
Hu et al. October 2003
Assigned 43,707 Schistosoma
japonicum ESTs to 13,131 gene
clusters
Discovered mammalian-like
receptors for hormones, cytokines
and neuropeptides
Significant resource for
molecular parasitology
researchers
Statistical analysis.
We did statistical analysis of expression profiles using tools available at
http://igs-server.cnrs-mrs.fr (ref. 46).
URLs.
More details of the results and the raw data are freely available for download from our website at
http://schistosoma.chgc.sh.cn.
GenBank accession numbers.
EST sequences, BU714506-BU725997, BU710635-BU714505, BU766051-BU780918
and BU791228-BU804512; full-length cDNAs, AY222864-AY223474.
Note: Supplementary information is available on the Nature Genetics website.
Systems
Gene networks
Lahav et al. Nat. Genet. 36, 147-150 (2004) Dynamics of the p53mdm2 feedback loop in individual cells.
• Number of
digital pulses
varies with
DNA damage
Epigenomics
Heterochromatin from RNAi
Cam et al. July 2005. Comprehensive analysis of heterochromatin- and RNAimediated epigenetic control of the fission yeast genome
Genome-wide chromatin
immunoprecipitation on tiling 60mer oligo arrays
Survey of histone H3 K4 and K9,
heterochromatin proteins and
RNAi machinery
Cloned RITS associated siRNAs
Supports active silencing of
heterochromatic regions
Development
Analysis of developmental networks
Van Driessche et al. May 2005. Epistasis with global transcriptional
phenotypes
Phenotypes associated with
Protein kinase A activity in
Dictyostelium
Epistasis analysis performed on
transcritptional profiles by
microarray
Infer known and unknown
regulatory hierarchies
Extends epistasis analysis to
similar phenotypes
Human genome variation
Ancestry predicts genotype?
Jorde and Wooding. October 2004 Suppl.
Genetic variation, classification and ‘race’.
190 polymorphisms.
246 sequence variants of the
angiotensinogen (AGT ) gene
Second human genome shows
widespread copy number variation
Tuzun et al. July 2005. Fine-scale structural variation of the human genome
Sequences of fosmid end
pairs compared to finished
genome sequence.
Verification by PCR and
aCGH
Published structural variants
of proven biomedical
importance
Common in population
Hypertension in pregnancy
Van Dijk et al. May 2005. Maternal segregation of the Dutch preeclampsia
locus at 10q22 with a new member of the winged helix gene family
Allele sharing of sisters with preeclampsia.
Maternal STOX1 gene is
expressed in invasive extravillus
trophoblast
Five shared missense mutations
in maternal copy
Possible involvement in
polyploidization
Natural selection on humans
Stefansson et al. February 2005. A common inversion under selection in
Europeans.
900kb inversion polymorphism in
17q21.31 is at 20% in some
European populations.
Largest block of extended
linkage disequilibrium in the
genome.
Perturbs meiotic linkage map.
Currently under selection,
conferring 3% more offspring per
generation in Iceland pedigrees.
Beneficial mutation
Cohen et al. February 2005. Low LDL cholesterol in individuals of
African descent resulting from frequent nonsense mutations in PKS9
 Up to 2% of African Americans and
<0.1% of European Americans have
missense mutations in the serine
protease gene PKS9 which confers up
to 40% lower serum LDL cholesterol.
 The mutations were also found in
Nigerian Yoruba speakers.
Technical reports
Ishkanian et al. Nat Genet. (AOP Feb 15th 2004). A tiling resolution
microarray with complete coverage of the human genome
• Useful for detecting microdeletions and amplified oncogenes