Myles Axton, Editor of Nature Genetics, presented a key note at the 4th Biennial Meeting of the Human Variome Project Consortium.

1. Genetics research for society and global understanding
Myles Axton
Editor,
Nature Genetics
4th HVP
UNESCO
Paris
June 14th 2012

2. Opportunities

3. Opportunities
“This is life, what can I do? we are just
keeping things together” – Sheikh Rashid
“There is a balance in raising them, I don’t
favor any one. We show love, keep harmony
and support one another. We don’t assume
things, if something goes on we just deal
with it.”

4. Evolution of mendelian genetics research

5. Variant identification in 2009 – genetic approach
A Kemal Topaloglu et al. Nature Genetics 40, 354 - 358 (2009).
doi:10.1038/ng.306
TAC3 and TACR3 mutations in familial hypogonadotropic
hypogonadism reveal a key role for Neurokinin B in the
central control of reproduction
 4 pedigrees with homozygous loss of function alleles in two genes
 Functional investigation of dose response of variant ligand and receptor
 Implicates hypothalamic tachykinin signaling in onset of puberty

6. Variant identification in 2009 – genomic approach
Patrick S Tarpey et al. Nature Genetics 41, 535 - 543 (2009)
doi:10.1038/ng.367
A systematic, large-scale resequencing screen of X-chromosome
coding exons in mental retardation
 Resequenced all exons of 718 genes in 208 families
 9 genes implicated in mental retardation (XLMR)
 “…loss of function of 1% or more of X-chromosome genes is compatible with
apparently normal existence”

7. Coding variants deposited in gene database

8. Variant identification in 2009
– whole coding genome approach
Sarah B Ng et al. Nature Genetics 42, 30-35 (2009)
doi:10.1038/ng.499
Exome sequencing identifies the cause of a mendelian
disorder
 Miller syndrome (MIM%263750)
 Resequenced all exons from two affected siblings and two unrelated affected
 Used both dbSNP129 variant database and the eight HapMap exomes as
bioinformatic filters, leaving just 26 candidate genes on dominant model and only
DHODH if autosomal recessive
 A new role for pyrimidine metabolism in craniofacial and limb
development as well as a newly discovered function of dihydroorotate
dehydrogenase. Phenotype resembles methotrexate embryopathy

9. Variant identification in 2010
– exome sequencing of parent-child trios
Lisenka Vissers et al. Nature Genetics
published online 14 November 2010; doi:10.1038/ng.712
A de novo paradigm for mental retardation
 10 exomes (42x) from individuals with mental retardation
 Normal karyotypes and aCGH, FMR1 repeats in normal range
 Filter by dbSNP and exomes of normal parents
 2-7 de novo nonsynonymous variants per individual
 Validate 9/13 variants in 7 individuals by Sanger sequencing

10. Genome-wide association studies (GWAS)

11. Progress in GWAS by June 2nd 2012
GWAS
http://www.genome.gov/gwastudies
666 diseases and traits
1271 publications
313 in Nature Genetics
1891/3869 P<5x10-8
6446 SNPs P<10-5
Mendelian disorders
www.genetests.org/

12. Rare and common variants in AMD
1) rs121913059 is rare
NM_000186.3: c.3628C>T (R1210C)
2) Exclusive haplotype H5 OR ~15
3) Adds 14% of genetic liability to the
17% from the two common risk
alleles rs1061170 Y402H and intronic
rs1410996 (proxy rs10737680 A )
A rare penetrant mutation in CFH confers high risk of age-related macular degeneration
Soumya Raychaudhuri et al. Nature Genetics 23 October 2011; doi:10.1038/ng.976

13. Pharmacogenetics of HCV treatment
Genetic variation in IL28B predicts hepatitis C treatment-induced viral clearance
Dongliang Ge et al. Nature September 2009; doi:10.1038/nature08309
IL28B is associated with response to chronic hepatitis C interferon-α and ribavirin therapy
Vijayaprakash Suppiah et al. Nat. Genet. Sept. 2009; doi:10.1038/ng.447
Genome-wide association of IL28B with response to pegylated interferon-α and ribavirin
therapy for chronic hepatitis C
Yasuhito Tanaka et al. Nat. Genet. Sept. 2009; doi:10.1038/ng.449
48 week course of PEG-Interferon alpha 2a or 2b
with ribavirin is not always curative
IL28B SNPs associated with sustained virological
response (SVR)
IL28B SNPs more frequent in Americans of
European ancestry than African ancestry, so
account for half of the differential response
to treatment between the two ancestries

14. Number needed to treat and altering outcomes
Medical genetics: A marker for Stevens–Johnson syndrome
Wen-Hung Chung et al. Nature 428, 486 (1 April 2004) doi:10.1038/428486a
Drug induced epidermal necrolysis (SJS) with carbamazepine (CBZ) occurs in 8 cases per million person-years in Han
Chinese
HLA-B*1502, Cw*0801, A*1101, DRB1*1202….. was present in 66% of the CBZ–SJS patients and in only 3% of the
normal subjects, but was absent in CBZ-tolerant patients.
Carbamazepine-Induced Toxic Effects and HLA-B*1502 Screening in Taiwan
Pei Chen et al. NEJM March 24, 2011, 10.1056/NEJMoa1009717
4.4% of 4877 developed skin rash or severe skin rash
HLA-B*1502 who were 7.7% of the total were advised not to take carbamazepine -> 0 SJS-TEN, expect 10
~35 Han Chinese would need to be tested to avoid one adverse reaction.
HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin
Ann K Daly et al. Nature Genetics May 2009; doi:10.1038/ng.379
In UK, drug-induced liver injury occurs in 8.5 in every 100,000 new users in days 1 to 45 after starting treatment.
Despite the strong association with HLA-B*5701, only 1 in every 500 to 1,000 individuals with this genotype will
develop drug-induced liver injury when treated with flucloxacillin
Prospective genotyping would have a very high false positive rate.
>14,000 Europeans need to be tested to avoid one adverse reaction.

15. Community annotation of the human genome

16. On not reinventing the wheel
http://www.nature.com/ng/journal/v44/n3/full/ng.2216.html
ENIGMA

17. Making data citation count

18. Human Variome Microattribution Review (Hemoglobin)
http://www.bx.psu.edu/~giardine/
Giardine, B. et al. Nat. Genet. 43, 295–301 (2011) doi:10.1038/ng.785

19. Pilot study in semantic data publishing and microcitation
Thomson Reuters
Joel Hammond
Leiden U.
Bruce Kiesel
Med. Cent.
Herman van Haagen
Erik Schultes
Barend Mons
Ivo Fokkema [Gene variant] [has] [frequency]
Erasmus Med. Cent. Johan den Dunnen
Bharat Singh
[Gene variant] [has] [OMIM ID]
Free U. Amsterdam
Paul Groth Penn. State U.
Belinda Giardine
NPG
Myles Axton
Tony Hammond

20. Scholarly communication
Barend Mons et al. 2011
Nature Genetics 43, 281–283
doi:10.1038/ng0411-281
The Value of Data
Current

21. Scholarly communication rewired
Barend Mons et al. 2011
Nature Genetics 43, 281–283
doi:10.1038/ng0411-281
The Value of Data
Proposed

22. Positive Exposure
Rick Guidotti
at ‘Al Amal’ school,
Ibra,
Sultanate of Oman

23. “A prevention program can be credible
and will enlist the confidence of the
people only if accompanied by the visible
commitment to the care of affected
people.”
– Drs Anna Rajab and Ali Jaffer
p66 in CAGS3 Oman
Genetic disorders of the Arab World,
Center for Arab Genomic Studies, Dubai
UAE.
http://www.cags.org.ae/cb36c3.pdf

25. “All siblings have normal cognition and
have to be given the maximum available
opportunity to pursue their studies in
order to become useful members of
society.”
– Consultant Geneticist to Social Services
“Are you a physician with a treatment?”
“No, we are here to tell the world that you
are number 1 in your high school class”

26. Thank you