2009 Vienna - European Society of Human Genetics

Evolutionary and population genetics, and Genetic epidemiology
genotyping was determined by PCR-RFLP methodology.
The genotype distribution for -308 region was observed: 1.3% in AA,
35.3% in AG and 63.4% in GG. The genotype distribution for -238 region
was observed in our population: 0% in AA, 4.7% in AG and 95.3%
in GG. Also the genotype distribution for -857 region were observed
in our population: 12.7% in TT, 30.7% in TC and 56.6% in CC. We
compared our results with the literature data of healthy populations
in 13 different countries. No deviation for -308 and -238 regions from
Hardy-Weinberg Equilibrium (HWE) were observed in our population
(p> 0.05) whereas deviation for -857 region from HWE was observed
(p< 0.05). These results show that these deviations occur due to the
fact that our region is the transition region of migrations. This is the first
study in Turkish healthy population for the TNFα promoter (-308,-238
and -857) polymorphisms.
P10.83
the USH A c.2299delG mutation: dating its common origin in
southern Europe population
E. Aller 1,2 , L. Larrieu 3 , D. Baux 3 , T. Jaijo 1,2 , C. Espinos 4,2 , F. González 5 , M.
Claustres 3,6 , A. F. Roux 3 , J. M. Millan 1,2 ;
1 Hospital Universitario La Fe, Valencia, Spain, 2 CIBER de Enfermedades
Raras (CIBERER), Valencia, Spain, 3 Centre Hospitalier Universitaire (CHU)
Montpellier, Laboratoire de Génétique Moléculaire, Montpellier, France, 4 Unidad
de Genética y Medicina Molecular. Instituto de Biomedicina de Valencia,
CSIC, Valencia, Spain, 5 Institut Cavanilles de Biodiversitat i Biologia Evolutiva
(ICBiBE), Valencia, Spain, 6 Inserm, U827, Montpellier, France.
Usher syndrome type II is the most common form of Usher syndrome.
Although 3 genes are known as disease causing, USH2A is the major
involved gene. It encodes two isoforms of the protein usherin. This
protein is part of an interactome that plays an essential role in the development
and the function of the stereocilia of inner ear hair cells. In
the photoreceptor, usherin is located at the periciliary region between
extern and inner segments. This gene contains 72 exons over a region
of 800 kb. Although numerous mutations have been described, the
c.2299delG mutation is the most prevalent in several populations. Its
ancestral origin was previously suggested with the identification of a
core haplotype restricted to 250 kb in the 5´ region of the gene. Because
we extended the haplotype analysis over the 800 kb region with
a total of 14 intragenic SNPs, we could define 10 different c.2299delG
haplotypes showing a high variability but with the conservation of the
previous described core haplotype. An exhaustive c.2299delG/control
haplotypes study suggests that the major source of haplotype variability
in USH2A gene is recombination. Furthermore, we have found
twice amount of recombination hotspots in the 500 kb 3´ region of the
gene, explaining the higher variability observed in this region comparing
to the first 250 kb. Our data confirm the common ancestral origin of
the c.2299delG mutation and suggest that it arose 5,500-6,000 years
ago.
P10.84
A complex selection signature at the human AVPR1B gene
R. Cagliani 1 , M. Fumagalli 1,2 , U. Pozzoli 1 , S. Riva 1 , M. Cereda 1 , L. Pattini 2 , G. P.
Comi 3 , N. Bresolin 1,3 , M. Sironi 1 ;
1 Scientific Institute IRCCS E. Medea, Bosisio Parini, Italy, 2 Bioengineering Department,
Politecnico di Milano, Milan, Italy, 3 Dino Ferrari Centre, Department
of Neurological Sciences, University of Milan, IRCCS Ospedale Maggiore Policlinico,
Mangiagalli and Regina Elena Foundation, Milan, Italy.
The vasopressin receptor type 1b (AVPR1B) is mainly expressed by
pituitary corticotropes and it mediates the stimulatory effects of AVP
on ACTH release; common AVPR1B haplotypes have been involved
in mood and anxiety disorders in humans, while rodents lacking a
functional receptor gene display behavioral defects and altered stress
responses.
Here we have analyzed the two exons of the gene and the data we
present suggest that AVPR1B has been subjected to natural selection
in humans. In particular, analysis of exon 2 strongly suggests the action
of balancing selection in African populations and Europeans: the
region displays high nucleotide diversity, an excess of intermediatefrequency
alleles, a higher level of within-species diversity compared
to interspecific divergence and a genealogy with common haplotypes
separated by deep branches. This relatively unambiguous situation
coexists with unusual features across exon 1, raising the possibility
that a nonsynonymous variant (Gly191Arg) in this region has been
subjected to directional selection.
Although the underlying selective pressure(s) remains to be identified,
we consider this to be among the first documented examples of a
gene involved in mood disorders and subjected to natural selection in
humans; this observation might add support to the long-debated idea
that depression/low mood might have played an adaptive role during
human evolution.
P10.85
Estimating the heritability of vitamin b12 levels: a study of adult
female twins
I. Cotlarciuc, T. Andrew, G. Surdulescu, T. Spector, K. Ahmadi;
Dept of twin research and genetic epidemiology, King’s College London, United
Kingdom.
Background: Vitamin B12 (cobalamin) is an essential cofactor involved
in one carbon metabolism (remethylation of homocysteine to methionine)
and in the metabolism of branched chain amino acids. Currently
the extent of the genetic and environmental influences on vitamin B12
levels has not yet been determined. Our aim was to determine the
first heritability estimate for vitamin B12 levels in an adult female twin
population.
Methods: We estimated the heritability of vitamin B12 levels in 1063
female twin pairs (262 monozygotic twin pairs and 801 dizygotic twin
pairs), aged 18 to 80 years from the TwinsUK Adult Twin Registry.
Structural genetic modeling was used to determine the influence of
genetic and environmental factors on vitamin B12 variation.
Results: Genetic factors showed to account for 52% (95%CI, 45-58%)
of vitamin B12 variation. The variance in vitamin B12 levels was explained
by additive genetic and non-shared environmental factors, with
the additive genetic variance estimated to 52% (95%CI, 45-58%) and
the non-shared environmental variance to 48% (95%CI, 41-54%).
Conclusions: Vitamin B12 levels were shown to be highly heritable and
here we report the first heritability estimation for vitamin B12 levels.
The high heritability obtained for vitamin B12 levels is suggesting that
further genetic analysis have to be considered in order to identify genetic
variants responsible for vitamin B12 variation.
P10.86
Comparison of VKORC1 haplotype profile and CYP2C9
polymorphisms as determinants of coumarin dose in Hungarian
and Roma population samples.
C. Sipeky 1 , E. Safrany 1 , V. Csongei 1 , L. Jaromi 1 , P. Kisfali 1 , A. Maasz 1 , N. Polgar
1 , J. Bene 1 , I. Takacs 2 , M. Szabo 3 , B. Melegh 1 ;
1 Department of Medical Genetics and Child Development, University of Pécs,
Pécs, Hungary, 2 2nd Department of Institute of Internal Medicine and Haematology,
Semmelweis Teaching Hospital, Miskolc, Hungary, 3 Koch Robert Hospital,
Edelény, Hungary.
Anticoagulant action of coumarins is mainly moderated by the VKORC1
and CYP2C9 genes. By means of haplotype tagging SNPs (G-1639A,
G9041A, C6009T) we characterized Hungarian (n=510) and Roma
(n=451) populations for the VKORC1*1, *2, *3, *4 haplotypes, and for
the CYP2C9*2, CYP2C9*3 allelic variants. The samples were analyzed
by PCR-RFLP assay and direct sequencing. In Hungarians the
VKORC1*1, *2, *3, *4 haplotypes were 3, 39, 37, 21%, by contrast,
in the Roma populations were 5, 30, 46,19%, respectively. Comparing
the genotypes of Roma and Hungarian populations difference was
found in the *2*2 (6.87 vs. 13.5%), *2*4 (13.9 vs. 19.2%), 3*3 (21.9
vs. 13.7%) VKORC1 genotypes. The frequencies of CYP2C9*1, *2,
*3 alleles in the Hungarian population were 0.787, 0.125, 0.088 and in
Roma 0.727, 0.118, 0.155, respectively. The distribution of *1/*1, *1/*2,
*1/*3, *2/*2, *2/*3, *3/*3 genotypes in Hungarians were 0.620, 0.195,
0.139, 0.021, 0.015, 0.011, while in Roma were 0.533, 0.168, 0.219,
0.011, 0.047, 0.022, respectively. Significant difference was found between
Hungarian and Roma population considering the CYP2C9*3
frequency and *1/*1, *1/*3, *2/*3 genotypes (p