2009 Vienna - European Society of Human Genetics

Evolutionary and population genetics, and Genetic epidemiology
an approach for genome-wide interaction analysis that overcomes the
computational issue by prioritizing SNPs for interaction analysis using
a priori information. Sources of information can be biological relevance
(common pathway, gene location ...) or statistical evidence (single
marker association at a moderate level). We present a respective software
product that implements different approaches to joint analysis of
multiple SNPs (full modelling of marginal and interaction effects as well
as explicit testing for association with a log-linear model). Moreover,
link to databases with the relevant biological information is provided.
We also present the results from an application to a GWAS.
P10.37
Hereditary Nervous system Diseases in Rostov Region
N. A. D. Z. Vetrova, N. Vetrova, S. Amelina;
Rostov Medical Institute, Rostov, Russian Federation.
Research of Hereditary Nervous System Diseases is important for the
following reasons: their prevalence among neurological disorders is
high. Many patients develop mental and physical handicap leading to
severe disability. The population of eight districts was examined to access
prevalence of hereditary nervous system disorders in Rostov Region.
Data collection and processing were done according to the protocol
of Genetic Epidemiology Laboratory of Medical Centre in Moscow.
The neuromuscular disorders in Rostov Region’ population composes
30.62% of all hereditary nervous system diseases. Their prevalence is
19.94 per 100,000 population. Hereditary Sensory-Motor Neuropathy
was prevailing not only in the group of neuromuscular diseases, but
also in hereditary nervous system disorders group. Total of 28 cases
were identified in 15 families. The prevalence was 8.72 per 100,000
population. DNA testing was performed to identify dup mutation in
gene RMR22 in all patients.
This study identified 13 cases of Duchene/Becker Muscular Dystrophy
in 10 families. Prevalence was 8,10 per 100,000 male population.
DNA testing was performed to identify mutations in gene DMD in 9
families.
Other common disorders such as oligophrenia, microcephaly and
congenital hydrocephalus comprise 47.6 % of all hereditary nervous
system diseases in Rostov Region; prevalence was 30,85 per 100,000
population.
Hereditary Nervous System Diseases, Duchenne/Becker Muscular
Dystrophy, Neurofibromatosis and Tuberous Sclerosis are prevaling
disorders among Rostov Region’s population. All this diseases are
single gene disorders, which is also true for Russian Federation neuropathology
spectrum.
P10.38
confounding factors in testing parent-of-origin effects:
illustration with Hirschsprung disease genetics.
A. Jannot 1,2 , J. Amiel 2,3 , A. Pelet 2,3 , S. Lyonnet 2,3 , F. Clerget-Darpoux 1,4 ;
1 INSERM U535, Villejuif Cedex, France, 2 INSERM U781, Paris, France, 3 Université
Paris Descartes, Faculté de médecine, Paris, France, 4 Université Paris
-sud, Villejuif, France.
Parent-of-origin effect may be tested on affected sib pairs or trio family
data by comparing paternal and maternal transmission to the affected
cases. However, the conclusion of these tests is not robust to non random
parental mating. In particular, we demonstrate, through theoretical
modelling, that reduced fertility and spermatic fitness can mimic a
parent-of-origin effect both for sib pairs and case-parents trios. In order
to distinguish between true parent-of-origin effect and bias resulting
from reduced fertility, we propose here a method which combines the
information on trios and sib-pairs.
We illustrate our findings with the International Hirschsprung disease
(HSCR) Consortium data. RET is the major HSCR locus and a parent-of-origin
effect has been suspected. Both the strong sex-ratio in
favour of females combined with a poor prognosis and the involvement
of RET in spermatogenesis have led to challenge a parent-of-origin
effect. Indeed, by combining the results of affected sib-pairs and trios,
we show that a reduced fertility is the most likely mechanism to explain
the observed allele sharing distortion in HSCR.
P10.39
Worldwide HLA class i and ii Diversity
N. M. Qutob, A. Manica, F. Balloux;
Department of Zoology, University of Cambridge, Cambridge, United Kingdom.
The Human Leukocyte Antigen (HLA) is a key component of the immune
system of vertebrate as it is responsible for the recognition and
presentation of antigens and comprises the most polymorphic genes
in vertebrates. Numerous hypotheses have been proposed to explain
how this diversity could be maintained. One such hypothesis (called
Pathogen-Driven Balancing Selection) states that different alleles provide
protection against different pathogens. A prediction under this
hypothesis is that populations exposed to a wider variety of diseases
should be characterised by higher diversity at their HLA genes. This
prediction has recently received some support in humans when it was
shown that once past demography was accounted for, there is a positive
correlation between HLA class I within-population genetic diversity
and the number of endemic diseases found in that area.
My work involves compiling a large database of HLA allele frequencies
from human populations worldwide, including class I and II genes.
One limitation of previous work was that a very simple measure of
genetic diversity was computed, and the different alleles were simply
considered as identical or different. Thus, my work involves using more
refined measures of genetic diversity and focuses on the residues
forming the Peptide Binding Region (PBR), as these are the expected
target of natural selection.
The work indicates that the geographic apportionment of HLA diversity
is the product of both past demography and complex selective pressures.
It also highlights the complexity of the selective process, with
the likely involvement of coevolution with KIR genes and marks differences
between different classes of genes.
P10.40
HLA polymorphisms in são tomé and Príncipe Archipelago
(West-Africa)
N. Saldanha, A. Lemos, A. Brehm, C. Spínola, H. Spínola;
Human Genetics Laboratory, Funchal, Portugal.
HLA-A, HLA-B, and HLA-DRB1 loci polymorphisms were high-resolution
typed through sequence based typing in Forros and Angolares
ethnic groups from São Tomé and Príncipe archipelago (West-Africa).
The most frequent HLA-A alleles found in Forros were A*0201,
A*2301 and A*6802, with 13% each. With a similar frequency (14%),
HLA-A*6802 was also a very common allele in Angolares, followed by
A*2301 (9.2%). HLA-B*5301 was the most frequent HLA-B allele in both
Forros (19%) and Angolares (24%). The most recurrent HLA-DRB1
alleles in São Tomé and Príncipe population were HLA-DRB1*0301
(12% in Forros and 18% in Angolares) and HLA-DRB1*1503 (11% in
both Forros and Angolares). Haplotypes A*6802-B*0702-DRB1*1301
in Forros (3%) and A*6802-B*5301-DRB1*0804 in Angolares (4.7%)
were the most common three loci found in each group.
Phylogenetic analysis reveals the West Coast of Africa as being the
place of origin of São Tomé and Príncipe main genetic pool, specifically
the area comprised between Guinea-Bissau and the Gulf of Guinea.
Forros and Angolares systematically cluster together in phylogenetic
analysis and are not statistically different, making the hypothesis that
Angolares are descendents of slaves who escaped from plantations
and kept themselves resistant to miscegenation plausible.
P10.41
Genomic runs of homozygosity: population history and disease
R. McQuillan1 , M. Kirin1 , C. S. Franklin1 , V. Vitart2 , P. McKeigue1 , A. F. Wright2 ,
H. Campbell1 , J. F. Wilson1 ;
1 2 University of Edinburgh, Edinburgh, United Kingdom, Medical Research
Council Human Genetics Unit, Edinburgh, United Kingdom.
Runs of homozygosity (ROH), resulting from the inheritance from both
parents of identical haplotypes, are abundant in the human genome.
ROH length is determined partly by the number of generations since
the common ancestor: offspring of cousin matings have long ROH,
while the numerous shorter ROH reflect shared ancestry tens and
hundreds of generations ago. In studies of European populations we
show that F , a multipoint estimate of individual autozygosity derived
roh
from genomic ROH, distinguishes clearly between subpopulations
classified in terms of demographic history and correlates strongly with
pedigree-derived inbreeding coefficients. In a global population da-
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