2008 Barcelona - European Society of Human Genetics

Concurrent Symposia
segregation of sister chromatids has been well characterized across
species . Recently regulators and structural components of cohesin
have been found to surprisingly cause specific human developmental
disorders (collectively termed “cohesinopathies”) when mutated . Mutations
in NIPBL, the vertebrate homolog of the yeast Sister chromatid
cohesion 2 (Scc2) protein, a regulator of cohesin loading and unloading,
are responsible for approximately 50% of cases of Cornelia de
Lange syndrome (CdLS) . Mutations in the cohesin structural components
SMC1A and SMC3 were also found to result in CdLS . CdLS
is a multisystem developmental disorder classically characterized by
facial dysmorphia, upper extremity malformations, hirsutism, cardiac
defects, growth and cognitive retardation, and gastrointestinal abnormalities
. A mild form of CdLS has been consistently reported, however,
it had not been clear if this is a distinct etiologic entity from classic
CdLS or truly a mild manifestation, however molecular testing of cohesin
genes has identified mutations in individuals with very subtle
features of CdLS bordering on apparent isolated mental retardation .
Mutations in another cohesin regulator, ESCO2, result in Roberts syndrome
(RBS) and SC phocomelia . Roberts syndrome is a recessively
inherited multisystem disorder with craniofacial, limb, cardiac, other
systemic abnormalities and neurocognitive dysfunction . While there is
some overlap between Roberts syndrome and CdLS they are clinically
readily differentiated . Other developmental disorders have also recently
been found to be associated with cohesin dysfunction . The recent
implication of the cohesin complex and its regulators in transcriptional
control has shed light on the mechanism by which alterations in this
complex leads to the specific phenotypes seen in these disorders. A
review of cohesin function, the disorders associated with disruption of
this pathway and future clinical and bench-top research directions will
be discussed .
s14.3
Nijmegen breakage syndrome: clinical manifestation of defective
response to DNA double-strand breaks
M. Digweed;
Charité - Institut für Humangenetik, Berlin, Germany.
Patients with the human genetic disorder, Nijmegen Breakage Syndrome
(NBS) display a characteristic facial appearance, microcephaly
and a range of symptoms including immunodeficiency, growth retardation
and chromosomal instability . NBS patients have an extremely
high risk of developing lymphoma . Patients were found to be highly
sensitive to ionising irradiation (IR) and this radiosensitivity had fatal
consequences in some undiagnosed patients . The most dangerous
DNA-lesion caused by IR is considered to be the double-strand break
(DSB) and indeed, NBS patient cells are sensitive to all mutagens
which produce DSBs directly or indirectly .
The underlying gene, NBN, codes for a protein, nibrin, involved on the
one hand, as a “caretaker”, in the processing/repair of DNA double
strand breaks and on the other hand, as a “gatekeeper”, in the regulation
of cell cycle checkpoints . The majority of patients are homozygous
for a founder mutation in NBN, a 5bp deletion in exon 6 . This mutation
leads to a truncated amino-terminal fragment containing FHA and
BRCT domains, and a carboxy-terminal protein (p70-nibrin) which is
produced by alternative initiation of translation from a cryptic upstream
start . NBN is an essential gene and it is clear that the carboxyterminal
p70-nibrin protein is sufficient to ensure patient survival.
We have been examining patient cells and conditional Nbn null mutant
mouse cells in order to establish which functions of full length nibrin
can be carried out by the carboxy terminal fragment and, more particularly,
how this partial functioning explains aspects of the human
disease . In this connection a further rare nibrin fragment, p80-nibrin,
which is associated with a milder course of the disease has been of
particular interest since it may define the basis of a potential anti-cancer
prophylactic treatment for NBS patients .
s15.1
Genomic Perspectives on Human Origins
S. Pääbo;
Max-Planck-Institute for Evolutionary Anthropology, Leipzig, Germany.
One approach to understanding what makes humans unique as a species
is to perform structural and functional comparisons between the
genomes of humans and our closest evolutionary relatives the great
apes . Recently, the draft sequences of the chimpanzee and rhesus
macaque genomes have opened up new possibilities in this area . I
will discuss work that compares functional and structural aspects of
the human and ape genes, using FOXP2, a gene involved in speech
and language, as an example . I will also discuss how a genome-wide
analysis of the Neandertal genome will enhance our ability to identify
genes that have been of importance during human evolution .
s15.2
Human genetic population structure: Patterns and underlying
processes
G. Barbujani;
University of Ferrara, Department of Biology and Evolution, Ferrara, Italy.
Classical studies of genetic diversity in humans consistently showed
that the largest proportion of human diversity occurs among members
of the same population . On average, differences among different
populations in the same continent represent 5% of the global human
variance, and differences among continents another 10% . Genetic
variation is largely discordant across the genome, meaning that different
loci show different spatial patterns, and implying that a good
description of population structure can only be based on the analysis
of multiple loci . Studies of single loci are also unlikely to reasonably
identify an individual’s place of origin . A general decline of genetic of
genetic diversity with distance from Africa, and a parallel increase in
linkage disequilibrium, can be accounted for by the effects of a series
of founder effects accompanying the spread of anatomically-modern
humans from Africa . Recent DNA analyses at the global level show
that most allelic variants are cosmopolitan and only a small percentage
are continent-specific, whereas a clearer continental structure emerges
when considering composite haplotypes . This suggests that, at the
global level, gene flow has had a strong impact on genetic diversity,
through both directional dispersal and successive short-range migratory
exchanges . At the local level, several factors have contributed to
genetic differentiation, and, in particular, language barriers have been
shown to be associated with small but non-negligible increases of the
genetic differences between neighboring populations .
s15.3
From genetic diversity to the understanding of basic biological
function: towards evolutionary systems biology
J. Bertranpetit;
Unitat de Biologia Evolutiva, , Departament de Ciències Experimentals i de la
Salut, Barcelona, Catalonia, SPAIN.