Structure
and Comparative Analysis of the Bovine Prion Gene Locus. Pp. 313-321.
S. Comincini,
B. Castiglioni, I. Del Vecchio, M.G. Foti and L. Ferretti
Functional Genomics in Drosophila melanogaster by Gene-Trapping. Pp. 323-338.
Tamas
Lukacsovich, Zoltan Asztalos and Daisuke Yamamoto
The
Genetics of Frontotemporal Dementia and Related Disorders. Pp. 339-352.
M.J. Sobrido,
M. Wiedau-Pazos and D.H. Geschwind
Fork
Head Transcription Factors. Pp. 353-382.
B. Granadino,
C. Pérez-Sánchez, and J. Rey-Campos
[Back to top] High Throughput Single Nucleotide Polymorphism Genotyping Technology.
Single nucleotide
polymorphisms (SNP) are the most abundant of all DNA polymorphisms. The rapid
progress of genome projects presents a unique opportunity to genetic
researchers if reliable high throughput methods can be developed for SNP
typing. In this review we will discuss the broad variety of SNP typing formats
and discuss their relative merits for direct and indirect association studies.
We will also mention some of the possible technical advances which may impact
SNP typing in the next few years.
[Back to
top] Structure and Comparative
Analysis of the Bovine Prion Gene Locus.
Prion diseases are
transmissible neurodegenerative disorders that affect a wide range of mammalian
species. The prion protein gene, Prnp,
modulates the incidence and incubation periods of the disease in sheep, goat,
mouse and man. Because of the current absence of such a correlation in cattle,
the bovine Prnp gene was investigated
and its outline skeleton, i.e. the exon/intron structure was determined. The
bovine prion gene was physically mapped on bovine chromosome 13 (BTA13q17): the
comparative analysis showed a high level of conservation between cattle and
other mammals. The bovine gene contains three exons: the first is contiguous to
the promoter and to the regulatory elements; the second is transcriptionally
active in most species, but does not contain coding information; the last
contains the entire coding region. Additional non-coding sequences, conserved
among different species, were also identified, particularly in the 3'
untranslated region. The neighbouring region of the prion gene in different
species was also examined in search of other genes that may shed light on the
prion function. The prion-gene chromosomal region showed a remarkable density
of coding sequences; one of them, the prion-doppel, Prnd, has structural similarities with the prion gene itself. This
finding, first reported in man and mouse, supports the existence of a "Prion-family", as the experimental
evidence in the mouse of chimaeric transcripts generated by intergenic splicing
between the genes Prnp and Prnd would confirm.
[Back to
top] Functional Genomics in Drosophila melanogaster by Gene-Trapping.
The Genome Project proceeds
towards the determination of the nucleotide sequence of the human genome.
Meanwhile the total genomic sequences of some of the less complex organisms (E. coli, yeast, C. elegans and most recently Drosophila
melanogaster) have already been determined. The identification and
functional analysis of the genes constituting those genomes have remained one
step behind. The simultaneous detection of the expression profiles of many
mRNAs present in a given cell, tissue or organ have become possible by the
recently developed DNA microarray technology. This approach will eventually
lead to a higher level understanding of the molecular processes underlying the
maintenance, regulation and mediation of all the functions of an organism
governed by gene actions. However, the automated DNA chip technology by itself
cannot replace the analysis of unique gene functions. New variants of the
classical reverse genetic approach (i.e. from gene to function) based on random
mutagenesis methods must be applied in a genome-wide scale to target every gene
and conclude its role from the resultant phenotype. Two opposite mutagenesis
methods, which complement each other well, exist: one results in recessive
loss-of function mutations by disrupting the targeted genes and the other
generates dominant gain-of-function mutations by overexpressing or ectopically
expressing the respective genes. The gene-trap methodology represents a
powerful strategy by which functional genes can be easily cloned and
identified. The method reliably generates the corresponding loss-of-function
mutations simultaneously even if those are not manifested in any visible
phenotype. These features make gene trapping particularly useful for genome
analysis by allowing the correlation between the physical and genetic maps to
be established.
[Back to top] The Genetics of Frontotemporal Dementia and Related Disorders.
Recent advances in genetics have revolutionized our
understanding of dementia. In the most common of the human dementing illnesses—Alzheimer’s
disease (AD)— mutations in three major genes causing rare dominantly inherited
AD (APP, PS1 and PS2), and other contributory genetic risk factors, such as
APOE have been identified. Although neurofibrillary tangles composed of tau protein
filaments are a diagnostic feature of AD, tau mutations have not been described
in AD. Frontotemporal dementia (FTD) encompasses a group of non-Alzheimer’s
degenerative dementias affecting mainly the frontal and temporal
neocortex. In contrast to AD, approximately 50% of FTD cases are inherited and
linkage of families with FTD to loci on chromosomes 17 (FTDP-17) and 3 has been
demonstrated. Mutations in the microtubule-associated protein tau cause most
cases of chromosome 17-linked FTD, demonstrating for the first time that tau
dysfunction can play a primary role in neurodegeneration. However, tau
mutations have been identified in only 10-20% of familial FTD cases and have
not been demonstrated in sporadic FTD. Thus, the etiology of sporadic FTD remains
unknown. Association studies have also suggested a role for tau in progressive
supranuclear palsy (PSP), with tau mutations reported in two families,
confirming previous pathological evidence of tau abnormalities in PSP. The
results of linkage disequilibrium studies between tau and Parkinson’s disease
(PD), AD and other neurodegenerative disorders are more controversial. In this
review, we summarize the relevant genetic aspects of FTD and related
neurodegenerative disorders, focusing on studies of linkage analysis and tau
mutations.
[Back to
top] Fork Head Transcription
Factors.
The Fork head family is a rapidly growing family of
transcription factors which share a common structurally related DNA binding
domain: the fork head domain. This domain is similar to DNA binding domains of
other proteins not included among the fork heads, which collectively have been
named "Winged helix" proteins. Fork head factors have been found in
species from yeast to humans with the exception of green plants. Although
winged helix proteins have been described in prokaryotes, no fork head factors
have yet been found in any prokaryotic organism. Fork head factors bind DNA as
monomers and regulate transcription on their own, either as activators or
repressors of transcription. In some cases, they can also serve as
transcriptionally inert docking factors for other proteins loaded with
transcriptional regulatory domains. Fork head factors have been found to be
involved in many biological roles. In vertebrates, most members of this family
have roles in embryonic development, but other functions have also been
described, such as circadian rhythm regulation, control of cell cycle, cell
growth, and life span, etc. Here, we review the current state of the knowledge
about this evolutionarily successful family. The ever growing amount of
bibliography published on fork head factors does not permit the exhaustive
discussion of all published work. We have rather focused on the most relevant
aspects of this growing family of transcription factors.