Current Genomics - Volume 1, Issue 4, 2000

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.

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.

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.

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-Alzheimers degenerative dementias affecting mainly the frontal and temporal neocortex. In contrast to AD, approximately 50PERCENT 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 10-20percent 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 Parkinsons 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.

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.