Biochemical studies of poly-T variants in the Alzheimer's disease associated TOMM40 gene.

The apolipoprotein E (APOE) gene remains the most strongly established risk factor for late onset Alzheimer's disease (LOAD). Recently the gene, TOMM40, which is in linkage disequilibrium with APOE, was identified to be associated with LOAD in genome-wide association studies. One of the identified polymorphisms in TOMM40 is rs10524523, which is located in intron 6 and composed of thymidine repeats varying between 14 to 36 base-pairs in length.

Evidence of linkage to chromosomes 10p15.3-p15.1, 14q24.3-q31.1 and 9q33.3-q34.3 in non-syndromic colorectal cancer families.

Up to 25% of colorectal cancer (CRC) may be caused by inherited genetic variants that have yet to be identified. Previous genome-wide linkage studies (GWLSs) have identified a new loci postulated to contain novel CRC risk genes amongst affected families carrying no identifiable mutations in any of the known susceptibility genes for familial CRC syndromes. To undertake a new GWLS, we recruited members from 54 non-syndromic families from Australia and Spain where at least two first-degree relatives were affected by CRC.

Linkage analysis of autopsy-confirmed familial Alzheimer disease supports an Alzheimer disease locus in 8q24.

Background/aims: We have previously reported the results of an extended genome-wide scan of Swedish Alzheimer disease (AD)-affected families; in this paper, we analyzed a subset of these families with autopsy-confirmed AD.

Methods: We report the fine-mapping, using both microsatellite markers and single-nucleotide polymorphisms (SNPs), in the observed maximum logarithm of the odds (LOD)-2 unit (LOD(max)-2) region under the identified linkage peak, linkage analysis of the fine-mapping data with additionally analyzed pedigrees, and association analysis of SNPs selected from candidate genes in the linked interval. The subset was made on the criterion of at least one autopsy-confirmed AD case per family, resulting in 24 families.

A DNA methylation study of the amyloid precursor protein gene in several brain regions from patients with familial Alzheimer disease.

Presence of extracellular amyloid plaques is a neuropathological hallmark of Alzheimer disease. Here the authors have compared the methylation status of a CpG-island in the amyloid precursor protein gene (APP) in DNA extracted from the more plaque-vulnerable cortex regions with DNA from the more plaque-resistant cerebellum using material from six familial Alzheimer disease cases. Bisulfite sequencing of a 188 bp fragment in the APP associated CpG-island showed no methylation in any sample, suggesting that APP is not transcriptionally regulated by methylation in any of the investigated brain regions.

Linkage to 20p13 including the ANGPT4 gene in families with mixed Alzheimer's disease and vascular dementia.

This study aimed at identifying novel susceptibility genes for a mixed phenotype of Alzheimer's disease and vascular dementia. Results from a genome scan showed strongest linkage to 20p13 in 18 families, and subsequent fine mapping was performed with both microsatellites and single-nucleotide polymorphisms in 18 selected candidate transcripts in an extended sample set of 30 families. The multipoint linkage peak was located at marker rs2144151 in the ANGPT4 gene, which is a strong candidate gene for vascular disease because of its involvement in angiogenesis.

Progranulin mutation causes frontotemporal dementia in the Swedish Karolinska family.

Background: Frontotemporal dementia (FTD) is a neurodegenerative disease characterized by cognitive impairment, language dysfunction, and/or changes in personality. Recently it has been shown that progranulin (GRN) mutations can cause FTD as well as other neurodegenerative phenotypes.

Methods: DNA from 30 family members, of whom seven were diagnosed with FTD, in the Karolinska family was available for GRN sequencing.

Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease.

Genetic heterogeneity is a difficulty frequently encountered in the search for genes conferring susceptibility to prostate cancer. To circumvent this issue, we selected a large prostate cancer pedigree for genome-wide linkage analysis from a population that is genetically homogeneous. Selected cases and first-degree relatives were genotyped with Affymetrix 10K SNP arrays, identifying a 14 Mb haplotype on chromosome 5 (5p13-q12) inherited identical-by-descent (IBD) by multiple cases.

Resolution of trisomic mosaicism in prenatal diagnosis: estimated performance of a 50K SNP microarray.

Objective: To evaluate the ability of a DNA single nucleotide polymorphism (SNP) microarray to detect chromosome mosaicism for trisomy in prenatal samples in order to compare this with conventional cytogenetics.

Method: We created a dilution series of mock mosaic samples, by mixing measured amounts of fibroblast cells containing trisomy 8 from a male with aliquots of cells with a normal female karyotype. DNAs were extracted from these mosaic mixtures, then analysed on the Affymetrix 50K Xba SNP chip.

Estimating genotyping error rates from Mendelian errors in SNP array genotypes and their impact on inference.

A simple method of inferring the genotyping error rate of SNP arrays and similar high-throughput genotyping methods from Mendelian errors is described. Application to genotypes from small families using the Affymetrix GeneChip Human Mapping 50 k Array indicates an error rate of about 0.1%, and this rate can be reduced by increasing the quality criterion for calls, though at the cost of a reduced genotype call rate, which limits the benefit available.

A range of simple summary genome-wide statistics for detecting genetic linkage using high density marker data.

A simple approach to design and analysis of genome-wide linkage scans is described, based on an approximation to the joint distribution of likelihood ratio statistics at a large number of single nucleotide polymorphism (SNP) loci. The approximation is readily calculated and makes it feasible to study the test properties of a range of summary statistics for the entire sequence of point-wise test values. Both the null distribution in the absence of genetic effects and the alternative distribution under various models of single or multi-gene inheritance can readily be simulated.

Evolutionary evidence suggests that CpG island-associated Alus are frequently unmethylated in human germline.

Most Alu elements are considered to belong to the methylated fraction of the genome that has undergone CpG depletion, whereas CpG islands are characteristically unmethylated. By analysing the CpG content of >12,000 autosomal CpG island-Alu Sx pairs we wanted to study what happens when an Alu is situated close to a CpG island. We have found that many Alus located close to CpG islands have retained a high proportion of CpG sites, which is consistent with these Alus being unmethylated in the human germline.

Chromosome 7 aberrations in a young girl with myelodysplasia and hepatoblastoma: an unusual association.

We report a 30-month-old female with intrauterine growth retardation, postnatal failure to thrive, pancytopoenia and myelodysplasia with monosomy 7 in the marrow. The child succumbed to overwhelming sepsis, following a bone marrow transplant to facilitate chemotherapy for metastatic hepatoblastoma--a tumour that has not been previously reported in myelodysplasia syndromes. Cytogenetic, molecular and microarray analysis of peripheral blood, skin fibroblasts and bone marrow revealed unusual results, suggestive of somatic chromosome instability.

PPC: an algorithm for accurate estimation of SNP allele frequencies in small equimolar pools of DNA using data from high density microarrays.

Robust estimation of allele frequencies in pools of DNA has the potential to reduce genotyping costs and/or increase the number of individuals contributing to a study where hundreds of thousands of genetic markers need to be genotyped in very large populations sample sets, such as genome wide association studies. In order to make accurate allele frequency estimations from pooled samples a correction for unequal allele representation must be applied. We have developed the polynomial based probe specific correction (PPC) which is a novel correction algorithm for accurate estimation of allele frequencies in data from high-density microarrays.

Individual variation in microsatellite mutation rate in barn swallows.

The hypermutable nature of some microsatellite loci implies realistic possibilities for the large-scale detection of germline mutations by pedigree analysis. We have developed a model system for mutation analysis by the characterisation of patterns of mutation at three hypervariable microsatellites (two tetranucleotide and one pentanucleotide repeat loci) in barn swallows, all three markers having mutation rates at the percentage level. Here, we study how the mutation rate varies between individual birds of a Spanish population of barn swallows.

Single-molecule analysis of the hypermutable tetranucleotide repeat locus D21S1245 through sperm genotyping: a heterogeneous pattern of mutation but no clear male age effect.

Single molecule genotyping of the hypermutable microsatellite locus D21S1245 was used for studying how the rate and pattern of mutation varied between alleles and different age groups. In total, 203 mutation events were scored from the genotyping of DNA corresponding to an estimated 8623 sperm cells from eight different men. Allele-specific mutation rates ranged from 0.

Heterogeneity in the rate and pattern of germline mutation at individual microsatellite loci.

There is a lack of information on how individual microsatellite loci differ with respect to their mutation properties. Such variation will have an important bearing on our understanding of the ubiquitous occurrence of simple repeat sequences in eukaryotic genomes and on deriving proper mutation models that can be incorporated into genetic distance estimates. We genotyped approximately 100 families of the bird barn swallow (Hirundo rustica) for two hypervariable (heterozygosity >95%) microsatellite markers: HrU6, an (AAAG)n tetranucleotide repeat, and HrU10, an (AAGAG)n pentanucleotide repeat.