People of the British Isles: preliminary analysis of genotypes and surnames in a UK control population

There is a great deal of interest in fine scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to play a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. Here we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK control population that can be used as a resource by the research community as well as providing fine scale genetic information on the British population. So far, some 4,000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3,865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1,057 samples demonstrates the value of these samples for investigating fine scale population structure within the UK, and shows how this can be enhanced by the use of surnames

Functional characterisation of the TSC1–TSC2 complex to assess multiple TSC2 variants identified in single families affected by tuberous sclerosis complex

BACKGROUND: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by seizures, mental retardation and the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, interact to form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). METHODS: We have used a combination of different assays to characterise the effects of a number of pathogenic TSC2 amino acid substitutions on TSC1-TSC2 complex formation and mTOR signalling. RESULTS: We used these assays to compare the effects of 9 different TSC2 variants (S132C, F143L, A196T, C244R, Y598H, I820del, T993M, L1511H and R1772C) identified in individuals with symptoms of TSC from 4 different families. In each case we were able to identify the pathogenic mutation. CONCLUSION: Functional characterisation of TSC2 variants can help identify pathogenic changes in individuals with TSC, and assist in the diagnosis and genetic counselling of the index cases and/or other family members

Identification of a region required for TSC1 stability by functional analysis of TSC1 missense mutations found in individuals with tuberous sclerosis complex

Background: Tuberous sclerosis complex (TSC) is an autosomal dominant disorder characterised by the development of hamartomas in a variety of organs and tissues. The disease is caused by mutations in either the TSC1 gene on chromosome 9q34, or the TSC2 gene on chromosome 16p13.3. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a protein complex that inhibits signal transduction to the downstream effectors of the mammalian target of rapamycin (mTOR). Recently it has been shown that missense mutations to the TSC1 gene can cause TSC. Methods: We have used in vitro biochemical assays to investigate the effects on TSC1 function of TSC1 missense variants submitted to the Leiden Open Variation Database. Results: We identified specific substitutions between amino acids 50 and 190 in the N-terminal region of TSC1 that result in reduced steady state levels of the protein and lead to increased mTOR signalling. Conclusion: Our results suggest that amino acid residues within the N-terminal region of TSC1 are important for TSC1 function and for maintaining the activity of the TSC1-TSC2 complex

Discovery of Western European R1b1a2 Y Chromosome Variants in 1000 Genomes Project Data: An Online Community Approach

The authors have used an online community approach, and tools that were readily available via the Internet, to discover genealogically and therefore phylogenetically relevant Y-chromosome polymorphisms within core haplogroup R1b1a2-L11/S127 (rs9786076). Presented here is the analysis of 135 unrelated L11 derived samples from the 1000 Genomes Project. We were able to discover new variants and build a much more complex phylogenetic relationship for L11 sub-clades. Many of the variants were further validated using PCR amplification and Sanger sequencing. The identification of these new variants will help further the understanding of population history including patrilineal migrations in Western and Central Europe where R1b1a2 is the most frequent haplogroup. The fine-grained phylogenetic tree we present here will also help to refine historical genetic dating studies. Our findings demonstrate the power of citizen science for analysis of whole genome sequence data

Global genome expression analysis of rice in response to drought and high-salinity stresses in shoot, flag leaf, and panicle

To elucidate genome-level responses to drought and high-salinity stress in rice, a 70mer oligomer microarray covering 36,926 unique genes or gene models was used to profile genome expression changes in rice shoot, flag leaf and panicle under drought or high-salinity conditions. While patterns of gene expression in response to drought or high-salinity stress within a particular organ type showed significant overlap, comparison of expression profiles among different organs showed largely organ-specific patterns of regulation. Moreover, both stresses appear to alter the expression patterns of a significant number of genes involved in transcription and cell signaling in a largely organ-specific manner. The promoter regions of genes induced by both stresses or induced by one stress in more than one organ types possess relative enrichment of two cis-elements (ABRE core and DRE core) known to be associated with water stress. An initial computational analysis indicated that novel promoter motifs are present in the promoters of genes involved in rehydration after drought. This analysis suggested that rice might possess a mechanism that actively detects rehydration and facilitates rapid recovery. Overall, our data supports a notion that organ-specific gene regulation in response to the two abiotic stresses may primarily be mediated by organ-specific transcription responses. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s11103-006-9111-1) contains supplementary material, which is available to authorized users

A Nomenclature System for the Tree of Human Y-Chromosomal Binary Haplogroups

The Y chromosome contains the largest nonrecombining block in the human genome. By virtue of its many polymorphisms, it is now the most informative haplotyping system, with applications in evolutionary studies, forensics, medical genetics, and genealogical reconstruction. However, the emergence of several unrelated and nonsystematic nomenclatures for Y-chromosomal binary haplogroups is an increasing source of confusion. To resolve this issue, 245 markers were genotyped in a globally representative set of samples, 74 of which were males from the Y Chromosome Consortium cell line repository. A single most parsimonious phylogeny was constructed for the 153 binary haplogroups observed. A simple set of rules was developed to unambiguously label the different clades nested within this tree. This hierarchical nomenclature system supersedes and unifies past nomenclatures and allows the inclusion of additional mutations and haplogroups yet to be discovered. [Supplementary Table 1, available as an online supplement at www.genome.org, lists all published markers included in this survey and primer information.