Wellcome Trust Centre for Human Genetics

About: Wellcome Trust Centre for Human Genetics is a facility organization based out in Oxford, United Kingdom. It is known for research contribution in the topics: Population & Genome-wide association study. The organization has 2122 authors who have published 4269 publications receiving 433899 citations.

Transplanted photoreceptor precursors transfer proteins to host photoreceptors by a mechanism of cytoplasmic fusion.

Abstract: Photoreceptor transplantation is a potential future treatment for blindness caused by retinal degeneration. Photoreceptor transplantation restores visual responses in end-stage retinal degeneration, but has also been assessed in non-degenerate retinas. In the latter scenario, subretinal transplantation places donor cells beneath an intact host outer nuclear layer (ONL) containing host photoreceptors. Here we show that host cells are labelled with the donor marker through cytoplasmic transfer-94±4.1% of apparently well-integrated donor cells containing both donor and host markers. We detect the occurrence of Cre-Lox recombination between donor and host photoreceptors, and we confirm the findings through FISH analysis of X and Y chromosomes in sex-discordant transplants. We do not find evidence of nuclear fusion of donor and host cells. The artefactual appearance of integrated donor cells in host retinas following transplantation is most commonly due to material transfer from donor cells. Understanding this novel mechanism may provide alternate therapeutic strategies at earlier stages of retinal degeneration.

Designing candidate gene and genome-wide case–control association studies

Abstract: This protocol describes how to appropriately design a genetic association case-control study, either focusing on a candidate gene (CG) or region or implementing a genome-wide approach. The steps described involve: (i) defining the case phenotype in adequate detail; (ii) checking the heritability of the disease in question; (iii) considering whether a population-based study is the appropriate design for the research question; (iv) the appropriate selection of controls; (v) sample size calculations and (vi) giving due consideration to whether it is a de novo or replication study. General guidelines are given, as well as specific examples of a CG and a genome-wide association study into type 2 diabetes. Software and websites used in this protocol include the International HapMap Consortium website, Genetic Power Calculator, CaT, and SNPSpD. Running each of the programs takes only a few seconds; the rate-limiting steps involve thinking through the designs and parameters in the disease models.

Tissue-specific CTCF-cohesin-mediated chromatin architecture delimits enhancer interactions and function in vivo.

Abstract: The genome is organized via CTCF–cohesin-binding sites, which partition chromosomes into 1–5 megabase (Mb) topologically associated domains (TADs), and further into smaller sub-domains (sub-TADs). Here we examined in vivo an ∼80 kb sub-TAD, containing the mouse α-globin gene cluster, lying within a ∼1 Mb TAD. We find that the sub-TAD is flanked by predominantly convergent CTCF–cohesin sites that are ubiquitously bound by CTCF but only interact during erythropoiesis, defining a self-interacting erythroid compartment. Whereas the α-globin regulatory elements normally act solely on promoters downstream of the enhancers, removal of a conserved upstream CTCF–cohesin boundary extends the sub-TAD to adjacent upstream CTCF–cohesin-binding sites. The α-globin enhancers now interact with the flanking chromatin, upregulating expression of genes within this extended sub-TAD. Rather than acting solely as a barrier to chromatin modification, CTCF–cohesin boundaries in this sub-TAD delimit the region of chromatin to which enhancers have access and within which they interact with receptive promoters. Hanssen et al. show that CTCF–cohesin binding sites at the α-globin gene cluster function as boundaries to restrict the interaction of enhancers with the flanking chromatin, thus preventing abnormal gene expression.

A major susceptibility locus for leprosy in India maps to chromosome 10p13

Abstract: Leprosy, a chronic infectious disease caused by Mycobacterium leprae, is prevalent in India, where about half of the world's estimated 800,000 cases occur. A role for the genetics of the host in variable susceptibility to leprosy has been indicated by familial clustering, twin studies, complex segregation analyses and human leukocyte antigen (HLA) association studies. We report here a genetic linkage scan of the genomes of 224 families from South India, containing 245 independent affected sibpairs with leprosy, mainly of the paucibacillary type. In a two-stage genome screen using 396 microsatellite markers, we found significant linkage (maximum lod score (MLS) = 4.09, P < 2x10-5) on chromosome 10p13 for a series of neighboring microsatellite markers, providing evidence for a major locus for this prevalent infectious disease. Thus, despite the polygenic nature of infectious disease susceptibility, some major, non-HLA-linked loci exist that may be mapped through obtainable numbers of affected sibling pairs.