Introduction
The human genome sequence provides an unrivalled new platform for research in human genetics. Projects at the Sanger Institute include genome annotation, development of new resources and technology, and their application to genetic disease.
See also the Cancer Genome Project, Immunogenomics.
Human genes
A full understanding of the information encoded in the human sequence is essential in order to maximise the benefit to research and human health. The experimental gene annotation group (EGAG) works closely with the sequence analysis group HAVANA in informatics to develop new gene resources. This work involves determining the structure of all the genes, and is extending to identify the promoters, regulatory elements, alternative splicing, and other factors that contribute to the encoded functional complexity of the genome. This work is assisted by comparisons with other genome sequences, notably mouse, zebrafish, nematode and yeast; and by parallel studies of protein domain families (Pfam).
Gene expression
Knowledge of all the genes in the human genome enables comprehensive studies of their expression, either globally or in response to specific signals or switches (such as the SCL gene in haematopoiesis) in cellular systems. Studies of specific responses using microarrays, and in the future in situ sections, may be correlated with analysis of genomic sequence to identify regulatory elements that are responsible for transcriptional regulation. See also protein expression studies.
Human sequence variation
Human sequence variation is an important factor in determining individual disease phenotypes, susceptibility to complex disease and variable response to environmental factors and drugs. Sequence variants, most of which are single-nucleotide polymorphisms (SNPs), are being catalogued globally. Targetted sequencing of exons in the Exoseq project aims to provide many new variants of functional importance which may be associated with specific phenotypes.
Disease association
Knowledge of sequence variation form the basis for studying the possible association of individual variants with specific phenotypes. Our large-scale genotyping facility will enable these studies to be undertaken using candidate gene or genome-wide approaches. Development of a map of common haplotypes will empower genome-wide approaches to study the role of common variants in common disease. Candidate gene studies may be coupled with the output from the Exoseq project to include evaluation of rare variants in disease phenotypes.
Molecular cytogenetics
Cytogenetic variations in the genome (translocations, deletions, amplifications) have long been associated with disease states such as dysmorphologies and cancers. The advent of genomic arrays derived from the human clone map for comparative genomic hybridisation studies enables rapid comprehensive study of all these kinds of variation at a new level of resolution. This is coupled with a wide range of high-precision cytogenetic techniques in a central cytometry facility to support future research.
Mapping
Genome mapping formed the core of human genetic research during the early years of the Sanger Institute, culminating in the Human GeneMap, chromosome maps, and more recently SNP maps and transcript maps. Clone resources continue to be refined and distributed for biological experiments such as genomic arrays or transgenics. Expertise in a diverse range of mapping techniques is now applied widely in the study of other genomes, including mouse, zebrafish, and pathogens.
Individual research groups
A range of individual research projects make use of the existing infrastructure within the Sanger Institute. They focus on new areas of research or new technology development. This work helps to direct the further evolution of the resources and to promote collaborations with biological, medical, and informatics groups worldwide.
