The gene-mapper's best friend

Genetic variants associated with dominant or recessive disease-related traits in dogs can be mapped efficiently and with high confidence, report two studies to be published online this week in Nature Genetics. As dogs and humans have a similar complement of genes, the mapping of disease-associated variants in dogs may make an important contribution to the study of human genetic disease.

There are more than 400 genetically distinct dog breeds. As each breed originated in a small number of founder dogs, there is a limited amount of genetic diversity within each breed. This sort of genome structure is ideal for the rough mapping of genes because it allows one to analyze most of the genome with a limited number of genetic markers. Kerstin Lindblad-Toh and colleagues found small regions of the genome to be associated with two traits by assessing a relatively small number of single-nucleotide polymorphisms (27,000) in only 20 dogs.

The authors identified a genomic region containing only one gene -- MITF -- as responsible for the absence of skin and coat pigmentation in white boxers, which also predisposes them to deafness. They also identified a region associated with the dorsal hair ridge in Ridgeback dogs, which are prone to dermoid sinus, a neural tube defect. In the accompanying paper, Leif Andersson and colleagues carried out fine mapping of the region associated with the Ridgeback hair ridge, and showed that the causative mutation is a duplication containing four different genes-- FGF3,FGF4, FGF19 and ORAOV1.

Genetic risk factor for colorectal cancer

Common variants in the gene SMAD7 are associated with an increased risk of colorectal cancer, reports a study to be published online this week in Nature Genetics.

Richard Houlston, Ian Tomlinson and colleagues carried out a genome-wide association study, genotyping more than 500,000 single nucleotide polymorphisms (SNPs) in several thousand individuals with familial colorectal cancer, as well as controls. Three SNPs in SMAD7 were associated with increased risk of the disease in an initial sample, as well as in three replication sample sets, with a high degree of statistical significance.

SMAD7 is an intracellular molecule that inhibits the TGF-beta pathway, which is involved in cell-cell signalling events in a wide range of tissues, including the colon. Although variation in SMAD7 contributes only modestly to risk of colorectal cancer-it contributes to approximately 15% of such cancers in the general population, and less than 1% of the familial risk -- this result suggests, together with other recent data, that common variants of modest effect underlying this disease exist and can be discovered.

Genetic variants in autoimmunity

Scientists report new genetic associations to four diseases in a large scale collaborative effort online this week in Nature Genetics. The Wellcome Trust Case Control Consortium (WTCCC), together with The Australo-Anglo-American Spondylitis Consortium (TASC), identify new genetic associations to three autoimmune diseases -- Ankylosing Spondylitis (AS), Autoimmune Thyroid Disease/Graves' Disease (AITD), and Multiple Sclerosis -- as well as Breast Cancer.

The study involved genome-wide association of protein-coding variants (known as non-synonymous SNPs) in 1000 independent cases of each of the four diseases, compared to a common control set of 1500 healthy individuals. The findings include a report of two new replicated genetic loci associated to AS. The strongest genetic associations were found in the Major Histocompatibility Complex (MHC) region, previously known to be strongly associated with autoimmunity. The authors also provide confirmation of a number of previously reported associations for these diseases.

Genetic variation in hair, eye and skin pigmentation

Several new genetic associations for human hair, eye and skin pigmentation in individuals of European ancestry is reported online this week in Nature Genetics.

Kari Stefansson and colleagues have conducted a genome-wide association study (GWAS) to identify genetic variation associated with human hair and eye pigmentation, as well as skin sensitivity to sun and freckling. The study included 2,986 Icelandic individuals in the initial genome-wide scan, followed by replication of significantly associated genetic loci in a second sample of 2,718 Icelandic and 1,214 Dutch individuals.

The authors identified 6 genetic loci associated with at least one of these pigmentation phenotypes, 4 of which have not been previously associated with pigmentation. The pigmentation characteristics of study participants were defined by self-assessment, and it is possible that more quantitative measures would identify further genetic associations. Most of the pigmentation variants identified in this study have, in previous studies, shown signals of positive selection in European populations.