Developmental genetics: Starting out on the road to maleness

Growing up male is a genetic lifestyle decision — early in embryonic development, genes on the Y chromosome activate the development of specialized cells that ultimately become the testes. Without this ‘on switch’ for maleness, the developing gonads become ovaries by default and the embryo develops as a female.A study of mice now shows how the developing gonads start out on this road to maleness. In a paper geneticists Robin Lovell-Badge and Ryohei Sekido describe how a gene called Sry, carried on the Y chromosome, boosts another gene elsewhere in the genome that in turn governs the development of sperm-producing cells called Sertoli cells — a crucial component of the testes.By studying gene expression patterns in developing mouse embryos, the researchers deduced that Sry produces a protein that combines with another protein, steroidogenic factor 1 (SF1). This complex then binds to a DNA region that boosts the expression of another gene, Sox9, which controls a host of genes involved in sperm development.Elucidating this pathway not only reveals how maleness develops from the ‘default’ female developmental pathway; defects in this process may also explain how people who are genetically ‘male’ or ‘female’ end up developing the ‘wrong’ sexual anatomy.
contact:
Robin Lovell-Badge (National Institute for Medical Research, London, UK)Tel: +44 20 8816 2126;

Genetic susceptibility to obesity

Scientists have discovered genetic variants that increase the risk of obesity and insulin resistance in the general population, according to two studies published online this week in Nature Genetics. Until now only one locus (FTO) has been associated convincingly with increased risk of obesity.A consortium of investigators led by Mark McCarthy, Ines Barroso and Nicholas Wareham analyzed the genomes of more than 90,000 individuals and found that a variant near MC4R, encoding the melanocortin-4 receptor, increases susceptibility to obesity. Previous studies had shown that the melanocortin-4 receptor is expressed in neurons in the hypothalamus and is a key regulator of food intake and energy expenditure. Although it is unclear how this variant affects MC4R expression or function, the fact that mutations in the gene are known to cause rare cases of severe childhood obesity lends confidence to the association.In a separate study, Jaspal Kooner and colleagues carried out a genome-wide scan of several thousand individuals of Indian Asian or European ancestry, and identified a variant near MC4R as increasing risk of obesity and insulin resistance. The risk variant was more frequent in individuals of Indian Asian ancestry, which the authors suggest may account for the increased burden of obesity in Indian Asians.Author contacts:Mark McCarthy (University of Oxford, UK) Author paper [7]Tel: +44 1865 857 298; E-mail: mark.mccarthy@drl.ox.ac.ukInês Barroso (Wellcome Trust Sanger Institute, Hinxton, UK) Co-author paper [7]Tel: +44 1223 495 341; E-mail: ib1@sanger.ac.ukNicholas Wareham (Addenbrooke’s Hospital, Cambridge, UK) Co-author paper [7]Tel: +44 1223 330 315; E-mail: nick.wareham@mrc-epid.cam.ac.ukJaspal Kooner (Imperial College London, UK) Author paper [8]Tel: +44 20 8383 4751; E-mail: j.kooner@imperial.ac.uk