Summary Background Quantification of the disease burden caused by different risks informs prevention by providing an account of health loss different to that provided by a disease-by-disease analysis. No complete revision of global disease burden caused by risk factors has been done since a comparative risk assessment in 2000, and no previous analysis has assessed changes in burden attributable to risk factors over time. Methods We estimated deaths and disability-adjusted life years (DALYs; sum of years lived with disability [YLD] and years of life lost [YLL]) attributable to the independent effects of 67 risk factors and clusters of risk factors for 21 regions in 1990 and 2010. We estimated exposure distributions for each year, region, sex, and age group, and relative risks per unit of exposure by systematically reviewing and synthesising published and unpublished data. We used these estimates, together with estimates of cause-specific deaths and DALYs from the Global Burden of Disease Study 2010, to calculate the burden attributable to each risk factor exposure compared with the theoretical-minimum-risk exposure. We incorporated uncertainty in disease burden, relative risks, and exposures into our estimates of attributable burden. Findings In 2010, the three leading risk factors for global disease burden were high blood pressure (7·0% [95% uncertainty interval 6·2–7·7] of global DALYs), tobacco smoking including second-hand smoke (6·3% [5·5–7·0]), and alcohol use (5·5% [5·0–5·9]). In 1990, the leading risks were childhood underweight (7·9% [6·8–9·4]), household air pollution from solid fuels (HAP; 7·0% [5·6–8·3]), and tobacco smoking including second-hand smoke (6·1% [5·4–6·8]). Dietary risk factors and physical inactivity collectively accounted for 10·0% (95% UI 9·2–10·8) of global DALYs in 2010, with the most prominent dietary risks being diets low in fruits and those high in sodium. Several risks that primarily affect childhood communicable diseases, including unimproved water and sanitation and childhood micronutrient deficiencies, fell in rank between 1990 and 2010, with unimproved water we and sanitation accounting for 0·9% (0·4–1·6) of global DALYs in 2010. However, in most of sub-Saharan Africa childhood underweight, HAP, and non-exclusive and discontinued breastfeeding were the leading risks in 2010, while HAP was the leading risk in south Asia. The leading risk factor in Eastern Europe, most of Latin America, and southern sub-Saharan Africa in 2010 was alcohol use; in most of Asia, North Africa and Middle East, and central Europe it was high blood pressure. Despite declines, tobacco smoking including second-hand smoke remained the leading risk in high-income north America and western Europe. High body-mass index has increased globally and it is the leading risk in Australasia and southern Latin America, and also ranks high in other high-income regions, North Africa and Middle East, and Oceania. Interpretation Worldwide, the contribution of different risk factors to disease burden has changed s...

Fraser syndrome (OMIM 219000) is a multisystem malformation usually comprising cryptophthalmos, syndactyly and renal defects. Here we report autozygosity mapping and show that the locus FS1 at chromosome 4q21 is associated with Fraser syndrome, although the condition is genetically heterogeneous. Mutation analysis identified five frameshift mutations in FRAS1, which encodes one member of a family of novel proteins related to an extracellular matrix (ECM) blastocoelar protein found in sea urchin. The FRAS1 protein contains a series of N-terminal cysteine-rich repeat motifs previously implicated in BMP metabolism, suggesting that it has a role in both structure and signal propagation in the ECM. It has been speculated that Fraser syndrome is a human equivalent of the blebbed phenotype in the mouse, which has been associated with mutations in at least five loci including bl. As mapping data were consistent with homology of FRAS1 and bl, we screened DNA from bl/bl mice and identified a premature termination of mouse Fras1. Thus, the bl mouse is a model for Fraser syndrome in humans, a disorder caused by disrupted epithelial integrity in utero.

Fraser syndrome is a recessive, multisystem disorder presenting with cryptophthalmos, syndactyly and renal defects and associated with loss-of-function mutations of the extracellular matrix protein FRAS1. Fras1 mutant mice have a blebbed phenotype characterized by intrauterine epithelial fragility generating serous and, later, hemorrhagic blisters. The myelencephalic blebs (my) strain has a similar phenotype. We mapped my to Frem2, a gene related to Fras1 and Frem1, and showed that a Frem2 gene-trap mutation was allelic to my. Expression of Frem2 in adult kidneys correlated with cyst formation in my homozygotes, indicating that the gene is required for maintaining the differentiated state of renal epithelia. Two individuals with Fraser syndrome were homozygous with respect to the same missense mutation of FREM2, confirming genetic heterogeneity. This is the only missense mutation reported in any blebbing mutant or individual with Fraser syndrome, suggesting that calcium binding in the CALXbeta-cadherin motif is important for normal functioning of FREM2.

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We have examined the numbers and distribution of primordial germ cells in We/We, We/+, and +/+ mouse embryos using Southern blotting to determine embryo genotypes. At early somite stages (5-7 somites: approximately 8 1/2 days post coitum [dpc]) there are 50 to 100 germ cells in embryos of all genotypes. The number of germ cells in We/+ and +/+ embryos then begins to increase: at later somite stages (17-19 somites: approximately 9 1/2 dpc) they number about 200, and by 10 1/2 dpc there are approximately 725 We/+ and 850 +/+ germ cells. During this time, however, the number of germ cells in We/We embryos remains less than 100. At 8 1/2 dpc, the distribution of germ cells in the hindgut endoderm is the same in all genotypes. By 9 1/2 dpc, 30% of We/We germ cells are found in ectopic sites (allantois and vitelline artery); germ cell distribution along the length of the hindgut appears normal, but germ cells remain confined to the floor of the gut in We/We embryos, rather than being distributed around its circumference as in the other two genotypes. By 10 1/2 days, the migration of We/We germ cells through the dorsal mesentery lags behind that of the other genotypes, and a larger proportion remains in the gut wall.

There is evidence from Y Chromosome (Chr) deletion mapping that there is a gene on the long arm of the mouse Y Chr that is needed for the normal development of the sperm head. Since mice with partial Y long arm deletions show incomplete penetrance of the sperm head defect, whereas mice with no Y long arm show complete penetrance, it has been suggested that the 'spermiogenesis' gene may be present in multiple copies. A Y-specific genomic DNA sequence (Y353/B) has previously been described that is present in multiple copies on the long arm of the mouse Y and identifies testis-specific transcripts. We have suggested that Y353/B could be the proposed multiple copy 'spermiogenesis' gene. In support of this suggestion, we show here that mice with a partial Y long arm deletion associated with a 3.5-fold increase in the frequency of abnormal sperm heads have a marked reduction in genomic Y353/B copies and a corresponding reduction in Y353/B-related transcripts. Thus, the incompletely penetrant phenotype correlates with a reduction in Y353/B-related transcription. Furthermore, by in situ hybridization with a Y353/B riboprobe to testis sections, we show that the Y353/B-related transcripts are confined to the round spermatid stage of spermiogenesis, just prior to the shaping of the sperm head. The transcripts sediment with the fraction of cytoplasmic RNA in adult testis that is loaded on polysomes, suggesting that the transcripts are actively translated.

The X/Y homologous gene MIC2 was shown to exchange between the sex chromosomes, thus demonstrating that it is a pseudoautosomal gene in man. MIC2 recombines with the sex-determining gene(s) TDF at a frequency of 2 to 3 percent. It is the most proximal pseudoautosomal locus thus far described and as such is an important marker for use in studies directed towards the isolation of TDF.

There is now a substantial body of data showing that in eutherian mammals (mouse, rat, cow and man) XY conceptuses are developmentally more advanced (and consequently larger) than XX conceptuses of equivalent gestational age. This developmental difference is already discernible in the preimplantation period and it has been suggested that the more advanced development of XY embryos may be a consequence of the preimplantation expression of Y chromosomal genes such as Sry or Zfy. In the present paper sex-chromosomally variant mice were used to analyse the genetic basis of XX-XY differences as manifest at 10.5 days post coitum. The results show that the XX-XY difference is due to a combination of a Y chromosome effect and an effect of the difference in X chromosome constitution (2X v 1X). The Y effect is not dependent on the presence of Sry. In the light of this and other studies, it is concluded that the Y chromosome of most mouse strains carries a factor which accelerates preimplantation development and that the resulting developmental advantage is carried over into the postimplantation period. The retarding effect of two X chromosomes is then superimposed on this Y effect subsequent to the blastocyst stage but prior to 9.5 days post coitum.