Resequencing of positional candidates identifies low frequency IL23R coding variants protecting against inflammatory bowel disease

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ～20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.     

The virophage as a unique parasite of the giant mimivirus

Viruses are obligate parasites of Eukarya, Archaea and Bacteria. Acanthamoeba polyphaga mimivirus (APMV) is the largest known virus; it grows only in amoeba and is visible under the optical microscope. Mimivirus possesses a 1,185-kilobase double-stranded linear chromosome whose coding capacity is greater than that of numerous bacteria and archaea1, 2, 3. Here we describe an icosahedral small virus, Sputnik, 50 nm in size, found associated with a new strain of APMV. Sputnik cannot multiply in Acanthamoeba castellanii but grows rapidly, after an eclipse phase, in the giant virus factory found in amoebae co-infected with APMV4. Sputnik growth is deleterious to APMV and results in the production of abortive forms and abnormal capsid assembly of the host virus. The Sputnik genome is an 18.343-kilobase circular double-stranded DNA and contains genes that are linked to viruses infecting each of the three domains of life Eukarya, Archaea and Bacteria. Of the 21 predicted protein-coding genes, eight encode proteins with detectable homologues, including three proteins apparently derived from APMV, a homologue of an archaeal virus integrase, a predicted primase-helicase, a packaging ATPase with homologues in bacteriophages and eukaryotic viruses, a distant homologue of bacterial insertion sequence transposase DNA-binding subunit, and a Zn-ribbon protein. The closest homologues of the last four of these proteins were detected in the Global Ocean Survey environmental data set5, suggesting that Sputnik represents a currently unknown family of viruses. Considering its functional analogy with bacteriophages, we classify this virus as a virophage. The virophage could be a vehicle mediating lateral gene transfer between giant viruses.     

First births by age and education in Britain, France and Norway

Progressively later starting of childbearing has been a feature of cohort change in fertility across Europe and elsewhere over recent decades. Growing differences in the age patterns of childbearing between the Anglo-American and continental European countries, however, have also been found. The present study uses large linked-record databases in Britain, France and Norway to analyse these differences in more detail, focussing on age at entry to motherhood (first childbearing) by level of educational attainment among women born in the 1950s and in the 1960s. The shift between these two cohorts towards a later pattern of first childbearing in Britain was confined to women with secondary school qualifications and above. For women born in the 1960s, the peak age for risk of first childbearing among those with secondary school qualifications grew to be between seven and eleven years later than among women without secondary school qualifications. In France and Norway, the peak ages for risk of first childbearing shifted more uniformly across education levels between the two cohorts. For these 1950s and 1960s cohorts, improvements in women's educational levels also occurred more uniformly in France and Norway, moving more women into education categories characterised by later patterns of first childbearing.     

Animal mimicry: choosing when to be a cleaner-fish mimic

Mimicry in vertebrates is usually a permanent state--mimics resemble and normally accompany their model throughout the life stages during which they act as mimics. Here we show that the bluestriped fangblenny fish (Plagiotremus rhinorhynchos), which aggressively attacks other coral-reef fish, can turn off the mimetic colours that disguise it as the benign bluestreak cleaner wrasse, Labroides dimidiatus, and assume a radically different appearance. This opportunistic facultative mimicry extends the fangblenny's scope by allowing it to blend into shoals of small reef fish as well as to remain inconspicuous at cleaning stations.     

Combining theoretical and experimental data to decipher CFTR 3D structures and functions

Cryo-electron microscopy (cryo-EM) has recently provided invaluable experimental data about the full-length cystic fibrosis transmembrane conductance regulator (CFTR) 3D structure. However, this experimental information deals with inactive states of the channel, either in an apo, quiescent conformation, in which nucleotide-binding domains (NBDs) are widely separated or in an ATP-bound, yet closed conformation. Here, we show that 3D structure models of the open and closed forms of the channel, now further supported by metadynamics simulations and by comparison with the cryo-EM data, could be used to gain some insights into critical features of the conformational transition toward active CFTR forms. These critical elements lie within membrane-spanning domains but also within NBD1 and the N-terminal extension, in which conformational plasticity is predicted to occur to help the interaction with filamin, one of the CFTR cellular partners.