Strong, Multi-Scale Heterogeneity in Earth's Lowermost Mantle.

The core mantle boundary (CMB) separates Earth's liquid iron outer core from the solid but slowly convecting mantle. The detailed structure and dynamics of the mantle within ~300 km of this interface remain enigmatic: it is a complex region, which exhibits thermal, compositional and phase-related heterogeneity, isolated pockets of partial melt and strong variations in seismic velocity and anisotropy. Nonetheless, characterising the structure of this region is crucial to a better understanding of the mantle's thermo-chemical evolution and the nature of core-mantle interactions. In this study, we examine the heterogeneity spectrum from a recent P-wave tomographic model, which is based upon trans-dimensional and hierarchical Bayesian imaging. Our tomographic technique avoids explicit model parameterization, smoothing and damping. Spectral analyses reveal a multi-scale wavelength content and a power of heterogeneity that is three times larger than previous estimates. Inter alia, the resulting heterogeneity spectrum gives a more complete picture of the lowermost mantle and provides a bridge between the long-wavelength features obtained in global S-wave models and the short-scale dimensions of seismic scatterers. The evidence that we present for strong, multi-scale lowermost mantle heterogeneity has important implications for the nature of lower mantle dynamics and prescribes complex boundary conditions for Earth's geodynamo.

The APC Variant p.Glu1317Gln predisposes to colorectal adenomas by a novel mechanism of relaxing the target for tumorigenic somatic APC mutations.

Multiple rare nonsynonymous variants in APC predispose to colorectal adenomas. The mechanisms through which such variants act have been unclear, but it has been proposed that a specific ("just-right") level of beta-catenin signaling is required for colorectal tumorigenesis. This appears to be mediated by selection for APC genotypes that retain one, or rarely two, 20 amino acid beta-catenin downregulating repeats (20AARs). We investigated the mechanism through which the variant p.Glu1317Gln (c.3949G>C) contributes to colorectal tumorigenesis. We compared the patterns of somatic APC mutations in tumors from patients with attenuated familial adenomatous polyposis (AFAP) who did, or did not, coinherit p.Glu1317Gln with their AFAP-causing APC mutations. Only 8.2% (4/49) of tumors carrying p.Glu1317Gln had somatic mutations predicted to result in mutant polypeptides retaining a single 20AAR, compared to 62.1% (36/58) of those which did not carry this variant (P=5.64 x 10(-9)). Furthermore, tumors with p.Glu1317Gln often carried somatic mutations that were unusually early or late (downstream of the second 20AAR) in the APC open reading frame. These data support a novel mechanism in which p.Glu1317Gln in combination with other weak mutant APC alleles (generating polypepetides with zero, two, or three 20AARs) can provide the necessary growth advantage for colorectal tumorigenesis.

Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors.

Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans.