Over the past few years, substantial effort has been put into the functional annotation of variation in human genome sequence. Such annotations can play a critical role in identifying putatively causal variants among the abundant natural variation that occurs at a locus of interest. The main challenges in using these various annotations include their large numbers, and their diversity. Here we develop an unsupervised approach to integrate these different annotations into one measure of functional importance (Eigen), that, unlike most existing methods, is not based on any labeled training data. We show that the resulting meta-score has better discriminatory ability using disease associated and putatively benign variants from published studies (in both coding and noncoding regions) compared with the recently proposed CADD score. Across varied scenarios, the Eigen score performs generally better than any single individual annotation, representing a powerful single functional score that can be incorporated in fine-mapping studies.

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The organic fraction of soil is known to be composed of the soil biomass, partially decomposed plant and animal residues, and the materials commonly referred to as humic substances. Knowledge of the persistence of these fractions in soil is vital to the understanding of their contribution to soil fertility and soil genesis. Much information concerning the biochemistry of the humus materials also could be obtained through a knowledge of the mean residence times of the various organic fractions.The nature of the organic compounds and of the organo-mineral bonds varies from soil to soil; consequently, the relative stability of the organic matter of different soils should also vary (8, 16). Tyurin investigated the nature of the humus of the main soil types of the U.S.S.R. He found that the chernozemic humic acids were relatively complex with a preponderance of calcium humates, which were said to be very stable. In contrast, the humus of podzolic soils was associated primarily with nonsilicate forms of iron and aluminum and consisted of relatively simple organic structures. These were thought to be relatively mobile and unstable (7, 17).The availability of the carbon-dating technique has made it feasible to determine the mean residence time of soil humic fractions (2, 4, 11). Thus, the general postulations concerning the relative stability of the soil humic components can now be tested. Campbell and Paul (3) discussed the factors which affect the accuracy of the carbon-dating method of analysis when applied to soils. Isotopic fractionation of the carbon isotopes results in a fairly constant correction to each apparent mean residence time (m.r.t.). No large error was observed to result from the increase of nuclear-bomb-produced C14 in the atmosphere; other errors were relatively small. The present study was undertaken to utilize the natural C14 activity of the carbon in the various organic fractions to provide an accurate comparison of the relative stability of a number of soil organic matter fractions.

Pinpointing the small number of causal variants among the abundant naturally occurring genetic variation is a difficult challenge, but a crucial one for understanding precise molecular mechanisms of disease and follow-up functional studies. We propose and investigate two complementary statistical approaches for identification of rare causal variants in sequencing studies: a backward elimination procedure based on groupwise association tests, and a hierarchical approach that can integrate sequencing data with diverse functional and evolutionary conservation annotations for individual variants. Using simulations, we show that incorporation of multiple bioinformatic predictors of deleteriousness, such as PolyPhen-2, SIFT and GERP++ scores, can improve the power to discover truly causal variants. As proof of principle, we apply the proposed methods to VPS13B, a gene mutated in the rare neurodevelopmental disorder called Cohen syndrome, and recently reported with recessive variants in autism. We identify a small set of promising candidates for causal variants, including two loss-of-function variants and a rare, homozygous probably-damaging variant that could contribute to autism risk.

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Saturated aqueous chloroform solutions (0.07 M) with p H ranging from 0.8 to 12.6 have been irradiated with 60Co y-radiation in the presence and absence of air. G(C1-+ C1O-) increases with increasing p H in the p H range 1-3 (aerated solutions) or 3-6 (deaerated solutions) and again at p H greater than 10.5. The variation in yield from aerated solutions in the region p H 1-3 is attributed to competition between chloroform and hydrogen ions for hydrated electrons. However, such competition cannot account for the p H effect observed in deaerated solutions between p H 3 and 6. Increased yields from both aerated and dcaerated solutions at high p H are attributed to the formation of Oby reaction of hydroxyl radicals and hydroxide ions. Formic acid and oxalic acid have been identified as minor products when aerated chloroform solutions are irradiated.

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