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Scozzari R.,University of Rome La Sapienza | Massaia A.,University of Rome La Sapienza | Trombetta B.,University of Rome La Sapienza | Bellusci G.,University of Rome Tor Vergata | And 3 more authors.
Genome Research | Year: 2014

Sequence diversity and the ages of the deepest nodes of the MSY phylogeny remain largely unexplored due to the severely biased collection of SNPs available for study. We characterized 68 worldwide Y chromosomes by high-coverage nextgeneration sequencing, including 18 deep-rooting ones, and identified 2386 SNPs, 80% of which were novel. Many aspects of this pool of variants resembled the pattern observed among genome-wide de novo events, suggesting that in the MSY, a large proportion of newly arisen alleles has survived in the phylogeny. Some degree of purifying selection emerged in the form of an excess of private missense variants. Our tree recapitulated the previously known topology, but the relative lengths of major branches were drastically modified and the associated node ages were remarkably older. We found significantly different branch lengths when comparing the rare deep-rootedA1b African lineage with the rest of the tree. Our dating results and phylogeography led to the following main conclusions: (1) Patrilineal lineages with ages approaching those of early AMH fossils survive today only in central-western Africa; (2) only a few evolutionarily successful MSY lineages survived between 160 and 115 kya; and (3) an early exit out of Africa (before 70 kya), which fits recent western Asian archaeological evidence, should be considered. Our experimental design produced an unbiased resource of new MSY markers informative for the initial formation of the anatomically modern human gene pool, i.e., a period of our evolution that had been previously considered to be poorly accessible with paternally inherited markers. © 2014 Scozzari et al. Source

Trombetta B.,University of Rome La Sapienza | D'Atanasio E.,University of Rome La Sapienza | Massaia A.,University of Rome La Sapienza | Massaia A.,Wellcome Trust Sanger Institute | And 5 more authors.
PLoS ONE | Year: 2015

Factors affecting the rate and pattern of the mutational process are being identified for human autosomes, but the same relationships for the male specific portion of the Y chromosome (MSY) are not established.We considered 3,390 mutations occurring in 19 sequence bins identified by sequencing 1.5 Mb of the MSY fromeach of 104 present-day chromosomes. The occurrence ofmutations was not proportional to the amount of sequenced bases in each bin, with a 2-fold variation. The regression of the number ofmutations per unit sequence against a number of indicators of the genomic features of each bin, revealed the same fundamental patterns as in the autosomes. By considering the sequences of the same region from two precisely dated ancient specimens, we obtained a calibrated region-specific substitution rate of 0.716 × 10-9/site/year. Despite its lack of recombination and other peculiar features, the MSY then resembles the autosomes in displaying a marked regional heterogeneity of the mutation rate. An immediate implication is that a given figure for the substitution rate only makes sense if bound to a specific DNA region. By strictly applying this principle we obtained an unbiased estimate of the antiquity of lineages relevant to the genetic history of the human Y chromosome. In particular, the two deepest nodes of the tree highlight the survival, in Central-Western Africa, of lineages whose coalescence (291 ky, 95%C.I. 253-343) predates the emergence of anatomicallymodern features in the fossil record. © 2015 Trombetta et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source

Noto K.,AncestryDNA | Majidi S.,Tufts University | Edlow A.G.,Tufts Medical Center | Wick H.C.,Tufts University | And 3 more authors.
Journal of Computational Biology | Year: 2015

Methods for translating gene expression signatures into clinically relevant information have typically relied upon having many samples from patients with similar molecular phenotypes. Here, we address the question of what can be done when it is relatively easy to obtain healthy patient samples, but when abnormalities corresponding to disease states may be rare and one-of-a-kind. The associated computational challenge, anomaly detection, is a well-studied machine-learning problem. However, due to the dimensionality and variability of expression data, existing methods based on feature space analysis or individual anomalously expressed genes are insufficient. We present a novel approach, CSAX, that identifies pathways in an individual sample in which the normal expression relationships are disrupted. To evaluate our approach, we have compiled and released a compendium of public expression data sets, reformulated to create a test bed for anomaly detection. We demonstrate the accuracy of CSAX on the data sets in our compendium, compare it to other leading methods, and show that CSAX aids in both identifying anomalies and explaining their underlying biology. We describe an approach to characterizing the difficulty of specific expression anomaly detection tasks. We then illustrate CSAX's value in two developmental case studies. Confirming prior hypotheses, CSAX highlights disruption of platelet activation pathways in a neonate with retinopathy of prematurity and identifies, for the first time, dysregulated oxidative stress response in second trimester amniotic fluid of fetuses with obese mothers. Our approach provides an important step toward identification of individual disease patterns in the era of precision medicine. © Mary Ann Liebert, Inc. 2015. Source

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