Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Clinical and molecular characteristics, and their relations to overall survival.

<p>Clinical and molecular characteristics, and their relations to overall survival.</p

Relations of clinical and molecular characteristics to MATH values.

<p>Relations of clinical and molecular characteristics to MATH values.</p

Multivariate relation of MATH value and standard prognostic variables to overall survival.

<p>Multivariate relation of MATH value and standard prognostic variables to overall survival.</p

Relations of clinical and molecular characteristics to MATH values, adjusting for HPV status.

<p>Relations of clinical and molecular characteristics to MATH values, adjusting for HPV status.</p

MATH receiver operating characteristic curves.

<p>Time-dependent ROC curves (solid lines) evaluated at 3-y survival, obtained by the nearest neighbor method of Heagerty et al. [<a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001786#pmed.1001786.ref044" target="_blank">44</a>], with a smoothing span of 0.1. Curves show the relation between sensitivity (true-positive fraction) and specificity (1 − false-positive fraction) as the MATH value used to distinguish high- from low-heterogeneity tumors (values shown along the curves) is altered. Dashed lines are lines of identity. Left, ROC curve for all 305 patients (95% CI for AUC, 0.60 to 0.74). Right, ROC curve for 78 patients receiving chemoradiation as primary therapy or as an adjuvant to surgery (95% CI for AUC, 0.54 to 0.82).</p

MATH value and mortality in patients with tumors in the oral cavity or the larynx.

<p>Left, patients with oral-cavity tumors; right, patients with laryngeal tumors. Top, Kaplan-Meier curves for all patients. Blue, low MATH; red, high MATH (MATH > 32). Cox proportional hazards analysis: oral cavity, high/low MATH HR, 1.69 (95% CI, 1.04 to 2.73; <i>p</i> = 0.033); larynx, high/low MATH HR, 3.55 (95% CI, 1.25 to 10.1; <i>p</i> = 0.018). Bottom, joint relation of MATH value and disease stage to survival; dashed, lines Stages I–III; solid lines, Stage IV. Cox proportional hazards analysis: oral cavity, high/low MATH HR, 1.67 (95% CI, 1.03 to 2.70; <i>p</i> = 0.037, Wald test); Stage IV/Stage I–III HR, 1.34 (95% CI, 0.87 to 2.08; <i>p</i> = 0.19); larynx, high/low MATH HR, 3.50 (95% CI, 1.18 to 10.4; <i>p</i> = 0.024); Stage IV/Stage I–III HR, 1.04 (95% CI, 0.44 to 2.49; <i>p</i> = 0.92).</p

Clinical and molecular characteristics, and their relations to overall survival.

<p>Clinical and molecular characteristics, and their relations to overall survival.</p

Examples of distributions of intra-tumor MAFs and their relation to MATH values.

<p>Density plots (smoothed histograms) of the distributions of MAFs for two HNSCCs. The horizontal-axis position of each circle represents the MAF for a tumor-specific mutated locus in the indicated tumor sample, for loci having MAFs no lower than 0.075: left, 117 loci; right, 106 loci. For each tumor, the median and the MAD of its MAFs are indicated; each tumor MATH value is the percentage ratio of its MAD to its median. The vertical density axis is scaled so that the area under the smoothed curve equals 1; a high peak density value indicates a sharp peak. MAFs of mutated loci in the high-heterogeneity tumor (right panel) show a lower median and higher MAD than those in the low-heterogeneity tumor (left panel), even though the total numbers of mutated loci, a measure of mutation rates within the tumors, are similar.</p

Combined relation of MATH and HPV or <i>TP53</i> mutation status to overall survival.

<p>Left, joint relation of intra-tumor heterogeneity and HPV status to overall survival in HNSCC among 278 patients whose tumor HPV status had been assessed by TCGA molecular criteria (see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001786#sec010" target="_blank">Methods</a>). Kaplan-Meier curves are for the indicated combinations of HPV and MATH status; high MATH is MATH > 32. Blue, low MATH value; red, high MATH value; dashed lines, HPV-positive; solid lines, HPV-negative. Cox proportional hazards analysis: high/low MATH HR, 1.85 (95% CI, 1.22 to 2.80; <i>p</i> = 0.004, Wald test); HPV-positive/-negative HR, 0.36 (95% CI, 0.18 to 0.74; <i>p</i> = 0.006). Right, joint relation of intra-tumor heterogeneity and <i>TP53</i> mutation status to overall survival in HNSCC among 242 patients with HPV-negative tumors. Kaplan-Meier curves are for the indicated combinations of <i>TP53</i> and MATH status. Dashed lines, wild-type (WT) <i>TP53</i>; solid lines, mutant <i>TP53</i>. Cox proportional hazards analysis: high/low MATH HR, 1.62 (95% CI, 1.04 to 2.52; <i>p</i> = 0.031, Wald test); mutant/wild-type <i>TP53</i> HR, 1.75 (95% CI, 1.002 to 3.05; <i>p</i> = 0.049).</p