Sequenciamento profundo de 10.000 genomas humanos revela 150 milhões de variações genéticas

terça-feira, outubro 04, 2016

Deep sequencing of 10,000 human genomes

Amalio Telenti a,b,1, Levi C. T. Pierce a,c,1, William H. Biggs a,1, Julia di Iulio a,b, Emily H. M. Wong a, Martin M. Fabani a, Ewen F. Kirkness a, Ahmed Moustafa a, Naisha Shah a, Chao Xie d, Suzanne C. Brewerton d, Nadeem Bulsara a, Chad Garner a, Gary Metzker a, Efren Sandoval a, Brad A. Perkins a, Franz J. Och a,c, Yaron Turpaz a,d, and J. Craig Venter a,b,2

Author Affiliations

Contributed by J. Craig Venter, August 18, 2016 (sent for review July 1, 2016; reviewed by David B. Goldstein and Stephen W. 


Large-scale initiatives toward personalized medicine are driving a massive expansion in the number of human genomes being sequenced. Therefore, there is an urgent need to define quality standards for clinical use. This includes deep coverage and sequencing accuracy of an individual’s genome. Our work represents the largest effort to date in sequencing human genomes at deep coverage with these new standards. This study identifies over 150 million human variants, a majority of them rare and unknown. Moreover, these data identify sites in the genome that are highly intolerant to variation—possibly essential for life or health. We conclude that high-coverage genome sequencing provides accurate detail on human variation for discovery and clinical applications.


We report on the sequencing of 10,545 human genomes at 30×–40× coverage with an emphasis on quality metrics and novel variant and sequence discovery. We find that 84% of an individual human genome can be sequenced confidently. This high-confidence region includes 91.5% of exon sequence and 95.2% of known pathogenic variant positions. We present the distribution of over 150 million single-nucleotide variants in the coding and noncoding genome. Each newly sequenced genome contributes an average of 8,579 novel variants. In addition, each genome carries on average 0.7 Mb of sequence that is not found in the main build of the hg38 reference genome. The density of this catalog of variation allowed us to construct high-resolution profiles that define genomic sites that are highly intolerant of genetic variation. These results indicate that the data generated by deep genome sequencing is of the quality necessary for clinical use.

genomics noncoding genome human genetic diversity


1A.T., L.C.T.P., and W.H.B. contributed equally to this work.

2To whom correspondence should be addressed. Email:

Author contributions: J.C.V. conceived the study; A.T. and J.C.V. designed research; L.C.T.P., J.d.I., E.H.M.W., M.M.F., E.F.K., A.M., N.S., C.X., and E.S. performed research; S.C.B., N.B., C.G., G.M., B.A.P., F.J.O., and Y.T. contributed new reagents/analytic tools; W.H.B., M.M.F., and E.S. led the sequencing process; S.C.B., N.B., C.G., and G.M. built informatic annotation and technology infrastructures; B.A.P., F.J.O., and Y.T. supervised research; and A.T., J.d.I., E.H.M.W., E.F.K., and J.C.V. wrote the paper.

Reviewers: D.B.G., Columbia University; and S.W.S., The Hospital for Sick Children.

The authors are employees of Human Longevity, Inc.

Data deposition: Data access is granted through the Human Longevity, Inc. gene browser ( In addition, 325 NA12878 reference genome sequences have been donated to Precision FDA (

This article contains supporting information online at

Freely available online through the PNAS open access option.