Original Research ARTICLE

Front. Genet., 01 November 2012 |

Clinical implications of human population differences in genome-wide rates of functional genotypes

Ali Torkamani1,2,3, Phillip Pham1,2, Ondrej Libiger1,3, Vikas Bansal1,2, Guangfa Zhang1,3, Ashley A. Scott-Van Zeeland1,2, Ryan Tewhey1,3, Eric J. Topol1,2,3 and Nicholas J. Schork1,2,3*
  • 1The Scripps Translational Science, La Jolla, CA, USA
  • 2Scripps Health, La Jolla, CA, USA
  • 3Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA

There have been a number of recent successes in the use of whole genome sequencing and sophisticated bioinformatics techniques to identify pathogenic DNA sequence variants responsible for individual idiopathic congenital conditions. However, the success of this identification process is heavily influenced by the ancestry or genetic background of a patient with an idiopathic condition. This is so because potential pathogenic variants in a patient’s genome must be contrasted with variants in a reference set of genomes made up of other individuals’ genomes of the same ancestry as the patient. We explored the effect of ignoring the ancestries of both an individual patient and the individuals used to construct reference genomes. We pursued this exploration in two major steps. We first considered variation in the per-genome number and rates of likely functional derived (i.e., non-ancestral, based on the chimp genome) single nucleotide variants and small indels in 52 individual whole human genomes sampled from 10 different global populations. We took advantage of a suite of computational and bioinformatics techniques to predict the functional effect of over 24 million genomic variants, both coding and non-coding, across these genomes. We found that the typical human genome harbors ∼5.5–6.1 million total derived variants, of which ∼12,000 are likely to have a functional effect (∼5000 coding and ∼7000 non-coding). We also found that the rates of functional genotypes per the total number of genotypes in individual whole genomes differ dramatically between human populations. We then created tables showing how the use of comparator or reference genome panels comprised of genomes from individuals that do not have the same ancestral background as a patient can negatively impact pathogenic variant identification. Our results have important implications for clinical sequencing initiatives.

Keywords: clinical sequencing, congenital disease, whole genome sequencing, population genetics

Citation: Torkamani A, Pham P, Libiger O, Bansal V, Zhang G, Scott-Van Zeeland AA, Tewhey R, Topol EJ and Schork NJ (2012) Clinical implications of human population differences in genome-wide rates of functional genotypes. Front. Gene. 3:211. doi: 10.3389/fgene.2012.00211

Received: 26 June 2012; Accepted: 26 September 2012;
Published online: 01 November 2012.

Edited by:

Jill Barnholtz-Sloan, Case Western Reserve University School of Medicine, USA

Reviewed by:

Hemant K. Tiwari, University of Alabama at Birmingham, USA
Indrani Halder, University of Pittsburgh, USA
Paola Raska, Case Western Reserve University, USA

Copyright: © 2012 Torkamani, Pham, Libiger, Bansal, Zhang, Scott-Van Zeeland, Tewhey, Topol and Schork. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.

*Correspondence: Nicholas J. Schork, Department of Molecular and Experimental Medicine, The Scripps Translational Science Institute, The Scripps Research Institute, 3344 North Torrey Pines Court, Suite 300, La Jolla, CA 92037, USA. e-mail: