Clinical implications of human population differences in genome-wide rates of functional genotypes.
Front Genet
; 3: 211, 2012.
Article
in En
| MEDLINE
| ID: mdl-23125845
ABSTRACT
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 â¼5.5-6.1 million total derived variants, of which â¼12,000 are likely to have a functional effect (â¼5000 coding and â¼7000 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Language:
En
Journal:
Front Genet
Year:
2012
Document type:
Article
Affiliation country:
United States
Country of publication:
CH
/
SUIZA
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SUÍÇA
/
SWITZERLAND