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Whole genome sequence analysis of serum amino acid levels.

ABSTRACT: Blood levels of amino acids are important biomarkers of disease and are influenced by synthesis, protein degradation, and gene-environment interactions. Whole genome sequence analysis of amino acid levels may establish a paradigm for analyzing quantitative risk factors.In a discovery cohort of 1872 African Americans and a replication cohort of 1552 European Americans we sequenced exons and whole genomes and measured serum levels of 70 amino acids. Rare and low-frequency variants (minor allele frequency ?5%) were analyzed by three types of aggregating motifs defined by gene exons, regulatory regions, or genome-wide sliding windows. Common variants (minor allele frequency >5%) were analyzed individually. Over all four analysis strategies, 14 gene-amino acid associations were identified and replicated. The 14 loci accounted for an average of 1.8% of the variance in amino acid levels, which ranged from 0.4 to 9.7%. Among the identified locus-amino acid pairs, four are novel and six have been reported to underlie known Mendelian conditions. These results suggest that there may be substantial genetic effects on amino acid levels in the general population that may underlie inborn errors of metabolism. We also identify a predicted promoter variant in AGA (the gene that encodes aspartylglucosaminidase) that is significantly associated with asparagine levels, with an effect that is independent of any observed coding variants.These data provide insights into genetic influences on circulating amino acid levels by integrating -omic technologies in a multi-ethnic population. The results also help establish a paradigm for whole genome sequence analysis of quantitative traits.

SUBMITTER: Yu B

PROVIDER: S-EPMC5123402 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Whole genome sequence analysis of serum amino acid levels.

Yu Bing B de Vries Paul S PS Metcalf Ginger A GA Wang Zhe Z Feofanova Elena V EV Liu Xiaoming X Muzny Donna Marie DM Wagenknecht Lynne E LE Gibbs Richard A RA Morrison Alanna C AC Boerwinkle Eric E

Genome biology 20161124 1

<h4>Background</h4>Blood levels of amino acids are important biomarkers of disease and are influenced by synthesis, protein degradation, and gene-environment interactions. Whole genome sequence analysis of amino acid levels may establish a paradigm for analyzing quantitative risk factors.<h4>Results</h4>In a discovery cohort of 1872 African Americans and a replication cohort of 1552 European Americans we sequenced exons and whole genomes and measured serum levels of 70 amino acids. Rare and low- ...[more]

PMID: 27884205

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Project description:BackgroundEquid gammaherpesvirus 2 (EHV2) is a gammaherpesvirus with a widespread distribution in horse populations globally. Although its pathogenic significance can be unclear in most cases of infection, EHV2 infection can cause upper respiratory tract disease in foals. Co-infection of different strains of EHV2 in an individual horse is common. Small regions of the EHV2 genome have shown considerable genetic heterogeneity. This could suggest genomic recombination between different strains of EHV2, similar to the extensive recombination networks that have been demonstrated for some alphaherpesviruses. This study examined natural recombination and genome diversity of EHV2 field isolates.ResultsWhole genome sequencing analysis of 18 EHV2 isolates, along with analysis of two publicly available EHV2 genomes, revealed variation in genomes sizes (from 173.7 to 184.8 kbp), guanine plus cytosine content (from 56.7 to 57.8%) and the size of the terminal repeat regions (from 17,196 to 17,551 bp). The nucleotide sequence identity between the genomes ranged from 86.2 to 99.7%. The estimated average inter-strain nucleotide diversity between the 20 EHV2 genomes was 2.9%. Individual gene sequences showed varying levels of nucleotide diversity and ranged between 0 and 38.1%. The ratio of nonsynonymous substitutions, Ka, to synonymous substitutions, Ks, (Ka/Ks) suggests that over 50% of EHV2 genes are undergoing diversifying selection. Recombination analyses of the 20 EHV2 genome sequences using the recombination detection program (RDP4) and SplitsTree revealed evidence of viral recombination.ConclusionsAnalysis of the 18 new EHV2 genomes alongside the 2 previously sequenced genomes revealed a high degree of genetic diversity and extensive recombination networks. Herpesvirus genome diversification and virus evolution can be driven by recombination, and our findings are consistent with recombination being a key mechanism by which EHV2 genomes may vary and evolve.

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Whole genome sequence analysis of serum amino acid levels.

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Whole genome sequence analysis of serum amino acid levels.

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