Academic journal article Genetics

Ultraconserved Elements in the Human Genome: Association and Transmission Analyses of Highly Constrained Single-Nucleotide Polymorphisms

Academic journal article Genetics

Ultraconserved Elements in the Human Genome: Association and Transmission Analyses of Highly Constrained Single-Nucleotide Polymorphisms

Article excerpt

ABSTRACT Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.

REFERENCE genome alignments of multiple distantly related species have identified thousands of elements that are 98-100% identical (Bejerano et al. 2004; Derti et al. 2006; Chiang et al. 2008; Stephen et al. 2008). These ultraconserved or nearly ultraconserved elements are expected to harbor important biological functions as they are dosage sensitive (Derti et al. 2006; Chiang et al. 2008), are enriched in or near specific classes of genes (Bejerano et al. 2004), and are under purifying selection (Drake et al. 2006; Chen et al. 2007; Katzman et al. 2007; Sakuraba et al. 2008). Indeed, a number of reports have demonstrated the ability of intergenic and intronic highly conserved elements to direct tissue-specific expression (Woolfe et al. 2005; McEwen et al. 2006; Pennacchio et al. 2006; Ahituv et al. 2007; Paparidis et al. 2007; Visel et al. 2008). As such, DNA sequence variants within highly conserved elements may have a higher likelihood of being associated with phenotypic traits, particularly if examined directly within suspected disease genomic regions (such as under linkage peaks, near candidate genes, or within genetic association loci defined by linkage disequilibrium).

Although comparative genomic approaches comparing human sequences to orthologous sequences have successfully identified variants in noncoding enhancer regions that contribute to the pathogenesis of complex human diseases [e.g., for Hirschsprung disease (Emison et al. 2005)], such investigations have mostly been limited to candidate gene studies. A recent evaluation of the types of variants reported by genome-wide association (GWA) studies showed some enrichment of trait-associated variants in conserved sequences (Hindorffet al. 2009), suggesting the potential utility of systematically screening variants in conserved sequences. Moreover, functionally important variants among conserved elements have not been as well assayed in recent GWA studies as they are expected to be of lower frequency in the population. Indeed, prioritizing variants on the basis of evolutionary constraint has been shown to narrow down the potential causal variant to Mendelian disease in resequenced exome data (Cooper et al. …

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