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

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.R EFERENCE 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.

Genetic Variations of Ultraconserved Elements in the Human Genome

“…Only four among all reviewed articles regarding polymorphism/phenotype associations have mentioned that locations of analyzed polymorphisms are within conserved genomic regions (Chen et al, 2007;Chiang et al, 2012;Senderek et al, 2009;Shen et al, 2011), which strongly indicates that UCEs mostly remain unnoticed by the authors. Simultaneously, our identification of the 37 polymorphisms within UCEs with phenotype annotations highlights the fact that a wealth of data regarding functional annotation of UCEs is readily available in established databases.…”

Long Noncoding RNAs in Cardiac Development and Pathophysiology

“…48,49 There is a dearth of SNPs in human UCRs, suggesting purifying selection and some association with SNPs and human disease traits. 50 Both exonic and intergenic UCRs can be transcribed, predominantly in a single orientation and often in a tissue-specific manner, with expression patterns altered in cancer, 51 suggesting that UCR transcription is important for its function. Although deletion of 4 nonexonic UCRs did not lead to observable phenotypes in mice, 52 many have been shown to function as enhancers in splicing or as coactivators within transcriptional complexes.…”

Combinatorial Gene Regulatory Functions Underlie Ultraconserved Elements in Drosophila

“…Despite the independent evolutionary origin of mammalian and Drosophila UCEs, their comparison reveals a number of common and distinct features. In regards to the latter, while in mammals it has been difficult to link mutations in UCEs to phenotypic outcomes ( Drake et al 2006 ; Ahituv et al 2007 ; Chen et al 2007 ; Yang et al 2008 ; Catucci et al 2009 ; Poitras et al 2010 ; Chiang et al 2012 ), a recent survey of 11 insertions into Drosophila UCEs identified four as recessive lethal ( Makunin et al 2013 ), illustrating a more straightforward association between UCEs and phenotypes in the fly, making Drosophila a promising model system to study the mechanisms that lead to ultraconservation. As for similarities, fly and mammalian UCEs tend to cluster around genes involved in developmental processes ( Bejerano et al 2004 ; Boffelli et al 2004 ; Sandelin et al 2004 ; Glazov et al 2005 ) and seem associated to related regulatory mechanisms including alternative splicing and RNA editing ( Glazov et al 2005 , 2006 ; Kern et al 2015 ); however, to date, Drosophila UCEs were not found to overlap with transcription factor (TF) binding sites ( Glazov et al 2005 ).…”