TY - JOUR
T1 - Genetic Variations of Ultraconserved Elements in the Human Genome
AU - Habic, Anamarija
AU - Mattick, John S.
AU - Calin, George Adrian
AU - Krese, Rok
AU - Konc, Janez
AU - Kunej, Tanja
N1 - Funding Information:
This work was supported by the Slovenian Research Agency (ARRS) through the Research program Comparative genomics and genome biodiversity (grant No. P4-0220). Dr. Calin is the Felix L. Haas Endowed Professor in Basic Science. Work in Dr. Calin’s laboratory is supported by National Institutes of Health (NIH/NCATS) grant UH3TR00943-01 through the NIH Common Fund, Office of Strategic Coordination (OSC), the NIH/NCI grant 1 R01 CA182905-01, a U54 grant No. CA096297/CA096300– UPR/MDACC Partnership for Excellence in Cancer Research 2016 Pilot Project, a Team DOD (CA160445P1) grant, a Ladies Leukemia League grant, a CLL Moonshot Flagship project, a SINF 2017 grant, and the Estate of C.G. Johnson, Jr.
Funding Information:
MAC = minor allele count MAF = minor allele frequency MAP2K5 = mitogen-activated protein kinase kinase 5 MBD5 = methyl-CpG-binding domain protein 5 NIH = National Institutes of Health SNP = single nucleotide polymorphism UCE = ultraconserved element ZEB2 = zinc finger E-box-binding homeobox 2
Publisher Copyright:
© Copyright 2019, Mary Ann Liebert, Inc., publishers.
PY - 2019/11
Y1 - 2019/11
N2 - Ultraconserved elements (UCEs) are among the most popular DNA markers for phylogenomic analysis. In at least three of five placental mammalian genomes (human, dog, cow, mouse, and rat), 2189 UCEs of at least 200 bp in length that are identical have been identified. Most of these regions have not yet been functionally annotated, and their associations with diseases remain largely unknown. This is an important knowledge gap in human genomics with regard to UCE roles in physiologically critical functions, and by extension, their relevance for shared susceptibilities to common complex diseases across several mammalian organisms in the event of their polymorphic variations. In the present study, we remapped the genomic locations of these UCEs to the latest human genome assembly, and examined them for documented polymorphisms in sequenced human genomes. We identified 29,983 polymorphisms within analyzed UCEs, but revealed that a vast majority exhibits very low minor allele frequencies. Notably, only 112 of the identified polymorphisms are associated with a phenotype in the Ensembl genome browser. Through literature analyses, we confirmed associations of 37 (i.e., out of the 112) polymorphisms within 23 UCEs with 25 diseases and phenotypic traits, including, muscular dystrophies, eye diseases, and cancers (e.g., familial adenomatous polyposis). Most reports of UCE polymorphism - disease associations appeared to be not cognizant that their candidate polymorphisms were actually within UCEs. The present study offers strategic directions and knowledge gaps for future computational and experimental work so as to better understand the thus far intriguing and puzzling role(s) of UCEs in mammalian genomes.
AB - Ultraconserved elements (UCEs) are among the most popular DNA markers for phylogenomic analysis. In at least three of five placental mammalian genomes (human, dog, cow, mouse, and rat), 2189 UCEs of at least 200 bp in length that are identical have been identified. Most of these regions have not yet been functionally annotated, and their associations with diseases remain largely unknown. This is an important knowledge gap in human genomics with regard to UCE roles in physiologically critical functions, and by extension, their relevance for shared susceptibilities to common complex diseases across several mammalian organisms in the event of their polymorphic variations. In the present study, we remapped the genomic locations of these UCEs to the latest human genome assembly, and examined them for documented polymorphisms in sequenced human genomes. We identified 29,983 polymorphisms within analyzed UCEs, but revealed that a vast majority exhibits very low minor allele frequencies. Notably, only 112 of the identified polymorphisms are associated with a phenotype in the Ensembl genome browser. Through literature analyses, we confirmed associations of 37 (i.e., out of the 112) polymorphisms within 23 UCEs with 25 diseases and phenotypic traits, including, muscular dystrophies, eye diseases, and cancers (e.g., familial adenomatous polyposis). Most reports of UCE polymorphism - disease associations appeared to be not cognizant that their candidate polymorphisms were actually within UCEs. The present study offers strategic directions and knowledge gaps for future computational and experimental work so as to better understand the thus far intriguing and puzzling role(s) of UCEs in mammalian genomes.
KW - UCEs
KW - complex diseases
KW - genome
KW - orthologous regions
KW - phenotype
KW - polymorphism
KW - ultraconserved elements
UR - http://www.scopus.com/inward/record.url?scp=85074586390&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074586390&partnerID=8YFLogxK
U2 - 10.1089/omi.2019.0156
DO - 10.1089/omi.2019.0156
M3 - Article
C2 - 31689173
AN - SCOPUS:85074586390
SN - 1536-2310
VL - 23
SP - 549
EP - 559
JO - OMICS A Journal of Integrative Biology
JF - OMICS A Journal of Integrative Biology
IS - 11
ER -