Comparative sequence analysis of imprinted genes between human and mouse to reveal imprinting signatures☆
Introduction
Genomic imprinting is an unusual mechanism of gene regulation that results in preferential expression of one specific parental allele of a gene. Abnormal imprinting can cause human diseases such as Beckwith–Wiedemann syndrome, Prader–Willi syndrome, or Angelman sydrome [1], [2], [3]. Loss of imprinting is often associated with human cancers [4], [5]. Although the exact mechanism of genomic imprinting is still largely unknown, differentially methylated CpG islands, imprinted antisense transcripts, and insulators may play important roles in the regulation of imprinting [6], [7], [8]. Most of the imprinted genes are located in the imprinting domains [9]. However, some genes in the imprinting domain can escape imprinting regulation [10]. Many imprinted genes are scattered throughout the human genome. Therefore, it is likely that local cis-elements as well as chromatin structure control genomic imprinting.
Since patterns of gene regulation and the corresponding regulatory elements are often conserved across species, sequence comparison between human and mouse is a powerful approach to identify regulatory sequences [11]. Such comparative sequence analysis has already identified a number of conserved sequences and novel imprinted genes in human 11p15 [12] and the Dlk1–Gtl2 locus [13], [14]. In this report, we extend the comparative genomic sequence analysis to the known imprinted genes in the entire human genome. We then go on to identify motifs shared among the conserved sequences and discover a new imprinting signature.
Section snippets
Conserved sequences between human and mouse imprinted genes
We set out to identify novel sequence motifs that are associated with imprinted genes. Our computation method is depicted in Fig. 1. Regulatory elements tend to locate on the conserved sequences [11]. Therefore, we searched conserved sequences between human and mouse imprinted genes using the PipMaker program [15]. We started with a list of 41 known imprinted genes that we generated from literatures (Supplemental Table 1). Genomic sequences of these 41 imprinted genes (including their 10-kb
Discussion
In this paper, we carried out a comparative sequence analysis to identify conserved sequences. We then went on to identify motifs that were shared among imprinted genes. These motifs were used in logistic regression analysis to discover the imprinting signature.
Comparative sequence analysis is a powerful way to identify regulatory elements [11]. It has been used to identify conserved sequences in human 11p15 [12] and the Dlk1–Gtl2 locus [13], [14]. However, the comparative sequence analysis for
Data source
We collected a list of 41 imprinted genes in human from the literature. The full list of the 41 imprinted genes can be found in Supplemental Table 1. The genomic DNA sequences of the imprinted genes were retrieved from NCBI's NT sequences which can be downloaded from ftp://ncbi.nlm.nih.gov/genomes/. The mouse homologous genes were determined from ftp://ftp.ncbi.nih.gov/pub/HomoloGene/hmlg.ftp and the literature. For each pair of human–mouse homologous genes, we collected genomic DNA of the
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Supplementary data for this article may be found on ScienceDirect, at doi: 10.1016/j.ygeno.2003.09.007.
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These authors contributed equally to this study.