Elsevier

Genomics

Volume 83, Issue 3, March 2004, Pages 395-401
Genomics

Comparative sequence analysis of imprinted genes between human and mouse to reveal imprinting signatures

https://doi.org/10.1016/j.ygeno.2003.09.007Get rights and content

Abstract

We performed a comparative genomic sequence analysis between human and mouse for 24 imprinted genes on human chromosomes 1, 6, 7, 11, 13, 14, 15, 18, 19, and 20. The MEME program was used to search for motifs within conserved sequences among the imprinted genes and we then used the MAST program to analyze for the presence or absence of motifs in the imprinted genes and 128 nonimprinted genes. Our analysis identified 15 motifs that were significantly enriched in the imprinted genes. We generated a logistic regression model by combining multiple motifs as input variables and the 24 imprinted genes and the 128 nonimprinted genes as a training set. The accuracy, sensitivity, and specificity of our model were 98, 92, and 99%, respectively. The model was further validated by an open test on 12 additional imprinted genes. The motifs identified in this study are novel imprinting signatures, which should improve our understanding of genomic imprinting and the role of genomic imprinting in human diseases.

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

References (21)

  • C. Burge et al.

    Prediction of complete gene structures in human genomic DNA

    J. Mol. Biol

    (1997)
  • R.D. Nicholls et al.

    Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader–Willi syndrome

    Nature

    (1989)
  • J. Clayton-Smith et al.

    Angelman syndrome

    J. Med. Genet

    (1992)
  • M. Mannens et al.

    Parental imprinting of human chromosome region 11p15.3–pter involved in the Beckwith–Wiedemann syndrome and various human neoplasia

    Eur. J. Hum. Genet

    (1994)
  • S. Rainier et al.

    Relaxation of imprinted genes in human cancer

    Nature

    (1993)
  • O. Ogawa et al.

    Relaxation of insulin-like growth factor II gene imprinting implicated in Wilms' tumour

    Nature

    (1993)
  • J.S. Sutcliffe et al.

    Deletions of a differentially methylated CpG island at the SNRPN gene define a putative imprinting control region

    Nat. Genet

    (1994)
  • A. Wutz et al.

    Imprinted expression of the Igf2r gene depends on an intronic CpG island

    Nature

    (1997)
  • M.P. Lee et al.

    Loss of imprinting of a paternally expressed transcript, with antisense orientation to KVLQT1, occurs frequently in Beckwith–Wiedemann syndrome and is independent of insulin-like growth factor II imprinting

    Proc. Natl. Acad. Sci. USA

    (1999)
  • A.P. Feinberg

    Imprinting of a genomic domain of 11p15 and loss of imprinting in cancer: an introduction

    Cancer Res

    (1999)
There are more references available in the full text version of this article.

Cited by (22)

  • Genetic variations and human health

    2016, Kexue Tongbao/Chinese Science Bulletin
  • Genome-wide identification of new imprinted genes

    2010, Briefings in Functional Genomics and Proteomics
View all citing articles on Scopus

Supplementary data for this article may be found on ScienceDirect, at doi: 10.1016/j.ygeno.2003.09.007.

1

These authors contributed equally to this study.

View full text