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Human Molecular Genetics Advance Access published online on July 21, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi257
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received May 20, 2005
Revised July 11, 2005
Accepted July 14, 2005

Article

Analysis of intronic conserved elements indicates that functional complexity might represent a major source of negative selection on noncoding sequences

Manuela Sironi 1, Giorgia Menozzi 1, Giacomo P. Comi 2, Rachele Cagliani 1, Nereo Bresolin 3, and Uberto Pozzoli 1*

1 Scientific Institute IRCCS E. Medea, Via Don Luigi Monza 20, 23842 Bosisio Parini (LC), Italy
2 Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università di Milano, IRCCS Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100 Milan, Italy
3 Scientific Institute IRCCS E. Medea, Via Don Luigi Monza 20, 23842 Bosisio Parini (LC), Italy; Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Università di Milano, IRCCS Ospedale Maggiore Policlinico, Via Francesco Sforza 35, 20100 Milan, Italy.

* To whom correspondence should be addressed.
Uberto Pozzoli, E-mail: upozzoli{at}BP.LNF.it


  Abstract

The noncoding portion of our genome is punctuated by a large number of multispecies conserved sequence elements (MCS) with largely unknown function. We demonstrate that MCSs are unevenly distributed in human introns with the majority of relatively short introns (length < 9 kb) displaying no or a few MCSs, and MCS density reaching up to 10% of total size in longer introns. After correction for intron length, MCSs result to be enriched within genes involved in development and transcription while depleted in immune response loci. Moreover, many central nervous system tissues show a preferential expression of MCS-rich genes and MCS enrichment significantly correlates with gene functional complexity in terms of distinct protein domains. Analysis of human-mouse orthologous pairs indicated a significant association between intronic MCS density and conservation of protein sequence, promoter regions and untranslated sequences. Moreover, MCS density correlates with the predicted occurrence of human-mouse conserved alternative splicing events. These observations suggest that evolution acts on human genes as integrated units of coding and regulatory capacity and that functional complexity might represent a major source of negative selection on noncoding sequences.

In order to substantiate our result we also searched previously experimentally identified intronic regulatory elements and indicate that about half of these sequences map to an MCS; in particular, support to the notion whereby mutations in MCSs can result in human genetic disease is provided since three previously identified intronic pathological variations were found to occur within MCSs and human disease and cancer genes were found significantly enriched in MCSs.


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