Correlated mutations in protein sequences: Phylogenetic and structural effects

Technical Report · Tue Dec 01 04:00:00 EST 1998

DOI:https://doi.org/10.2172/296863· OSTI ID:296863

Lapedes, A S ^[1]; Giraud, B G ^[2]; Liu, L C ^[1]; Stormo, G D ^[3]

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1. Los Alamos National Lab., NM (United States). Theoretical Div.
2. C.E.N. Saclay, Gif/Yvette (France). Service Physique Theorique
3. Univ. of Colorado, Boulder, CO (United States). Dept. of Molecular, Cellular and Developmental Biology

Covariation analysis of sets of aligned sequences for RNA molecules is relatively successful in elucidating RNA secondary structure, as well as some aspects of tertiary structure. Covariation analysis of sets of aligned sequences for protein molecules is successful in certain instances in elucidating certain structural and functional links, but in general, pairs of sites displaying highly covarying mutations in protein sequences do not necessarily correspond to sites that are spatially close in the protein structure. In this paper the authors identify two reasons why naive use of covariation analysis for protein sequences fails to reliably indicate sequence positions that are spatially proximate. The first reason involves the bias introduced in calculation of covariation measures due to the fact that biological sequences are generally related by a non-trivial phylogenetic tree. The authors present a null-model approach to solve this problem. The second reason involves linked chains of covariation which can result in pairs of sites displaying significant covariation even though they are not spatially proximate. They present a maximum entropy solution to this classic problem of causation versus correlation. The methodologies are validated in simulation.

• Research Organization: Los Alamos National Lab., Theoretical Div., NM (United States)
• Sponsoring Organization: USDOE Office of Energy Research, Washington, DC (United States)
• DOE Contract Number: W-7405-ENG-36
• OSTI ID: 296863
• Report Number(s): LA-UR--98-1091; CONF-9707181--; ON: DE99000640
• Country of Publication: United States
• Language: English

Related Subjects

55 BIOLOGY AND MEDICINE
BASIC STUDIES
AMINO ACID SEQUENCE
EXPERIMENTAL DATA
MOLECULAR BIOLOGY
PROTEIN STRUCTURE
RNA