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Significant Selective Constraint at 4-Fold Degenerate Sites in the Avian Genome and Its Consequence for Detection of Positive Selection
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.
2011 (English)In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 3, 1381-1389 p.Article in journal (Refereed) Published
Abstract [en]

A major conclusion from comparative genomics is that many sequences that do not code for proteins are conserved beyond neutral expectations, indicating that they evolve under the influence of purifying selection and are likely to have functional roles. Due to the degeneracy of the genetic code, synonymous sites within protein-coding genes have previously been seen as "silent" with respect to function and thereby invisible to selection. However, there are indications that synonymous sites of vertebrate genomes are also subject to selection and this is not necessarily because of potential codon bias. We used divergence in ancestral repeats as a neutral reference to estimate the constraint on 4-fold degenerate sites of avian genes in a whole-genome approach. In the pairwise comparison of chicken and zebra finch, constraint was estimated at 24-32%. Based on three-species alignments of chicken, turkey, and zebra finch, lineage-specific estimates of constraint were 43%, 29%, and 24%, respectively. The finding of significant constraint at 4-fold degenerate sites from data on interspecific divergence was replicated in an analysis of intraspecific diversity in the chicken genome. These observations corroborate recent data from mammalian genomes and call for a reappraisal of the use of synonymous substitution rates as neutral standards in molecular evolutionary analysis, for example, in the use of the well-known d(N)/d(S) ratio and in inferences on positive selection. We show by simulations that the rate of false positives in the detection of positively selected genes and sites increases several-fold at the levels of constraint at 4-fold degenerate sites found in this study.

Place, publisher, year, edition, pages
2011. Vol. 3, 1381-1389 p.
Keyword [en]
Chicken, turkey, zebra finch, 4-fold degenerate sites, purifying selection, nearly neutral theory, comparative genomics
National Category
Evolutionary Biology
Research subject
Biology with specialization in Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-159765DOI: 10.1093/gbe/evr112ISI: 000301535100030OAI: oai:DiVA.org:uu-159765DiVA: diva2:446820
Available from: 2011-10-10 Created: 2011-10-10 Last updated: 2017-12-08Bibliographically approved
In thesis
1. Birds as a Model for Comparative Genomic Studies
Open this publication in new window or tab >>Birds as a Model for Comparative Genomic Studies
2011 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Comparative genomics provides a tool to investigate large biological datasets, i.e. genomic datasets. In my thesis I focused on inferring patterns of selection in coding and non-coding regions of avian genomes. Until recently, large comparative studies on selection were mainly restricted to model species with sequenced genomes. This limitation has been overcome with advances in sequencing technologies and it is now possible to gather large genomic data sets for non-model species. 

Next-generation sequencing data was used to study patterns of nucleotide substitutions and from this we inferred how selection has acted in the genomes of 10 non-model bird species. In general, we found evidence for a negative correlation between neutral substitution rate and chromosome size in birds. In a follow up study, we investigated two closely related bird species, to study expression levels in different tissues and pattern of selection. We found that between 2% and 18% of all genes were differentially expressed between the two species.

We showed that non-coding regions adjacent to genes are under evolutionary constraint in birds, which suggests that noncoding DNA plays an important functional role in the genome. Regions downstream to genes (3’) showed particularly high level of constraint. The level of constraint in these regions was not correlated to the length of untranslated regions, which suggests that other causes play also a role in sequence conservation.

We compared the rate of nonsynonymous substitutions to the rate of synonymous substitutions in order to infer levels of selection in protein-coding sequences. Synonymous substitutions are often assumed to evolve neutrally. We studied synonymous substitutions by estimating constraint on 4-fold degenerate sites of avian genes and found significant evolutionary constraint on this category of sites (between 24% and 43%). These results call for a reappraisal of synonymous substitution rates being used as neutral standards in molecular evolutionary analysis (e.g. the dN/dS ratio to infer positive selection).

Finally, the problem of sequencing errors in next-generation sequencing data was investigated. We developed a program that removes erroneous bases from the reads. We showed that low coverage sequencing projects and large genome sequencing projects will especially gain from trimming erroneous reads.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2011. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 868
Keyword
Birds, Selection, Gene expression, Sequence evolution, Next-generation sequencing, Comparative genomics, Molecular evolution, Genomics, Substitution Rates, Non-coding DNA
National Category
Evolutionary Biology Bioinformatics and Systems Biology
Research subject
Biology with specialization in Molecular Evolution
Identifiers
urn:nbn:se:uu:diva-159766 (URN)978-91-554-8186-5 (ISBN)
Public defence
2011-11-25, Lindahlsalen, Evolutionary Biology Centre, Norbyvägen 18A, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2011-11-04 Created: 2011-10-10 Last updated: 2011-11-10Bibliographically approved

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