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Gene regulatory evolution in flycatchers: statistical approaches for the analysis of allele-specific expression
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Ecology and Genetics, Evolutionary Biology.ORCID iD: 0000-0002-1509-587X
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

Understanding the molecular mechanisms underlying evolutionary changes in gene expression is a major research topic in biology. While a powerful approach to study this is the analysis of allele-specific expression (ASE), most of previously published methods can only be applied to lab organisms. In this thesis, to enable the analysis of ASE in natural organisms, I developed two methods for ASE detection. The first one was Bayesian negative binomial approach, and the second one was Read-backed Phasing-based ASE approach. Both methods performed well in simulations and comparisons. By applying those methods, I found that ASE was prevalent in natural flycatcher species. Combining the analyses of differential gene expression and ASE, I found a widespread cis-trans compensation and a critical role of tissue-specific regulatory mechanism during gene expression evolution. Moreover, for cis-regulatory sequences, there was a larger proportion of slightly deleterious mutations and weaker signatures of positive selection for genes with ASE than genes without ASE. For coding sequence, no such difference was observed. These results indicated that the evolution of gene expression and coding sequences could be uncoupled and occurred independently.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2019. , p. 46
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1823
Keywords [en]
ASE, gene expression evolution, bayesian, RPASE, flycatcher.
National Category
Evolutionary Biology
Research subject
Biology with specialization in Evolutionary Genetics
Identifiers
URN: urn:nbn:se:uu:diva-384493ISBN: 978-91-513-0686-5 (print)OAI: oai:DiVA.org:uu-384493DiVA, id: diva2:1320803
Public defence
2019-09-04, Lindahlsalen, Norbyvägen 14, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2019-08-13 Created: 2019-06-05 Last updated: 2019-08-13
List of papers
1. Bayesian Inference of Allele-Specific Gene Expression Indicates Abundant Cis-Regulatory Variation in Natural Flycatcher Populations
Open this publication in new window or tab >>Bayesian Inference of Allele-Specific Gene Expression Indicates Abundant Cis-Regulatory Variation in Natural Flycatcher Populations
2017 (English)In: Genome Biology and Evolution, ISSN 1759-6653, E-ISSN 1759-6653, Vol. 9, no 5, p. 1266-1279Article in journal (Refereed) Published
Abstract [en]

Polymorphism in cis-regulatory sequences can lead to different levels of expression for the two alleles of a gene, providing a starting point for the evolution of gene expression. Little is known about the genome-wide abundance of genetic variation in gene regulation in natural populations but analysis of allele-specific expression (ASE) provides a means for investigating such variation. We performed RNA-seq of multiple tissues from population samples of two closely related flycatcher species and developed a Bayesian algorithm that maximizes data usage by borrowing information from the whole data set and combines several SNPs per transcript to detect ASE. Of 2,576 transcripts analyzed in collared flycatcher, ASE was detected in 185 (7.2%) and a similar frequency was seen in the pied flycatcher. Transcripts with statistically significant ASE commonly showed the major allele in > 90% of the reads, reflecting that power was highest when expression was heavily biased toward one of the alleles. This would suggest that the observed frequencies of ASE likely are underestimates. The proportion of ASE transcripts varied among tissues, being lowest in testis and highest in muscle. Individuals often showed ASE of particular transcripts in more than one tissue (73.4%), consistent with a genetic basis for regulation of gene expression. The results suggest that genetic variation in regulatory sequences commonly affects gene expression in natural populations and that it provides a seedbed for phenotypic evolution via divergence in gene expression.

Place, publisher, year, edition, pages
OXFORD UNIV PRESS, 2017
Keywords
ASE, gene expression evolution, regulatory sequences, RNA-seq
National Category
Biological Sciences
Identifiers
urn:nbn:se:uu:diva-333414 (URN)10.1093/gbe/evx080 (DOI)000406760400013 ()28453623 (PubMedID)
Funder
Swedish Research Council, 2010-5650, 2013-8271EU, European Research Council, AdG 249976Knut and Alice Wallenberg Foundation
Available from: 2017-11-15 Created: 2017-11-15 Last updated: 2019-06-11Bibliographically approved
2. RPASE: Individual-based allele-specific expression detection without prior knowledge of haplotype phase
Open this publication in new window or tab >>RPASE: Individual-based allele-specific expression detection without prior knowledge of haplotype phase
2018 (English)In: Molecular Ecology Resources, ISSN 1755-098X, E-ISSN 1755-0998, Vol. 18, no 6, p. 1247-1262Article in journal (Refereed) Published
Abstract [en]

Variation in gene expression is believed to make a significant contribution to phenotypic diversity and divergence. The analysis of allele-specific expression (ASE) can reveal important insights into gene expression regulation. We developed a novel method called RPASE (Read-backed Phasing-based ASE detection) to test for genes that show ASE. With mapped RNA-seq data from a single individual and a list of SNPs from the same individual as the only input, RPASE is capable of aggregating information across multiple dependent SNPs and producing individual-based gene-level tests for ASE. RPASE performs well in simulations and comparisons. We applied RPASE to multiple bird species and found a potentially rich landscape of ASE.

Keywords
allele-specific expression, gene expression evolution, regulatory variation, RNA-seq
National Category
Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-369587 (URN)10.1111/1755-0998.12909 (DOI)000449535600007 ()29858523 (PubMedID)
Funder
Swedish Research CouncilKnut and Alice Wallenberg Foundation
Available from: 2018-12-19 Created: 2018-12-19 Last updated: 2019-06-11Bibliographically approved
3. Gene regulatory evolution in natural flycatcher populations is highly tissue-specific and shows distinctive patterns in the testis
Open this publication in new window or tab >>Gene regulatory evolution in natural flycatcher populations is highly tissue-specific and shows distinctive patterns in the testis
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-384395 (URN)
Available from: 2019-06-04 Created: 2019-06-04 Last updated: 2019-06-11
4. Cis-regulatory variation and allele-specific expression in the collared flycatcher (Ficedula albicollis) genome
Open this publication in new window or tab >>Cis-regulatory variation and allele-specific expression in the collared flycatcher (Ficedula albicollis) genome
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Evolutionary Biology
Identifiers
urn:nbn:se:uu:diva-384392 (URN)
Available from: 2019-06-04 Created: 2019-06-04 Last updated: 2019-06-11

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