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Patterns of variation in cis-regulatory regions: examining evidence of purifying selection
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution. (Evolutionär organismbiologi)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution. (Evolutionär organismbiologi)
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution. (Evolutionär organismbiologi)ORCID iD: 0000-0002-8160-9621
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Human Evolution. (Evolutionär organismbiologi)ORCID iD: 0000-0001-7840-7853
2018 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 19, article id 95Article in journal (Refereed) Published
Abstract [en]

Background: With only 2 % of the human genome consisting of protein coding genes, functionality across the rest of the genome has been the subject of much debate. This has gained further impetus in recent years due to a rapidly growing catalogue of genomic elements, based primarily on biochemical signatures (e.g. the ENCODE project). While the assessment of functionality is a complex task, the presence of selection acting on a genomic region is a strong indicator of importance. In this study, we apply population genetic methods to investigate signals overlaying several classes of regulatory elements.

Results: We disentangle signals of purifying selection acting directly on regulatory elements from the confounding factors of demography and purifying selection linked to e.g. nearby protein coding regions. We confirm the importance of regulatory regions proximal to coding sequence, while also finding differential levels of selection at distal regions. We note differences in purifying selection among transcription factor families. Signals of constraint at some genomic classes were also strongly dependent on their physical location relative to coding sequence. In addition, levels of selection efficacy across genomic classes differed between African and non-African populations.

Conclusions: In order to assign a valid signal of selection to a particular class of genomic sequence, we show that it is crucial to isolate the signal by accounting for the effects of demography and linked-purifying selection. Our study highlights the intricate interplay of factors affecting signals of selection on functional elements.

Place, publisher, year, edition, pages
BIOMED CENTRAL LTD , 2018. Vol. 19, article id 95
Keywords [en]
Regulatory regions, Purifying selection, Selection efficacy, Non-coding DNA, Functional elements, Population genetics
National Category
Genetics Developmental Biology
Identifiers
URN: urn:nbn:se:uu:diva-343792DOI: 10.1186/s12864-017-4422-yISI: 000423443900002PubMedID: 29373957OAI: oai:DiVA.org:uu-343792DiVA, id: diva2:1187552
Funder
Göran Gustafsson Foundation for Research in Natural Sciences and MedicineKnut and Alice Wallenberg FoundationSwedish Research CouncilAvailable from: 2018-03-05 Created: 2018-03-05 Last updated: 2018-09-28Bibliographically approved
In thesis
1. Population Genetics of Human Genomic Elements
Open this publication in new window or tab >>Population Genetics of Human Genomic Elements
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The genomes of living organisms are composed of a multitude of functional units, which interact with each other and their environment in a highly regulated fashion, to facilitate the expression of an enduring (and evolving) phenotype. Several approaches have emerged in the effort to identify these functional units and explore their activities. In this thesis, I have taken a population genetics approach; evaluating how the distribution of genetic variation in the human genome has been shaped through the actions of natural selection on functional genomic elements. In the first paper, I interrogate a catalogue of elements derived from biochemical signatures for signals of selection; finding significant signals of purifying selection on regulatory elements, independent of linked-purifying selection. In the second paper, I explore the pseudogene class of genomic elements, and find that a large proportion of a particular subclass, transcribed duplicated pseudogenes, has experienced significant amounts of positive selection. In the third paper, I focus on protein coding genes and variants that disrupt their open reading frames. Specifically, I examine the distribution of loss-of-function variants in the Khoe-San population; gauging their functional significance and exploring the biological roles of affected genes. In the final paper, instead of using population genetics to uncover and explore genomic elements, I use a major genomic element – the Y chromosome – as an effective tool to study the evolutionary history of a human population.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 58
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1724
Keywords
population genetics, human genome, functional elements, natural selection, pseudogenes, loss-of-function, gene regulation, Y chromosome
National Category
Genetics Evolutionary Biology
Research subject
Biology with Specialisation in Human Evolution and Genetics
Identifiers
urn:nbn:se:uu:diva-361125 (URN)978-91-513-0447-2 (ISBN)
Public defence
2018-11-08, Lindahlsalen, 05:01058, EBC, Norbyvägen 18A, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2018-10-16 Created: 2018-09-20 Last updated: 2018-11-19

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