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Death of PRDM9 coincides with stabilization of the recombination landscape in the dog genome
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
Univ Oxford, MRC Funct Genom Unit, Dept Physiol Anat & Genet, Oxford OX1 3QX, England.
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2011 (Engelska)Ingår i: Genome Research, ISSN 1088-9051, E-ISSN 1549-5469, Vol. 22, nr 1, s. 51-63Artikel i tidskrift (Refereegranskat) Published
Abstract [en]

Analysis of diverse eukaryotes has revealed that recombination events cluster in discrete genomic locations known as hotspots. In humans, a zinc-finger protein, PRDM9, is believed to initiate recombination in >40% of hotspots by binding to a specific DNA sequence motif. However, the PRDM9 coding sequence is disrupted in the dog genome assembly, raising questions regarding the nature and control of recombination in dogs. By analyzing the sequences of PRDM9 orthologs in a number of dog breeds and several carnivores, we show here that this gene was inactivated early in canid evolution. We next use patterns of linkage disequilibrium using more than 170,000 SNP markers typed in almost 500 dogs to estimate the recombination rates in the dog genome using a coalescent-based approach. Broad-scale recombination rates show good correspondence with an existing linkage-based map. Significant variation in recombination rate is observed on the fine scale, and we are able to detect over 4000 recombination hotspots with high confidence. In contrast to human hotspots, 40% of canine hotspots are characterized by a distinct peak in GC content. A comparative genomic analysis indicates that these peaks are present also as weaker peaks in the panda, suggesting that the hotspots have been continually reinforced by accelerated and strongly GC biased nucleotide substitutions, consistent with the long-term action of biased gene conversion on the dog lineage. These results are consistent with the loss of PRDM9 in canids, resulting in a greater evolutionary stability of recombination hotspots. The genetic determinants of recombination hotspots in the dog genome may thus reflect a fundamental process of relevance to diverse animal species.

Ort, förlag, år, upplaga, sidor
2011. Vol. 22, nr 1, s. 51-63
Nationell ämneskategori
Biokemi och molekylärbiologi Genetik
Identifikatorer
URN: urn:nbn:se:uu:diva-162828DOI: 10.1101/gr.124123.111ISI: 000298854200005PubMedID: 22006216OAI: oai:DiVA.org:uu-162828DiVA, id: diva2:461762
Forskningsfinansiär
Swedish National Infrastructure for Computing (SNIC), b2009001VetenskapsrådetEU, Europeiska forskningsrådetTillgänglig från: 2011-12-05 Skapad: 2011-12-05 Senast uppdaterad: 2017-12-08Bibliografiskt granskad
Ingår i avhandling
1. Detecting Signatures of Selection within the Dog Genome
Öppna denna publikation i ny flik eller fönster >>Detecting Signatures of Selection within the Dog Genome
2013 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Deciphering the genetic basis of phenotypic diversity is one of the central aims of biological research. Domestic animals provide a unique opportunity for making substantial progress towards this goal. Intense positive selection has lead to a rich reservoir of phenotypes and underlying genotypes that can be interrogated using genetic tools to gain insight into the genetic basis of phenotypic diversity.

The dog is the most phenotypically diverse mammal. It was domesticated from the grey wolf 11-30,000 years ago. After domestication, a period of intense breeding has lead to the massive phenotypic diversity seen amongst dog breeds today. These two phases of strong positive selection at domestication and at breed creation are likely to have left their signature on the genome. In this thesis, we have analysed genome-wide patterns to detect genomic regions involved in selection in both of these phases. We used whole genome sequences from 60 dogs and 12 wolves, to detect dog domestication selective sweeps. We find evidence for genes involved in memory formation, neurotransmission and starch digestion.

To decipher the genetic signals underlying breed diversity, we used genome-wide genotype data from >170,000 SNPs in 509 dogs from 46 different breeds. We find evidence for genes under selection in many breeds, and only a few breeds. In addition, we identify novel sweeps underlying morphology and behavior.

Recombination can influence the configuration of alleles present on a haplotype, and can thus increase or decrease the efficiency of selection. The PRDM9 protein has been shown to be important for determining recombination hotspot locations in humans and other mammals, but of all the mammals studied so far the dog is the only one to have a non-functional PRDM9.

We used the genome-wide genotype data described above to characterise the fine scale recombination map in dogs. We find that recombination hotspots exist in dogs despite the absence of PRDM9. Moreover, we show that these hotspots are enriched for GC rich peaks and that these peaks are getting stronger over time. Our results show that the absence of PRDM9 has lead to the stabilisation of the recombination landscape in dogs.

 

Ort, förlag, år, upplaga, sidor
Uppsala: Acta Universitatis Upsaliensis, 2013. s. 38
Serie
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 938
Nyckelord
dog, evolution, domestication, PRDM9, recombination, positive selection, selective sweep
Nationell ämneskategori
Evolutionsbiologi Bioinformatik och systembiologi Genetik
Identifikatorer
urn:nbn:se:uu:diva-209335 (URN)978-91-554-8783-6 (ISBN)
Disputation
2013-12-04, B42, BMC, Husargatan 3, Uppsala, 09:00 (Engelska)
Opponent
Handledare
Tillgänglig från: 2013-11-13 Skapad: 2013-10-17 Senast uppdaterad: 2014-01-23

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Axelsson, ErikWebster, Matthew T.Ratnakumar, AbhiramiLindblad-Toh, Kerstin

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