uu.seUppsala University Publications
Change search
ReferencesLink to record
Permanent link

Direct link
Evolutionary toggling of the MAPT 17q21.31 inversion region
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
Show others and affiliations
2008 (English)In: Nature Genetics, ISSN 1061-4036, Vol. 40, no 9, 1076-83 p.Article in journal (Refereed) Published
Abstract [en]

Using comparative sequencing approaches, we investigated the evolutionary history of the European-enriched 17q21.31 MAPT inversion polymorphism. We present a detailed, BAC-based sequence assembly of the inverted human H2 haplotype and compare it to the sequence structure and genetic variation of the corresponding 1.5-Mb region for the noninverted H1 human haplotype and that of chimpanzee and orangutan. We found that inversion of the MAPT region is similarly polymorphic in other great ape species, and we present evidence that the inversions occurred independently in chimpanzees and humans. In humans, the inversion breakpoints correspond to core duplications with the LRRC37 gene family. Our analysis favors the H2 configuration and sequence haplotype as the likely great ape and human ancestral state, with inversion recurrences during primate evolution. We show that the H2 architecture has evolved more extensive sequence homology, perhaps explaining its tendency to undergo microdeletion associated with mental retardation in European populations.

Place, publisher, year, edition, pages
2008. Vol. 40, no 9, 1076-83 p.
National Category
Biological Sciences
URN: urn:nbn:se:uu:diva-100873DOI: 10.1038/ng.193ISI: 000258761200020PubMedID: 19165922OAI: oai:DiVA.org:uu-100873DiVA: diva2:211173
Available from: 2009-04-09 Created: 2009-04-09 Last updated: 2011-03-18Bibliographically approved
In thesis
1. Investigation of Mechanics of Mutation and Selection by Comparative Sequencing
Open this publication in new window or tab >>Investigation of Mechanics of Mutation and Selection by Comparative Sequencing
2009 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The process of evolution is of both scientific and medical interest. This thesis presents several studies using complete genomic reference sequences, comparative genomic data, and intraspecific diversity data to study the two key processes of evolution: mutation and selection.

Large duplications, deletions, inversions, and translocations of DNA contribute to genomic variation both between and within species. Human chromosomes 15 and 17 contain a high percentage of dispersed, recently duplicated sequences. Examination of the relationships between these sequences showed that the majority of all duplications within each chromosome could be linked through core sequences that are prone to duplication. Comparison to orthologous sequences in other mammals allowed a reconstruction of the ancestral state of the human chromosomes, revealing that regions of rearrangement specific to the human lineage are highly enriched in chromosome-specific duplications. Comparison to copy number variation data from other studies also shows that these regions are enriched in current human structural variation. One specific region, the MAPT locus at 17q21.31, known to contain an inversion polymorphism in Europeans, was resequenced completely across both human orientation haplotypes and in chimpanzee and orangutan, revealing complex duplication structures at the inversion breakpoints, with the human region being more complex than chimpanzee or orangutan. Fluorescent in-situ hybridization analysis of human, chimpanzee, and orangutan chromosomes showed inversion polymorphisms of independent origin in all three species, demonstrating that this region has been a hotspot of genomic rearrangement for at least twelve million years. These results reveal a mechanistic relationship between sequence duplication and rearrangement in the great apes.

We also generated a draft sequence of the chimpanzee genome and compared it to that of the human. Among other findings, this showed that CpG dinucleotides contribute 25% of all single base mutations, with a rate of mutation ~10-fold that of other bases, and that the male mutation rate in great apes is ~5-6 times the female rate, a higher ratio than had been observed in comparisons of primates and rodents. We detected six regions of probable recent positive selection in humans with a statistical method relying on chimpanzee sequence to control for regional variation in mutation rates.

Finally, resequencing of several lines of domestic chicken and comparison to the reference chicken genome identified a number of gene deletions fixed in domestic lines and also several potential selective sweeps. Of particular interest are a missense mutation in TSHR nearly fixed in all domestic chickens and a partial deletion of SH3RF2 fixed in a high growth line. The TSHR mutation may play a role in relaxation of seasonal reproduction. A high-resolution QTL mapping experiment showed that the SH3RF2 deletion is significantly associated with increased growth.

This work provides important new insights into the mechanics of evolutionary change at both the single nucleotide and structural level and identifies potential targets of natural and artificial selection in humans and chickens.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2009. 63 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 482
chicken, chimpanzee, human, evolution, segmental duplication, structural variation, chromosomal rearrangement, comparative genomics, positive selection, selective sweep
National Category
Research subject
urn:nbn:se:uu:diva-108266 (URN)978-91-554-7604-5 (ISBN)
Public defence
2009-10-23, C8:305, BMC, Husargatan 3, Uppsala, 13:15 (English)
Available from: 2009-10-01 Created: 2009-09-10 Last updated: 2009-10-01

Open Access in DiVA

No full text

Other links

Publisher's full textPubMed
By organisation
Department of Medical Biochemistry and Microbiology
In the same journal
Nature Genetics
Biological Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 372 hits
ReferencesLink to record
Permanent link

Direct link