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Genome and Transcriptome Comparisons between Human and Chimpanzee
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology, Genomics. (Ulf Gyllensten)
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The chimpanzee is humankind’s closest living relative and the two species diverged ~6 million years ago. Comparative studies of the human and chimpanzee genomes and transcriptomes are of great interest to understand the molecular mechanisms of speciation and the development of species-specific traits.

The aim of this thesis is to characterize differences between the two species with regard to their genome sequences and the resulting transcript profiles. The first two papers focus on indel divergence and in particular, indels causing premature termination codons (PTCs) in 8% of the chimpanzee genes. The density of PTC genes is correlated with both the distance to the telomere and the indel divergence. Many PTC genes have several associated transcripts and since not all are affected by the PTC we propose that PTCs may affect the pattern of expressed isoforms. In the third paper, we investigate the transcriptome divergence in cerebellum, heart and liver, using high-density exon arrays. The results show that gene expression differs more between tissues than between species. Approximately 15% of the genes are differentially expressed between species, and half of the genes show different splicing patterns. We identify 28 cassette exons which are only included in one of the species, often in a tissue-specific manner. In the fourth paper, we use massive parallel sequencing to study the chimpanzee transcriptome in frontal cortex and liver. We estimate gene expression and search for novel transcribed regions (TRs). The majority of TRs are located close to genes and possibly extend the annotations. A subset of TRs are not found in the human genome. The brain transcriptome differs substantially from that of the liver and we identify a subset of genes enriched with TRs in frontal cortex.

In conclusion, this thesis provides evidence of extensive genomic and transcriptomic variability between human and chimpanzee. The findings provide a basis for further studies of the underlying differences affecting phenotypic divergence between human and chimpanzee.

 

 

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2010. , p. 61
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 522
Keywords [en]
human, chimpanzee, genome, transcriptome, comparative studies, exon arrays, next-generation sequencing, premature termination codon, alternative splicing, primate evolution
National Category
Medical Genetics
Research subject
Bioinformatics
Identifiers
URN: urn:nbn:se:uu:diva-112893ISBN: 978-91-554-7720-2 (print)OAI: oai:DiVA.org:uu-112893DiVA, id: diva2:291529
Public defence
2010-03-24, Rudbeck Hall, Rudbeck laboratory, SE-751 85 Uppsala, Uppsala, 09:00 (English)
Opponent
Supervisors
Available from: 2010-03-02 Created: 2010-01-21 Last updated: 2018-01-12Bibliographically approved
List of papers
1. Comparative genomic analysis of human and chimpanzee indicates a key role for indels in primate evolution
Open this publication in new window or tab >>Comparative genomic analysis of human and chimpanzee indicates a key role for indels in primate evolution
2006 (English)In: Journal of Molecular Evolution, ISSN 0022-2844, E-ISSN 1432-1432, Vol. 63, no 5, p. 682-690Article in journal (Refereed) Published
Abstract [en]

Sequence comparison of humans and chimpanzees is of interest to understand the mechanisms behind primate evolution. Here we present an independent analysis of human chromosome 21 and the high-quality BAC clone sequences of the homologous chimpanzee chromosome 22. In contrast to previous studies, we have used global alignment methods and Ensembl predictions of protein coding genes (n = 224) for the analysis. Divergence due to insertions and deletions (indels) along with substitutions was examined separately for different genomic features (coding, noncoding genic, and intergenic sequence). The major part of the genomic divergence could be attributed to indels (5.07%), while the nucleotide divergence was estimated as 1.52%. Thus the total divergence was estimated as 6.58%. When excluding repeats and low-complexity DNA the total divergence decreased to 2.37%. The chromosomal distribution of nucleotide substitutions and indel events was significantly correlated. To further examine the role of indels in primate evolution we focused on coding sequences. Indels were found within the coding sequence of 13% of the genes and approximately half of the indels have not been reported previously. In 5% of the chimpanzee genes, indels or substitutions caused premature stop codons that rendered the affected transcripts nonfunctional. Taken together, our findings demonstrate that indels comprise the majority of the genomic divergence. Furthermore, indels occur frequently in coding sequences. Our results thereby support the hypothesis that indels may have a key role in primate evolution.

Keywords
indels, comparative genomics, chimpanzee, primate evolution
National Category
Genetics
Identifiers
urn:nbn:se:uu:diva-10256 (URN)10.1007/s00239-006-0045-7 (DOI)000242014800010 ()17075697 (PubMedID)
Available from: 2007-04-20 Created: 2007-04-20 Last updated: 2017-12-11Bibliographically approved
2. Genome-wide analysis of chimpanzee genes with premature termination codons
Open this publication in new window or tab >>Genome-wide analysis of chimpanzee genes with premature termination codons
2009 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 10, p. 56-Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: Premature termination codons (PTCs) cause mRNA degradation or a truncated protein and thereby contribute to the transcriptome and proteome divergence between species. Here we present the first genome-wide study of PTCs in the chimpanzee. By comparing the human and chimpanzee genome sequences we identify and characterize genes with PTCs, in order to understand the contribution of these mutations to the transcriptome diversity between the species. RESULTS: We have studied a total of 13,487 human-chimpanzee gene pairs and found that ~8% were affected by PTCs in the chimpanzee. A majority (764/1,109) of PTCs were caused by insertions or deletions and the remaining part was caused by substitutions. The distribution of PTC genes varied between chromosomes, with Y having the highest proportion. Furthermore, the density of PTC genes varied on a megabasepair scale within chromosomes and we found the density to be correlated both with indel divergence and proximity to the telomere. Within genes, PTCs were more common close to the 5' and 3' ends of the amino acid sequence. Gene Ontology classification revealed that olfactory receptor genes were over represented among the PTC genes. CONCLUSION: Our results showed that the density of PTC genes fluctuated across the genome depending on the local genomic context. PTCs were preferentially located in the terminal parts of the transcript, which generally have a lower frequency of functional domains, indicating that selection was operating against PTCs at sites central to protein function. The enrichment of GO terms associated with olfaction suggests that PTCs may have influenced the difference in the repertoire of olfactory genes between humans and chimpanzees. In summary, 8% of the chimpanzee genes were affected by PTCs and this type of variation is likely to have an important effect on the transcript and proteomic divergence between humans and chimpanzees.

Keywords
cervical carcinoma, HLA, HPV 16 E6
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-102555 (URN)10.1186/1471-2164-10-56 (DOI)000264122500002 ()19178713 (PubMedID)
Available from: 2009-05-08 Created: 2009-05-08 Last updated: 2017-12-13Bibliographically approved
3. Global comparison of the human and chimpanzee transcriptomes using Affymetrix exon arrays
Open this publication in new window or tab >>Global comparison of the human and chimpanzee transcriptomes using Affymetrix exon arrays
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

We have used high-density exon arrays to study the human and chimpanzee transcriptome in cerebellum, heart and liver excluding probesets with mismatches to the chimpanzee. A total of 6281 RefSeq genes were expressed in our samples, the majority being expressed in two or more tissues, while ~ 6 % lacked expression in one of the species. A total of 923 RefSeq genes showed differences in expression between human and chimpanzes. More genes were differentially expressed in cerebellum (8.4 %) than in liver (6.9 %) and heart (4.5 %). Genes showing differential expression between species to a large extent also showed strong tissue-specific expression within species. Of the differentially expressed genes, more were upregulated in human versus chimpanzee, than the other way around. Liver had the highest proportion of genes with spliced genes (50 %), followed by cerebellum (40 %) and heart (30 %). Differentially expressed genes were often detected also as spliced (66-78 %). As one type of splice variation, we identified 26 genes with cassette exons, i.e. the exon is only included in one species. Cassette exon usage was tissue specific to a large extent and for the majority of cassette exons we observed expression in both human and chimpanzee in the other tissues. Taken together, our results indicate that splicing differences represents an extensive and important source of variation between species.

Keywords
chimpanzee human transcriptome comparison
National Category
Medical Genetics
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-113576 (URN)
Available from: 2010-01-30 Created: 2010-01-30 Last updated: 2018-01-12
4. Deep sequencing of the chimpanzee transcriptome identifies numerous novel transcribed regions in frontal cortex and liver
Open this publication in new window or tab >>Deep sequencing of the chimpanzee transcriptome identifies numerous novel transcribed regions in frontal cortex and liver
Show others...
(English)Manuscript (preprint) (Other academic)
Abstract [en]

We have performed the first global profiling of the chimpanzee transcriptome by using deep sequencing of cDNA from brain and liver. This enabled us to quantify expression of RefSeq transcripts, identify novel transcribed regions with no previous annotations in databases and additionally search for transcribed regions with no support in the human genome.

Using stringent criteria for transcription, we identified 9,061 expressed RefSeq transcripts and 5,532 novel transcribed regions., of which the vast majority were found intronically in RefSeq transcripts and ~ 15 % mapped intergenically. In addition,  a little less than 150 novel transcribed regions in the chimpanzee appeared to be absent from the human reference sequence. Novel transcribed regions may represent new coding regions, untranslated regions unspliced mRNAs or diferent types of non-coding transcripts. The transcriptional profile of the brain stands out in several ways: a higher number of RefSeq transcripts were expressed in brain than in liver and novel transcribed regions were also more abundant in brain. Furthermore, we identified an interesting subset of RefSeq genes with a high density of novel transcribed regions scattered across the introns. These genes clustered in central pathways of the nervous system, with an overrepresentation of genes acting in the synapse and many of which have been associated to cognitive disorders in the human.

Our results support the prevailing view of wide-spread transcription in mammalian genomes and further highlight the vast, mostly uncharacterized, transcript variability in the primate brain.

 

Keywords
chimpanzee, transcriptome profiling, deep sequencing
National Category
Medical Genetics
Research subject
Bioinformatics
Identifiers
urn:nbn:se:uu:diva-113577 (URN)
Available from: 2010-01-30 Created: 2010-01-30 Last updated: 2018-01-12

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