Understanding the evolutionary basis for human-specific phenotypes
such as complex speech and language, advanced cognition or the unique
preparation of their food is a topic of broad interest. Approaches
focusing on comparisons of the genomic DNA (deoxyribonucleic acid) or
RNA (ribonucleic acid) sequence between species, individuals or
tissues allow for the identification of evolutionary sequence changes,
some of these changes may underlie differences in phenotypes. In
addition, differences in when, where and how much of a particular gene
is present may also contribute to functional changes and therefore
also to phenotypic differences.
The resources to make such comparisons using genetic data are now
available. The genome sequences of a number of outgroups: all living
great apes, as well two archaic humans, are now publically
available. Studying gene expression on the RNA level - a precursor of
the protein expression - is considerably easier and cheaper than the
measurement of expression of the protein itself. It has been shown
that the RNA and protein expression levels are well correlated and
therefore measuring RNA levels provides a good proxy for the
expression of the protein. Using high-throughput sequencing
techniques, relatively unbiased expression comparison is now possible
because the RNA from any species can be sequenced directly, rather
than being captured on arrays which are designed based on a particular
reference sequence.
The aim of this research was to use gene expression as a molecular
phenotype to identify changes relevant to human-specific biology and
study the difference between humans and their closest living relatives
to understand patterns and differences in the gene expression and in
gene expression regulation in multiple tissues in primates using
high-throughput sequencing techniques. In my thesis, I describe two
analyses to address open questions in the field of gene expression and
genes expression regulation in humans.
In the first part I will analyze how the effect of different diets
impact gene expression using a mouse model. Two key components of the
human diet that differ substantially from the diet of other primates,
the frequent use of meat of many humans and the cooking of their food
which is common for almost all human populations, are modeled in the
experiment. I tested for their impact on liver gene expression. I
found that both the differences in food substrates - meat and tuber -
as well as in their preparation affect gene expression in mice
significantly. The effect is bigger between food substrates than
between methods of preparation. Differentially expressed genes between
food substrates and food preparation were predominantly related to
metabolic functions. In addition, immune-genes showed differential
expression between the comparisons of raw meat to both, raw tuber and
cooked meat, respectively. The results indicate that different food
substrates and food preparations activate different metabolic pathways
and that the cooking of food and particularly of meat has an influence
on the immune also changes immune-reactions of the body. I showed that
expression differences in these mice are correlated with the
differences observed between humans and other primates, and that there
is evidence that adaptation to these diets dates to more than 300.000
years. Finally, I showed that transcription factors play in important
role in regulation of gene expression with respect to different food
preparation.
In the second part I analyzed the expression of one key regulator of
gene expression: microRNAs (miRNAs). Using miRNA expression data from
multiple primate species and for multiple tissues I found that
expression differences vary between tissues. While heart and brain
show only few expression differences between primates, other tissues
are more variable in expression. The most extreme expression
differences in all three primate species were found in the brain,
which may reflect the importance of miRNAs in the regulation of gene
expression in the brain. Expression differences in testis were
significantly larger between humans and macaques than between
chimpanzees and macaques, indicating that miRNAs evolved differently
in human compared to chimpanzees. MiRNA expression differences were
correlated with expression differences of their target genes
genome-wide which underlines the regulatory importance of miRNAs. I
also showed that differentially expressed miRNAs between
species/tissues preferentially targeted transcription factors, which
are important gene expression regulators as well. This finding that
suggests complex regulatory pathways involving both miRNAs and
transcription factors in the control of gene expression. Finally, I
used the miRNA sequencing data to annotate new miRNAs in primates and
was able to increase the number of annotated miRNAs substantially,
especially for the non-human primates which were previously not
extensively annotated. The overlap of miRNAs annotated in multiple
primate species thereby also increased which will support future
studies to investigate the evolutionary changes of miRNAs between
these primates.
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa.de:bsz:15-qucosa-144285 |
| Date | 05 June 2014 |
| Creators | Dannemann, Michael |
| Contributors | Universität Leipzig, Fakultät für Mathematik und Informatik, PhD Janet Kelso, Prof. Dr. Cathal Seoighe, Prof. Dr. Peter Stadler |
| Publisher | Universitätsbibliothek Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | doc-type:doctoralThesis |
| Format | application/pdf |
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