The ability to retrieve DNA from the skeletal remains of ancient humans has yielded many insights into the relationship between humans living today and our nearest evolutionary relatives, the Neandertals and Denisovans. Two important insights emerged from the first high-quality genome sequences of Neandertals and Denisovans: 1) these archaic humans had very low genetic diversity in comparison to most populations of present-day humans, and 2) there was gene flow from archaic humans into the ancestors of present-day people. In my thesis, I explored aspects of both these insights. In my first project, I analysed the consequences of low genetic diversity of archaic humans for immune genes, using genetic diversity in protein-coding genes (‘gene diversity’) as a proxy for functional diversity. I conclude that low gene diversity in archaic humans did not affect immune genes more severely than any other class of protein-coding genes. I then show that the MHC genes, that typical have high genetic diversity and are a component of the adaptive immune system, have substantially higher gene diversity than expected from the genome-wide gene diversity in archaic humans. Moreover, I find no detectable reduction in gene diversity between two Neandertals that lived more than 70,000 years apart. This is first evidence indicating that diversity in late Neandertals did not decrease over the last ~100,000 years of their existence, which would be expected if low gene diversity had played a considerable role in Neandertal extinction, as has been proposed. In my second project I analysed genomic regions depleted of both Neandertal and Denisovan ancestry in the genomes of humans living today (‘shared deserts’). It has been suggested that shared deserts reflect incompatibilities between archaic humans and the ancestors of present-day humans, and were created by negative selection against archaic alleles. By analysing archaic ancestry in almost 2,000 published present-day human genomes, including 155 published genomes from Oceania, I generated a further refined set of genomic regions that are most depleted of archaic ancestry. I discuss candidate variants in these regions that may underlie important phenotypic or functional differences between archaic and modern humans, such as in the brain-expressed genes CADM2 and KCND2, and propose this refined list as a set of candidates for future molecular testing.:Bibliographische Darstellung iii
Table of contents iv
Summary 8
Zusammenfassung 14
1. Introduction 21
1.1. A strange fossil and its genome 21
1.2. Archaic humans had low genetic diversity 26
1.3. Evidence of gene flow between archaic humans and AMH 29
1.3.1. Identification of archaic sequence and its impact on humans today 32
1.3.1.1. The distribution of archaic sequence in AMH is heterogeneous 34
1.3.1.2. Negative selection against introgressed archaic sequence 37
1.3.1.3. Adaptive introgression: Archaic sequence under positive selection in AMH 39
1.3.1.4. Association of introgressed variants with phenotypes of present-day people 41
1.3.2. Deserts: Gene flow left regions depleted of archaic introgression 43
2. Thesis outline 46
3. Methods 47
3.1. Methods for study of immune gene diversity 47
3.1.1. Data 47
3.1.2. Measure of gene diversity 47
3.1.3. Diversity in innate immune and MHC genes 48
3.1.4. GO enrichment analysis 49
3.2. Methods for study of deserts of archaic ancestry 50
3.2.1. Data sets and processing 50
3.2.2. Identification of introgressed haplotypes 51
3.2.2.1. Hidden Markov Model (HMM) 51
3.2.2.2. Probability cut-off for haplotypes to be archaic 51
3.2.3. Reanalysis of published deserts of archaic ancestry 52
3.2.3.1. Shared deserts 52
3.2.3.2. Sliding windows 52
3.2.3.3. Mean percentage introgression 53
3.2.3.4. Comparison to random regions 53
3.2.3.5. Definition of refined shared desert regions 54
3.2.3.6. Overlap of refined shared deserts with genes 54
3.2.3.7. Enrichment analyses in refined shared desert regions 55
3.2.3.8. Overlap with regions under ancient positive selection on the AMH lineage 55
3.2.3.9. Overlap with (nearly) fixed differences between present-day and archaic humans 56
4. Results 57
4.1. Immune gene diversity in archaic and present-day humans 57
4.1.1. Abstract 58
4.1.2. Introduction 59
4.1.3. Results 61
4.1.3.1. Archaic humans had lower overall gene diversity than present-day humans 61
4.1.3.2. Archaic humans had similarly low gene diversity in innate immune genes
compared with non-immune genes 62
4.1.3.3. High MHC gene diversity in archaic humans 64
4.1.3.4. Genes with highest/lowest diversity show similar GO enrichments in archaic and
present-day humans 66
4.1.4. Discussion 69
4.1.5. Supplementary results 71
4.1.6. Acknowledgements and author contributions 72
4.2. Refining deserts of archaic ancestry 73
4.2.1. Abstract 73
4.2.2. Introduction 75
4.2.3. Results 78
4.2.3.1. Genome-wide patterns of archaic introgression are consistent with previous maps 78
4.2.3.2. The published shared desert regions are not the most depleted regions in the genome 79
4.2.3.3. Levels of archaic introgression in shared deserts for the IGDP data set are comparable 82
4.2.3.4. Shared deserts unique to either the Vernot or Sankararaman set have lower
mean percentage introgression 84
4.2.3.5. Refined shared deserts 84
4.2.3.6. Overlap of refined shared deserts with genes 87
4.2.3.7. Enrichment analyses 88
4.2.3.8. Overlap with regions under ancient positive selection on the AMH lineage 89
4.2.3.9. Overlap of refined shared deserts with (nearly) fixed differences (nFD) 89
4.2.4. Discussion 94
4.2.5. Acknowledgements 98
5. Discussion and outlook 99
5.1. Interpreting immune gene diversity in archaic humans 99
5.2. Implications from refined deserts of archaic ancestry 104
5.2.1. Comments on the origin of desert regions 106
5.2.2. Candidates for functional molecular testing in refined deserts 107
5.2.3. Future directions in the characterisation and definition of shared deserts 110
5.3. Future directions beyond shared deserts 115
6. Outlook: Molecular functional testing of candidate variants 118
7. Conclusions and final remark 122
8. Supplementary information (SI) 124
8.1. SI: Immune gene diversity in archaic and present-day humans 124
8.2. SI: Refining deserts of archaic ancestry 152
Index of figures 216
Index of tables 218
Index of supplementary data files 220
References 221
Abbreviations 240
Acknowledgements/Danksagungen 242
Curriculum vitae 244
Publications 248
Selected talks 249
Poster presentations 249
Selbstständigkeitserklärung 250
Nachweis über Anteile der Co-Autor:innen 251
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:76952 |
| Date | 13 December 2021 |
| Creators | Reher, David |
| Contributors | Universität Leipzig |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/acceptedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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