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"Mailund, Thomas"
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Breaking Free
The merging of distinct genomes, allopolyploidization, is a widespread phenomenon in plants. It generates adaptive potential through increased genetic diversity, but examples demonstrating its exploitation remain scarce. White clover (Trifolium repens) is a ubiquitous temperate allotetraploid forage crop derived from two European diploid progenitors confined to extreme coastal or alpine habitats. We sequenced and assembled the genomes and transcriptomes of this species complex to gain insight into the genesis of white clover and the consequences of allopolyploidization. Based on these data, we estimate that white clover originated ∼15,000 to 28,000 years ago during the last glaciation when alpine and coastal progenitors were likely colocated in glacial refugia. We found evidence of progenitor diversity carryover through multiple hybridization events and show that the progenitor subgenomes have retained integrity and gene expression activity as they traveled within white clover from their original confined habitats to a global presence. At the transcriptional level, we observed remarkably stable subgenome expression ratios across tissues. Among the few genes that show tissue-specific switching between homeologous gene copies, we found flavonoid biosynthesis genes strongly overrepresented, suggesting an adaptive role of some allopolyploidy-associated transcriptional changes. Our results highlight white clover as an example of allopolyploidy-facilitated niche expansion, where two progenitor genomes, adapted and confined to disparate and highly specialized habitats, expanded to a ubiquitous global presence after glaciation-associated allopolyploidization.
Journal Article
Domain-specific languages in R : advanced statistical programming
\"Gain an accelerated introduction to domain-specific languages in R, including coverage of regular expressions. This compact, in-depth book shows you how DSLs are programming languages specialized for a particular purpose, as opposed to general purpose programming languages. Along the way, you'll learn to specify tasks you want to do in a precise way and achieve programming goals within a domain-specific context. Domain-Specific Languages in R includes examples of DSLs including large data sets or matrix multiplication; pattern matching DSLs for application in computer vision; and DSLs for continuous time Markov chains and their applications in data science. After reading and using this book, you'll understand how to write DSLs in R and have skills you can extrapolate to other programming languages.\" -- Back cover.
Book
Bayesian inference of admixture graphs on Native American and Arctic populations
Admixture graphs are mathematical structures that describe the ancestry of populations in terms of divergence and merging (admixing) of ancestral populations as a graph. An admixture graph consists of a graph topology, branch lengths, and admixture proportions. The branch lengths and admixture proportions can be estimated using numerous numerical optimization methods, but inferring the topology involves a combinatorial search for which no polynomial algorithm is known. In this paper, we present a reversible jump MCMC algorithm for sampling high-probability admixture graphs and show that this approach works well both as a heuristic search for a single best-fitting graph and for summarizing shared features extracted from posterior samples of graphs. We apply the method to 11 Native American and Siberian populations and exploit the shared structure of high-probability graphs to characterize the relationship between Saqqaq, Inuit, Koryaks, and Athabascans. Our analyses show that the Saqqaq is not a good proxy for the previously identified gene flow from Arctic people into the Na-Dene speaking Athabascans.
Journal Article
The joys of Hashing : Hash table programming with C
Build working implementations of hash tables, written in the C programming language. This book starts with simple first attempts devoid of collision resolution strategies, and moves through improvements and extensions illustrating different design ideas and approaches, followed by experiments to validate the choices. Hash tables, when implemented and used appropriately, are exceptionally efficient data structures for representing sets and lookup tables, providing low overhead, constant time, insertion, deletion, and lookup operations. \"The joys of Hashing\" walks you through the implementation of efficient hash tables and the pros and cons of different design choices when building tables. The source code used in the book is available on GitHub for your re-use and experiments. You will: Master the basic ideas behind hash tables ; Carry out collision resolution, including strategies for handling collisions and their consequences for performance ; Resize or grow and shrink tables as needed ; Store values by handling when values must be stored with keys to make general sets and maps.
Book
Novel variation and de novo mutation rates in population-wide de novo assembled Danish trios
Building a population-specific catalogue of single nucleotide variants (SNVs), indels and structural variants (SVs) with frequencies, termed a national pan-genome, is critical for further advancing clinical and public health genetics in large cohorts. Here we report a Danish pan-genome obtained from sequencing 10 trios to high depth (50 × ). We report 536k novel SNVs and 283k novel short indels from mapping approaches and develop a population-wide
de novo
assembly approach to identify 132k novel indels larger than 10 nucleotides with low false discovery rates. We identify a higher proportion of indels and SVs than previous efforts showing the merits of high coverage and
de novo
assembly approaches. In addition, we use trio information to identify
de novo
mutations and use a probabilistic method to provide direct estimates of 1.27e−8 and 1.5e−9 per nucleotide per generation for SNVs and indels, respectively.
The generation of a national pan-genome, a population-specific catalogue of genetic variation, may advance the impact of clinical genetics studies. Here the Besenbacher
et al
. carry out deep sequencing and
de novo
assembly of 10 parent–child trios to generate a Danish pan-genome that provides insight into structural variation,
de novo
mutation rates and variant calling.
Journal Article
Direct estimation of mutations in great apes reconciles phylogenetic dating
The human mutation rate per generation estimated from trio sequencing has revealed an almost linear relationship with the age of the father and the age of the mother, with fathers contributing about three times as many mutations per year as mothers. The yearly trio-based mutation rate estimate of around 0.43 × 10
−9
is markedly lower than previous indirect estimates of about 1 × 10
−9
per year from phylogenetic comparisons of the great apes calibrated by fossil evidence. This suggests either a slowdown in the accumulation of mutations per year in the human lineage over the past 10 million years or an inaccurate interpretation of the fossil record. Here we inferred de novo mutations in chimpanzee, gorilla, and orangutan parent-offspring trios. Extrapolating the relationship between the mutation rate and the age of parents from humans to these other great apes, we estimated that each species has higher mutation rates per year by factors of 1.50 ± 0.10, 1.51 ± 0.23, and 1.42 ± 0.22 for chimpanzee, gorilla, and orangutan, respectively, and by a factor of 1.48 ± 0.08 for the three species combined. These estimates suggest an appreciable slowdown in the yearly mutation rate in the human lineage that is likely to be recent as genome comparisons almost adhere to a molecular clock. If the nonhuman rates rather than the human rate are extrapolated over the phylogeny of the great apes, we estimate divergence and speciation times that are much more in line with the fossil record and the biogeography.
Analysis of de novo mutations in sequences of great ape parent-offspring trios suggests that mutation rates slowed down in the recent human lineage, reconciling dates from the fossil record.
Journal Article
Polar and brown bear genomes reveal ancient admixture and demographic footprints of past climate change
Polar bears (PBs) are superbly adapted to the extreme Arctic environment and have become emblematic of the threat to biodiversity from global climate change. Their divergence from the lower-latitude brown bear provides a textbook example of rapid evolution of distinct phenotypes. However, limited mitochondrial and nuclear DNA evidence conflicts in the timing of PB origin as well as placement of the species within versus sister to the brown bear lineage. We gathered extensive genomic sequence data from contemporary polar, brown, and American black bear samples, in addition to a 130,000- to 110,000-y old PB, to examine this problem from a genome-wide perspective. Nuclear DNA markers reflect a species tree consistent with expectation, showing polar and brown bears to be sister species. However, for the enigmatic brown bears native to Alaska's Alexander Archipelago, we estimate that not only their mitochondrial genome, but also 5–10% of their nuclear genome, is most closely related to PBs, indicating ancient admixture between the two species. Explicit admixture analyses are consistent with ancient splits among PBs, brown bears and black bears that were later followed by occasional admixture. We also provide paleodemographic estimates that suggest bear evolution has tracked key climate events, and that PB in particular experienced a prolonged and dramatic decline in its effective population size during the last ca. 500,000 years. We demonstrate that brown bears and PBs have had sufficiently independent evolutionary histories over the last 4–5 million years to leave imprints in the PB nuclear genome that likely are associated with ecological adaptation to the Arctic environment.
Journal Article
Nationwide Genomic Study in Denmark Reveals Remarkable Population Homogeneity
Denmark has played a substantial role in the history of Northern Europe. Through a nationwide scientific outreach initiative, we collected genetic and anthropometrical data from ∼800 high school students and used them to elucidate the genetic makeup of the Danish population, as well as to assess polygenic predictions of phenotypic traits in adolescents. We observed remarkable homogeneity across different geographic regions, although we could still detect weak signals of genetic structure reflecting the history of the country. Denmark presented genomic affinity with primarily neighboring countries with overall resemblance of decreasing weight from Britain, Sweden, Norway, Germany, and France. A Polish admixture signal was detected in Zealand and Funen, and our date estimates coincided with historical evidence of Wend settlements in the south of Denmark. We also observed considerably diverse demographic histories among Scandinavian countries, with Denmark having the smallest current effective population size compared to Norway and Sweden. Finally, we found that polygenic prediction of self-reported adolescent height in the population was remarkably accurate (R2 = 0.639 ± 0.015). The high homogeneity of the Danish population could render population structure a lesser concern for the upcoming large-scale gene-mapping studies in the country.
Journal Article
Genomic Relationships and Speciation Times of Human, Chimpanzee, and Gorilla Inferred from a Coalescent Hidden Markov Model
The genealogical relationship of human, chimpanzee, and gorilla varies along the genome. We develop a hidden Markov model (HMM) that incorporates this variation and relate the model parameters to population genetics quantities such as speciation times and ancestral population sizes. Our HMM is an analytically tractable approximation to the coalescent process with recombination, and in simulations we see no apparent bias in the HMM estimates. We apply the HMM to four autosomal contiguous human-chimp-gorilla-orangutan alignments comprising a total of 1.9 million base pairs. We find a very recent speciation time of human-chimp (4.1 +/- 0.4 million years), and fairly large ancestral effective population sizes (65,000 +/- 30,000 for the human-chimp ancestor and 45,000 +/- 10,000 for the human-chimp-gorilla ancestor). Furthermore, around 50% of the human genome coalesces with chimpanzee after speciation with gorilla. We also consider 250,000 base pairs of X-chromosome alignments and find an effective population size much smaller than 75% of the autosomal effective population sizes. Finally, we find that the rate of transitions between different genealogies correlates well with the region-wide present-day human recombination rate, but does not correlate with the fine-scale recombination rates and recombination hot spots, suggesting that the latter are evolutionarily transient.
Journal Article