Author Archives: cooplab

Global Epistasis Makes Adaptation Predictable Despite Sequence-Level Stochasticity

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Global Epistasis Makes Adaptation Predictable Despite Sequence-Level Stochasticity
Sergey Kryazhimskiy, Daniel Paul Rice, Elizabeth Jerison, Michael M Desai

Epistasis can make adaptation highly unpredictable, rendering evolutionary trajectories contingent on the chance effects of initial mutations. We used experimental evolution in Saccharomyces cerevisiae to quantify this effect, finding dramatic differences in adaptability between 64 closely related genotypes. Despite these differences, sequencing of 105 evolved clones showed no significant effect of initial genotype on future sequence-level evolution. Instead, reconstruction experiments revealed a consistent pattern of diminishing returns epistasis. Our results suggest that many beneficial mutations affecting a variety of biological processes are globally coupled: they interact strongly, but only through their combined effect on fitness. Sequence-level adaptation is thus highly stochastic. Nevertheless, fitness evolution is strikingly predictable because differences in adaptability are determined only by global fitness-mediated epistasis, not by the identity of individual mutations.

Human paternal and maternal demographic histories: insights from high-resolution Y chromosome and mtDNA sequences

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Human paternal and maternal demographic histories: insights from high-resolution Y chromosome and mtDNA sequences
Sebastian Lippold, Hongyang Xu, Albert Ko, Mingkun Li, Gabriel Renaud, Anne Butthof, Roland Schroeder, Mark Stoneking

To investigate in detail the paternal and maternal demographic histories of humans, we obtained ~500 kb of non-recombining Y chromosome (NRY) sequences and complete mtDNA genome sequences from 623 males from 51 populations in the CEPH Human Genome Diversity Panel (HGDP). Our results: confirm the controversial assertion that genetic differences between human populations on a global scale are bigger for the NRY than for mtDNA; suggest very small ancestral effective population sizes (<100) for the out-of-Africa migration as well as for many human populations; and indicate that the ratio of female effective population size to male effective population size (Nf/Nm) has been greater than one throughout the history of modern humans, and has recently increased due to faster growth in Nf. However, we also find substantial differences in patterns of mtDNA vs. NRY variation in different regional groups; thus, global patterns of variation are not necessarily representative of specific geographic regions.

Entropy Rates of the Multidimensional Moran Processes and Generalizations

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Entropy Rates of the Multidimensional Moran Processes and Generalizations
Marc Harper
(Submitted on 13 Jan 2014)

The interrelationships of the fundamental biological processes natural selection, mutation, and stochastic drift are quantified by the entropy rate of Moran processes with mutation, measuring the long-run variation of a Markov process. The entropy rate is shown to behave intuitively with respect to evolutionary parameters such as monotonicity with respect to mutation probability (for the neutral landscape), relative fitness, and strength of selection. Strict upper bounds, depending only on the number of replicating types, for the entropy rate are given and the neutral fitness landscape attains the maximum in the large population limit. Various additional limits are computed including small mutation, weak and strong selection, and large population holding the other parameters constant, revealing the individual contributions and dependences of each evolutionary parameter on the long-run outcomes of the processes.

Sifting through 2013 with Haldane’s Sieve

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2013 was the first full year of Haldane’s Sieve, which we started in 2012 to bring attention to preprints in evolutionary and population genetics. Perhaps the most exciting development of the year was the expansion of preprint server options–instead of arXiv, some biologists are now using bioRxiv or PeerJ Preprints. This year at Haldane’s Sieve, we received over 100,000 visitors from all over the world. Our most viewed posts of the year were:

Most viewed on Haldane’s Sieve: December 2013

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The most viewed posts on Haldane’s Sieve in December 2013 were:

Happy New Year Homo erectus? More evidence for interbreeding with archaics predating the modern human/Neanderthal split

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Happy New Year Homo erectus? More evidence for interbreeding with archaics predating the modern human/Neanderthal split
Peter J. Waddell
(Submitted on 30 Dec 2013)

A range of a priori hypotheses about the evolution of modern and archaic genomes are further evaluated and tested. In addition to the well-known splits/introgressions involving Neanderthal genes into out-of- Africa people, or Denisovan genes into Oceanians, a further series of archaic splits and hypotheses proposed in Waddell et al. (2011) are considered in detail. These include signals of Denisovans with something markedly more archaic and possibly something more archaic into Papuans as well. These are compared and contrasted with some well-advertised introgressions such as Denisovan genes across East Asia, archaic genes into San or non-tree mixing between Oceanians, East Asians and Europeans. The general result is that these less appreciated and surprising archaic splits have just as much or more support in genome sequence data. Further, evaluation confirms the hypothesis that archaic genes are much rarer on modern X chromosomes, and may even be near totally absent, suggesting strong selection against their introgression. Modeling of relative split weights allows an inference of the proportion of the genome the Denisovan seems to have gotten from an older archaic, and the best estimate is around 2%. Using a mix of quantitative and qualitative morphological data and novel phylogenetic methods, robust support is found for multiple distinct middle Pleistocene lineages. Of these, fossil hominids such as SH5, Petralona, and Dali, in particular, look like prime candidates for contributing pre-Neanderthal/Modern archaic genes to Denisovans, while the Jinniu-Shan fossil looks like the best candidate for a close relative of the Denisovan. That the Papuans might have received some truly archaic genes appears a good possibility and they might even be from Homo erectus.

Sequence Capture Versus Restriction Site Associated DNA Sequencing for Phylogeography

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Sequence Capture Versus Restriction Site Associated DNA Sequencing for Phylogeography
Michael G. Harvey, Brian Tilston Smith, Travis C. Glenn, Brant C. Faircloth, Robb T. Brumfield
(Submitted on 22 Dec 2013)

Genomic datasets generated with massively parallel sequencing methods have the potential to propel systematics in new and exciting directions, but selecting appropriate markers and methods is not straightforward. We applied two approaches with particular promise for systematics, restriction site associated DNA sequencing (RAD-Seq) and sequence capture (Seq-cap) of ultraconserved elements (UCEs), to the same set of samples from a non-model, Neotropical bird. We found that both RAD-Seq and Seq-cap produced genomic datasets containing thousands of loci and SNPs and that the inferred population assignments and species trees were concordant between datasets. However, model-based estimates of demographic parameters differed between datasets, particularly when we estimated the parameters using a method based on allele frequency spectra. The differences we observed may result from differences in assembly, alignment, and filtering of sequence data between methods, and our findings suggest that caution is warranted when using allele frequencies to estimate parameters from low-coverage sequencing data. We further explored the differences between methods using simulated Seq-cap- and RAD-Seq-like datasets. Analyses of simulated data suggest that increasing the number of loci from 500 to 5000 increased phylogenetic concordance factors and the accuracy and precision of demographic parameter estimates, but increasing the number of loci past 5000 resulted in minimal gains. Increasing locus length from 64 bp to 500 bp improved phylogenetic concordance factors and minimal gains were observed with loci longer than 500 bp, but locus length did not influence the accuracy and precision of demographic parameter estimates. We discuss our results relative to the diversity of data collection methods available, and we provide advice for harnessing next-generation sequencing for systematics research.

Ancient human genomes suggest three ancestral populations for present-day Europeans

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Ancient human genomes suggest three ancestral populations for present-day Europeans
Iosif Lazaridis, Nick Patterson, Alissa Mittnik, Gabriel Renaud, Swapan Mallick, Peter H. Sudmant, Joshua G. Schraiber, Sergi Castellano, Karola Kirsanow, Christos Economou, Ruth Bollongino, Qiaomei Fu, Kirsten Bos, Susanne Nordenfelt, Cesare de Filippo, Kay Prüfer, Susanna Sawyer, Cosimo Posth, Wolfgang Haak, Fredrik Hallgren, Elin Fornander, George Ayodo, Hamza A. Babiker, Elena Balanovska, Oleg Balanovsky, Haim Ben-Ami, Judit Bene, Fouad Berrada, Francesca Brisighelli, George B.J. Busby, Francesco Cali, Mikhail Churnosov, David E.C. Cole, Larissa Damba, Dominique Delsate, George van Driem, Stanislav Dryomov, Sardana A. Fedorova, Michael Francken, Irene Gallego Romero, Marina Gubina, Jean-Michel Guinet, Michael Hammer, Brenna Henn, Tor Helvig, Ugur Hodoglugil, Aashish R. Jha, Rick Kittles, Elza Khusnutdinova, Toomas Kivisild, Vaidutis Kučinskas, Rita Khusainova, Alena Kushniarevich, Leila Laredj, Sergey Litvinov, Robert W. Mahley, Béla Melegh, Ene Metspalu, Joanna Mountain, Thomas Nyambo, Ludmila Osipova, Jüri Parik, Fedor Platonov, Olga L. Posukh, Valentino Romano, Igor Rudan, Ruslan Ruizbakiev, Hovhannes Sahakyan, Antonio Salas, Elena B. Starikovskaya, Ayele Tarekegn, Draga Toncheva, Shahlo Turdikulova, Ingrida Uktveryte, Olga Utevska, Mikhail Voevoda, Joachim Wahl, Pierre Zalloua, Levon Yepiskoposyan, Tatijana Zemunik, Alan Cooper, Cristian Capelli, Mark G. Thomas, Sarah A. Tishkoff, Lalji Singh, Kumarasamy Thangaraj, Richard Villems, David Comas, Rem Sukernik, Mait Metspalu, Matthias Meyer, Evan E. Eichler, Joachim Burger, Montgomery Slatkin, Svante Pääbo, Janet Kelso, David Reich, Johannes Krause

Analysis of ancient DNA can reveal historical events that are difficult to discern through study of present-day individuals. To investigate European population history around the time of the agricultural transition, we sequenced complete genomes from a ~7,500 year old early farmer from the Linearbandkeramik (LBK) culture from Stuttgart in Germany and an ~8,000 year old hunter-gatherer from the Loschbour rock shelter in Luxembourg. We also generated data from seven ~8,000 year old hunter-gatherers from Motala in Sweden. We compared these genomes and published ancient DNA to new data from 2,196 samples from 185 diverse populations to show that at least three ancestral groups contributed to present-day Europeans. The first are Ancient North Eurasians (ANE), who are more closely related to Upper Paleolithic Siberians than to any present-day population. The second are West European Hunter-Gatherers (WHG), related to the Loschbour individual, who contributed to all Europeans but not to Near Easterners. The third are Early European Farmers (EEF), related to the Stuttgart individual, who were mainly of Near Eastern origin but also harbored WHG-related ancestry. We model the deep relationships of these populations and show that about ~44% of the ancestry of EEF derived from a basal Eurasian lineage that split prior to the separation of other non-Africans.

The causal meaning of genomic predictors and how it affects the construction and comparison of genome-enabled selection models

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The causal meaning of genomic predictors and how it affects the construction and comparison of genome-enabled selection models
Bruno D Valente, Gota Morota, Guilherme JM Rosa, Daniel Gianola, Kent Weigel

The additive genetic effect is arguably the most important quantity inferred in animal and plant breeding analyses. The term effect indicates that it represents causal information, which is different from standard statistical concepts as regression coefficient and association. The process of inferring causal information is also different from standard statistical learning, as the former requires causal (i.e. non-statistical) assumptions and involves extra complexities. Remarkably, the task of inferring genetic effects is largely seen as a standard regression/prediction problem, contradicting its label. This widely accepted analysis approach is by itself insufficient for causal learning, suggesting that causality is not the point for selection. Given this incongruence, it is important to verify if genomic predictors need to represent causal effects to be relevant for selection decisions, especially because applying regression studies to answer causal questions may lead to wrong conclusions. The answer to this question defines if genomic selection models should be constructed aiming maximum genomic predictive ability or aiming identifiability of genetic causal effects. Here, we demonstrate that selection relies on a causal effect from genotype to phenotype, and that genomic predictors are only useful for selection if they distinguish such effect from other sources of association. Conversely, genomic predictors capturing non-causal signals provide information that is less relevant for selection regardless of the resulting predictive ability. Focusing on covariate choice decision, simulated examples are used to show that predictive ability, which is the criterion normally used to compare models, may not indicate the quality of genomic predictors for selection. Additionally, we propose using alternative criteria to construct models aiming for the identification of the genetic causal effects.

Author post: Sex-biased microRNAs in Drosophila melanogaster

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This guest post is by Antonio Marco (@amarcobio) on his paper: Sex-biased microRNAs in Drosophila melanogaster

The expression profile of a gene affects its evolutionary fate. Conversely, the evolutionary history of a gene is reflected in its expression pattern. Understanding the complex relationship between expression and evolution is a major challenge in evolutionary genetics. In particular, the evolution of sex-biased gene expression is an all-time favourite. With the advent of high-throughput technologies, sex-biased expression has been widely studied, and a number of significant observations are generally accepted.

First, there is a paucity of male-biased genes in the X chromosome (in X/Y species). However, recently emerged genes in the X tend to be male-biased. An ongoing demasculinization of X chromosomes may explain this pattern. (Interestingly, recent works suggest that demasculinization may not be happening in Drosophila.) On the contrary, female-biased genes are enriched in the X chromosome and less frequently found in the autosomes. However, these studies are based on protein-coding genes, and little is known about other genes.

MicroRNAs are short regulatory RNAs which repress translation. MicroRNAs are now known to be involved in many developmental process, including sex differentiation. Unlike protein-coding genes, microRNA genes frequently emerge de novo in the genome. Also, a microRNA transcript frequently produces multiple products, including other microRNAs or protein-coding genes. In summary, the biology of microRNAs is substantially different to that of protein-coding genes, and so must be its evolutionary dynamics. In a recent paper deposited in arXiv, I explore the evolutionary origin of sex-biased microRNAs in Drosophila melanogaster.

By analysing deep sequencing data from multiple sources I observed that sex-biased microRNAs are, as expected, involved in the reproductive function. Contrary to protein-coding genes, there is an enrichment of male-biased genes in the X chromosome. Also, there is no conclusive evidence of demasculinization affecting microRNAs. On the other hand, female-biased microRNAs are encoded in the autosomes. Interestingly, many female-biased microRNAs are encoded within the introns of female-biased protein-coding genes. A detailed analysis reveals that maternally transmitted microRNAs may be hitch-hiked by the maternal deposition of the host gene transcript. Ongoing work in the lab is aimed to confirm this hypothesis.

In summary, the chromosomal distribution of sex-biased expressed microRNAs is exactly the opposite we observe in protein-coding genes. This analysis suggests that this is a consequence of a differential evolutionary dynamics. As novel microRNAs frequently emerge in the X chromosome, they acquire ‘at birth’ male biased expression. However, instead of a movement out-of-the-X, these microRNAs get eventually lost. Hence, there is an enrichment of male-biased microRNAs in the X. On the contrary, female-biased expression is frequently acquired by microRNAs encoded in the intron of female expressed host genes. The origin and evolution of sex-biased microRNAs is, therefore, a consequence of a high rate of de novo emergence.