A systematic survey of an intragenic epistatic landscape

A systematic survey of an intragenic epistatic landscape
Claudia Bank, Ryan T. Hietpas, Jeffrey D. Jensen, Daniel N.A. Bolon
doi: http://dx.doi.org/10.1101/010645

Mutations are the source of evolutionary variation. The interactions of multiple mutations can have important effects on fitness and evolutionary trajectories. We have recently described the distribution of fitness effects of all single mutations for a nine amino acid region of yeast Hsp90 (Hsp82) implicated in substrate binding. Here, we report and discuss the distribution of intragenic epistatic effects within this region in seven Hsp90 point mutant backgrounds of neutral to slightly deleterious effect, resulting in an analysis of more than 1000 double-mutants. We find negative epistasis between substitutions to be common, and positive epistasis to be rare – resulting in a pattern that indicates a drastic change in the distribution of fitness effects one step away from the wild type. This can be well explained by a concave relationship between phenotype and genotype (i.e., a concave shape of the local fitness landscape), suggesting mutational robustness intrinsic to the local sequence space. Structural analyses indicate that, in this region, epistatic effects are most pronounced when a solvent-inaccessible position is involved in the interaction. In contrast, all 18 observations of positive epistasis involved at least one mutation at a solvent-exposed position. By combining the analysis of evolutionary and biophysical properties of an epistatic landscape, these results contribute to a more detailed understanding of the complexity of protein evolution.

Bayesian analyses of Yemeni mitochondrial genomes suggest multiple migration events with Africa and Western Eurasia

Bayesian analyses of Yemeni mitochondrial genomes suggest multiple migration events with Africa and Western Eurasia
Deven N Vyas, Andrew Kitchen, Aida T Miró-Herrans, Laurel N Pearson, Ali Al-Meeri, Connie J Mulligan
doi: http://dx.doi.org/10.1101/010629

Anatomically modern humans (AMHs) left Africa ~60,000 years ago, marking the first of multiple dispersal events by AMH between Africa and the Arabian Peninsula. The southern dispersal route (SDR) out of Africa (OOA) posits that early AMHs crossed the Bab el-Mandeb strait from the Horn of Africa into what is now Yemen and followed the coast of the Indian Ocean into eastern Eurasia. If AMHs followed the SDR and left modern descendants in situ, Yemeni populations should retain old autochthonous mitogenome lineages. Alternatively, if AMHs did not follow the SDR or did not leave modern descendants in the region, only young autochthonous lineages will remain as evidence of more recent dispersals. We sequenced 113 whole mitogenomes from multiple Yemeni regions with a focus on haplogroups M, N, and L3(xM,N) as they are considered markers of the initial OOA migrations. We performed Bayesian evolutionary analyses to generate time-measured phylogenies calibrated by Neanderthal and Denisovan mitogenome sequences in order to determine the age of Yemeni-specific clades in our dataset. Our results indicate that the M1, N1, and L3(xM,N) sequences in Yemen are the product of recent migration from Africa and western Eurasia. Although these data suggest that modern Yemeni mitogenomes are not markers of the original OOA migrants, we hypothesize that recent population dynamics may obscure any genetic signature of an ancient SDR migration.

Conflations of short IBD blocks can bias inferred length of IBD

Conflations of short IBD blocks can bias inferred length of IBD
Charleston W.K. Chiang, Peter Ralph, John Novembre
Comments: 12 figures, 1 table
Subjects: Populations and Evolution (q-bio.PE)

Identity-by-descent (IBD) is a fundamental concept in genetics with many applications. Often, segments between two haplotypes are said to be IBD if they are inherited from a recent shared common ancestor without intervening recombination. Long IBD blocks (> 1cM) can be efficiently detected by a number of computer programs using high-density SNP array data from a population sample. However, all programs detect IBD based on contiguous segments of identity-by-state, and can therefore be due to the conflation of smaller, nearby IBD blocks. We quantified this effect using coalescent simulations, finding that nearly 40% of inferred blocks 1-2cM long are false conflations of two or more longer blocks, under demographic scenarios typical for modern humans. This biases the inferred IBD block length distribution, and so can affect downstream inferences. We observed this conflation effect universally across different IBD detection programs and human demographic histories, and found inference of segments longer than 2cM to be much more reliable (less than 5% conflation rate). We then present and analyze a novel estimator of the de novo mutation rate using IBD blocks, and demonstrate that the biased length distribution of the IBD segments due to conflation can strongly affect this estimator if the conflation is not modeled. Thus, the conflation effect should be carefully considered, especially as methods to detect shorter IBD blocks using sequencing data are being developed.

Second-generation PLINK: rising to the challenge of larger and richer datasets

Second-generation PLINK: rising to the challenge of larger and richer datasets
Christopher C. Chang, Carson C. Chow, Laurent C.A.M. Tellier, Shashaank Vattikuti, Shaun M. Purcell, James J. Lee
Comments: 2 figures, 1 additional file
Subjects: Genomics (q-bio.GN); Computation (stat.CO)

PLINK 1 is a widely used open-source C/C++ toolset for genome-wide association studies (GWAS) and research in population genetics. However, the steady accumulation of data from imputation and whole-genome sequencing studies has exposed a strong need for even faster and more scalable implementations of key functions. In addition, GWAS and population-genetic data now frequently contain probabilistic calls, phase information, and/or multiallelic variants, none of which can be represented by PLINK 1’s primary data format.
To address these issues, we are developing a second-generation codebase for PLINK. The first major release from this codebase, PLINK 1.9, introduces extensive use of bit-level parallelism, O(sqrt(n))-time/constant-space Hardy-Weinberg equilibrium and Fisher’s exact tests, and many other algorithmic improvements. In combination, these changes accelerate most operations by 1-4 orders of magnitude, and allow the program to handle datasets too large to fit in RAM. This will be followed by PLINK 2.0, which will introduce (a) a new data format capable of efficiently representing probabilities, phase, and multiallelic variants, and (b) extensions of many functions to account for the new types of information.
The second-generation versions of PLINK will offer dramatic improvements in performance and compatibility. For the first time, users without access to high-end computing resources can perform several essential analyses of the feature-rich and very large genetic datasets coming into use.

An extended reply to Mendez et al.: The ‘extremely ancient’ chromosome that still isn’t

An extended reply to Mendez et al.: The ‘extremely ancient’ chromosome that still isn’t

Eran Elhaik, Tatiana V. Tatarinova, Anatole A. Klyosov, Dan Graur
(Submitted on 15 Oct 2014)

Earlier this year, we published a scathing critique of a paper by Mendez et al. (2013) in which the claim was made that a Y chromosome was 237,000-581,000 years old. Elhaik et al. (2014) also attacked a popular article in Scientific American by the senior author of Mendez et al. (2013), whose title was “Sex with other human species might have been the secret of Homo sapiens’s [sic] success” (Hammer 2013). Five of the 11 authors of Mendez et al. (2013) have now written a “rebuttal,” and we were allowed to reply.
Unfortunately, our reply was censored for being “too sarcastic and inflamed.” References were removed, meanings were castrated, and a dedication in the Acknowledgments was deleted. Now, that the so-called rebuttal by 45% of the authors of Mendez et al. (2013) has been published together with our vasectomized reply, we decided to make public our entire reply to the so called “rebuttal.” In fact, we go one step further, and publish a version of the reply that has not even been self-censored.
Now, that the so-called rebuttal by 45% of the authors of Mendez et al. (2013) has been published together with our vasectomized reply, we decided to make public our entire reply to the so called “rebuttal.” In fact, we go one step further, and publish a version of the reply that has not even been self-censored.

Recent evolution of the mutation rate and spectrum in Europeans

Recent evolution of the mutation rate and spectrum in Europeans
Kelley Harris
doi: http://dx.doi.org/10.1101/010314

As humans dispersed out of Africa, they adapted to new environmental challenges including changes in exposure to mutagenic solar radiation. This raises the possibility that different populations experienced different selective pressures affecting genome integrity. Prior work has uncovered divergent selection in tropical versus temperate latitudes on eQTLs that regulate the DNA damage response, as well as evidence that the human mutation rate per year has changed at least 2-fold since we shared a common ancestor with chimpanzees. Here, I present evidence that the rate of a particular mutation type has recently increased in the European lineage, rising in frequency by 50% during the 30,000–50,000 years since Europeans diverged from Asians. A comparison of single nucleotide polymorphisms (SNPs) private to Africa, Asia, and Europe in the 1000 Genomes data reveals that private European variation is enriched for the transition 5’-TCC-3’→5’-TTC-3’. Although it is not clear whether UV played a causal role in the changing the European mutational spectrum, 5’-TCC-3’→5’-TTC-3’ is known to be the most common somatic mutation present in melanoma skin cancers, as well as the mutation most frequently induced in vitro by UV. Regardless of its causality, this change indicates that DNA replication fidelity has not remained stable even since the origin of modern humans and might have changed numerous times during our recent evolutionary history.

Massive bursts of transposable element activity in Drosophila

Massive bursts of transposable element activity in Drosophila

Robert Kofler, Viola Nolte, Christian Schlötterer
doi: http://dx.doi.org/10.1101/010231

The evolutionary dynamics of transposable element (TE) insertions have been of continued interest since TE activity has important implications for genome evolution and adaptation. Here, we infer the transposition dynamics of TEs by comparing their abundance in natural D. melanogaster and D. simulans populations. Sequencing pools of more than 550 South African flies to at least 320-fold coverage, we determined the genome wide TE insertion frequencies in both species. We show that 46 (49%) TE families in D. melanogaster and 44 (47%) in D. simulans experienced a recent burst of activity. The bursts of activity affected different TE families in the two species. While in D. melanogaster retrotransposons predominated, DNA transposons showed higher activity levels in D. simulans. We propose that the observed TE dynamics are the outcome of the demographic history of the two species, with habitat expansion triggering a period of rapid evolution.