Error-prone polymerase activity causes multinucleotide mutations in humans
Kelley Harris, Rasmus Nielsen
(Submitted on 5 Dec 2013)
About 2% of human genetic polymorphisms have been hypothesized to arise via multinucleotide mutations (MNMs), complex events that generate SNPs at multiple sites in a single generation. MNMs have the potential to accelerate the pace at which single genes evolve and to confound studies of demography and selection that assume all SNPs arise independently. In this paper, we examine clustered mutations that are segregating in a set of 1,092 human genomes, demonstrating that MNMs become enriched as large numbers of individuals are sampled. We leverage the size of the dataset to deduce new information about the allelic spectrum of MNMs, estimating the percentage of linked SNP pairs that were generated by simultaneous mutation as a function of the distance between the affected sites and showing that MNMs exhibit a high percentage of transversions relative to transitions. These findings are reproducible in data from multiple sequencing platforms. Among tandem mutations that occur simultaneously at adjacent sites, we find an especially skewed distribution of ancestral and derived dinucleotides, with GC→AA, GA→TT and their reverse complements making up 36% of the total. These same mutations dominate the spectrum of tandem mutations produced by the upregulation of low-fidelity Polymerase ζ in mutator strains of S. cerevisiae that have impaired DNA excision repair machinery. This suggests that low-fidelity DNA replication by Pol ζ is at least partly responsible for the MNMs that are segregating in the human population, and that useful information about the biochemistry of MNM can be extracted from ordinary population genomic data. We incorporate our findings into a mathematical model of the multinucleotide mutation process that can be used to correct phylogenetic and population genetic methods for the presence of MNMs.
High Genetic Diversity and Adaptive Potential of Two Simian Hemorrhagic Fever Viruses in a Wild Primate Population
Adam L. Bailey, Michael Lauck, Andrea Weiler, Samuel D. Sibley, Jorge M. Dinis, Zachary Bergman, Chase W. Nelson, Michael Correll, Michael Gleicher, David Hyeroba, Alex Tumukunde, Geoffrey Weny, Colin Chapman, Jens Kuhn, Austin Hughes, Thomas C. Friedrich, Tony L. Goldberg, David H. O’Connor
Key biological properties such as high genetic diversity and high evolutionary rate enhance the potential of certain RNA viruses to adapt and emerge. Identifying viruses with these properties in their natural hosts could dramatically improve disease forecasting and surveillance. Recently, we discovered two novel members of the viral family Arteriviridae: simian hemorrhagic fever virus (SHFV)-krc1 and SHFV-krc2, infecting a single wild red colobus (Procolobus rufomitratus tephrosceles) in Kibale National Park, Uganda. Nearly nothing is known about the biological properties of SHFVs in nature, although the SHFV type strain, SHFV-LVR, has caused devastating outbreaks of viral hemorrhagic fever in captive macaques. Here we detected SHFV-krc1 and SHFV-krc2 in 40% and 47% of 60 wild red colobus tested, respectively. We found viral loads in excess of 1×10^6-1×10^7 RNA copies per milliliter of blood plasma for each of these viruses. SHFV-krc1 and SHFV-krc2 also showed high genetic diversity at both the inter- and intra-host levels. Analyses of synonymous and non-synonymous nucleotide diversity across viral genomes revealed patterns suggestive of positive selection in SHFV open reading frames (ORF) 5 (SHFV-krc2 only) and 7 (SHFV-krc1 and SHFV-krc2). Thus, these viruses share several important properties with some of the most rapidly evolving, emergent RNA viruses.
Population genetics and substitution models of adaptive evolution
Mario dos Reis
(Submitted on 26 Nov 2013)
The ratio of non-synonymous to synonymous substitutions ω(=dN/dS) has been widely used as a measure of adaptive evolution in protein coding genes. Omega can be defined in terms of population genetics parameters as the fixation ratio of selected vs. neutral mutants. Here it is argued that approaches based on the infinite sites model are not appropriate to define ω for single codon locations. Simple models of amino acid substitution with reversible mutation and selection are analysed, and used to define ω under several evolutionary scenarios. In most practical cases ω1 can be sometimes expected for single locations at equilibrium. An example with influenza data is discussed.
Interspecific Introgressive Origin of Genomic Diversity in the House Mouse
Kevin J. Liu, Ying Song, Michael H. Kohn, Luay Nakhleh
(Submitted on 22 Nov 2013)
We report on a genome-wide scan for introgression in a eukaryote. The scan identified kilobase-to-megabase-long regions of introgressive origin involving Mus spretus in six Mus musculus domesticus chromosomes, based on genomes sampled from and near the European range of sympatry. Our analyses point to the introgression of both adaptive driver and linked passenger loci. Introgression could transfer traits, such as the discovered warfarin resistance in European M. m. domesticus, and could create new traits, as we infer using a functional network analysis. Our study sheds new light on the extent of adaptive introgession and calls for new analyses of eukaryotic genomes that explicitly account for the possibility of introgression.
A Complete Public Domain Family Genomics Dataset
Manuel Corpas, Mike Cariaso, Alain Coletta, David Weiss, Andrew P Harrison, Federico Moran, Huanming Yang
BACKGROUND: The availability of open access genomic data is essential for the personal genomics field. Public genomic data allow comparative analyses, testing of new tools and genotype-phenotype association studies. Personal genomics data of unrelated individuals are available in the public domain, notably the Personal Genome Project; however, to date genomics family data and metadata are severely lacking, mainly due to cost, privacy concerns or restricted access to Next Generation Sequencing (NGS) technology. Family data have a lot to offer as they allow the study of heritability, something which is impossible to do just by using unrelated individuals. FINDINGS: A whole family from Southern Spain decided to genotype, sequence and analyse their personal genomes making them publicly available under a Creative Commons 0 license (CC0; commonly denominated as public domain). These data include a) five 23andMe SNP chip genotype bed files, b) four raw exomes with their assorted bam files and VCF files, c) a metagenomic raw sequencing data file and d) derived data of likely phenotypes using SNPedia-derived tools. CONCLUSIONS: To our knowledge this is the first CC0 released set of genomic, phenotypic and metagenomic data for a whole family. This dataset is also unique in that it was obtained through direct-to-consumer genetic tests. Hence any ordinary citizen with enough budget and samples should be able to reproduce this experiment. We envisage this dataset to be a useful resource for a variety of applications in the personal genomics field as a) negative control data for trait association discovery, b) testing data for development of new software and c) sample data for heritability studies. We encourage prospective users to share with us derived results so that they can be added to our existing collection.
Population genomics of parallel hybrid zones in the mimetic butterflies, H. melpomene and H. erato
Nicola Nadeau, Mayte Ruiz, Patricio Salazar, Brian Counterman, Jose Alejandro Medina, Humberto Ortiz-Zuazaga, Anna Morrison, W. Owen McMillan, Chri Jiggins, Riccardo Papa
Hybrid zones can be valuable tools for studying evolution and identifying genomic regions responsible for adaptive divergence and underlying phenotypic variation. Hybrid zones between subspecies of Heliconius butterflies can be very narrow and are maintained by strong selection acting on colour pattern. The co-mimetic species H. erato and H. melpomene have parallel hybrid zones where both species undergo a change from one colour pattern form to another. We use restriction associated DNA sequencing to obtain several thousand genome wide sequence markers and use these to analyse patterns of population divergence across two pairs of parallel hybrid zones in Peru and Ecuador. We compare two approaches for analysis of this type of data; alignment to a reference genome and de novo assembly, and find that alignment gives the best results for species both closely (H. melpomene) and distantly (H. erato, ~15% divergent) related to the reference sequence. Our results confirm that the colour pattern controlling loci account for the majority of divergent regions across the genome, but we also detect other divergent regions apparently unlinked to colour pattern differences. We also use association mapping to identify previously unmapped colour pattern loci, in particular the Ro locus. Finally, we identify within our sample a new cryptic population of H. timareta in Ecuador, which occurs at relatively low altitude and is mimetic with H. melpomene malleti.
The genomic landscape of meiotic crossovers and gene conversions in Arabidopsis thaliana
Erik Wijnker, Geo Velikkakam James, Jia Ding, Frank Becker, Jonas R. Klasen, Vimal Rawat, Beth A. Rowan, Daniel F. de Jong, C. Bastiaan de Snoo, Luis Zapata, Bruno Huettel, Hans de Jong, Stephan Ossowski, Detlef Weigel, Maarten Koornneef, Joost J.B. Keurentjes, Korbinian Schneeberger
(Submitted on 13 Nov 2013)
Knowledge of the exact distribution of meiotic crossovers (COs) and gene conversions (GCs) is essential for understanding many aspects of population genetics and evolution, from haplotype structure and long-distance genetic linkage to the generation of new allelic variants of genes. To this end, we resequenced the four products of 13 meiotic tetrads along with 10 doubled haploids derived from Arabidopsis thaliana hybrids. GC detection through short reads has previously been confounded by genomic rearrangements. Rigid filtering for misaligned reads allowed GC identification at high accuracy and revealed an ~80-kb transposition, which undergoes copy-number changes mediated by meiotic recombination. Non-crossover associated GCs were extremely rare most likely due to their short average length of ~25-50 bp, which is significantly shorter than the length of CO associated GCs. Overall, recombination preferentially targeted non-methylated nucleosome-free regions at gene promoters, which showed significant enrichment of two sequence motifs.
The first steps of adaptation of Escherichia coli to the gut are dominated by soft sweeps
João Barroso-Batista, Ana Sousa, Marta Lourenço, Marie-Louise Bergman, Jocelyne Demengeot, Karina B. Xavier, Isabel Gordo
(Submitted on 11 Nov 2013)
The accumulation of adaptive mutations is essential for survival in novel environments. However, in clonal populations with a high mutational supply, the power of natural selection is expected to be limited. This is due to clonal interference – the competition of clones carrying different beneficial mutations – which leads to the loss of many small effect mutations and fixation of large effect ones. If interference is abundant, then mechanisms for horizontal transfer of genes, which allow the immediate combination of beneficial alleles in a single background, are expected to evolve. However, the relevance of interference in natural complex environments, such as the gut, is poorly known. To address this issue, we studied the invasion of beneficial mutations responsible for Escherichia coli’s adaptation to the mouse gut and demonstrate the pervasiveness of clonal interference. The observed dynamics of change in frequency of beneficial mutations are consistent with soft sweeps, where a similar adaptive mutation arises repeatedly on different haplotypes without reaching fixation. The genetic basis of the adaptive mutations revealed a striking parallelism in independently evolving populations. This was mainly characterized by the insertion of transposable elements in both coding and regulatory regions of a few genes. Interestingly in most populations, we observed a complete phenotypic sweep without loss of genetic variation. The intense clonal interference during adaptation to the gut environment, here demonstrated, may be important for our understanding of the levels of strain diversity of E. coli inhabiting the human gut microbiota and of its recombination rate.
Global patterns of sex-biased migrations in humans
Chuan-Chao Wang, Li Jin, Hui Li
(Submitted on 29 Oct 2013)
A series of studies have revealed the among-population components of genetic variation are higher for the paternal Y chromosome than for the maternal mitochondrial DNA (mtDNA), which indicates sex-biased migrations in human populations. However, this phenomenon might be also an ascertainment bias due to nonrandom sampling of SNPs. To eliminate the possible bias, we used the whole Y chromosome and mtDNA sequence data of 491 individuals from the 1000 Genomes Project Phase I to address the sex-biased migration dispute. We found that genetic differentiation between populations was higher for Y chromosome than for the mtDNA at global scales. The migration rate of female might be three times higher than that of male, assuming the effective population size is the same for male and female.
Can we predict the mutation rate at the single nucleotide scale in the human genome?
Adam Eyre-Walker, Ying Chen
(Submitted on 29 Oct 2013)
It has been recently claimed that it is possible to predict the rate of de novo mutation of each site in the human genome with almost perfect accuracy (Michaelson et al. (2012) Cell, 151, 1431-1442). We show that this claim is unwarranted. By considering the correlation between the rate of de novo mutation and the predictions from the model of Michaelson et al., we show that there could be substantial unexplained variance in the mutation rate. We also demonstrate that the model of Michaelson et al. fails to capture a major component of the variation in the mutation rate, that which is local but not associated with simple context.