Biology subjects

Kelleher, J.

Publications and source records attributed to Kelleher, J..

3 recordsLinked to original sources

bioRxiv2018

Tree-sequence recording in SLiM opens new horizons for forward-time simulation of whole genomes

There is an increasing demand for evolutionary models to incorporate relatively realistic dynamics, ranging from selection at many genomic sites to complex demography, population structure, and ecological interactions. Such models can generally be implemented as individual-based forward simulations, but the large computational overhead of these models often makes simulation of whole chromosome sequences in large populations infeasible. This situation presents an important obstacle to the field that requires conceptual advances to overcome. The recently developed tree-sequence recording method (Kelleher et al., 2018), which stores the genealogical history of all genomes in the simulated population, could provide such an advance. This method has several benefits: (1) it allows neutral mutations to be omitted entirely from forward-time simulations and added later, thereby dramatically improving computational efficiency; (2) it allows neutral burn-in to be constructed extremely efficiently after the fact, using \"recapitation\"; (3) it allows direct examination and analysis of the genealogical trees along the genome; and (4) it provides a compact representation of a populations genealogy that can be analyzed in Python using the msprime package. We have implemented the tree-sequence recording method in SLiM 3 (a free, open-source evolutionary simulation software package) and extended it to allow the recording of non-neutral mutations, greatly broadening the utility of this method. To demonstrate the versatility and performance of this approach, we showcase several practical applications that would have been beyond the reach of previously existing methods, opening up new horizons for the modeling and exploration of evolutionary processes.

evolutionary biology↗

bioRxiv2018

Efficient pedigree recording for fast population genetics simulation

In this paper we describe how to efficiently record the entire genetic history of a population in forwards-time, individual-based population genetics simulations with arbitrary breeding models, population structure and demography. This approach dramatically reduces the computational burden of tracking individual genomes by allowing us to simulate only those loci that may affect reproduction (those having non-neutral variants). The genetic history of the population is recorded as a succinct tree sequence as introduced in the software package msprime, on which neutral mutations can be quickly placed afterwards. Recording the results of each breeding event requires storage that grows linearly with time, but there is a great deal of redundancy in this information. We solve this storage problem by providing an algorithm to quickly simplify a tree sequence by removing this irrelevant history for a given set of genomes. By periodically simplifying the history with respect to the extant population, we show that the total storage space required is modest and overall large efficiency gains can be made over classical forward-time simulations. We implement a general-purpose framework for recording and simplifying genealogical data, which can be used to make simulations of any population model more efficient. We modify two popular forwards-time simulation frameworks to use this new approach and observe efficiency gains in large, whole-genome simulations of one to two orders of magnitude. In addition to speed, our method for recording pedigrees has several advantages: (1) All marginal genealogies of the simulated individuals are recorded, rather than just genotypes. (2) A population of N individuals with M polymorphic sites can be stored in O(N log N + M) space, making it feasible to store a simulations entire final generation as well as its history. (3) A simulation can easily be initialized with a more efficient coalescent simulation of deep history. The software for recording and processing tree sequences is named tskit.\n\nAuthor SummarySexually reproducing organisms are related to the others in their species by the complex web of parent-offspring relationships that constitute the pedigree. In this paper, we describe a way to record all of these relationships, as well as how genetic material is passed down through the pedigree, during a forwards-time population genetic simulation. To make effective use of this information, we describe both efficient storage methods for this embellished pedigree as well as a way to remove all information that is irrelevant to the genetic history of a given set of individuals, which dramatically reduces the required amount of storage space. Storing this information allows us to produce whole-genome sequence from simulations of large populations in which we have not explicitly recorded new genomic mutations; we find that this results in computational run times of up to 50 times faster than simulations forced to explicitly carry along that information.

bioinformatics↗

bioRxiv2017

Genome Graphs

There is increasing recognition that a single, monoploid reference genome is a poor universal reference structure for human genetics, because it represents only a tiny fraction of human variation. Adding this missing variation results in a structure that can be described as a mathematical graph: a genome graph. We demonstrate that, in comparison to the existing reference genome (GRCh38), genome graphs can substantially improve the fractions of reads that map uniquely and perfectly. Furthermore, we show that this fundamental simplification of read mapping transforms the variant calling problem from one in which many non-reference variants must be discovered de-novo to one in which the vast majority of variants are simply re-identified within the graph. Using standard benchmarks as well as a novel reference-free evaluation, we show that a simplistic variant calling procedure on a genome graph can already call variants at least as well as, and in many cases better than, a state-of-the-art method on the linear human reference genome. We anticipate that graph-based references will supplant linear references in humans and in other applications where cohorts of sequenced individuals are available.

bioinformatics↗