Biology subjects

Pier Francesco Palamara

Publications and source records attributed to Pier Francesco Palamara.

5 recordsLinked to original sources

bioRxiv2016

Reference-based phasing using the Haplotype Reference Consortium panel

Haplotype phasing is a fundamental problem in medical and population genetics. Phasing is generally performed via statistical phasing within a genotyped cohort, an approach that can attain high accuracy in very large cohorts but attains lower accuracy in smaller cohorts. Here, we instead explore the paradigm of reference-based phasing. We introduce a new phasing algorithm, Eagle2, that attains high accuracy across a broad range of cohort sizes by efficiently leveraging information from large external reference panels (such as the Haplotype Reference Consortium, HRC) using a new data structure based on the positional BurrowsWheeler transform. We demonstrate that Eagle2 attains a {approx}20x speedup and {approx}10% increase in accuracy compared to reference-based phasing using SHAPEIT2. On European-ancestry samples, Eagle2 with the HRC panel achieves >2x the accuracy of 1000 Genomes-based phasing. Eagle2 is open source and freely available for HRC-based phasing via the Sanger Imputation Service and the Michigan Imputation Server.

Genetics↗

bioRxiv2016

ARGON: fast, whole-genome simulation of the discrete time Wright-Fisher process

MotivationSimulation under the coalescent model is ubiquitous in the analysis of genetic data. The rapid growth of real data sets from multiple human populations led to increasing interest in simulating very large sample sizes at whole-chromosome scales. When the sample size is large, the coalescent model becomes an increasingly inaccurate approximation of the discrete time Wright-Fisher model (DTWF). Analytical and computational treatment of the DTWF, however, is generally harder.\n\nResultsWe present a simulator (ARGON) for the DTWF process that scales up to hundreds of thousands of samples and whole-chromosome lengths, with a time/memory performance comparable or superior to currently available methods for coalescent simulation. The simulator supports arbitrary demographic history, migration, Newick tree output, variable mutation/recombination rates and gene conversion, and efficiently outputs pairwise identical-bydescent (IBD) sharing data.\n\nAvailabilityARGON (version 0.1) is written in Java, open source, and freely available at https://github.com/pierpal/ARGON.\n\nContactppalama@hsph.harvard.edu\n\nSupplementary informationSupplementary data are available online.

Bioinformatics↗

bioRxiv2015

Fast and accurate long-range phasing in a UK Biobank cohort

Recent work has leveraged the extensive genotyping of the Icelandic population to perform long-range phasing (LRP), enabling accurate imputation and association analysis of rare variants in target samples typed on genotyping arrays. Here, we develop a fast and accurate LRP method, Eagle, that extends this paradigm to populations with much smaller proportions of genotyped samples by harnessing long (>4cM) identical-by-descent (IBD) tracts shared among distantly related individuals. We applied Eagle to N=150K samples (0.2% of the British population) from the UK Biobank, and we determined that it is 1-2 orders of magnitude faster than existing methods while achieving similar or better phasing accuracy (switch error rate {approx}0.3%, corresponding to perfect phase in most 10Mb segments). We also observed that when used within an imputation pipeline, Eagle pre-phasing improved downstream imputation accuracy compared to pre-phasing in batches using existing methods (as necessary to achieve comparable computational cost).

Genetics↗

bioRxiv2015

Purging of deleterious variants due to drift and founder effect in Italian populations with extended autozygosity

Purging through inbreeding occurs when consanguineous marriages increases the rate at which deleterious alleles are present in a homozygous state. In this study we carried out low-read depth (4-10x) whole-genome sequencing in 568 individuals from three Italian founder populations, and compared it to data from other Italian and European populations from the 1000 Genomes Project. We show extended consanguinity and depletion of homozygous genotypes at potentially detrimental sites in the founder populations compared to outbred populations. However these patterns are not compatible with the hypothesis of consanguinity driving the purging of highly deleterious mutations according to simulations. Therefore we conclude that genetic drift and the founder effect should be responsible for the observed purging of deleterious variants.

Evolutionary Biology↗

bioRxiv2015

Leveraging distant relatedness to quantify human mutation and gene conversion rates

The rate at which human genomes mutate is a central biological parameter that has many implications for our ability to understand demographic and evolutionary phenomena. We present a method for inferring mutation and gene conversion rates using the number of sequence differences observed in identical-by-descent (IBD) segments together with a reconstructed model of recent population size history. This approach is robust to, and can quantify, the presence of substantial genotyping error, as validated in coalescent simulations. We applied the method to 498 trio-phased Dutch individuals from the Genome of the Netherlands (GoNL) project, sequenced at an average depth of 13x. We infer a point mutation rate of 1.66 {+/-} 0.04 x 10-8 per base per generation, and a rate of 1.26 {+/-} 0.06 x 10-9 for < 20 bp indels. Our estimated average genome-wide mutation rate is higher than most pedigree-based estimates reported thus far, but lower than estimates obtained using substitution rates across primates. By quantifying how estimates vary as a function of allele frequency, we infer the probability that a site is involved in non-crossover gene conversion as 5.99 {+/-} 0.69 x 10-6, consistent with recent reports. We find that recombination does not have observable mutagenic effects after gene conversion is accounted for, and that local gene conversion rates reflect recombination rates. We detect a strong enrichment for recent deleterious variation among mismatching variants found within IBD regions, and observe summary statistics of local IBD sharing to closely match previously proposed metrics of background selection, but find no significant effects of selection on our estimates of mutation rate. We detect no evidence for strong variation of mutation rates in a number of genomic annotations obtained from several recent studies.

Genetics↗