Filters








68 Hits in 0.64 sec

Mutation rates and the evolution of germline structure [article]

Aylwyn Scally
2015 biorxiv/medrxiv   pre-print
Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities with our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from our longstanding model of spermatogenesis. I consider possible explanations for these discrepancies,
more » ... ing evolutionary changes in life history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem cell state transitions during spermatogenesis, in which 'dark' gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates.
doi:10.1101/034298 fatcat:2klnxw44jnfrjciataq5mvrr74

The mutation rate in human evolution and demographic inference [article]

Aylwyn Scally
2016 bioRxiv   pre-print
The germline mutation rate has long been a major source of uncertainty in human evolutionary and demographic analyses based on genetic data, but estimates have improved substantially in recent years. I discuss our current knowledge of the mutation rate in humans and the underlying biological factors affecting it, which include generation time, parental age and other developmental and reproductive timescales. There is good evidence for a slowdown in mean mutation rate during great ape evolution,
more » ... but not for a more recent change within the timescale of human genetic diversity. Hence, pending evidence to the contrary, it is reasonable to use a present-day rate of approximately 0.5 x 10−9bp−1yr−1in all human or hominin demographic analyses.
doi:10.1101/061226 fatcat:6rvkrygycbcxlcet4dt5gftify

What is ancestry?

Iain Mathieson, Aylwyn Scally, Jonathan Flint
2020 PLoS Genetics  
doi:10.1371/journal.pgen.1008624 pmid:32150538 fatcat:xrijgsriwzdk3bbzdhizbqjx6i

Global clues to the nature of genomic mutations in humans

Aylwyn Scally
2017 eLife  
Aylwyn Scally is in the Department of Genetics, University of Cambridge, Cambridge, United Kingdom a.scally@gen.cam.ac.uk http://orcid.org/0000-0002-0807-1167 individual's continent of origin based solely  ...  Modern humans originated in Africa (top left) Scally. eLife 2017;6:e27605. DOI: 10.7554/eLife.27605  ... 
doi:10.7554/elife.27605 pmid:28513430 pmcid:PMC5435459 fatcat:k2es5hni5vclthsig7zqpfm6im

Detecting archaic introgression without archaic reference genomes [article]

Laurits Skov, Ruoyun Hui, Asger Hobolth, Aylwyn Scally, Mikkel Heide Schierup, Richard Durbin
2018 bioRxiv   pre-print
Human populations out of Africa have experienced at least two bouts of introgression from archaic humans, Neandertal and Denisovans. In Papuans there is prior evidence of both these introgressions. Here we present a new approach to detect segments of individual genomes of archaic origin without using an archaic reference genome. The approach is based on the detection of genomic regions with a high SNV density of SNVs not seen in unadmixed populations. We show using simulations that this
more » ... a powerful approach to identifying segments of archaic introgression with a small rate of false detection. Furthermore our approach is able to accurately infer admixture proportions and divergence time of human and archaic populations. We apply the model to detect archaic introgression in 89 Papuans and show how the identified segments can be assigned to likely Neandertal or Denisovan origin. We report more Denisovan admixture than previous studies and directly find a shift in size distribution of fragments of Neandertal and Denisovan origin that is compatible with a difference in admixture time. Furthermore we identify small amounts of Denisova ancestry in West Eurasians, South East Asians and South Asians.
doi:10.1101/283606 fatcat:kth72qn2bbf4pelqcgqp7imroq

Destruction of protoplanetary disks in the Orion Nebula Cluster [article]

Aylwyn Scally and Cathie Clarke (Institute of Astronomy, Cambridge, UK)
2000 arXiv   pre-print
Scally is grateful for the support of a European Union Marie Curie Fellowship.  ...  Also, reasonable initial velocity distributions tend to evolve to a density distribution which is much too flat when compared to that of the ONC (Scally, in preparation). † † Note that the asymptotic density  ... 
arXiv:astro-ph/0012098v1 fatcat:zqznruflyzbzjllgixo3mhw2g4

Inference of candidate germline mutator loci in humans from genome-wide haplotype data [article]

Cathal Seoighe, Aylwyn Scally
2016 bioRxiv   pre-print
Scally A. The mutation rate in human evolution and demographic inference.  ...  Narasimhan VM, Rahbari R, Scally A, Wuster A, Mason D, Xue Y, Wright J, Trembath R, Maher ER, van Heel DA, Auton A, Hurles ME, Tyler-Smith C, Durbin R.  ... 
doi:10.1101/089623 fatcat:47c247yu2nhjxl3d2dxbwkogja

The language of race, ethnicity, and ancestry in human genetic research [article]

Ewan Birney, Michael Inouye, Jennifer Raff, Adam Rutherford, Aylwyn Scally
2021 arXiv   pre-print
The language commonly used in human genetics can inadvertently pose problems for multiple reasons. Terms like "ancestry", "ethnicity", and other ways of grouping people can have complex, often poorly understood, or multiple meanings within the various fields of genetics, between different domains of biological sciences and medicine, and between scientists and the general public. Furthermore, some categories in frequently used datasets carry scientifically misleading, outmoded or even racist
more » ... pectives derived from the history of science. Here, we discuss examples of problematic lexicon in genetics, and how commonly used statistical practices to control for the non-genetic environment may exacerbate difficulties in our terminology, and therefore understanding. Our intention is to stimulate a much-needed discussion about the language of genetics, to begin a process to clarify existing terminology, and in some cases adopt a new lexicon that both serves scientific insight, and cuts us loose from various aspects of a pernicious past.
arXiv:2106.10041v1 fatcat:fqrv6ia6unfith27orfbhx6y6q

The mutation rate in human evolution and demographic inference

Aylwyn Scally
2016 Current Opinion in Genetics and Development  
The germline mutation rate has long been a major source of uncertainty in human evolutionary and demographic analyses based on genetic data, but estimates have improved substantially in recent years. I discuss our current knowledge of the mutation rate in humans and the underlying biological factors affecting it, which include generation time, parental age and other developmental and reproductive timescales. There is good evidence for a slowdown in mean mutation rate during great ape evolution,
more » ... but not for a more recent change within the timescale of human genetic diversity. Hence, pending evidence to the contrary, it is reasonable to use a present-day rate of approximately 0.5 × 10 −9 bp −1 yr −1 in all human or hominin demographic analyses. *
doi:10.1016/j.gde.2016.07.008 pmid:27589081 fatcat:rb53dsdfffhmdezlpe5yfp3zhq

Short-range template switching in great ape genomes explored using a pair hidden Markov model [article]

Conor Reece Walker, Aylwyn Scally, Nicola De Maio, Nick Goldman
2020 bioRxiv   pre-print
Many complex genomic rearrangements arise through template switch errors, which occur in DNA replication when there is a transient polymerase switch to an alternate template nearby in three-dimensional space. While typically investigated at kilobase-to-megabase scales, the genomic and evolutionary consequences of this mutational process are not well characterised at smaller scales, where they are often interpreted as clusters of independent substitutions, insertions and deletions. Here we
more » ... t an improved statistical approach using pair hidden Markov models, and use it to detect and describe short-range template switches underlying clusters of mutations in the multi-way alignment of hominid genomes. Using robust statistics derived from evolutionary genomic simulations, we show that template switch events have been widespread in the evolution of the great apes' genomes and provide a parsimonious explanation for the presence of many complex mutation clusters in their phylogenetic context. Larger-scale mechanisms of genome rearrangement are typically associated with structural features around breakpoints, and accordingly we show that atypical patterns of secondary structure formation and DNA bending are present at the initial template switch loci. Our methods improve on previous non-probabilistic approaches for computational detection of template switch mutations, allowing the statistical significance of events to be assessed. By specifying realistic evolutionary parameters based on the genomes and taxa involved, our methods can be readily adapted to other intra- or inter-species comparisons.
doi:10.1101/2020.11.09.374694 fatcat:zlmzs7atkjaqfkq3txgnhypapu

Mutation rates and the evolution of germline structure

Aylwyn Scally
2016 Philosophical Transactions of the Royal Society of London. Biological Sciences  
One contribution of 15 to a discussion meeting issue 'Dating species divergences using rocks and clocks'. Genome sequencing studies of de novo mutations in humans have revealed surprising incongruities in our understanding of human germline mutation. In particular, the mutation rate observed in modern humans is substantially lower than that estimated from calibration against the fossil record, and the paternal age effect in mutations transmitted to offspring is much weaker than expected from
more » ... long-standing model of spermatogenesis. I consider possible explanations for these discrepancies, including evolutionary changes in life-history parameters such as generation time and the age of puberty, a possible contribution from undetected post-zygotic mutations early in embryo development, and changes in cellular mutation processes at different stages of the germline. I suggest a revised model of stem-cell state transitions during spermatogenesis, in which 'dark' gonial stem cells play a more active role than hitherto envisaged, with a long cycle time undetected in experimental observations. More generally, I argue that the mutation rate and its evolution depend intimately on the structure of the germline in humans and other primates. This article is part of the themed issue 'Dating species divergences using rocks and clocks'.
doi:10.1098/rstb.2015.0137 pmid:27325834 pmcid:PMC4920338 fatcat:mn4so3e3uzh3loa757g3bxmiay

Short-range template switching in great ape genomes explored using pair hidden Markov models

Conor R Walker, Aylwyn Scally, Nicola De Maio, Nick Goldman
2021 PLoS Genetics  
Many complex genomic rearrangements arise through template switch errors, which occur in DNA replication when there is a transient polymerase switch to an alternate template nearby in three-dimensional space. While typically investigated at kilobase-to-megabase scales, the genomic and evolutionary consequences of this mutational process are not well characterised at smaller scales, where they are often interpreted as clusters of independent substitutions, insertions and deletions. Here we
more » ... t an improved statistical approach using pair hidden Markov models, and use it to detect and describe short-range template switches underlying clusters of mutations in the multi-way alignment of hominid genomes. Using robust statistics derived from evolutionary genomic simulations, we show that template switch events have been widespread in the evolution of the great apes' genomes and provide a parsimonious explanation for the presence of many complex mutation clusters in their phylogenetic context. Larger-scale mechanisms of genome rearrangement are typically associated with structural features around breakpoints, and accordingly we show that atypical patterns of secondary structure formation and DNA bending are present at the initial template switch loci. Our methods improve on previous non-probabilistic approaches for computational detection of template switch mutations, allowing the statistical significance of events to be assessed. By specifying realistic evolutionary parameters based on the genomes and taxa involved, our methods can be readily adapted to other intra- or inter-species comparisons.
doi:10.1371/journal.pgen.1009221 pmid:33651813 pmcid:PMC7954356 fatcat:ecwugi5durgb7ohhypgmnnumty

BCFtools/RoH: a hidden Markov model approach for detecting autozygosity from next-generation sequencing data

Vagheesh Narasimhan, Petr Danecek, Aylwyn Scally, Yali Xue, Chris Tyler-Smith, Richard Durbin
2016 Bioinformatics  
Runs of homozygosity (RoHs) are genomic stretches of a diploid genome that show identical alleles on both chromosomes. Longer RoHs are unlikely to have arisen by chance but are likely to denote autozygosity, whereby both copies of the genome descend from the same recent ancestor. Early tools to detect RoH used genotype array data, but substantially more information is available from sequencing data. Here, we present and evaluate BCFtools/RoH, an extension to the BCFtools software package, that
more » ... etects regions of autozygosity in sequencing data, in particular exome data, using a hidden Markov model. By applying it to simulated data and real data from the 1000 Genomes Project we estimate its accuracy and show that it has higher sensitivity and specificity than existing methods under a range of sequencing error rates and levels of autozygosity. Availability and implementation: BCFtools/RoH and its associated binary/source files are freely available from https://github.com/samtools/BCFtools. Contact:
doi:10.1093/bioinformatics/btw044 pmid:26826718 pmcid:PMC4892413 fatcat:zjbwyuebqrfnvicvwinmrbhd2e

A large genome center's improvements to the Illumina sequencing system

Michael A Quail, Iwanka Kozarewa, Frances Smith, Aylwyn Scally, Philip J Stephens, Richard Durbin, Harold Swerdlow, Daniel J Turner
2008 Nature Methods  
The Wellcome Trust Sanger Institute is one of the world's largest genome centers, and a substantial amount of our sequencing is performed with 'next-generation' massively parallel sequencing technologies: in June 2008 the quantity of purityfiltered sequence data generated by our Genome Analyzer (Illumina) platforms reached 1 terabase, and our average weekly Illumina production output is currently 64 gigabases. Here we describe a set of improvements we have made to the standard Illumina
more » ... to make the library preparation more reliable in a high-throughput environment, to reduce bias, tighten insert size distribution and reliably obtain high yields of data.
doi:10.1038/nmeth.1270 pmid:19034268 pmcid:PMC2610436 fatcat:furwyrfttje5vj6v4xgpmoke7e
« Previous Showing results 1 — 15 out of 68 results