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Mutation rates and the evolution of germline structure
[article]
2015
biorxiv/medrxiv
pre-print
Preserved Fulltext
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,
doi:10.1101/034298
fatcat:2klnxw44jnfrjciataq5mvrr74
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.
The mutation rate in human evolution and demographic inference
[article]
2016
bioRxiv
pre-print
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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,
doi:10.1101/061226
fatcat:6rvkrygycbcxlcet4dt5gftify
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.
What is ancestry?
2020
PLoS Genetics
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Global clues to the nature of genomic mutations in humans
2017
eLife
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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]
2018
bioRxiv
pre-print
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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
doi:10.1101/283606
fatcat:kth72qn2bbf4pelqcgqp7imroq
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... 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.
Destruction of protoplanetary disks in the Orion Nebula Cluster
[article]
2000
arXiv
pre-print
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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]
2016
bioRxiv
pre-print
Preserved Fulltext
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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]
2021
arXiv
pre-print
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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
arXiv:2106.10041v1
fatcat:fqrv6ia6unfith27orfbhx6y6q
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... 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.
The mutation rate in human evolution and demographic inference
2016
Current Opinion in Genetics and Development
Preserved Fulltext
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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,
doi:10.1016/j.gde.2016.07.008
pmid:27589081
fatcat:rb53dsdfffhmdezlpe5yfp3zhq
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. *
Primordial substructure in the Orion Nebula Cluster
2002
Monthly notices of the Royal Astronomical Society
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Some of the implications of this for protoplanetary discs there have been addressed by Scally & Clarke (2001) and Bonnell et al. (2001) , with the finding that although systems spending a lot of time ...
doi:10.1046/j.1365-8711.2002.05503.x
fatcat:p42eexigzvdufch6j2aen2toei
Short-range template switching in great ape genomes explored using a pair hidden Markov model
[article]
2020
bioRxiv
pre-print
Preserved Fulltext
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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
doi:10.1101/2020.11.09.374694
fatcat:zlmzs7atkjaqfkq3txgnhypapu
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.
Mutation rates and the evolution of germline structure
2016
Philosophical Transactions of the Royal Society of London. Biological Sciences
Preserved Fulltext
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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
doi:10.1098/rstb.2015.0137
pmid:27325834
pmcid:PMC4920338
fatcat:mn4so3e3uzh3loa757g3bxmiay
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'.
Short-range template switching in great ape genomes explored using pair hidden Markov models
2021
PLoS Genetics
Preserved Fulltext
A copy of this work was available on the public web and has been preserved in the Wayback Machine. The capture dates from 2021; you can also visit the original URL.
The file type is application/pdf.
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
doi:10.1371/journal.pgen.1009221
pmid:33651813
pmcid:PMC7954356
fatcat:ecwugi5durgb7ohhypgmnnumty
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.
BCFtools/RoH: a hidden Markov model approach for detecting autozygosity from next-generation sequencing data
2016
Bioinformatics
Preserved Fulltext
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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
doi:10.1093/bioinformatics/btw044
pmid:26826718
pmcid:PMC4892413
fatcat:zjbwyuebqrfnvicvwinmrbhd2e
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:
A large genome center's improvements to the Illumina sequencing system
2008
Nature Methods
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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
doi:10.1038/nmeth.1270
pmid:19034268
pmcid:PMC2610436
fatcat:furwyrfttje5vj6v4xgpmoke7e
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.
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