scholarly journals Patterns of genetic variability in genomic regions with low rates of recombination

2019 ◽  
Author(s):  
Hannes Becher ◽  
Benjamin C. Jackson ◽  
Brian Charlesworth
Keyword(s):  
Genetic Variability ◽  
Rare Variants ◽  
Genomic Region ◽  
Human Populations ◽  
Crossing Over ◽  
Deleterious Mutations ◽  
Effective Population ◽  
Genomic Studies ◽  
New Perspective ◽  
Genomic Regions

SUMMARYSurveys of DNA sequence variation have shown that the level of genetic variability in a genomic region is often strongly positively correlated with its rate of crossing over (CO) [1–3]. This pattern is caused by selection acting on linked sites, which reduces genetic variability and can also cause the frequency distribution of segregating variants to contain more rare variants than expected without selection (skew). These effects of selection may involve the spread of beneficial mutations (selective sweeps, SSWs), the elimination of deleterious mutations (background selection, BGS) or both together, and are expected to be stronger with lower rates of crossing over [1–3]. However, in a recent study of human populations, the skew was reduced in the lowest CO regions compared with regions with somewhat higher CO rates [4]. A similar pattern is seen in the population genomic studies of Drosophila simulans described here. We propose an explanation for this paradoxical observation, and validate it using computer simulations. This explanation is based on the finding that partially recessive, linked deleterious mutations can increase rather than reduce neutral variability when the product of the effective population size (Ne) and the selection coefficient against homozygous carriers of mutations (s) is ≤ 1, i.e. there is associative overdominance (AOD) rather than BGS [5]. We show that AOD can operate in a genomic region with a low rate of CO, opening up a new perspective on how selection affects patterns of variability at linked sites.

scholarly journals Demographic history shaped geographical patterns of deleterious mutation load in a broadly distributed Pacific Salmon

2019 ◽  
Author(s):  
Quentin Rougemont ◽  
Jean-Sébastien Moore ◽  
Thibault Leroy ◽  
Eric Normandeau ◽  
Eric B. Rondeau ◽  
...  
Keyword(s):  
Genetic Diversity ◽  
Coho Salmon ◽  
Pacific Salmon ◽  
Demographic History ◽  
Glacial Refugium ◽  
Human Populations ◽  
Deleterious Mutations ◽  
Effective Population ◽  
Geographical Patterns ◽  
Genome Wide Data

AbstractA thorough reconstruction of historical processes is essential for a comprehensive understanding the mechanisms shaping patterns of genetic diversity. Indeed, past and current conditions influencing effective population size have important evolutionary implications for the efficacy of selection, increased accumulation of deleterious mutations, and loss of adaptive potential. Here, we gather extensive genome-wide data that represent the extant diversity of the Coho salmon (Oncorhynchus kisutch) to address two objectives. We demonstrate that a single glacial refugium is the source of most of the present-day genetic diversity, with detectable inputs from a putative secondary micro-refugium. We found statistical support for a scenario whereby ancestral populations located south of the ice sheets expanded in postglacial time, swamping out most of the diversity from other putative micro-refugia. Demographic inferences revealed that genetic diversity was also affected by linked selection in large parts of the genome. Moreover, we demonstrate that the recent demographic history of this species generated regional differences in the load of deleterious mutations among populations, a finding that mirrors recent results from human populations and provides increased support for models of expansion load. We propose that insights from these historical inferences should be better integrated in conservation planning of wild organisms, which currently focuses largely on neutral genetic diversity and local adaptation, with the role of potentially maladaptive variation being generally ignored.

scholarly journals Efficient phasing and imputation of low-coverage sequencing data using large reference panels

2020 ◽  
Author(s):  
S. Rubinacci ◽  
D.M. Ribeiro ◽  
R. Hofmeister ◽  
O. Delaneau
Keyword(s):  
Paradigm Shift ◽  
Rare Variants ◽  
Association Studies ◽  
Cost Effective ◽  
Human Populations ◽  
Sequencing Data ◽  
Snp Arrays ◽  
Genomic Studies ◽  
Low Coverage ◽  
The Impact

AbstractLow-coverage whole genome sequencing followed by imputation has been proposed as a cost-effective genotyping approach for disease and population genetics studies. However, its competitiveness against SNP arrays is undermined as current imputation methods are computationally expensive and unable to leverage large reference panels.Here, we describe a method, GLIMPSE, for phasing and imputation of low-coverage sequencing datasets from modern reference panels. We demonstrate its remarkable performance across different coverages and human populations. It achieves imputation of a full genome for less than $1, outperforming existing methods by orders of magnitude, with an increased accuracy of more than 20% at rare variants. We also show that 1x coverage enables effective association studies and is better suited than dense SNP arrays to access the impact of rare variations. Overall, this study demonstrates the promising potential of low-coverage imputation and suggests a paradigm shift in the design of future genomic studies.

Regions of Lower Crossing Over Harbor More Rare Variants in African Populations ofDrosophila melanogaster

Genetics ◽  
2001 ◽  
Vol 158 (2) ◽  
pp. 657-665 ◽  
Author(s):  
Peter Andolfatto ◽  
Molly Przeworski
Keyword(s):  
Frequency Spectrum ◽  
Nucleotide Diversity ◽  
Rare Variants ◽  
Purifying Selection ◽  
Crossing Over ◽  
Background Selection ◽  
Deleterious Mutations ◽  
African Populations ◽  
Rapid Fixation ◽  
Parameter Values

AbstractA correlation between diversity levels and rates of recombination is predicted both by models of positive selection, such as hitchhiking associated with the rapid fixation of advantageous mutations, and by models of purifying selection against strongly deleterious mutations (commonly referred to as “background selection”). With parameter values appropriate for Drosophila populations, only the first class of models predicts a marked skew in the frequency spectrum of linked neutral variants, relative to a neutral model. Here, we consider 29 loci scattered throughout the Drosophila melanogaster genome. We show that, in African populations, a summary of the frequency spectrum of polymorphic mutations is positively correlated with the meiotic rate of crossing over. This pattern is demonstrated to be unlikely under a model of background selection. Models of weakly deleterious selection are not expected to produce both the observed correlation and the extent to which nucleotide diversity is reduced in regions of low (but nonzero) recombination. Thus, of existing models, hitchhiking due to the recurrent fixation of advantageous variants is the most plausible explanation for the data.

scholarly journals De Novo Assembly of the Northern Cardinal (Cardinalis cardinalis) Genome Reveals Candidate Regulatory Regions for Sexually Dichromatic Red Plumage Coloration

2020 ◽  
Vol 10 (10) ◽  
pp. 3541-3548
Author(s):  
Simon Yung Wa Sin ◽  
Lily Lu ◽  
Scott V. Edwards
Keyword(s):  
De Novo ◽  
Draft Genome ◽  
Single Copy ◽  
Genomic Region ◽  
Plumage Coloration ◽  
Sexual Dichromatism ◽  
Effective Population ◽  
Cardinalis Cardinalis ◽  
Northern Cardinal ◽  
Genomic Studies

Northern cardinals (Cardinalis cardinalis) are common, mid-sized passerines widely distributed in North America. As an iconic species with strong sexual dichromatism, it has been the focus of extensive ecological and evolutionary research, yet genomic studies investigating the evolution of genotype–phenotype association of plumage coloration and dichromatism are lacking. Here we present a new, highly-contiguous assembly for C. cardinalis. We generated a 1.1 Gb assembly comprised of 4,762 scaffolds, with a scaffold N50 of 3.6 Mb, a contig N50 of 114.4 kb and a longest scaffold of 19.7 Mb. We identified 93.5% complete and single-copy orthologs from an Aves dataset using BUSCO, demonstrating high completeness of the genome assembly. We annotated the genomic region comprising the CYP2J19 gene, which plays a pivotal role in the red coloration in birds. Comparative analyses demonstrated non-exonic regions unique to the CYP2J19 gene in passerines and a long insertion upstream of the gene in C. cardinalis. Transcription factor binding motifs discovered in the unique insertion region in C. cardinalis suggest potential androgen-regulated mechanisms underlying sexual dichromatism. Pairwise Sequential Markovian Coalescent (PSMC) analysis of the genome reveals fluctuations in historic effective population size between 100,000–250,000 in the last 2 millions years, with declines concordant with the beginning of the Pleistocene epoch and Last Glacial Period. This draft genome of C. cardinalis provides an important resource for future studies of ecological, evolutionary, and functional genomics in cardinals and other birds.

scholarly journals Joint nonparametric coalescent inference of mutation spectrum history and demography

2020 ◽  
Author(s):  
William S. DeWitt ◽  
Kameron Decker Harris ◽  
Kelley Harris
Keyword(s):  
Evolutionary History ◽  
Genomic Variation ◽  
Mutation Spectrum ◽  
Human Populations ◽  
Effective Population ◽  
Joint Inference ◽  
Time Calibration ◽  
Constant Rate ◽  
Genomic Regions ◽  
Mutational Processes

AbstractBooming and busting populations modulate the accumulation of genetic diversity, encoding histories of living populations in present-day variation. Many methods exist to decode these histories, and all must make strong model assumptions. It is typical to assume that mutations accumulate uniformly across the genome at a constant rate that does not vary between closely related populations. However, recent work shows that mutational processes in human and great ape populations vary across genomic regions and evolve over time. This perturbs the mutation spectrum: the relative mutation rates in different local nucleotide contexts. Here, we develop theoretical tools in the framework of Kingman’s coalescent to accommodate mutation spectrum dynamics. We describe mushi: a method to perform fast, nonparametric joint inference of demographic and mutation spectrum histories from allele frequency data. We use mushi to reconstruct trajectories of effective population size and mutation spectrum divergence between human populations, identify mutation signatures and their dynamics in different human populations, and produce more accurate time calibration for a previously-reported mutational pulse in the ancestors of Europeans. We show that mutation spectrum histories can be productively incorporated in a well-studied theoretical setting, and rigorously inferred from genomic variation data like other features of evolutionary history.

scholarly journals Nonparametric coalescent inference of mutation spectrum history and demography

2021 ◽  
Vol 118 (21) ◽  
pp. e2013798118
Author(s):  
William S. DeWitt ◽  
Kameron Decker Harris ◽  
Aaron P. Ragsdale ◽  
Kelley Harris
Keyword(s):  
Evolutionary History ◽  
Genomic Variation ◽  
Mutation Spectrum ◽  
Human Populations ◽  
Effective Population ◽  
Allele Frequency Data ◽  
Constant Rate ◽  
Boom And Bust ◽  
Genomic Regions ◽  
Mutational Processes

As populations boom and bust, the accumulation of genetic diversity is modulated, encoding histories of living populations in present-day variation. Many methods exist to decode these histories, and all must make strong model assumptions. It is typical to assume that mutations accumulate uniformly across the genome at a constant rate that does not vary between closely related populations. However, recent work shows that mutational processes in human and great ape populations vary across genomic regions and evolve over time. This perturbs the mutation spectrum (relative mutation rates in different local nucleotide contexts). Here, we develop theoretical tools in the framework of Kingman’s coalescent to accommodate mutation spectrum dynamics. We present mutation spectrum history inference (mushi), a method to perform nonparametric inference of demographic and mutation spectrum histories from allele frequency data. We use mushi to reconstruct trajectories of effective population size and mutation spectrum divergence between human populations, identify mutation signatures and their dynamics in different human populations, and calibrate the timing of a previously reported mutational pulse in the ancestors of Europeans. We show that mutation spectrum histories can be placed in a well-studied theoretical setting and rigorously inferred from genomic variation data, like other features of evolutionary history.

scholarly journals Relaxed selection during a recent human expansion

2016 ◽  
Author(s):  
S. Peischl ◽  
I. Dupanloup ◽  
A. Foucal ◽  
M. Jomphe ◽  
V. Bruat ◽  
...  
Keyword(s):  
Wave Front ◽  
Rare Variants ◽  
Genetic Diseases ◽  
Low Frequency ◽  
Purifying Selection ◽  
Genomic Diversity ◽  
Human Populations ◽  
Deleterious Mutations ◽  
Relaxed Selection ◽  
French Canadians

AbstractHumans have colonized the planet through a series of range expansions, which deeply impacted genetic diversity in newly settled areas and potentially increased the frequency of deleterious mutations on expanding wave fronts. To test this prediction, we studied the genomic diversity of French Canadians who colonized Quebec in the 17th century. We used historical information and records from ∼4000 ascending genealogies to select individuals whose ancestors lived mostly on the colonizing wave front and individuals whose ancestors remained in the core of the settlement. Comparison of exomic diversity reveals that i) both new and low frequency variants are significantly more deleterious in front than in core individuals, ii) equally deleterious mutations are at higher frequencies in front individuals, and iii) front individuals are two times more likely to be homozygous for rare very deleterious mutations present in Europeans. These differences have emerged in the past 6-9 generations and cannot be explained by differential inbreeding, but are consistent with relaxed selection on the wave front. Modeling the evolution of rare variants allowed us to estimate their associated selection coefficients as well as front and core effective sizes. Even though range expansions had a limited impact on the overall fitness of French Canadians, they could explain the higher prevalence of recessive genetic diseases in recently settled regions. Since we show that modern human populations are experiencing differential strength of purifying selection, similar processes might have happened throughout human history, contributing to a higher mutation load in populations that have undergone spatial expansions.

scholarly journals Establishment and equilibrium levels of deleterious mutations in large populations

2018 ◽  
Author(s):  
Johan W. Viljoen ◽  
J. Pieter de Villiers ◽  
Augustus J. Van Zyl ◽  
Massimo Mezzavilla ◽  
Michael S. Pepper
Keyword(s):  
Cystic Fibrosis ◽  
Social Relationships ◽  
Sickle Cell ◽  
Computer Modelling ◽  
Large Population ◽  
Selective Advantage ◽  
Human Populations ◽  
Deleterious Mutations ◽  
Effective Population ◽  
Community Size

AbstractAnalytical and statistical stochastic approaches are used to model and predict the dispersion of mutations through a large population. These approaches are used to quantify the magnitude of a heterozygous selective advantage of a mutation in the presence of a homozygous disadvantage. Random effects such as genetic drift are accounted for, which are likely to extinguish even highly advantageous mutations while the prevalence is still low. Dunbar’s results regarding the cognitive upper limit of the number of stable social relationships that humans can maintain are used to determine a realistic community size - a reduced local subset of the total population - from which an individual can select mates. This reduction in effective population size has a dramatic effect on the probability of establishing mutations, as well as the eventual equilibrium values that are reached in the case of mutations conferring a heterozygous selective advantage, but a homozygous disadvantage, as in the case of cystic fibrosis and sickle cell disease. The magnitude of this selective advantage can then be estimated based on observed occurrence levels of a specific mutation in a population, without requiring prior information regarding its phenotypic manifestation.Author summaryDeleterious mutations such as cystic fibrosis and sickle cell anemia can disperse through human populations due to the selective advantage that it bestows on heterozygous carriers, depending on environmental conditions. As its prevalence increases, the probability of generating homozygous offspring, with its concomitant selective disadvantage, also grows until an eventual equilibrium is reached between the number of carriers and wild-type individuals. In this work computer modelling is used to combine Dunbar’s anthropological observations predicting upper bounds to the number of stable human social relationships with observed prevalence levels, to estimate the absolute magnitude of the heterozygous selective advantage bestowed by such a deleterious genetic variation, without requiring knowledge regarding the specific mechanism whereby such an advantage is manifested.

scholarly journals De Novo Assembly of the Northern Cardinal (Cardinalis cardinalis) Genome Reveals Candidate Regulatory Regions for Sexually Dichromatic Red Plumage Coloration

2020 ◽  
Author(s):  
Simon Yung Wa Sin ◽  
Lily Lu ◽  
Scott V. Edwards
Keyword(s):  
De Novo ◽  
Draft Genome ◽  
Single Copy ◽  
Genomic Region ◽  
Plumage Coloration ◽  
Sexual Dichromatism ◽  
Effective Population ◽  
Cardinalis Cardinalis ◽  
Northern Cardinal ◽  
Genomic Studies

AbstractNorthern cardinals (Cardinalis cardinalis) are common, mid-sized passerines widely distributed in North America. As an iconic species with strong sexual dichromatism, it has been the focus of extensive ecological and evolutionary research, yet genomic studies investigating the evolution of genotype–phenotype association of plumage coloration and dichromatism are lacking. Here we present a new, highly contiguous assembly for C. cardinalis. We generated a 1.1 Gb assembly comprised of 4,762 scaffolds, with a scaffold N50 of 3.6 Mb, a contig N50 of 114.4 kb and a longest scaffold of 19.7 Mb. We identified 93.5% complete and single-copy orthologs from an Aves dataset using BUSCO, demonstrating high completeness of the genome assembly. We annotated the genomic region comprising the CYP2J19 gene, which plays a pivotal role in the red coloration in birds. Comparative analyses demonstrated non-exonic regions unique to the CYP2J19 gene in passerines and a long insertion upstream of the gene in C. cardinalis. Transcription factor binding motifs discovered in the unique insertion region in C. cardinalis suggest potential androgen-regulated mechanisms underlying sexual dichromatism. Pairwise Sequential Markovian Coalescent (PSMC) analysis of the genome reveals fluctuations in historic effective population size between 100,000–250,000 in the last 2 millions years, with declines concordant with the beginning of the Pleistocene epoch and Last Glacial Period. This draft genome of C. cardinalis provides an important resource for future studies of ecological, evolutionary, and functional genomics in cardinals and other birds.

scholarly journals Recombination impacts damaging and disease mutation accumulation in human populations

2014 ◽  
Author(s):  
Julie Hussin ◽  
Alan Hodgkinson ◽  
Youssef Idaghdour ◽  
Jean-Christophe Grenier ◽  
Jean-Philippe Goulet ◽  
...  
Keyword(s):  
Disease Susceptibility ◽  
Human Populations ◽  
Crossing Over ◽  
Deleterious Mutations ◽  
Sequencing Data ◽  
Cellular Functions ◽  
High Coverage ◽  
1000 Genomes ◽  
Conserved Genes ◽  
Slightly Deleterious Mutations

MMany decades of theory have demonstrated that in non-recombining systems, slightly deleterious mutations accumulate non-reversibly1, potentially driving the extinction of many asexual species. Non-recombining chromosomes in sexual organisms are thought to have degenerated in a similar fashion2, however it is not clear the extent to which these processes operate along recombining chromosomes with highly variable rates of crossing over. Using high coverage sequencing data from over 1400 individuals in The 1000 Genomes and CARTaGENE projects, we show that recombination rate modulates the genomic distribution of putatively deleterious variants across the entire human genome. We find that exons in regions of low recombination are significantly enriched for deleterious and disease variants, a signature that varies in strength across worldwide human populations with different demographic histories. As low recombining regions are enriched for highly conserved genes with essential cellular functions, and show an excess of mutations with demonstrated effect on health, this phenomenon likely affects disease susceptibility in humans.

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