A Pathway-Centered Analysis of Pig Domestication and Breeding in Eurasia

Abstract Ascertaining the molecular and physiological basis of domestication and breeding is an active area of research. Due to the current wide distribution of its wild ancestor, the wild boar, the pig (Sus scrofa) is an excellent model to study these processes, which occurred independently in East Asia and Europe ca. 9000 yr ago. Analyzing genome variability patterns in terms of metabolic pathways is attractive since it considers the impact of interrelated functions of genes, in contrast to genome-wide scans that treat genes or genome windows in isolation. To that end, we studied 40 wild boars and 123 domestic pig genomes from Asia and Europe when metabolic pathway was the unit of analysis. We computed statistical significance for differentiation (Fst) and linkage disequilibrium (nSL) statistics at the pathway level. In terms of Fst, we found 21 and 12 pathways significantly differentiated at a q-value < 0.05 in Asia and Europe, respectively; five were shared across continents. In Asia, we found six significant pathways related to behavior, which involved essential neurotransmitters like dopamine and serotonin. Several significant pathways were interrelated and shared a variable percentage of genes. There were 12 genes present in >10 significant pathways (in terms of Fst), comprising genes involved in the transduction of a large number of signals, like phospholipase PCLB1, which is expressed in the brain, or ITPR3, which has an important role in taste transduction. In terms of nSL, significant pathways were mainly related to reproductive performance (ovarian steroidogenesis), a similarly important target trait during domestication and modern animal breeding. Different levels of recombination cannot explain these results, since we found no correlation between Fst and recombination rate. However, we did find an increased ratio of deleterious mutations in domestic vs. wild populations, suggesting a relaxed functional constraint associated with the domestication and breeding processes. Purifying selection was, nevertheless, stronger in significantly differentiated pathways than in random pathways, mainly in Europe. We conclude that pathway analysis facilitates the biological interpretation of genome-wide studies. Notably, in the case of pig, behavior played an important role, among other physiological and developmental processes.

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Developmental cannabidiol exposure increases anxiety and modifies genome-wide brain DNA methylation in adult female mice

Clinical Epigenetics ◽

10.1186/s13148-020-00993-4 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Nicole M. Wanner ◽

Mathia Colwell ◽

Chelsea Drown ◽

Christopher Faulk

Keyword(s):

Dna Methylation ◽

Molecular Mechanisms ◽

Coat Color ◽

Brain Regions ◽

Functional Enrichment ◽

Positive Effects ◽

Genome Wide ◽

Nulliparous Female ◽

The Impact ◽

The Brain

Abstract Background Use of cannabidiol (CBD), the primary non-psychoactive compound found in cannabis, has recently risen dramatically, while relatively little is known about the underlying molecular mechanisms of its effects. Previous work indicates that direct CBD exposure strongly impacts the brain, with anxiolytic, antidepressant, antipsychotic, and other effects being observed in animal and human studies. The epigenome, particularly DNA methylation, is responsive to environmental input and can direct persistent patterns of gene regulation impacting phenotype. Epigenetic perturbation is particularly impactful during embryogenesis, when exogenous exposures can disrupt critical resetting of epigenetic marks and impart phenotypic effects lasting into adulthood. The impact of prenatal CBD exposure has not been evaluated; however, studies using the psychomimetic cannabinoid Δ9-tetrahydrocannabinol (THC) have identified detrimental effects on psychological outcomes in developmentally exposed adult offspring. We hypothesized that developmental CBD exposure would have similar negative effects on behavior mediated in part by the epigenome. Nulliparous female wild-type Agouti viable yellow (Avy) mice were exposed to 20 mg/kg CBD or vehicle daily from two weeks prior to mating through gestation and lactation. Coat color shifts, a readout of DNA methylation at the Agouti locus in this strain, were measured in F1 Avy/a offspring. Young adult F1 a/a offspring were then subjected to tests of working spatial memory and anxiety/compulsive behavior. Reduced-representation bisulfite sequencing was performed on both F0 and F1 cerebral cortex and F1 hippocampus to identify genome-wide changes in DNA methylation for direct and developmental exposure, respectively. Results F1 offspring exposed to CBD during development exhibited increased anxiety and improved memory behavior in a sex-specific manner. Further, while no significant coat color shift was observed in Avy/a offspring, thousands of differentially methylated loci (DMLs) were identified in both brain regions with functional enrichment for neurogenesis, substance use phenotypes, and other psychologically relevant terms. Conclusions These findings demonstrate for the first time that despite positive effects of direct exposure, developmental CBD is associated with mixed behavioral outcomes and perturbation of the brain epigenome.

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Epigenetic mechanisms in sexual differentiation of the brain and behaviour

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2015.0114 ◽

2016 ◽

Vol 371 (1688) ◽

pp. 20150114 ◽

Cited By ~ 34

Author(s):

Nancy G. Forger

Keyword(s):

Gene Expression ◽

Sex Differences ◽

Sexual Differentiation ◽

Wide Distribution ◽

Epigenetic Modifications ◽

Epigenetic Mechanism ◽

Epigenetic Mechanisms ◽

Genome Wide ◽

The Brain

Circumstantial evidence alone argues that the establishment and maintenance of sex differences in the brain depend on epigenetic modifications of chromatin structure. More direct evidence has recently been obtained from two types of studies: those manipulating a particular epigenetic mechanism, and those examining the genome-wide distribution of specific epigenetic marks. The manipulation of histone acetylation or DNA methylation disrupts the development of several neural sex differences in rodents. Taken together, however, the evidence suggests there is unlikely to be a simple formula for masculine or feminine development of the brain and behaviour; instead, underlying epigenetic mechanisms may vary by brain region or even by dependent variable within a region. Whole-genome studies related to sex differences in the brain have only very recently been reported, but suggest that males and females may use different combinations of epigenetic modifications to control gene expression, even in cases where gene expression does not differ between the sexes. Finally, recent findings are discussed that are likely to direct future studies on the role of epigenetic mechanisms in sexual differentiation of the brain and behaviour.

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Contribution of retrotransposition to developmental disorders

Nature Communications ◽

10.1038/s41467-019-12520-y ◽

2019 ◽

Vol 10 (1) ◽

Cited By ~ 10

Author(s):

Eugene J. Gardner ◽

Elena Prigmore ◽

Giuseppe Gallone ◽

Petr Danecek ◽

Kaitlin E. Samocha ◽

...

Keyword(s):

Developmental Disorders ◽

De Novo ◽

Purifying Selection ◽

Selective Constraint ◽

Protein Coding ◽

Genome Wide ◽

De Novo Gene ◽

The Impact ◽

Transcribed Sequences

Abstract Mobile genetic Elements (MEs) are segments of DNA which can copy themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. Here we identify RT-derived events in 9738 exome sequenced trios with DD-affected probands. We ascertain 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04%), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we estimate genome-wide germline ME mutation rate and selective constraint and demonstrate that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

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Demography and mating system shape the genome-wide impact of purifying selection in Arabis alpina

10.1101/127209 ◽

2017 ◽

Cited By ~ 2

Author(s):

Benjamin Laenen ◽

Andrew Tedder ◽

Michael D. Nowak ◽

Per Toräng ◽

Jörg Wunder ◽

...

Keyword(s):

Genetic Diversity ◽

Mating System ◽

Purifying Selection ◽

Mixed Mating ◽

Genome Wide ◽

Outcrossing Rates ◽

Arabis Alpina ◽

Whole Genome Resequencing ◽

Evolutionary Consequences ◽

The Impact

Plant mating systems have profound effects on levels and structuring of genetic variation, and can affect the impact of natural selection. While theory predicts that intermediate outcrossing rates may allow plants to prevent accumulation of deleterious alleles, few studies have empirically tested this prediction using genomic data. Here, we study the effect of mating system on purifying selection by conducting population genomic analyses on whole-genome resequencing data from 38 European individuals of the arctic-alpine crucifer Arabis alpina. We find that outcrossing and mixed-mating populations maintain genetic diversity at similar levels, whereas highly self-fertilizing Scandinavian A. alpina show a strong reduction in genetic diversity, most likely as a result of a postglacial colonization bottleneck. We further find evidence for accumulation of genetic load in highly self-fertilizing populations, whereas the genome-wide impact of purifying selection does not differ greatly between mixed-mating and outcrossing populations. Our results demonstrate that intermediate levels of outcrossing may allow efficient selection against harmful alleles whereas demographic effects can be important for relaxed purifying selection in highly selfing populations. Thus, both mating system and demography shape the impact of purifying selection on genomic variation in A. alpina. These results are important for an improved understanding of the evolutionary consequences of mating system variation and the maintenance of mixed-mating strategies.SignificanceIntermediate outcrossing rates are theoretically predicted to maintain effective selection against harmful alleles, but few studies have empirically tested this prediction using genomic data. We used whole-genome resequencing data from alpine rock-cress to study how genetic variation and purifying selection vary with mating system. We find that populations with intermediate outcrossing rates have similar levels of genetic diversity as outcrossing populations, and that purifying selection against harmful alleles is efficient in mixed-mating populations. In contrast, self-fertilizing populations from Scandinavia have strongly reduced genetic diversity, and accumulate harmful mutations, likely as a result of demographic effects of postglacial colonization. Our results suggest that mixed-mating populations can avoid the negative evolutionary consequences of high self-fertilization rates.

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Genetic Diversity in Yeast Assessed With Whole-Genome Oligonucleotide Arrays

Genetics ◽

10.1093/genetics/163.1.79 ◽

2003 ◽

Vol 163 (1) ◽

pp. 79-89 ◽

Cited By ~ 3

Author(s):

Elizabeth A Winzeler ◽

Cristian I Castillo-Davis ◽

Guy Oshiro ◽

David Liang ◽

Daniel R Richards ◽

...

Keyword(s):

Wide Distribution ◽

Oligonucleotide Arrays ◽

Gene Deletions ◽

Genome Variability ◽

Yeast Strains ◽

Genome Wide ◽

Single Feature ◽

Central Regions ◽

Intraspecies Variability ◽

Common Laboratory

Abstract The availability of a complete genome sequence allows the detailed study of intraspecies variability. Here we use high-density oligonucleotide arrays to discover 11,115 single-feature polymorphisms (SFPs) existing in one or more of 14 different yeast strains. We use these SFPs to define regions of genetic identity between common laboratory strains of yeast. We assess the genome-wide distribution of genetic variation on the basis of this yeast population. We find that genome variability is biased toward the ends of chromosomes and is more likely to be found in genes with roles in fermentation or in transport. This subtelomeric bias may arise through recombination between nonhomologous sequences because full-gene deletions are more common in these regions than in more central regions of the chromosome.

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Mutation distribution density in tumors reconstructs human’s lost diversity

10.1101/773317 ◽

2019 ◽

Author(s):

José María Heredia-Genestar ◽

Tomàs Marquès-Bonet ◽

David Juan ◽

Arcadi Navarro

Keyword(s):

Somatic Mutations ◽

Distribution Density ◽

Population Data ◽

Wide Distribution ◽

Great Ape ◽

Mutation Density ◽

Genome Wide ◽

Human Mutation ◽

Mutation Distribution ◽

The Impact

Introductory ParagraphMutations do not accumulate uniformly across the genome. Human germline and tumor mutation density correlate poorly, and each is associated with different genomic features. Here, we analyze the genome-wide distribution of mutation densities in human and non-human Great Ape (NHGA) germlines as well as human tumors. Strikingly, non-human Great Ape germlines present higher correlation with tumors than the human germline does. This situation is mediated by a different distribution in the human germline of mutations at non-CpG sites, but not of CpG>T transitions. We propose that the impact of ancestral and historical human demographic events on human mutation density leads to this specific disruption in its expected genome-wide distribution. Tumors partially recover this distribution by the accumulation of pre-neoplastic-like somatic mutations. Our results highlight the potential utility of using Great Ape population data, rather than human controls, to establish the expected mutational background of healthy somatic cells.

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Demography and mating system shape the genome-wide impact of purifying selection in Arabis alpina

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1707492115 ◽

2018 ◽

Vol 115 (4) ◽

pp. 816-821 ◽

Cited By ~ 23

Author(s):

Benjamin Laenen ◽

Andrew Tedder ◽

Michael D. Nowak ◽

Per Toräng ◽

Jörg Wunder ◽

...

Keyword(s):

Genetic Diversity ◽

Mating System ◽

Purifying Selection ◽

Mating Strategies ◽

Genomic Variation ◽

The Arctic ◽

Mixed Mating ◽

Genome Wide ◽

Arabis Alpina ◽

The Impact

Plant mating systems have profound effects on levels and structuring of genetic variation and can affect the impact of natural selection. Although theory predicts that intermediate outcrossing rates may allow plants to prevent accumulation of deleterious alleles, few studies have empirically tested this prediction using genomic data. Here, we study the effect of mating system on purifying selection by conducting population-genomic analyses on whole-genome resequencing data from 38 European individuals of the arctic-alpine crucifer Arabis alpina. We find that outcrossing and mixed-mating populations maintain genetic diversity at similar levels, whereas highly self-fertilizing Scandinavian A. alpina show a strong reduction in genetic diversity, most likely as a result of a postglacial colonization bottleneck. We further find evidence for accumulation of genetic load in highly self-fertilizing populations, whereas the genome-wide impact of purifying selection does not differ greatly between mixed-mating and outcrossing populations. Our results demonstrate that intermediate levels of outcrossing may allow efficient selection against harmful alleles, whereas demographic effects can be important for relaxed purifying selection in highly selfing populations. Thus, mating system and demography shape the impact of purifying selection on genomic variation in A. alpina. These results are important for an improved understanding of the evolutionary consequences of mating system variation and the maintenance of mixed-mating strategies.

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Contribution of Retrotransposition to Developmental Disorders

10.1101/471375 ◽

2018 ◽

Cited By ~ 2

Author(s):

Eugene J. Gardner ◽

Elena Prigmore ◽

Giuseppe Gallone ◽

Petr Danecek ◽

Kaitlin E. Samocha ◽

...

Keyword(s):

Developmental Disorders ◽

De Novo ◽

Purifying Selection ◽

Mobile Genetic Elements ◽

Protein Coding ◽

Protein Coding Genes ◽

Genome Wide ◽

The Impact ◽

Transcribed Sequences

AbstractMobile genetic Elements (MEs) are segments of DNA which, through an RNA intermediate, can generate new copies of themselves and other transcribed sequences through the process of retrotransposition (RT). In humans several disorders have been attributed to RT, but the role of RT in severe developmental disorders (DD) has not yet been explored. As such, we have identified RT-derived events in 9,738 exome sequenced trios with DD-affected probands as part of the Deciphering Developmental Disorders (DDD) study. We have ascertained 9 de novo MEs, 4 of which are likely causative of the patient’s symptoms (0.04% of probands), as well as 2 de novo gene retroduplications. Beyond identifying likely diagnostic RT events, we have estimated genome-wide germline ME mutagenesis and constraint and demonstrated that coding RT events have signatures of purifying selection equivalent to those of truncating mutations. Overall, our analysis represents a comprehensive interrogation of the impact of retrotransposition on protein coding genes and a framework for future evolutionary and disease studies.

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Estimating the Selective Effect of Heterozygous Protein Truncating Variants from Human Exome Data

10.1101/075523 ◽

2016 ◽

Cited By ~ 1

Author(s):

Christopher A. Cassa ◽

Donate Weghorn ◽

Daniel J. Balick ◽

Daniel M. Jordan ◽

David Nusinow ◽

...

Keyword(s):

Age Of Onset ◽

Sequence Data ◽

Human Tumor ◽

Purifying Selection ◽

Wide Distribution ◽

Disease Genes ◽

Mendelian Disease ◽

Large Set ◽

Critical Function ◽

Genome Wide

The dispensability of individual genes for viability has interested generations of geneticists. For some genes it is essential to maintain two functional chromosomal copies, while other genes may tolerate the loss of one or both copies. Exome sequence data from 60,706 individuals provide sufficient observations of rare protein truncating variants (PTVs) to make genome-wide estimates of selection against heterozygous loss of gene function. The cumulative frequency of rare deleterious PTVs is primarily determined by the balance between incoming mutations and purifying selection rather than genetic drift. This enables the estimation of the genome-wide distribution of selection coefficients for heterozygous PTVs and corresponding Bayesian estimates for individual genes. The strength of selection can help discriminate the severity, age of onset, and mode of inheritance in Mendelian exome sequencing cases. We find that genes under the strongest selection are enriched in embryonic lethal mouse knockouts, putatively cell-essential genes inferred from human tumor cells, Mendelian disease genes, and regulators of transcription. Using an essentiality screen, we find a large set of genes under strong selection that are likely to have critical function but that have not yet been studied extensively.

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The impact of genetic modifiers on variation in germline mutation rates within and among human populations

10.1101/2021.08.25.457718 ◽

2021 ◽

Author(s):

William R. Milligan ◽

Guy Amster ◽

Guy Sella

Keyword(s):

Genetic Modifier ◽

Purifying Selection ◽

Mutation Rates ◽

Ancestral Population ◽

Human Populations ◽

Demographic Model ◽

Genetic Modifiers ◽

Genome Wide ◽

Demographic Processes ◽

The Impact

AbstractMutation rates and spectra differ among human populations. Here, we examine whether this variation could be explained by evolution at mutation modifiers. To this end, we consider genetic modifier sites at which mutations, “mutator alleles”, increase genome-wide mutation rates and model their evolution under purifying selection due to the additional deleterious mutations that they cause, genetic drift, and demographic processes. We solve the model analytically for a constant population size and characterize how evolution at modifier sites impacts variation in mutation rates within and among populations. We then use simulations to study the effects of modifier sites under a plausible demographic model for Africans and Europeans. When comparing populations that evolve independently, weakly selected modifier sites (2Nes ≈ 1), which evolve slowly, contribute the most to variation in mutation rates. In contrast, when populations recently split from a common ancestral population, strongly selected modifier sites (2Nes ≫ 1), which evolve rapidly, contribute the most to variation between them. Moreover, a modest number of modifier sites (e.g., 10 per mutation type in the standard classification into 96 types) subject to moderate to strong selection (2Nes > 1) could account for the variation in mutation rates observed among human populations. If such modifier sites indeed underlie differences among populations, they should also cause variation in mutation rates within populations and their effects should be detectable in pedigree studies.

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