scholarly journals Expansion load: recessive mutations and the role of standing genetic variation

2014 ◽  
Author(s):  
Stephan Peischl ◽  
Laurent Excoffier
Keyword(s):  
Genetic Variation ◽  
Species Range ◽  
Human Populations ◽  
Deleterious Mutations ◽  
Recessive Mutations ◽  
Mutation Burden ◽  
Natural Range ◽  
Mean Fitness ◽  
Expansion Load

Expanding populations incur a mutation burden – the so-called expansion load. Previous studies of expansion load have focused on co-dominant mutations. An important consequence of this assumption is that expansion load stems exclusively from the accumulation of new mutations occurring in individuals living at the wave front. Using individual-based simulations we study here the dynamics of standing genetic variation at the front of expansions, and its consequences on mean fitness if mutations are recessive. We find that deleterious genetic diversity is quickly lost at the front of the expansion, but the loss of deleterious mutations at some loci is compensated by an increase of their frequencies at other loci. The frequency of deleterious homozygotes therefore increases along the expansion axis whereas the average number of deleterious mutations per individual remains nearly constant across the species range. This reveals two important differences to co-dominant models: (i) mean fitness at the front of the expansion drops much faster if mutations are recessive, and (ii) mutation load can increase during the expansion even if the total number of deleterious mutations per individual remains constant. We use our model to make predictions about the shape of the site frequency spectrum at the front of range expansion, and about correlations between heterozygosity and fitness in different parts of the species range. Importantly, these predictions provide opportunities to empirically validate our theoretical results. We discuss our findings in the light of recent results on the distribution of deleterious genetic variation across human populations, and link them to empirical results on the correlation of heterozygosity and fitness found in many natural range expansions.

scholarly journals Expansion load: recessive mutations and the role of standing genetic variation

2015 ◽  
Vol 24 (9) ◽  
pp. 2084-2094 ◽  
Author(s):  
Stephan Peischl ◽  
Laurent Excoffier
Keyword(s):  
Genetic Variation ◽  
Recessive Mutations ◽  
Expansion Load

scholarly journals Genetic sex determination and sex-specific lifespan in tetrapods – evidence of a toxic Y effect

2020 ◽  
Author(s):  
Zahida Sultanova ◽  
Philip A. Downing ◽  
Pau Carazo
Keyword(s):  
Sex Chromosomes ◽  
Alternative Hypothesis ◽  
Z Chromosome ◽  
W Chromosome ◽  
Deleterious Mutations ◽  
Recessive Mutations ◽  
Y Chromosomes ◽  
Heterogametic Sex ◽  
Taxonomic Patterns

ABSTRACTSex-specific lifespans are ubiquitous across the tree of life and exhibit broad taxonomic patterns that remain a puzzle, such as males living longer than females in birds and vice versa in mammals. The prevailing “unguarded-X” hypothesis (UXh) explains this by differential expression of recessive mutations in the X/Z chromosome of the heterogametic sex (e.g., females in birds and males in mammals), but has only received indirect support to date. An alternative hypothesis is that the accumulation of deleterious mutations and repetitive elements on the Y/W chromosome might lower the survival of the heterogametic sex (“toxic Y” hypothesis). Here, we report lower survival of the heterogametic relative to the homogametic sex across 138 species of birds, mammals, reptiles and amphibians, as expected if sex chromosomes shape sex-specific lifespans. We then analysed bird and mammal karyotypes and found that the relative sizes of the X and Z chromosomes are not associated with sex-specific lifespans, contrary to UXh predictions. In contrast, we found that Y size correlates negatively with male survival in mammals, where toxic Y effects are expected to be particularly strong. This suggests that small Y chromosomes benefit male lifespans. Our results confirm the role of sex chromosomes in explaining sex differences in lifespan, but indicate that, at least in mammals, this is better explained by “toxic Y” rather than UXh effects.

scholarly journals Signatures of genetic variation in human microRNAs point to processes of positive selection related to population-specific disease risks

2021 ◽  
Author(s):  
Pablo Villegas Mirón ◽  
Alicia Gallego ◽  
Jaume Bertranpetit ◽  
Hafid Laayouni ◽  
Yolanda Espinosa-Parrilla
Keyword(s):  
Genetic Variation ◽  
Disease Risk ◽  
In Silico Analysis ◽  
Human Populations ◽  
Evolutionary Constraint ◽  
Seed Region ◽  
Specific Disease ◽  
A Minor ◽  
Diversity Profiles

The occurrence of natural variation in human microRNAs has been the focus of numerous studies during the last twenty years. Most of them have been dedicated to study the role of specific mutations in diseases, like cancer, while a minor fraction seek to analyse the diversity profiles of microRNAs in the genomes of human populations. In the present study we analyse the latest human microRNA annotations in the light of the most updated catalog of genetic variation provided by the 1000 Genomes Project. We show by means of the in silico analysis of noncoding variation of microRNAs that the level of evolutionary constraint of these sequences is governed by the interplay of different factors, like their evolutionary age or the genomic location where they emerged. The role of mutations in the shaping of microRNA-driven regulatory interactions is emphasized with the acknowledgement that, while the whole microRNA sequence is highly conserved, the seed region shows a pattern of higher genetic diversity that appears to be caused by the dramatic frequency shifts of a fraction of human microRNAs. We highlight the participation of these microRNAs in population-specific processes by identifying that not only the seed, but also the loop, are particularly differentiated regions among human populations. The quantitative computational comparison of signatures of population differentiation showed that candidate microRNAs with the largest differences are enriched in variants implicated in gene expression levels (eQTLs), selective sweeps and pathological processes. We explore the implication of these evolutionary-driven microRNAs and their SNPs in human diseases, such as different types of cancer, and discuss their role in population-specific disease risk.

scholarly journals Mutation-Selection Balance, Dominance and the Maintenance of Sex

Genetics ◽  
2000 ◽  
Vol 156 (3) ◽  
pp. 1419-1425
Author(s):  
J R Chasnov
Keyword(s):  
Mutation Rate ◽  
Gene Locus ◽  
Necessary Conditions ◽  
Deleterious Mutations ◽  
Sexual Population ◽  
Recessive Mutations ◽  
Maintenance Of Sex ◽  
A Genome ◽  
Evolutionary Function ◽  
Mean Fitness

Abstract A leading hypothesis for the evolutionary function of sex postulates that sex is an adaptation that purges deleterious mutations from the genome, thereby increasing the equilibrium mean fitness of a sexual population relative to its asexual competitor. This hypothesis requires two necessary conditions: first, the mutation rate per genome must be of order one, and, second, multiple mutations within a genome must act with positive epistasis, that is, two or more mutations of different genes must be more harmful together than if they acted independently. Here, by reconsidering the theory of mutation-selection balance at a single diploid gene locus, we demonstrate a significant advantage of sex due to nearly recessive mutations provided the mutation rate per genome is of order one. The assumption of positive epistasis is unnecessary, and multiple mutations may be assumed to act independently.

Effect of Genotype on Micronutrient Absorption and Metabolism: a Review of Iron, Copper, Iodine and Selenium, and Folates

2007 ◽  
Vol 77 (3) ◽  
pp. 205-216 ◽  
Author(s):  
Mithen
Keyword(s):  
Genetic Variation ◽  
Severe Phenotype ◽  
Folic Acid Fortification ◽  
Biochemical Pathways ◽  
Iron Copper ◽  
Natural Range ◽  
Nutritional Effects ◽  
Range Of Variation ◽  
Homeostatic Mechanisms

For the majority of micronutrients, there are very little data, or none at all, on the role of genetic polymorphisms on their absorption and metabolism. In many cases, the elucidation of biochemical pathways and regulators of homeostatic mechanisms have come from studies of individuals that have mutations in certain genes. Other polymorphisms in these genes that result in a less severe phenotype may be important in determining the natural range of variation in absorption and metabolism that is commonly observed. To illustrate some of these aspects, I briefly review the increased understanding of iron metabolism that has arisen from our knowledge of the effects of mutations in several genes, the role of genetic variation in mediating the nutritional effects of iodine and selenium, and finally, the interaction between a genetic polymorphism in folate metabolism and folic acid fortification.

scholarly journals Signatures of Genetic Variation in Human microRNAs Point to Processes of Positive Selection and Population-specific Disease Risks

2021 ◽  
Author(s):  
Pablo Villegas-Mirón ◽  
Alcia Gallego ◽  
Jaume Bertranpetit ◽  
Hafid Laayouni ◽  
Yolanda Espinosa Parrilla
Keyword(s):  
Genetic Variation ◽  
Disease Risk ◽  
Human Populations ◽  
Evolutionary Constraint ◽  
Seed Region ◽  
Single Nucleotide Variants ◽  
Specific Disease ◽  
Genomic Location ◽  
A Minor

Abstract The occurrence of natural variation in human microRNAs has been the focus of numerous studies during the last twenty years. Most of them have been centered on the role of specific mutations in disease, while a minor proportion seek to analyse microRNA diversity in the genomes of human populations. We investigate the latest human microRNA annotations in the light of the most updated catalog of genetic variation provided by the 1000 Genomes Project. By means of the in silico analysis of microRNA variants we show that the level of evolutionary constraint of these sequences is governed by the interplay of different factors, like their evolutionary age or genomic location. The role of mutations in the shaping of microRNA-driven regulatory interactions is emphasized with the acknowledgement that, while the whole microRNA sequence is highly conserved, the seed region shows a pattern of higher genetic diversity that appears to be caused by the dramatic frequency shifts of a fraction of human microRNAs. We highlight the participation of these microRNAs in population-specific processes by identifying that not only the seed, but also the loop, are particularly differentiated regions among human populations. The quantitative computational comparison of signatures of population differentiation showed that candidate microRNAs with the largest differences are enriched in variants related to gene expression levels (eQTLs), selective sweeps and pathological processes. We explore the implication of these evolutionary-driven microRNAs and their single nucleotide variants in human diseases, such as different types of cancer, and discuss their role in population-specific disease risk.

scholarly journals Cassava HapMap: Masking deleterious mutations in a clonal crop species

2016 ◽  
Author(s):  
Punna Ramu ◽  
Williams Esuma ◽  
Robert Kawuki ◽  
Ismail Y Rabbi ◽  
Chiedozie Egesi ◽  
...  
Keyword(s):  
Manihot Esculenta ◽  
Clonal Propagation ◽  
Human Consumption ◽  
Deleterious Mutations ◽  
Common Variants ◽  
Food Crop ◽  
Crop Species ◽  
Recessive Mutations ◽  
Mutational Burden ◽  
Mutation Burden

Cassava (Manihot esculenta Crantz) is an important staple food crop in Africa and South America, however, ubiquitous deleterious mutations may severely reduce its fitness. To evaluate these deleterious mutations in the cassava genome, we constructed a cassava haplotype map using deep sequencing from 241 diverse accessions and identified over 28 million segregating variants. We found that, 1) while domestication modified starch and ketone metabolism pathways for human consumption, the concomitant bottleneck and clonal propagation resulted in a large proportion of fixed deleterious amino acid changes, raised the number of deleterious mutations by 26%, and shifted the mutational burden towards common variants; 2) deleterious mutations are ineffectively purged due to limited recombination in cassava genome; 3) recent breeding efforts maintained the yield by masking the most damaging recessive mutations in the heterozygous state, but unable to purge the mutation burden, which should be a key target for future cassava breeding.

scholarly journals Deleterious Mutation Accumulation and the Long-Term Fate of Chromosomal Inversions

2019 ◽  
Author(s):  
Emma L. Berdan ◽  
Alexandre Blanckaert ◽  
Roger K. Butlin ◽  
Claudia Bank
Keyword(s):  
Selective Advantage ◽  
Inversion Polymorphism ◽  
Adaptive Divergence ◽  
Deleterious Mutations ◽  
Dynamic Features ◽  
Chromosomal Inversions ◽  
Recessive Mutations ◽  
Standard Arrangement

AbstractChromosomal inversions contribute widely to adaptation and speciation, yet they present a unique evolutionary puzzle as both their allelic content and frequency evolve in a feedback loop. In this simulation study, we quantified the role of the allelic content in determining the long-term fate of the inversion. Recessive deleterious mutations accumulated on both arrangements with most of them being private to a given arrangement. This led to increasing overdominance, allowing for the maintenance of the inversion polymorphism and generating strong non-adaptive divergence between arrangements. The accumulation of mutations was mitigated by gene conversion but nevertheless led to the fitness decline of at least one homokaryotype under all considered conditions. Surprisingly, this fitness degradation could be permanently halted by the branching of an arrangement into multiple highly divergent haplotypes. Our results highlight the dynamic features of inversions by showing how the non-adaptive evolution of allelic content can play a major role in the fate of the inversion.Author SummaryA chromosomal inversion is a segment of the chromosome that is flipped (inverted arrangement) relative to the normal orientation (standard arrangement). Such structural mutations may facilitate evolutionary processes such as adaptation and speciation, because reduced recombination in inverted regions allows beneficial combinations of alleles to behave as a “single unit”. This locally reduced recombination can have major consequences for the evolution of the allelic content inside the inversion. We used simulations to investigate some of these consequences. Inverted regions tended to accumulate more deleterious recessive mutations than the rest of the genome, which decreased the fitness of homokarotypes (individuals with two copies of the same arrangement). This led to a strong selective advantage for heterokaryotypes (individuals with one copy of each arrangement), maintaining the inversion polymorphism in the population. The accumulation of deleterious mutations also resulted in strong divergence between arrangements. We occasionally observed an arrangement that diverged into a small number of highly differentiated haplotypes, stopping the fitness decrease in homokaryotypes. Our results highlight the dynamic features of inversions by showing how the evolution of allelic content can greatly affect the fate of an inversion.

Genetic background of cholesterol absorption efficacy. The role of Niemann–Pick C1-like 1 receptor and its genetic variation in lipid metabolism

2010 ◽  
Vol 151 (34) ◽  
pp. 1376-1383 ◽  
Author(s):  
Mariann Harangi ◽  
István Balogh ◽  
János Harangi ◽  
György Paragh
Keyword(s):  
Genetic Variation ◽  
Lipid Metabolism ◽  
Genetic Background ◽  
Cholesterol Absorption ◽  
Niemann Pick

A Niemann–Pick C1-like-1 egy szterolfelismerő domént tartalmazó membránfehérje, amelyet nagy számban expresszálnak csúcsi felszínükön a bélhámsejtek. Az utóbbi évek vizsgálatai azt igazolták, hogy ez a fehérje szükséges a szabad koleszterin bejutásához a bélhámsejtekbe a bél lumenéből. Biokémiai vizsgálatok azt igazolták, hogy a Niemann–Pick C1-like-1-hez kötődik az ezetimib, amely egy hatékony koleszterinfelszívódást gátló szer. A bélből történő koleszterinfelszívódás ütemében és az ezetimibkezelés hatékonyságában tapasztalt egyéni eltérések hátterében felmerült néhány Niemann–Pick C1-like-1 génvariáció oki szerepe.

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