scholarly journals Extreme distribution of deleterious variation in a historically small and isolated population - insights from the Greenlandic Inuit

2016 ◽  
Author(s):  
Casper-Emil T. Pedersen ◽  
Kirk E. Lohmueller ◽  
Niels Grarup ◽  
Peter Bjerregaard ◽  
Torben Hansen ◽  
...  
Keyword(s):  
Genetic Model ◽  
Genetic Load ◽  
Recessive Model ◽  
Deleterious Alleles ◽  
African Populations ◽  
Large Populations ◽  
Population Sizes ◽  
Extreme Distribution ◽  
Inuit Population ◽  
Recent Bottleneck

AbstractThe genetic consequences of a severe bottleneck on genetic load in humans are widely disputed. Based on exome sequencing of 18 Greenlandic Inuit we show that the Inuit have undergone a severe ~20,000 yearlong bottleneck. This has led to a markedly more extreme distribution of deleterious alleles than seen for any other human population. Compared to populations with much larger population sizes, we see an overall reduction in the number of variable sites, increased numbers of fixed sites, a lower heterozygosity, and increased mean allele frequency as well as more homozygous deleterious genotypes. This means, that the Inuit population is the perfect population to examine the effect of a bottleneck on genetic load. Compared to the European, Asian and African populations, we do not observe a difference in the overall number of derived alleles. In contrast, using proxies for genetic load we find that selection has acted less efficiently in the Inuit, under a recessive model. This fits with our simulations that predict a similar number of derived alleles but a true higher genetic load for the Inuit regardless of the genetic model. Finally, we find that the Inuit population has a great potential for mapping of disease-causing variants that are rare in large populations. In fact, we show that these alleles are more likely to be common, and thus easy to map, in the Inuit than in the Finnish and Latino populations; populations considered highly valuable for mapping studies due to recent bottleneck events.

scholarly journals Functional architecture of deleterious genetic variants in the Wrangel Island mammoth genome

2017 ◽  
Author(s):  
Erin Fry ◽  
Sun K. Kim ◽  
Sravanthi Chigurapti ◽  
Katelyn M. Mika ◽  
Aakrosh Ratan ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Small Population ◽  
Developmental Defects ◽  
Wrangel Island ◽  
Relict Populations ◽  
Deleterious Alleles ◽  
Large Populations ◽  
Population Sizes ◽  
Functional Consequences

Woolly mammoths were among the most abundant cold adapted species during the Pleistocene. Their once large populations went extinct in two waves, an end-Pleistocene extinction of continental populations followed by the mid-Holocene extinction of relict populations on St. Paul Island ~5,600 years ago and Wrangel Island ~4,000 years ago. Wrangel Island mammoths experienced an episode of rapid demographic decline coincident with their isolation, leading to a small population, reduced genetic diversity, and the fixation of putatively deleterious alleles, but the functional consequences of these processes are unclear. Here we show that the Wrangel Island mammoth accumulated many putative deleterious mutations that are predicted to cause diverse behavioral and developmental defects. Resurrection and functional characterization of Wrangel Island mammoth genes carrying these substitutions identified both loss and gain of function mutations in genes associated with developmental defects (HYLS1), oligozoospermia and reduced male fertility (NKD1), diabetes (NEUROG3), and the ability to detect floral scents (OR5A1). These results suggest that Wrangel Island mammoths may have suffered adverse consequences from their reduced population sizes and isolation.

The Influence of Val66Met Polymorphism in Brain-Derived Neurotrophic Factor on Stroke Recovery Outcome: A Systematic Review and Meta-analysis

2021 ◽  
pp. 154596832110141
Author(s):  
Xuan Liu ◽  
Jun-Chao Fang ◽  
Xin-Yue Zhi ◽  
Qiu-Yu Yan ◽  
Hong Zhu ◽  
...  
Keyword(s):  
Neurotrophic Factor ◽  
Genetic Model ◽  
Meta Analysis ◽  
Brain Derived Neurotrophic Factor ◽  
Recessive Model ◽  
Stroke Recovery ◽  
Stroke Severity ◽  
Val66met Polymorphism ◽  
Asian Patients ◽  
Caucasian Patients

Background and purpose. A single nucleotide polymorphism at nucleotide 196 (G/A) in the human brain-derived neurotrophic factor ( BDNF) gene produces an amino acid substitution (valine to methionine) at codon 66(Val66Met). It is unclear whether carriers of this substitution may have worse functional outcomes after stroke. We aimed to explore the distribution of Val66Met polymorphism and evaluate the effect of different genotypes on stroke functional recovery. Methods. Several databases were searched using the keywords BDNF or brain-derived neurotrophic factor, codon66, G196A, rs6265, or Val66Met, and stroke. Results. A total of 25 articles were relevant to estimate the distribution of alleles; 5 reports were applied in the meta-analysis to assess genetic differences on recovery outcomes. The genetic model analysis showed that the recessive model should be used; we combined data for AA versus GA+GG (GG—Val/Val, GA—Val/Met, AA—Met/Met). The results showed that stroke patients with AA might have worse recovery outcomes than those with GA+GG (odds ratio = 1.90; 95% CI: 1.17-3.10; P = .010; I2 = 69.2%). Overall, the A allele may be more common in Asian patients (48.6%; 95% CI: 45.8%-51.4%, I2 = 54.2%) than Caucasian patients (29.8%; 95% CI: 7.5%-52.1%; I2 = 99.1%). However, in Caucasian patients, the frequency of the A allele in Iranians (87.9%; 95% CI: 83.4%-92.3%) was quite higher than that in other Caucasians (18.7%; 95% CI: 16.6%-20.9%; I2 = 0.00%). Conclusion. Val66Met AA carriers may have worse rehabilitation outcomes than GA+GG carriers. Further studies are needed to determine the effect of Val66Met polymorphism on stroke recovery and to evaluate this relationship with ethnicity, sex, age, stroke type, observe duration, stroke severity, injury location, and therapies.

Genetic load and biological changes to extant humans

2020 ◽  
pp. 1-4
Author(s):  
Arthur Saniotis ◽  
Maciej Henneberg ◽  
Kazhaleh Mohammadi
Keyword(s):  
Natural Selection ◽  
Current Knowledge ◽  
Genetic Load ◽  
Differential Fertility ◽  
Medical Interventions ◽  
Deleterious Alleles ◽  
Gradual Process ◽  
Genetic Complexity ◽  
Sexual Recombination ◽  
Improved Sanitation

Abstract Extant humans are currently increasing their genetic load, which is informing present and future human microevolution. This has been a gradual process that has been rising over the last centuries as a consequence of improved sanitation, nutritional improvements, advancements in microbiology and medical interventions, which have relaxed natural selection. Moreover, a reduction in infant and child mortality and changing societal attitudes towards fertility have led to a decrease in total fertility rates (TFRs) since the 19th century. Generally speaking, decreases in differential fertility and mortality have meant that there is less opportunity for natural selection to eliminate deleterious mutations from the human gene pool. It has been argued that the average human may carry ~250–300 mutations that are mostly deleterious, as well as several hundred less-deleterious variants. These deleterious alleles in extant humans mean that our fitness is being constrained. While such alleles are viewed as reducing human fitness, they may also have had an adaptive function in the past, such as assisting in genetic complexity, sexual recombination and diploidy. Saying this, our current knowledge on these fitness compromising alleles is still lacking.

scholarly journals Inbreeding depression due to mildly deleterious mutations in finite populations: size does matter

2000 ◽  
Vol 75 (1) ◽  
pp. 75-81 ◽  
Author(s):  
THOMAS BATAILLON ◽  
MARK KIRKPATRICK
Keyword(s):  
Population Size ◽  
Inbreeding Depression ◽  
Deleterious Mutation ◽  
Large Population ◽  
Genetic Load ◽  
Breeding Systems ◽  
Deleterious Mutations ◽  
Single Locus Analysis ◽  
Population Sizes ◽  
Inbreeding Rate

We studied the effects of population size on the inbreeding depression and genetic load caused by deleterious mutations at a single locus. Analysis shows how the inbreeding depression decreases as population size becomes smaller and/or the rate of inbreeding increases. This pattern contrasts with that for the load, which increases as population size becomes smaller but decreases as inbreeding rate goes up. The depression and load both approach asymptotic limits when the population size becomes very large or very small. Numerical results show that the transition between the small and the large population regimes is quite rapid, and occurs largely over a range of population sizes that vary by a factor of 10. The effects of drift on inbreeding depression may bias some estimates of the genomic rate of deleterious mutation. These effects could also be important in the evolution of breeding systems in hermaphroditic organisms and in the conservation of endangered populations.

scholarly journals Methylene tetrahydrofolate reductase (MTHFR) gene rs1801133 C>T polymorphisms and response to 5-FU based chemotherapy in patients with colorectal cancer: a meta-analysis

Pteridines ◽  
2019 ◽  
Vol 30 (1) ◽  
pp. 126-132
Author(s):  
Huafeng Jiang ◽  
Yi Shen
Keyword(s):  
Colorectal Cancer ◽  
Statistical Difference ◽  
Genetic Model ◽  
Meta Analysis ◽  
Recessive Model ◽  
Funnel Plot ◽  
Methylene Tetrahydrofolate Reductase ◽  
Dominant Genetic Model ◽  
Regression Test ◽  
Methylene Tetrahydrofolate

Abstract Background: Methylene tetrahydrofolate reductase (MTHFR) catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Single nucleotide polymorphisms (SNP) of MTHF rs1801133 C>T can influence susceptibility to colorectal cancer. However, an association between MTHFR rs1801133 C>T polymorphisms and response to 5-Fluorouracil (5-FU) based chemotherapy in patients with colorectal cancer was not clear. Methods: Studies relevant to MTHFR rs1801133 C>T polymorphisms and response to 5-FU based chemotherapy in patients with colorectal cancer were systematic searched in the electronic databases of PubMed, Web of Science, Embase, and China National Knowledge Infrastructure (CNKI). The genotypes of CC, CT, and TT were extracted from each included publication. The genotypes CC, CT, and TT distribution in 5-FU based chemotherapy response and resistance groups were calculated and pooled through random or fixed effect model by the effect size of odds ratio (OR) and 95% confidence interval (95% CI). The publication bias was evaluated through Begg’s funnel plot and Egger’s line regression test. Results: After searching the electronic databases, 16 studies related to MTHFR gene rs1801133 C>T polymorphisms and a response to 5-FU based chemotherapy in patients with colorectal cancer were included in the present meta-analysis. The pooled data showed no statistical difference in tumor response rate between CT+TT and CC groups in the dominant genetic model CT+CC vs CC (OR=1.21, 95% CI: 0.93~1.59, p>0.05) and recessive model TT vs CT+CC (OR=1.37, 95% CI: 0.91~2.06, p>0.05). The grade 3-4 adverse reaction rate between CT+TT and CC groups also had no statistical difference in the dominant genetic model CT+CC vs CC (OR=0.90, 95% CI: 0.76~1.07, p>0.05) and recessive model TT vs CT+CC (OR=1.12, 95% CI: 0.84~1.50, p>0.05). The Begg’s funnel plot and Egger’s line regression test demonstrated no publication bias. Conclusion: The response and adverse reaction of 5-FU based chemotherapy in colorectal patients were not different in terms of MTHFR rs1801133 C>T polymorphisms.

scholarly journals Repeatability of adaptation in experimental populations of different sizes

2015 ◽  
Vol 282 (1805) ◽  
pp. 20143033 ◽  
Author(s):  
Josianne Lachapelle ◽  
Joshua Reid ◽  
Nick Colegrave
Keyword(s):  
Population Size ◽  
Large Contribution ◽  
Unicellular Alga ◽  
Effective Population ◽  
Fitness Level ◽  
Relative Contribution ◽  
Large Populations ◽  
Population Sizes ◽  
Evolutionary Trajectories ◽  
Experimental Populations

The degree to which evolutionary trajectories and outcomes are repeatable across independent populations depends on the relative contribution of selection, chance and history. Population size has been shown theoretically and empirically to affect the amount of variation that arises among independent populations adapting to the same environment. Here, we measure the contribution of selection, chance and history in different-sized experimental populations of the unicellular alga Chlamydomonas reinhardtii adapting to a high salt environment to determine which component of evolution is affected by population size. We find that adaptation to salt is repeatable at the fitness level in medium ( N e = 5 × 10 4 ) and large ( N e = 4 × 10 5 ) populations because of the large contribution of selection. Adaptation is not repeatable in small ( N e = 5 × 10 3 ) populations because of large constraints from history. The threshold between stochastic and deterministic evolution in this case is therefore between effective population sizes of 10 3 and 10 4 . Our results indicate that diversity across populations is more likely to be maintained if they are small. Experimental outcomes in large populations are likely to be robust and can inform our predictions about outcomes in similar situations.

scholarly journals Evolution of Drift Robustness in Small Populations

2016 ◽  
Author(s):  
Thomas LaBar ◽  
Christoph Adami
Keyword(s):  
Mathematical Modeling ◽  
Experimental Evolution ◽  
Small Population ◽  
Small Populations ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
Mutational Robustness ◽  
Large Populations ◽  
Slightly Deleterious Mutations ◽  
Population Sizes

AbstractMost mutations are deleterious and cause a reduction in population fitness known as the mutational load. In small populations, weakened selection against slightly-deleterious mutations results in an additional fitness reduction. Many studies have established that populations can evolve a reduced mutational load by evolving mutational robustness, but it is uncertain whether small populations can evolve a reduced susceptibility to drift-related fitness declines. Here, using mathematical modeling and digital experimental evolution, we show that small populations do evolve a reduced vulnerability to drift, or “drift robustness”. We find that, compared to genotypes from large populations, genotypes from small populations have a decreased likelihood of small-effect deleterious mutations, thus causing small-population genotypes to be drift-robust. We further show that drift robustness is not adaptive, but instead arises because small populations preferentially adapt to drift-robust fitness peaks. These results have implications for genome evolution in organisms with small population sizes.

scholarly journals Sex differences in deleterious genetic variants in a haplodiploid social insect

2021 ◽  
Author(s):  
Sara E. Miller ◽  
Michael J. Sheehan
Keyword(s):  
Genetic Load ◽  
Low Frequency ◽  
Paper Wasp ◽  
Deleterious Mutations ◽  
Wild Populations ◽  
Nonsense Mutations ◽  
Low Frequencies ◽  
Complete Dominance ◽  
Deleterious Alleles ◽  
Population Allele Frequency

AbstractDeleterious variants are selected against but can linger in populations at low frequencies for long periods of time, decreasing fitness and contributing to disease burden in humans and other species. Deleterious variants occur at low frequency but distinguishing deleterious variants from low frequency neutral variation is challenging based on population genetics data. As a result, we have little sense of the number and identity of deleterious variants in wild populations. For haplodiploid species, it has been hypothesized that deleterious alleles will be directly exposed to selection in haploid males, but selection can be masked in diploid females due to partial or complete dominance, resulting in more efficient purging of deleterious mutations in males. Therefore, comparisons of the differences between haploid and diploid genomes from the same population may be a useful method for inferring rare deleterious variants. This study provides the first formal test of this hypothesis. Using wild populations of Northern paper wasps (Polistes fuscatus), we find that males have fewer overall variants, and specifically fewer missense and nonsense variants, than females from the same population. Allele frequency differences are especially pronounced for rare missense and nonsense mutations and these differences lead to a lower genetic load in males than females. Based on these data we estimate that a large number of highly deleterious mutations are segregating in the paper wasp population. Stronger selection against deleterious alleles in haploid males may have implications for adaptation in other haplodiploid insects and provides evidence that wild populations harbor abundant deleterious variants.

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