scholarly journals Current relaxation of selection on the human genome: Tolerance of deleterious mutations on olfactory receptors

2013 ◽  
Vol 66 (2) ◽  
pp. 558-564 ◽  
Author(s):  
Denis Pierron ◽  
Nicolás Gutiérrez Cortés ◽  
Thierry Letellier ◽  
Lawrence I. Grossman
Keyword(s):  
Human Genome ◽  
Olfactory Receptors ◽  
Deleterious Mutations ◽  
Current Relaxation

Genetics and genetic instability in cancer

2019 ◽  
pp. 43-55
Author(s):  
Mark A. Glaire ◽  
David N. Church
Keyword(s):  
Dna Replication ◽  
Human Genome ◽  
Genomic Instability ◽  
Genetic Instability ◽  
Important Determinant ◽  
Human Cancer ◽  
Deleterious Mutations ◽  
Cellular Processes ◽  
Repair Mechanisms ◽  
Genomic Damage

"The Integrity"of the human genome is under continual threat from endogenous and exogenous mutagens, and as a result of errors introduced during DNA replication. As the lesions generated by these processes, if left uncorrected, may lead to deleterious mutations, cells employ several sophisticated mechanisms to both prevent and repair such genomic damage. Failure of these repair mechanisms, leading to genomic instability, is common in cancer, and has even been suggested to be a universal characteristic of malignancy. This chapter outlines these cellular processes and reviews the both the mechanisms and consequences of their dysregulation in human cancer. It also highlights the emerging evidence suggesting that genomic instability is an important determinant of tumour behaviour. Finally, it discusses the possibility that targeting genomic instability may benefit patients with genomically unstable tumours in the clinic.

scholarly journals Evidence for Hitchhiking of Deleterious Mutations within the Human Genome

PLoS Genetics ◽  
2011 ◽  
Vol 7 (8) ◽  
pp. e1002240 ◽  
Author(s):  
Sung Chun ◽  
Justin C. Fay
Keyword(s):  
Human Genome ◽  
Deleterious Mutations

scholarly journals An Upper Limit on the Functional Fraction of the Human Genome

2017 ◽  
Vol 9 (7) ◽  
pp. 1880-1885 ◽  
Author(s):  
Dan Graur
Keyword(s):  
Human Genome ◽  
Human Population ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
Replacement Level ◽  
Functional Regions ◽  
Upper Limit ◽  
Constant Size ◽  
Mean Fitness ◽  
The Mean

AbstractFor the human population to maintain a constant size from generation to generation, an increase in fertility must compensate for the reduction in the mean fitness of the population caused, among others, by deleterious mutations. The required increase in fertility due to this mutational load depends on the number of sites in the genome that are functional, the mutation rate, and the fraction of deleterious mutations among all mutations in functional regions. These dependencies and the fact that there exists a maximum tolerable replacement level fertility can be used to put an upper limit on the fraction of the human genome that can be functional. Mutational load considerations lead to the conclusion that the functional fraction within the human genome cannot exceed 15%.

The Human Genome

2015 ◽  
Vol 27 (1) ◽  
pp. 25-44
Author(s):  
Gerald Bergman ◽  
Keyword(s):  
Genetic Variation ◽  
Adverse Effects ◽  
Beneficial Effect ◽  
Human Genome ◽  
Scientific Literature ◽  
Genetic Change ◽  
Medical Community ◽  
Deleterious Mutations ◽  
Beneficial Effects ◽  
Gene Damage

This essay explores the influence of randomness in genetic change based on findings in the scientific literature. In many cases, random mutations are not the source of genetic variation that allows adaptation to an environmental change. Rather, innate mechanisms are the cause. Typical examples are used to illustrate how these systems work, and the evidence for them. Randomness appears to have less effect in causing micro-evolution then once assumed. But it has a significant influence in causing near neutral and deleterious mutations, resulting in genetic entropy. Some random mutations have a beneficial effect. However, all are due to gene damage that in some situations have limited beneficial effects. This suggests that major steps should be taken by the medical community to help ameliorate the adverse effects of random mutations on the human genome.

scholarly journals Mutational Load and the Functional Fraction of the Human Genome

2020 ◽  
Vol 12 (4) ◽  
pp. 273-281 ◽  
Author(s):  
Benjamin Galeota-Sprung ◽  
Paul Sniegowski ◽  
Warren Ewens
Keyword(s):  
Human Genome ◽  
Practical Importance ◽  
Sequence Divergence ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
Functional Sites ◽  
Large N ◽  
Systematic Effort ◽  
Selection Equilibrium ◽  
Mean Fitness

Abstract The fraction of the human genome that is functional is a question of both evolutionary and practical importance. Studies of sequence divergence have suggested that the functional fraction of the human genome is likely to be no more than ∼15%. In contrast, the ENCODE project, a systematic effort to map regions of transcription, transcription factor association, chromatin structure, and histone modification, assigned function to 80% of the human genome. In this article, we examine whether and how an analysis based on mutational load might set a limit on the functional fraction. In order to do so, we characterize the distribution of fitness of a large, finite, diploid population at mutation-selection equilibrium. In particular, if mean fitness is ∼1, the fitness of the fittest individual likely to occur cannot be unreasonably high. We find that at equilibrium, the distribution of log fitness has variance nus, where u is the per-base deleterious mutation rate, n is the number of functional sites (and hence incorporates the functional fraction f), and s is the selection coefficient of deleterious mutations. In a large (N=109) reproducing population, the fitness of the fittest individual likely to exist is ∼e5nus. These results apply to both additive and recessive fitness schemes. Our approach is different from previous work that compared mean fitness at mutation-selection equilibrium with the fitness of an individual who has no deleterious mutations; we show that such an individual is exceedingly unlikely to exist. We find that the functional fraction is not very likely to be limited substantially by mutational load, and that any such limit, if it exists, depends strongly on the selection coefficients of new deleterious mutations.

scholarly journals The Impact of Recessive Deleterious Variation on Signals of Adaptive Introgression in Human Populations

Genetics ◽  
2020 ◽  
Vol 215 (3) ◽  
pp. 799-812 ◽  
Author(s):  
Xinjun Zhang ◽  
Bernard Kim ◽  
Kirk E. Lohmueller ◽  
Emilia Huerta-Sánchez
Keyword(s):  
Human Genome ◽  
False Positive ◽  
False Positive Rate ◽  
Genomic Variation ◽  
Human Populations ◽  
Deleterious Mutations ◽  
Recombination Rates ◽  
Adaptive Mutations ◽  
Adaptive Introgression ◽  
The Impact

Admixture with archaic hominins has altered the landscape of genomic variation in modern human populations. Several gene regions have been identified previously as candidates of adaptive introgression (AI) that facilitated human adaptation to specific environments. However, simulation-based studies have suggested that population genetic processes other than adaptive mutations, such as heterosis from recessive deleterious variants private to populations before admixture, can also lead to patterns in genomic data that resemble AI. The extent to which the presence of deleterious variants affect the false-positive rate and the power of current methods to detect AI has not been fully assessed. Here, we used extensive simulations under parameters relevant for human evolution to show that recessive deleterious mutations can increase the false positive rates of tests for AI compared to models without deleterious variants, especially when the recombination rates are low. We next examined candidates of AI in modern humans identified from previous studies, and show that 24 out of 26 candidate regions remain significant, even when deleterious variants are included in the null model. However, two AI candidate genes, HYAL2 and HLA, are particularly susceptible to high false positive signals of AI due to recessive deleterious mutations. These genes are located in regions of the human genome with high exon density together with low recombination rate, factors that we show increase the rate of false-positives due to recessive deleterious mutations. Although the combination of such parameters is rare in the human genome, caution is warranted in such regions, as well as in other species with more compact genomes and/or lower recombination rates. In sum, our results suggest that recessive deleterious mutations cannot account for the signals of AI in most, but not all, of the top candidates for AI in humans, suggesting they may be genuine signals of adaptation.

scholarly journals The Sniffing Kidney: Roles for Renal Olfactory Receptors in Health and Disease

Kidney360 ◽  
2021 ◽  
pp. 10.34067/KID.0000712021
Author(s):  
Blythe D. Shepard
Keyword(s):  
Blood Pressure ◽  
Gene Family ◽  
Human Genome ◽  
Recent Progress ◽  
Blood Pressure Response ◽  
Olfactory Receptors ◽  
Pressure Response ◽  
Health And Disease

Olfactory receptors (ORs) represent the largest gene family in the human genome. Despite their name, functions exist for these receptors outside of the nose. Among the tissues known to take advantage of OR signaling is the kidney. From mouse to man, the list of renal ORs continues to expand and they have now been linked to a variety of processes involved in the maintenance of renal homeostasis including the modulation of blood pressure, response to acidemia, and the development of diabetes. In this review, we highlight the recent progress made on the growing appreciation for renal ORs in physiology and pathophysiology.

scholarly journals Negative linkage disequilibrium between amino acid changing variants reveals interference among deleterious mutations in the human genome

PLoS Genetics ◽  
2021 ◽  
Vol 17 (7) ◽  
pp. e1009676
Author(s):  
Jesse A. Garcia ◽  
Kirk E. Lohmueller
Keyword(s):  
Linkage Disequilibrium ◽  
Human Genome ◽  
Natural Populations ◽  
Physical Distance ◽  
Deleterious Mutations ◽  
High Coverage ◽  
Evolutionary Forces ◽  
Recessive Mutations ◽  
Genome Wide ◽  
Negative Epistasis

Evolutionary forces like Hill-Robertson interference and negative epistasis can lead to deleterious mutations being found on distinct haplotypes. However, the extent to which these forces depend on the selection and dominance coefficients of deleterious mutations and shape genome-wide patterns of linkage disequilibrium (LD) in natural populations with complex demographic histories has not been tested. In this study, we first used forward-in-time simulations to predict how negative selection impacts LD. Under models where deleterious mutations have additive effects on fitness, deleterious variants less than 10 kb apart tend to be carried on different haplotypes relative to pairs of synonymous SNPs. In contrast, for recessive mutations, there is no consistent ordering of how selection coefficients affect LD decay, due to the complex interplay of different evolutionary effects. We then examined empirical data of modern humans from the 1000 Genomes Project. LD between derived alleles at nonsynonymous SNPs is lower compared to pairs of derived synonymous variants, suggesting that nonsynonymous derived alleles tend to occur on different haplotypes more than synonymous variants. This result holds when controlling for potential confounding factors by matching SNPs for frequency in the sample (allele count), physical distance, magnitude of background selection, and genetic distance between pairs of variants. Lastly, we introduce a new statistic HR(j) which allows us to detect interference using unphased genotypes. Application of this approach to high-coverage human genome sequences confirms our finding that nonsynonymous derived alleles tend to be located on different haplotypes more often than are synonymous derived alleles. Our findings suggest that interference may play a pervasive role in shaping patterns of LD between deleterious variants in the human genome, and consequently influences genome-wide patterns of LD.

scholarly journals Mutational load and the functional fraction of the human genome

2019 ◽  
Author(s):  
Benjamin Galeota-Sprung ◽  
Paul Sniegowski ◽  
Warren Ewens
Keyword(s):  
Human Genome ◽  
Practical Importance ◽  
Sequence Divergence ◽  
Mutational Load ◽  
Deleterious Mutations ◽  
Encode Project ◽  
Functional Sites ◽  
Systematic Effort ◽  
Selection Equilibrium ◽  
Mean Fitness

AbstractThe fraction of the human genome that is functional is a question of both evolutionary and practical importance. Studies of sequence divergence have suggested that the functional fraction of the human genome is likely to be no more than ∼15%. In contrast, the ENCODE project, a systematic effort to map regions of transcription, transcription factor association, chromatin structure, and histone modification, assigned function to 80% of the human genome. In this paper we examine whether and how an analysis based on mutational load might set a limit on the functional fraction. In order to do so, we characterize the distribution of fitness of a large, finite, diploid population at mutation-selection equilibrium. In particular, if mean fitness is ∼1, the fitness of the fittest individual likely to occur cannot be unreasonably high. We find that at equilibrium, the distribution of log fitness has variance nus, where u is the per-base deleterious mutation rate, n is the number of functional sites (and hence incorporates the functional fraction f), and s is the selection coefficient of deleterious mutations. In a large (N = 109) reproducing population, the fitness of the fittest individual likely to exist is . These results apply to both additive and recessive fitness schemes. Our approach is different from previous work that compared mean fitness at mutation-selection equilibrium to the fitness of an individual who has no deleterious mutations; we show that such an individual is exceedingly unlikely to exist. We find that the functional fraction is not very likely to be limited substantially by mutational load, and that any such limit, if it exists, depends strongly on the selection coefficients of new deleterious mutations.

Sign in / Sign up

Export Citation Format

Share Document