Gene variation
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Gene Variation: Insights from Recent Research
Heritable Variation in Gene Expression
Heritable variation in gene expression is a common phenomenon observed both within and between species. This variation primarily arises from mutations that impact the molecular gene regulatory networks, which are then subject to natural selection. High-throughput methods have been instrumental in introducing mutations and characterizing their cis- and trans-regulatory effects on gene expression, particularly transcription. These methods have elucidated the molecular mechanisms generating regulatory variation and have helped differentiate between neutral and non-neutral evolutionary processes1.
Natural Variation in Gene Expression
Studies have shown that natural variation in gene expression is significant within and among populations. For instance, research on teleost fish of the genus Fundulus revealed statistically significant differences in gene expression among individuals within the same population for approximately 18% of 907 genes. These differences often exceeded a factor of 2.0, indicating substantial natural variation. Such variation is crucial for understanding evolutionary processes, as it suggests that gene expression differences are not solely dependent on evolutionary distance but also on random factors2.
Inherited Variation and Phenotypic Diversity
Inherited variation in gene expression is a key contributor to phenotypic diversity within and between populations. Advances in genome-scale dissection of transcriptional variation have provided insights into the genetic architecture of this variation and the nature of regulatory alleles. Human studies have been particularly informative, highlighting the importance of experimental designs that can handle large and complex datasets to further our understanding of gene expression variation3.
Human Genetic Variation and Disease
Large-scale datasets, such as those from the Exome Aggregation Consortium (ExAC) and the 1000 Genomes Project, have been pivotal in understanding human genetic variation. These datasets have revealed widespread mutational recurrence and have identified genes subject to strong selection against various classes of mutations. For example, ExAC data identified 3,230 genes with near-complete depletion of predicted protein-truncating variants, many of which have no established human disease phenotype. Such resources are invaluable for filtering candidate disease-causing variants and discovering human 'knockout' variants in protein-coding genes4 5.
Genome-Wide Associations and Regulatory Polymorphism
Genome-wide association studies (GWAS) have been essential in identifying variants that contribute to complex traits. For instance, a study on 630 genes in 60 unrelated individuals from the International HapMap project found significant associations of single nucleotide polymorphisms (SNPs) with expression variation. These findings suggest that regulatory polymorphism is widespread in the human genome, enhancing our ability to annotate non-coding regions and interpret functional variation6.
Impacts of Genetic Variation on Gene Regulation
Genetic variations, including single-nucleotide variants, indels, and structural changes, significantly impact gene regulation. Advances in RNA sequencing and large consortia projects like the 1000 Genomes Project and ENCODE have provided comprehensive maps of genetic variants and functional elements. These resources have enabled the resolution of how genetic variants affect gene regulation, either by altering transcript sequences and isoforms or by changing transcript abundance through dosage or regulatory variants9.
Cell-to-Cell Variation and Aging
Variation in gene expression is not only a result of genetic differences but also of stochastic and programmed variation. This variation can contribute to differences in traits, including the rate of aging. Recent findings suggest that changes in cell-to-cell variation in gene expression emerge as part of the aging process and may be linked to disease vulnerability with age. Understanding these variations is crucial for biomedical research and may provide insights into biological aging10.
Conclusion
The study of gene variation, particularly in gene expression, has provided profound insights into the mechanisms driving phenotypic diversity and evolutionary processes. Advances in high-throughput methods, large-scale genetic datasets, and genome-wide association studies have been instrumental in uncovering the complexities of gene regulation and its implications for human health and disease. As research continues to evolve, these insights will undoubtedly enhance our understanding of genetic variation and its role in shaping biological diversity.
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Molecular and evolutionary processes generating variation in gene expression
High-throughput methods reveal how molecular mechanisms generate regulatory variation in gene expression, allowing us to understand its origin and predict its evolution in the future.
Highly CitedVariation in gene expression within and among natural populations
Substantial natural variation exists in gene expression, which is important in evolution, with 18% of 907 genes showing significant differences between individuals within the same population and between populations.
Highly CitedInherited variation in gene expression.
Recent advances in gene expression studies have enabled a better understanding of inherited variation in gene expression, contributing to phenotypic diversity and advancing our understanding of gene expression evolution.
Highly CitedAnalysis of protein-coding genetic variation in 60,706 humans
This large-scale exome data set reveals widespread mutational recurrence and can efficiently filter disease-causing variants and discover human 'knockout' variants in protein-coding genes.
Rigorous JournalHighly CitedA global reference for human genetic variation
The 1000 Genomes Project has reconstructed the genomes of 2,504 individuals from 26 populations, revealing over 88 million genetic variants and providing a comprehensive resource for common disease studies.
Rigorous JournalHighly CitedGenome-Wide Associations of Gene Expression Variation in Humans
Regulatory polymorphism is widespread in the human genome, and the 5-kb HapMap data provides sufficient density for linkage disequilibrium mapping, enhancing our ability to annotate non-coding regions and interpret functional variation.
Highly CitedThe genetics of variation in gene expression
The genetic basis of variation in gene expression can be studied using microarrays, offering insights into transcriptional regulation and other complex traits.
Highly CitedComprehensive variation discovery in single human genomes
DISCOVAR, a new algorithm, improves variant calling in challenging regions of the human genome, increasing sensitivity by several fold.
Rigorous JournalHighly CitedImpacts of variation in the human genome on gene regulation.
Genetic variations in the human genome impact gene regulation locally and globally, affecting transcript sequences and isoforms through coding variants and transcript abundance through dosage or regulatory variants.
Highly CitedCell-to-cell variation in gene expression and the aging process
Cell-to-cell variation in gene expression contributes to biological traits and aging, potentially linking disease vulnerability to age.
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