scholarly journals Shifting epigenetic contexts influence regulatory variation and disease risk

Aging ◽  
2021 ◽  
Author(s):  
Daniel Richard ◽  
Terence D. Capellini
Keyword(s):  
Disease Risk ◽  
Regulatory Variation

scholarly journals Modified penetrance of coding variants by cis-regulatory variation shapes human traits

2017 ◽  
Author(s):  
Stephane E. Castel ◽  
Alejandra Cervera ◽  
Pejman Mohammadi ◽  
François Aguet ◽  
Ferran Reverter ◽  
...  
Keyword(s):  
Genetic Architecture ◽  
Target Gene ◽  
Direct Evidence ◽  
Disease Risk ◽  
Purifying Selection ◽  
Functional Genomic ◽  
Regulatory Variation ◽  
Regulatory Variant ◽  
Coding Variants ◽  
Variable Penetrance

SummaryCoding variants represent many of the strongest associations between genotype and phenotype, however they exhibit inter-individual differences in effect, known as variable penetrance. In this work, we study how cis-regulatory variation modifies the penetrance of coding variants in their target gene. Using functional genomic and genetic data from GTEx, we observed that in the general population, purifying selection has depleted haplotype combinations that lead to higher penetrance of pathogenic coding variants. Conversely, in cancer and autism patients, we observed an enrichment of haplotype combinations that lead to higher penetrance of pathogenic coding variants in disease implicated genes, which provides direct evidence that regulatory haplotype configuration of causal coding variants affects disease risk. Finally, we experimentally demonstrated that a regulatory variant can modify the penetrance of a coding variant by introducing a Mendelian SNP using CRISPR/Cas9 on distinct expression haplotypes and using the transcriptome as a phenotypic readout. Our results demonstrate that joint effects of regulatory and coding variants are an important part of the genetic architecture of human traits, and contribute to modified penetrance of disease-causing variants.

scholarly journals Probing the dark matter of the human genome with big DNA

2019 ◽  
Vol 41 (3) ◽  
pp. 46-48
Author(s):  
Jon M. Laurent ◽  
Sudarshan Pinglay ◽  
Leslie Mitchell ◽  
Ran Brosh
Keyword(s):  
Dark Matter ◽  
Human Genome ◽  
Human Disease ◽  
Disease Risk ◽  
Regulatory Elements ◽  
Base Pairs ◽  
Protein Coding ◽  
Regulatory Variation ◽  
Expression Of Genes ◽  
Regulatory Dna

Less than 2% of our genome is protein-coding DNA. The vast expanses of non-coding DNA make up the genome's “dark matter”, where introns, repetitive and regulatory elements reside. Variation between individuals in non-coding regulatory DNA is emerging as a major factor in the genetics of numerous diseases and traits, yet very little is known about how such variations contribute to disease risk. Studying the genetics of regulatory variation is technically challenging as regulatory elements can affect genes located tens of thousands of base pairs away, and often, multiple distal regulatory variations, each with a very small effect, combine in an unknown way to significantly modulate the expression of genes. At the Center for Synthetic Regulatory Genomics (SyRGe) we directly tackle these problems in order to systematically elucidate the mechanisms of regulatory variation underlying human disease.

scholarly journals Modified penetrance of coding variants by cis-regulatory variation contributes to disease risk

2018 ◽  
Vol 50 (9) ◽  
pp. 1327-1334 ◽  
Author(s):  
Stephane E. Castel ◽  
Alejandra Cervera ◽  
Pejman Mohammadi ◽  
François Aguet ◽  
Ferran Reverter ◽  
...  
Keyword(s):  
Disease Risk ◽  
Regulatory Variation ◽  
Coding Variants

Irregular Menses Linked To Coronary Disease Risk

Ob Gyn News ◽  
2007 ◽  
Vol 42 (24) ◽  
pp. 1-7
Author(s):  
MITCHEL L. ZOLER
Keyword(s):  
Coronary Disease ◽  
Disease Risk ◽  
Irregular Menses
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