Evolutionary evidence of the effect of rare variants on disease etiology

Abstract

The common disease/common variant hypothesis has been popular for describing the genetic architecture of common human diseases for several years. According to the originally stated hypothesis, one or a few common genetic variants with a relatively large effect size control the risk of common diseases. A growing body of evidence, however, suggests that rare single-nucleotide polymorphisms (SNPs), i.e., those with a minor allele frequency of less than 5%, are also an important component of the genetic architecture of common human diseases. In this study, we analyzed the relevance of rare SNPs to the risk of common disease from an evolutionary perspective and found that rare SNPs are more likely than common SNPs to be functional and tend to have a stronger effect size than do common SNPs. This observation, plus the fact that most of the SNPs in the human genome are rare, suggests that rare SNPs are a crucial element of the genetic architecture of common human diseases. We propose that the next generation of genomic studies should focus on analyzing rare SNPs. Further, targeting patients with a family history of the disease, an extreme phenotype, or early disease onset may facilitate the detection of risk-associated rare SNPs.

Unraveling Genetic Origin of Aging-Related Traits: Evolving Concepts

“…32 The CDCV hypothesis, however, becomes discouraging 21 whereas the role of rare variants is promoted. [35][36][37] For rare variants there is a fundamental problem of explaining individualized risks of aging-related traits in the context of their inheritance.…”

Inactivating Mutations in GT198 in Familial and Early-Onset Breast and Ovarian Cancers

“…Table S3). Some rare variants may have pathogenic potential, 22 which has been observed in cancer genes. 23,24 To evaluate the functional impact, we focused our subsequent studies on 2 reoccurring mutations, c.310C>T and c.-37A>T. In summary, our data suggest that germline variants in GT198 are present at a low frequency in familial and early-onset breast and ovarian cancers.…”

Using Gene Genealogies to Detect Rare Variants Associated with Complex Traits

“…Sequencing studies have shown that the number of rare variants in the human genome is larger than previously expected [1][2][3] . Rare variants are also predicted to be more damaging than variants with larger minor allele frequencies (MAF) [1,4] . In addition, a number of recent studies have associated rare variants with common diseases.…”