Faculty Collaboration Database

Single nucleotide polymorphism spectra in newborns and centenarians: identification of genes coding for rise of mortal disease. Gene 1998 Nov 26;223(1-2):381-91

Date

12/22/1998

Pubmed ID

9858772

DOI

10.1016/s0378-1119(98)00408-9

Scopus ID

2-s2.0-0032570015 (requires institutional sign-in at Scopus site)   26 Citations

Abstract

Some single-nucleotide polymorphisms (SNPs) increase the risk of mortal disease. Identifying these SNPs and the genes in which they reside is an important area in human genomics. Such qualitative observations are important in themselves. However, an accurate assessment of the numerical distribution and age-dependent decline of SNPs in the population would permit calculation of the rises represented by each SNP. Such analyses have not been attempted because of a lack of an efficient and cost-effective method to detect multiple SNPs in a large number of individuals and a large number of genes. Here, we suggest the use of an analytical procedure that can scan for SNPs in 100-bp DNA sequences from as many as 10000 donors' blood cell samples, or 20000 alleles, simultaneously. Our suggestion is based on technology developed for studies of somatic mutations in human tissue DNA for point mutations at frequencies equal to or greater than 10(-6). In a simplified version of this technology, any SNP arising at frequencies at or above 5x10(-4) would be identified with useful precision. A gene would be represented by 10 or more sections of 100bp. This strategy includes splice-site mutations that represent a significant fraction of gene inactivating point mutations and would not be observed in strategies using cDNA. To illustrate the logic of the suggested approach, we use American mortality records to calculate the expected decrease in SNPs coding for premature mortality in newborns and centenarians. We consider several elementary cases: SNPs in one gene only, any of several genes, or all of several genes that create a risk of death by pancreatic cancer. The fraction of expressed polymorphisms affecting mortality should be simultaneously increased in probands and decreased in the aged relative to newborns. Silent polymorphisms in the same gene would remain unchanged in all three groups and serve as internal standards. A key point is that scanning a gene, in which loss of gene function creates the risk of mortality is expected to reveal not one, but multiple SNPs, which decline with age, as carriers die earlier in life than non-carriers. Several SNPs in a scanned gene would suggest that the decreasing SNP was genetically linked to a different polymorphism that creates the disease risk.

Author List

Tomita-Mitchell A, Muniappan BP, Herrero-Jimenez P, Zarbl H, Thilly WG

Author

Aoy Tomita Mitchell PhD Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Age Factors
Aged
Aged, 80 and over
Blood Specimen Collection
Electrophoresis, Capillary
Female
Genetic Diseases, Inborn
Genetic Predisposition to Disease
Genetics, Population
Humans
Infant, Newborn
Male
Models, Biological
Models, Genetic
Mutation
Pancreatic Neoplasms
Polymerase Chain Reaction
Polymorphism, Genetic
Risk Factors
United States