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Global analysis of ATM polymorphism reveals significant functional constraint
Y R Thorstenson1, P Shen, V G Tusher
1Stanford Genome Technology Center, Palo Alto, CA, 94304, USA. yvonne@sequence.stanford.edu
American Journal of Human Genetics
|July 10, 2001
Summary
Researchers surveyed sequence variation in the ATM gene across diverse human populations. They found low coding region diversity, suggesting strong evolutionary constraints, and identified African-specific ATM polymorphisms potentially driven by population expansion or selection.
Area of Science:
- Human Genetics
- Evolutionary Biology
- Molecular Biology
Background:
- Mutations in the ATM gene are linked to ataxia-telangiectasia, characterized by cerebellar degeneration, vascular abnormalities, and cancer.
- Clinical significance of ATM mutations necessitates understanding its sequence variation across human populations.
Purpose of the Study:
- To conduct a comprehensive survey of sequence variation in the human ATM gene.
- To analyze ATM sequence variation in diverse human populations and compare it with non-human primates.
- To investigate evolutionary constraints and population-specific genetic patterns within the ATM gene.
Main Methods:
- Analyzed protein-encoding exons, adjacent introns, and untranslated sequences of the ATM gene in 93 individuals from seven major human populations.
- Sequenced ATM in one chimpanzee, one gorilla, one orangutan, and one Old World monkey for comparative analysis.
- Employed denaturing high-performance liquid chromatography (DHPLC) for variant site detection and calculated nucleotide diversity, comparing ATM to 14 other autosomal genes.
Main Results:
- Discovered 88 variant sites in human ATM using DHPLC, demonstrating high sensitivity for DNA sequence variation detection.
- Observed significantly low nucleotide diversity in ATM's coding regions, particularly the latter 29% of the protein sequence, indicating strong evolutionary constraint.
- Identified seven distinct haplotypes, with two common globally. Two other haplotypes, carrying the D126E missense polymorphism, were frequent in Africa but absent elsewhere, suggesting potential population-specific selective pressures or expansion.
Conclusions:
- The ATM gene exhibits significant evolutionary constraint in its coding regions, especially in the C-terminal portion.
- Extensive linkage disequilibrium in ATM suggests suppressed meiotic recombination.
- The high frequency of specific ATM polymorphisms in African populations may indicate recent population expansion or positive selection.