New insights on the evolution of the SMN1 and SMN2 region: simulation and meta-analysis for allele and haplotype frequency calculations

• Published in: European journal of human genetics : EJHG Vol. 12; no. 12; pp. 1015 - 1023
• Main Authors: OGINO, Shuji, WILSON, Robert B, GOLD, Bert
• Format: Journal Article
• Language: English
• Published: Avenel, NJ Nature Publishing 01.12.2004; Nature Publishing Group
• Subjects: Alleles; Binding sites; Biological and medical sciences; Chromosomes; Clonal deletion; Computer Simulation; Copy number; Cyclic AMP Response Element-Binding Protein; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease; Evolution; Evolution, Molecular; Gene conversion; Gene deletion; Gene duplication; Gene Frequency; Genes; Genetic counseling; Genetics; Genomes; Haplotypes; Health risk assessment; Hospitals; Humans; Laboratories; Medical sciences; Mutation; Mutation rates; Nerve Tissue Proteins - genetics; Neurology; New orders; Pathology; Risk Assessment; RNA-Binding Proteins; SMN Complex Proteins; SMN protein; Spinal muscular atrophy; Statistical analysis; Survival of Motor Neuron 1 Protein; Survival of Motor Neuron 2 Protein; United States > US; Human; Neuromuscular diseases; Nervous system diseases; Spinal amyotrophy; Metaanalysis; Molecular evolution; Allele; Simulation; Central nervous system disease; Frequency; Degenerative disease; Calculation; Spinal cord disease; Haplotype
• ISSN: 1018-4813; 1476-5438
• DOI: 10.1038/sj.ejhg.5201288

Most spinal muscular atrophy patients lack both copies of SMN1. Loss of SMN1 ('0-copy alleles') can occur by gene deletion or SMN1-to-SMN2 gene conversion. Despite worldwide efforts to map the segmental duplications within the SMN region, most assemblies do not correctly delineate these genes. A near pericentromeric location provides impetus for the strong evidence that SMN1 and SMN2 arose from a primate-specific paralogous gene duplication. Here we meta-analyzed our recent laboratory results together with available published data, in order to calculate new mutation rates and allele/haplotype frequencies in this recalcitrant and highly unstable region of the human genome. Based on our tested assumption of compliance with Hardy-Weinberg equilibrium, we conclude that the SMN1 allele frequencies are: '0-copy disease alleles,' 0.013; '1-copy normal alleles,' 0.95; '2-copy normal alleles (ie, two copies of SMN1 on one chromosome),' 0.038; and '1(D) disease alleles (SMN1 with a small intragenic mutation),' 0.00024. The SMN1 haplotype ['(SMN1 copy number)-(SMN2 copy number)'] frequencies are: '0-0,' 0.00048; '0-1,' 0.0086; '0-2,' 0.0042; '1-0,' 0.27; '1-1,' 0.66; '1-2,' 0.015; '2-0,' 0.027; and '2-1,' 0.012. Paternal and maternal de novo mutation rates are 2.1 x 10(-4) and 4.2 x 10(-5), respectively. Our data provide the basis for the most accurate genetic risk calculations, as well as new insights on the evolution of the SMN region, with evidence that nucleotide position 840 (where a transition 840C>T functionally distinguishes SMN2 from SMN1) constitutes a mutation hotspot. Our data also suggest selection of the 1-1 haplotype and the presence of rare chromosomes with three copies of SMN1.