Journal
GENETICA
Volume 151, Issue 1, Pages 61-73Publisher
SPRINGER
DOI: 10.1007/s10709-022-00166-6
Keywords
Amyloid-beta precursor protein; Beta-amyloid peptides; Autonomous transcription; Mutational pressure; Germline mutations
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Amyloid-beta precursor protein (APP) is highly conserved in mammals. While cytosine usage is highest in fourfold degenerated sites of the APP coding region in placental mammals, in marsupial mammals, thymine usage is favored. However, in the human APP coding region, C to T and G to A transitions are the most frequent germline and somatic mutations. Mutational AT-pressure is also common in germline mutations in introns of the human APP gene, although several exceptional introns show deviations in germline mutation rates. The presence of lncRNA genes in complementary DNA strands may explain exceptional nucleotide usage biases observed in certain exons.
Amyloid-beta precursor protein (APP) is highly conserved in mammals. This feature allowed us to compare nucleotide usage biases in fourfold degenerated sites along the length of its coding region for 146 species of mammals and birds in search of fragments with significant deviations. Even though cytosine usage has the highest value in fourfold degenerated sites in APP coding region from all tested placental mammals, in contrast to marsupial mammals with the bias toward thymine usage, the most frequent germline and somatic mutations in human APP coding region are C to T and G to A transitions. The same mutational AT-pressure is characteristic for germline mutations in introns of human APP gene. However, surprisingly, there are several exceptional introns with deviations in germline mutations rates. The most of those introns surround exons with exceptional biases in nucleotide usage in fourfold degenerated sites. Existence of such fragments in exons 4 and 5, as well as in exon 14, can be connected with the presence of lncRNA genes in complementary strand of DNA. Exceptional nucleotide usage bias in exons 16 and 17 that contain a sequence encoding amyloid-beta peptides can be explained either by the presence of yet unmapped lncRNA(s), or by the autonomous expression of a short mRNA that encodes just C-terminal part of the APP providing an alternative source of amyloid-beta peptides. This hypothesis is supported by the increased rate of T to C transitions in introns 16-17 and 17-18 of Human APP gene relatively to other introns.
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